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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Open Source Drug Discovery: Highly Potent Antimalarial
Compounds Derived from the Tres Cantos Arylpyrroles</title>
<author><name sortKey="Williamson, Alice E" sort="Williamson, Alice E" uniqKey="Williamson A" first="Alice E." last="Williamson">Alice E. Williamson</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ylioja, Paul M" sort="Ylioja, Paul M" uniqKey="Ylioja P" first="Paul M." last="Ylioja">Paul M. Ylioja</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robertson, Murray N" sort="Robertson, Murray N" uniqKey="Robertson M" first="Murray N." last="Robertson">Murray N. Robertson</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antonova Koch, Yevgeniya" sort="Antonova Koch, Yevgeniya" uniqKey="Antonova Koch Y" first="Yevgeniya" last="Antonova-Koch">Yevgeniya Antonova-Koch</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Avery, Vicky" sort="Avery, Vicky" uniqKey="Avery V" first="Vicky" last="Avery">Vicky Avery</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Baell, Jonathan B" sort="Baell, Jonathan B" uniqKey="Baell J" first="Jonathan B." last="Baell">Jonathan B. Baell</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batchu, Harikrishna" sort="Batchu, Harikrishna" uniqKey="Batchu H" first="Harikrishna" last="Batchu">Harikrishna Batchu</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batra, Sanjay" sort="Batra, Sanjay" uniqKey="Batra S" first="Sanjay" last="Batra">Sanjay Batra</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Burrows, Jeremy N" sort="Burrows, Jeremy N" uniqKey="Burrows J" first="Jeremy N." last="Burrows">Jeremy N. Burrows</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhattacharyya, Soumya" sort="Bhattacharyya, Soumya" uniqKey="Bhattacharyya S" first="Soumya" last="Bhattacharyya">Soumya Bhattacharyya</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Calderon, Felix" sort="Calderon, Felix" uniqKey="Calderon F" first="Felix" last="Calderon">Felix Calderon</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Charman, Susan A" sort="Charman, Susan A" uniqKey="Charman S" first="Susan A." last="Charman">Susan A. Charman</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Clark, Julie" sort="Clark, Julie" uniqKey="Clark J" first="Julie" last="Clark">Julie Clark</name>
<affiliation><nlm:aff id="aff8">Department of Chemical Biology & Therapeutics,<institution>St. Jude Children’s Research Hospital</institution>
, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crespo, Benigno" sort="Crespo, Benigno" uniqKey="Crespo B" first="Benigno" last="Crespo">Benigno Crespo</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dean, Matin" sort="Dean, Matin" uniqKey="Dean M" first="Matin" last="Dean">Matin Dean</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Debbert, Stefan L" sort="Debbert, Stefan L" uniqKey="Debbert S" first="Stefan L." last="Debbert">Stefan L. Debbert</name>
<affiliation><nlm:aff id="aff9">Department of Chemistry,<institution>Lawrence University</institution>
, 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Delves, Michael" sort="Delves, Michael" uniqKey="Delves M" first="Michael" last="Delves">Michael Delves</name>
<affiliation><nlm:aff id="aff10">Department of Life Sciences,<institution>Imperial College London</institution>
, South Kensington, London SW7 2AZ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dennis, Adelaide S M" sort="Dennis, Adelaide S M" uniqKey="Dennis A" first="Adelaide S. M." last="Dennis">Adelaide S. M. Dennis</name>
<affiliation><nlm:aff id="aff11">Research School of Biology,<institution>The Australian National University</institution>
, Canberra, ACT 2601,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Deroose, Frederik" sort="Deroose, Frederik" uniqKey="Deroose F" first="Frederik" last="Deroose">Frederik Deroose</name>
<affiliation><nlm:aff id="aff12"><institution>Asclepia Outsourcing Solutions</institution>
, Damvalleistraat 49, B-9070 Destelbergen,<country>Belgium</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fletcher, Sabine" sort="Fletcher, Sabine" uniqKey="Fletcher S" first="Sabine" last="Fletcher">Sabine Fletcher</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giaever, Guri" sort="Giaever, Guri" uniqKey="Giaever G" first="Guri" last="Giaever">Guri Giaever</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hallyburton, Irene" sort="Hallyburton, Irene" uniqKey="Hallyburton I" first="Irene" last="Hallyburton">Irene Hallyburton</name>
<affiliation><nlm:aff id="aff14">Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery,<institution>University of Dundee</institution>
, Dundee, DD1 5EH,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gamo, Francisco Javier" sort="Gamo, Francisco Javier" uniqKey="Gamo F" first="Francisco-Javier" last="Gamo">Francisco-Javier Gamo</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gebbia, Marinella" sort="Gebbia, Marinella" uniqKey="Gebbia M" first="Marinella" last="Gebbia">Marinella Gebbia</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guy, R Kiplin" sort="Guy, R Kiplin" uniqKey="Guy R" first="R. Kiplin" last="Guy">R. Kiplin Guy</name>
<affiliation><nlm:aff id="aff8">Department of Chemical Biology & Therapeutics,<institution>St. Jude Children’s Research Hospital</institution>
, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hungerford, Zoe" sort="Hungerford, Zoe" uniqKey="Hungerford Z" first="Zoe" last="Hungerford">Zoe Hungerford</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kirk, Kiaran" sort="Kirk, Kiaran" uniqKey="Kirk K" first="Kiaran" last="Kirk">Kiaran Kirk</name>
<affiliation><nlm:aff id="aff11">Research School of Biology,<institution>The Australian National University</institution>
, Canberra, ACT 2601,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lafuente Monasterio, Maria X0a J" sort="Lafuente Monasterio, Maria X0a J" uniqKey="Lafuente Monasterio M" first="Maria X0a J." last="Lafuente-Monasterio">Maria X0a J. Lafuente-Monasterio</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Anna" sort="Lee, Anna" uniqKey="Lee A" first="Anna" last="Lee">Anna Lee</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meister, Stephan" sort="Meister, Stephan" uniqKey="Meister S" first="Stephan" last="Meister">Stephan Meister</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nislow, Corey" sort="Nislow, Corey" uniqKey="Nislow C" first="Corey" last="Nislow">Corey Nislow</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Overington, John P" sort="Overington, John P" uniqKey="Overington J" first="John P." last="Overington">John P. Overington</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papadatos, George" sort="Papadatos, George" uniqKey="Papadatos G" first="George" last="Papadatos">George Papadatos</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Patiny, Luc" sort="Patiny, Luc" uniqKey="Patiny L" first="Luc" last="Patiny">Luc Patiny</name>
<affiliation><nlm:aff id="aff16">Institute of Chemical Sciences and Engineering (ISIC),<institution>Ecole Polytechnique Fédérale de Lausanne (EPFL)</institution>
, Lausanne 1015,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pham, James" sort="Pham, James" uniqKey="Pham J" first="James" last="Pham">James Pham</name>
<affiliation><nlm:aff id="aff17">Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute,<institution>The University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ralph, Stuart X0a A" sort="Ralph, Stuart X0a A" uniqKey="Ralph S" first="Stuart X0a A." last="Ralph">Stuart X0a A. Ralph</name>
<affiliation><nlm:aff id="aff17">Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute,<institution>The University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation><nlm:aff id="aff10">Department of Life Sciences,<institution>Imperial College London</institution>
, South Kensington, London SW7 2AZ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ryan, Eileen" sort="Ryan, Eileen" uniqKey="Ryan E" first="Eileen" last="Ryan">Eileen Ryan</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Southan, Christopher" sort="Southan, Christopher" uniqKey="Southan C" first="Christopher" last="Southan">Christopher Southan</name>
<affiliation><nlm:aff id="aff18">IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences,<institution>University of Edinburgh</institution>
, Edinburgh, EH8 9XD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Srivastava, Kumkum" sort="Srivastava, Kumkum" uniqKey="Srivastava K" first="Kumkum" last="Srivastava">Kumkum Srivastava</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Swain, Chris" sort="Swain, Chris" uniqKey="Swain C" first="Chris" last="Swain">Chris Swain</name>
<affiliation><nlm:aff id="aff19"><institution>Cambridge MedChem Consulting</institution>
, 8 Mangers Lane, Duxford, Cambridge CB22 4RN,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tarnowski, Matthew X0a J" sort="Tarnowski, Matthew X0a J" uniqKey="Tarnowski M" first="Matthew X0a J." last="Tarnowski">Matthew X0a J. Tarnowski</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomson, Patrick" sort="Thomson, Patrick" uniqKey="Thomson P" first="Patrick" last="Thomson">Patrick Thomson</name>
<affiliation><nlm:aff id="aff20">School of Chemistry,<institution>The University of Edinburgh</institution>
, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Turner, Peter" sort="Turner, Peter" uniqKey="Turner P" first="Peter" last="Turner">Peter Turner</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wallace, Iain M" sort="Wallace, Iain M" uniqKey="Wallace I" first="Iain M." last="Wallace">Iain M. Wallace</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wells, Timothy X0a N C" sort="Wells, Timothy X0a N C" uniqKey="Wells T" first="Timothy X0a N. C." last="Wells">Timothy X0a N. C. Wells</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Karen" sort="White, Karen" uniqKey="White K" first="Karen" last="White">Karen White</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Laura" sort="White, Laura" uniqKey="White L" first="Laura" last="White">Laura White</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Willis, Paul" sort="Willis, Paul" uniqKey="Willis P" first="Paul" last="Willis">Paul Willis</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Winzeler, Elizabeth A" sort="Winzeler, Elizabeth A" uniqKey="Winzeler E" first="Elizabeth A." last="Winzeler">Elizabeth A. Winzeler</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation><nlm:aff id="aff21"><institution>Swiss Tropical and Public Health Institute</institution>
, Socinstrasse 57, 4051 Basel,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Todd, Matthew H" sort="Todd, Matthew H" uniqKey="Todd M" first="Matthew H." last="Todd">Matthew H. Todd</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27800551</idno>
<idno type="pmc">5084075</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084075</idno>
<idno type="RBID">PMC:5084075</idno>
<idno type="doi">10.1021/acscentsci.6b00086</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000116</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Open Source Drug Discovery: Highly Potent Antimalarial
Compounds Derived from the Tres Cantos Arylpyrroles</title>
<author><name sortKey="Williamson, Alice E" sort="Williamson, Alice E" uniqKey="Williamson A" first="Alice E." last="Williamson">Alice E. Williamson</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ylioja, Paul M" sort="Ylioja, Paul M" uniqKey="Ylioja P" first="Paul M." last="Ylioja">Paul M. Ylioja</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robertson, Murray N" sort="Robertson, Murray N" uniqKey="Robertson M" first="Murray N." last="Robertson">Murray N. Robertson</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antonova Koch, Yevgeniya" sort="Antonova Koch, Yevgeniya" uniqKey="Antonova Koch Y" first="Yevgeniya" last="Antonova-Koch">Yevgeniya Antonova-Koch</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Avery, Vicky" sort="Avery, Vicky" uniqKey="Avery V" first="Vicky" last="Avery">Vicky Avery</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Baell, Jonathan B" sort="Baell, Jonathan B" uniqKey="Baell J" first="Jonathan B." last="Baell">Jonathan B. Baell</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batchu, Harikrishna" sort="Batchu, Harikrishna" uniqKey="Batchu H" first="Harikrishna" last="Batchu">Harikrishna Batchu</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batra, Sanjay" sort="Batra, Sanjay" uniqKey="Batra S" first="Sanjay" last="Batra">Sanjay Batra</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Burrows, Jeremy N" sort="Burrows, Jeremy N" uniqKey="Burrows J" first="Jeremy N." last="Burrows">Jeremy N. Burrows</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhattacharyya, Soumya" sort="Bhattacharyya, Soumya" uniqKey="Bhattacharyya S" first="Soumya" last="Bhattacharyya">Soumya Bhattacharyya</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Calderon, Felix" sort="Calderon, Felix" uniqKey="Calderon F" first="Felix" last="Calderon">Felix Calderon</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Charman, Susan A" sort="Charman, Susan A" uniqKey="Charman S" first="Susan A." last="Charman">Susan A. Charman</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Clark, Julie" sort="Clark, Julie" uniqKey="Clark J" first="Julie" last="Clark">Julie Clark</name>
<affiliation><nlm:aff id="aff8">Department of Chemical Biology & Therapeutics,<institution>St. Jude Children’s Research Hospital</institution>
, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crespo, Benigno" sort="Crespo, Benigno" uniqKey="Crespo B" first="Benigno" last="Crespo">Benigno Crespo</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dean, Matin" sort="Dean, Matin" uniqKey="Dean M" first="Matin" last="Dean">Matin Dean</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Debbert, Stefan L" sort="Debbert, Stefan L" uniqKey="Debbert S" first="Stefan L." last="Debbert">Stefan L. Debbert</name>
<affiliation><nlm:aff id="aff9">Department of Chemistry,<institution>Lawrence University</institution>
, 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Delves, Michael" sort="Delves, Michael" uniqKey="Delves M" first="Michael" last="Delves">Michael Delves</name>
<affiliation><nlm:aff id="aff10">Department of Life Sciences,<institution>Imperial College London</institution>
, South Kensington, London SW7 2AZ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dennis, Adelaide S M" sort="Dennis, Adelaide S M" uniqKey="Dennis A" first="Adelaide S. M." last="Dennis">Adelaide S. M. Dennis</name>
<affiliation><nlm:aff id="aff11">Research School of Biology,<institution>The Australian National University</institution>
, Canberra, ACT 2601,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Deroose, Frederik" sort="Deroose, Frederik" uniqKey="Deroose F" first="Frederik" last="Deroose">Frederik Deroose</name>
<affiliation><nlm:aff id="aff12"><institution>Asclepia Outsourcing Solutions</institution>
, Damvalleistraat 49, B-9070 Destelbergen,<country>Belgium</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fletcher, Sabine" sort="Fletcher, Sabine" uniqKey="Fletcher S" first="Sabine" last="Fletcher">Sabine Fletcher</name>
<affiliation><nlm:aff id="aff3">Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Giaever, Guri" sort="Giaever, Guri" uniqKey="Giaever G" first="Guri" last="Giaever">Guri Giaever</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hallyburton, Irene" sort="Hallyburton, Irene" uniqKey="Hallyburton I" first="Irene" last="Hallyburton">Irene Hallyburton</name>
<affiliation><nlm:aff id="aff14">Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery,<institution>University of Dundee</institution>
, Dundee, DD1 5EH,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gamo, Francisco Javier" sort="Gamo, Francisco Javier" uniqKey="Gamo F" first="Francisco-Javier" last="Gamo">Francisco-Javier Gamo</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gebbia, Marinella" sort="Gebbia, Marinella" uniqKey="Gebbia M" first="Marinella" last="Gebbia">Marinella Gebbia</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guy, R Kiplin" sort="Guy, R Kiplin" uniqKey="Guy R" first="R. Kiplin" last="Guy">R. Kiplin Guy</name>
<affiliation><nlm:aff id="aff8">Department of Chemical Biology & Therapeutics,<institution>St. Jude Children’s Research Hospital</institution>
, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hungerford, Zoe" sort="Hungerford, Zoe" uniqKey="Hungerford Z" first="Zoe" last="Hungerford">Zoe Hungerford</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kirk, Kiaran" sort="Kirk, Kiaran" uniqKey="Kirk K" first="Kiaran" last="Kirk">Kiaran Kirk</name>
<affiliation><nlm:aff id="aff11">Research School of Biology,<institution>The Australian National University</institution>
, Canberra, ACT 2601,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lafuente Monasterio, Maria X0a J" sort="Lafuente Monasterio, Maria X0a J" uniqKey="Lafuente Monasterio M" first="Maria X0a J." last="Lafuente-Monasterio">Maria X0a J. Lafuente-Monasterio</name>
<affiliation><nlm:aff id="aff7">Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Anna" sort="Lee, Anna" uniqKey="Lee A" first="Anna" last="Lee">Anna Lee</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meister, Stephan" sort="Meister, Stephan" uniqKey="Meister S" first="Stephan" last="Meister">Stephan Meister</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nislow, Corey" sort="Nislow, Corey" uniqKey="Nislow C" first="Corey" last="Nislow">Corey Nislow</name>
<affiliation><nlm:aff id="aff13">Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Overington, John P" sort="Overington, John P" uniqKey="Overington J" first="John P." last="Overington">John P. Overington</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papadatos, George" sort="Papadatos, George" uniqKey="Papadatos G" first="George" last="Papadatos">George Papadatos</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Patiny, Luc" sort="Patiny, Luc" uniqKey="Patiny L" first="Luc" last="Patiny">Luc Patiny</name>
<affiliation><nlm:aff id="aff16">Institute of Chemical Sciences and Engineering (ISIC),<institution>Ecole Polytechnique Fédérale de Lausanne (EPFL)</institution>
, Lausanne 1015,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pham, James" sort="Pham, James" uniqKey="Pham J" first="James" last="Pham">James Pham</name>
<affiliation><nlm:aff id="aff17">Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute,<institution>The University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ralph, Stuart X0a A" sort="Ralph, Stuart X0a A" uniqKey="Ralph S" first="Stuart X0a A." last="Ralph">Stuart X0a A. Ralph</name>
<affiliation><nlm:aff id="aff17">Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute,<institution>The University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation><nlm:aff id="aff10">Department of Life Sciences,<institution>Imperial College London</institution>
, South Kensington, London SW7 2AZ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ryan, Eileen" sort="Ryan, Eileen" uniqKey="Ryan E" first="Eileen" last="Ryan">Eileen Ryan</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Southan, Christopher" sort="Southan, Christopher" uniqKey="Southan C" first="Christopher" last="Southan">Christopher Southan</name>
<affiliation><nlm:aff id="aff18">IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences,<institution>University of Edinburgh</institution>
, Edinburgh, EH8 9XD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Srivastava, Kumkum" sort="Srivastava, Kumkum" uniqKey="Srivastava K" first="Kumkum" last="Srivastava">Kumkum Srivastava</name>
<affiliation><nlm:aff id="aff5"><institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Swain, Chris" sort="Swain, Chris" uniqKey="Swain C" first="Chris" last="Swain">Chris Swain</name>
<affiliation><nlm:aff id="aff19"><institution>Cambridge MedChem Consulting</institution>
, 8 Mangers Lane, Duxford, Cambridge CB22 4RN,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tarnowski, Matthew X0a J" sort="Tarnowski, Matthew X0a J" uniqKey="Tarnowski M" first="Matthew X0a J." last="Tarnowski">Matthew X0a J. Tarnowski</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomson, Patrick" sort="Thomson, Patrick" uniqKey="Thomson P" first="Patrick" last="Thomson">Patrick Thomson</name>
<affiliation><nlm:aff id="aff20">School of Chemistry,<institution>The University of Edinburgh</institution>
, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Turner, Peter" sort="Turner, Peter" uniqKey="Turner P" first="Peter" last="Turner">Peter Turner</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wallace, Iain M" sort="Wallace, Iain M" uniqKey="Wallace I" first="Iain M." last="Wallace">Iain M. Wallace</name>
<affiliation><nlm:aff id="aff15"><institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wells, Timothy X0a N C" sort="Wells, Timothy X0a N C" uniqKey="Wells T" first="Timothy X0a N. C." last="Wells">Timothy X0a N. C. Wells</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Karen" sort="White, Karen" uniqKey="White K" first="Karen" last="White">Karen White</name>
<affiliation><nlm:aff id="aff4">Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Laura" sort="White, Laura" uniqKey="White L" first="Laura" last="White">Laura White</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Willis, Paul" sort="Willis, Paul" uniqKey="Willis P" first="Paul" last="Willis">Paul Willis</name>
<affiliation><nlm:aff id="aff6"><institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Winzeler, Elizabeth A" sort="Winzeler, Elizabeth A" uniqKey="Winzeler E" first="Elizabeth A." last="Winzeler">Elizabeth A. Winzeler</name>
<affiliation><nlm:aff id="aff2">Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation><nlm:aff id="aff21"><institution>Swiss Tropical and Public Health Institute</institution>
, Socinstrasse 57, 4051 Basel,<country>Switzerland</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Todd, Matthew H" sort="Todd, Matthew H" uniqKey="Todd M" first="Matthew H." last="Todd">Matthew H. Todd</name>
<affiliation><nlm:aff id="aff1">School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">ACS Central Science</title>
<idno type="ISSN">2374-7943</idno>
<idno type="eISSN">2374-7951</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="oc-2016-000863_0009" id="ab-d31e657"></graphic>
</p>
<p>The
development of new antimalarial compounds remains a pivotal part of
the strategy for malaria elimination. Recent large-scale phenotypic
screens have provided a wealth of potential starting points for hit-to-lead
campaigns. One such public set is explored, employing an open source
research mechanism in which all data and ideas were shared in real
time, anyone was able to participate, and patents were not sought.
One chemical subseries was found to exhibit oral activity but contained
a labile ester that could not be replaced without loss of activity,
and the original hit exhibited remarkable sensitivity to minor structural
change. A second subseries displayed high potency, including activity
within gametocyte and liver stage assays, but at the cost of low solubility.
As an open source research project, unexplored avenues are clearly
identified and may be explored further by the community; new findings
may be cumulatively added to the present work.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Snow, R W" uniqKey="Snow R">R. W. Snow</name>
</author>
<author><name sortKey="Craig, M" uniqKey="Craig M">M. Craig</name>
</author>
<author><name sortKey="Newton, C" uniqKey="Newton C">C. Newton</name>
</author>
<author><name sortKey="Steketee, R" uniqKey="Steketee R">R. Steketee</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Carrara, V X0a I" uniqKey="Carrara V">V.
I. Carrara</name>
</author>
<author><name sortKey="Zwang, J" uniqKey="Zwang J">J. Zwang</name>
</author>
<author><name sortKey="Ashley, E A" uniqKey="Ashley E">E. A. Ashley</name>
</author>
<author><name sortKey="Price, R N" uniqKey="Price R">R. N. Price</name>
</author>
<author><name sortKey="Stepniewska, K" uniqKey="Stepniewska K">K. Stepniewska</name>
</author>
<author><name sortKey="Barends, M" uniqKey="Barends M">M. Barends</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dondorp, A M" uniqKey="Dondorp A">A. M. Dondorp</name>
</author>
<author><name sortKey="Nosten, F" uniqKey="Nosten F">F. Nosten</name>
</author>
<author><name sortKey="Yi, P" uniqKey="Yi P">P. Yi</name>
</author>
<author><name sortKey="Das, D" uniqKey="Das D">D. Das</name>
</author>
<author><name sortKey="Phyo, A P" uniqKey="Phyo A">A. P. Phyo</name>
</author>
<author><name sortKey="Tarning, J" uniqKey="Tarning J">J. Tarning</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Phyo, A P" uniqKey="Phyo A">A. P. Phyo</name>
</author>
<author><name sortKey="Nkhoma, S" uniqKey="Nkhoma S">S. Nkhoma</name>
</author>
<author><name sortKey="Stepniewska, K" uniqKey="Stepniewska K">K. Stepniewska</name>
</author>
<author><name sortKey="Ashley, E A" uniqKey="Ashley E">E. A. Ashley</name>
</author>
<author><name sortKey="Nair, S" uniqKey="Nair S">S. Nair</name>
</author>
<author><name sortKey="Mcgready, R" uniqKey="Mcgready R">R. McGready</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Olotu, A" uniqKey="Olotu A">A. Olotu</name>
</author>
<author><name sortKey="Fegan, G" uniqKey="Fegan G">G. Fegan</name>
</author>
<author><name sortKey="Wambua, J" uniqKey="Wambua J">J. Wambua</name>
</author>
<author><name sortKey="Nyangweso, G" uniqKey="Nyangweso G">G. Nyangweso</name>
</author>
<author><name sortKey="Awuondo, K O" uniqKey="Awuondo K">K. O. Awuondo</name>
</author>
<author><name sortKey="Leach, A" uniqKey="Leach A">A. Leach</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wells, T N C" uniqKey="Wells T">T. N. C. Wells</name>
</author>
<author><name sortKey="Van Huijsduijnen, R H" uniqKey="Van Huijsduijnen R">R. H. van Huijsduijnen</name>
</author>
<author><name sortKey="Van Voorhis, W C" uniqKey="Van Voorhis W">W. C. Van Voorhis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Flannery, E X0a L" uniqKey="Flannery E">E.
L. Flannery</name>
</author>
<author><name sortKey="Chatterjee, A K" uniqKey="Chatterjee A">A. K. Chatterjee</name>
</author>
<author><name sortKey="Winzeler, E A" uniqKey="Winzeler E">E. A. Winzeler</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Burrows, J N" uniqKey="Burrows J">J. N. Burrows</name>
</author>
<author><name sortKey="Elliott, R L" uniqKey="Elliott R">R. L. Elliott</name>
</author>
<author><name sortKey="Kaneko, T" uniqKey="Kaneko T">T. Kaneko</name>
</author>
<author><name sortKey="Mowbray, C E" uniqKey="Mowbray C">C. E. Mowbray</name>
</author>
<author><name sortKey="Waterson, D" uniqKey="Waterson D">D. Waterson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Peatey, C L" uniqKey="Peatey C">C. L. Peatey</name>
</author>
<author><name sortKey="Leroy, D" uniqKey="Leroy D">D. Leroy</name>
</author>
<author><name sortKey="Gardiner, D L" uniqKey="Gardiner D">D. L. Gardiner</name>
</author>
<author><name sortKey="Trenholme, K R" uniqKey="Trenholme K">K. R. Trenholme</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Duffy, S" uniqKey="Duffy S">S. Duffy</name>
</author>
<author><name sortKey="Avery, V M" uniqKey="Avery V">V. M. Avery</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mcnamara, C W" uniqKey="Mcnamara C">C. W. McNamara</name>
</author>
<author><name sortKey="Lee, M C S" uniqKey="Lee M">M. C. S. Lee</name>
</author>
<author><name sortKey="Lim, C S" uniqKey="Lim C">C. S. Lim</name>
</author>
<author><name sortKey="Lim, S H" uniqKey="Lim S">S. H. Lim</name>
</author>
<author><name sortKey="Roland, J" uniqKey="Roland J">J. Roland</name>
</author>
<author><name sortKey="Nagle, A" uniqKey="Nagle A">A. Nagle</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dembele, L" uniqKey="Dembele L">L. Dembélé</name>
</author>
<author><name sortKey="Franetich, J F" uniqKey="Franetich J">J.-F. Franetich</name>
</author>
<author><name sortKey="Lorthiois, A" uniqKey="Lorthiois A">A. Lorthiois</name>
</author>
<author><name sortKey="Gego, A" uniqKey="Gego A">A. Gego</name>
</author>
<author><name sortKey="Zeeman, A M" uniqKey="Zeeman A">A.-M. Zeeman</name>
</author>
<author><name sortKey="Kocken, C H M" uniqKey="Kocken C">C. H. M. Kocken</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Scannell, J X0a W" uniqKey="Scannell J">J.
W. Scannell</name>
</author>
<author><name sortKey="Blanckley, A" uniqKey="Blanckley A">A. Blanckley</name>
</author>
<author><name sortKey="Boldon, H" uniqKey="Boldon H">H. Boldon</name>
</author>
<author><name sortKey="Warrington, B" uniqKey="Warrington B">B. Warrington</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Paul, S M" uniqKey="Paul S">S. M. Paul</name>
</author>
<author><name sortKey="Mytelka, D S" uniqKey="Mytelka D">D. S. Mytelka</name>
</author>
<author><name sortKey="Dunwiddie, C T" uniqKey="Dunwiddie C">C. T. Dunwiddie</name>
</author>
<author><name sortKey="Persinger, C C" uniqKey="Persinger C">C. C. Persinger</name>
</author>
<author><name sortKey="Munos, B H" uniqKey="Munos B">B. H. Munos</name>
</author>
<author><name sortKey="Lindborg, S R" uniqKey="Lindborg S">S. R. Lindborg</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kneller, R" uniqKey="Kneller R">R. Kneller</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Jorgensen, W L" uniqKey="Jorgensen W">W. L. Jorgensen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lezaun, J" uniqKey="Lezaun J">J. Lezaun</name>
</author>
<author><name sortKey="Montgomery, C M" uniqKey="Montgomery C">C. M. Montgomery</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Hopkins, A L" uniqKey="Hopkins A">A. L. Hopkins</name>
</author>
<author><name sortKey="Witty, M J" uniqKey="Witty M">M. J. Witty</name>
</author>
<author><name sortKey="Nwaka, S" uniqKey="Nwaka S">S. Nwaka</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Orti, L" uniqKey="Orti L">L. Ortí</name>
</author>
<author><name sortKey="Carbajo, R J" uniqKey="Carbajo R">R. J. Carbajo</name>
</author>
<author><name sortKey="Pieper, U" uniqKey="Pieper U">U. Pieper</name>
</author>
<author><name sortKey="Eswar, N" uniqKey="Eswar N">N. Eswar</name>
</author>
<author><name sortKey="Maurer, S M" uniqKey="Maurer S">S. M. Maurer</name>
</author>
<author><name sortKey="Rai, A K" uniqKey="Rai A">A. K. Rai</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Jakobsen, P X0a H" uniqKey="Jakobsen P">P.
H. Jakobsen</name>
</author>
<author><name sortKey="Wang, M W" uniqKey="Wang M">M.-W. Wang</name>
</author>
<author><name sortKey="Nwaka, S" uniqKey="Nwaka S">S. Nwaka</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lotharius, J" uniqKey="Lotharius J">J. Lotharius</name>
</author>
<author><name sortKey="Gamo Benito, F J" uniqKey="Gamo Benito F">F. J. Gamo-Benito</name>
</author>
<author><name sortKey="Angulo Barturen, I" uniqKey="Angulo Barturen I">I. Angulo-Barturen</name>
</author>
<author><name sortKey="Clark, J" uniqKey="Clark J">J. Clark</name>
</author>
<author><name sortKey="Connelly, M" uniqKey="Connelly M">M. Connelly</name>
</author>
<author><name sortKey="Ferrer Bazaga, S" uniqKey="Ferrer Bazaga S">S. Ferrer-Bazaga</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hunter, J" uniqKey="Hunter J">J. Hunter</name>
</author>
<author><name sortKey="Stephens, S" uniqKey="Stephens S">S. Stephens</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Maurer, S X0a M" uniqKey="Maurer S">S.
M. Maurer</name>
</author>
<author><name sortKey="Rai, A" uniqKey="Rai A">A. Rai</name>
</author>
<author><name sortKey="Sali, A" uniqKey="Sali A">A. Sali</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Munos, B" uniqKey="Munos B">B. Munos</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Singh, S" uniqKey="Singh S">S. Singh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Munos, B" uniqKey="Munos B">B. Munos</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Woelfle, M" uniqKey="Woelfle M">M. Woelfle</name>
</author>
<author><name sortKey="Olliaro, P" uniqKey="Olliaro P">P. Olliaro</name>
</author>
<author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Orti, L" uniqKey="Orti L">L. Ortí</name>
</author>
<author><name sortKey="Carbajo, R J" uniqKey="Carbajo R">R. J. Carbajo</name>
</author>
<author><name sortKey="Pieper, U" uniqKey="Pieper U">U. Pieper</name>
</author>
<author><name sortKey="Eswar, N" uniqKey="Eswar N">N. Eswar</name>
</author>
<author><name sortKey="Maurer, S M" uniqKey="Maurer S">S. M. Maurer</name>
</author>
<author><name sortKey="Rai, A K" uniqKey="Rai A">A. K. Rai</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey=" Rdal, C" uniqKey=" Rdal C">C. Årdal</name>
</author>
<author><name sortKey="Alstads Ter, A" uniqKey="Alstads Ter A">A. Alstadsæter</name>
</author>
<author><name sortKey="R Ttingen, J A" uniqKey="R Ttingen J">J. A. Røttingen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Delano, W L" uniqKey="Delano W">W. L. DeLano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Woelfle, M" uniqKey="Woelfle M">M. Woelfle</name>
</author>
<author><name sortKey="Seerden, J P" uniqKey="Seerden J">J.-P. Seerden</name>
</author>
<author><name sortKey="De Gooijer, J" uniqKey="De Gooijer J">J. de Gooijer</name>
</author>
<author><name sortKey="Pouwer, K" uniqKey="Pouwer K">K. Pouwer</name>
</author>
<author><name sortKey="Olliaro, P" uniqKey="Olliaro P">P. Olliaro</name>
</author>
<author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Reaves, M L" uniqKey="Reaves M">M. L. Reaves</name>
</author>
<author><name sortKey="Sinha, S" uniqKey="Sinha S">S. Sinha</name>
</author>
<author><name sortKey="Rabinowitz, J D" uniqKey="Rabinowitz J">J. D. Rabinowitz</name>
</author>
<author><name sortKey="Kruglyak, L" uniqKey="Kruglyak L">L. Kruglyak</name>
</author>
<author><name sortKey="Redfield, R J" uniqKey="Redfield R">R. J. Redfield</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Anand, P" uniqKey="Anand P">P. Anand</name>
</author>
<author><name sortKey="Sankaran, S" uniqKey="Sankaran S">S. Sankaran</name>
</author>
<author><name sortKey="Mukherjee, S" uniqKey="Mukherjee S">S. Mukherjee</name>
</author>
<author><name sortKey="Yeturu, K" uniqKey="Yeturu K">K. Yeturu</name>
</author>
<author><name sortKey="Laskowski, R" uniqKey="Laskowski R">R. Laskowski</name>
</author>
<author><name sortKey="Bhardwaj, A" uniqKey="Bhardwaj A">A. Bhardwaj</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bhardwaj, A" uniqKey="Bhardwaj A">A. Bhardwaj</name>
</author>
<author><name sortKey="Scaria, V" uniqKey="Scaria V">V. Scaria</name>
</author>
<author><name sortKey="Raghava, G P S" uniqKey="Raghava G">G. P. S. Raghava</name>
</author>
<author><name sortKey="Lynn, A M" uniqKey="Lynn A">A. M. Lynn</name>
</author>
<author><name sortKey="Chandra, N" uniqKey="Chandra N">N. Chandra</name>
</author>
<author><name sortKey="Banerjee, S" uniqKey="Banerjee S">S. Banerjee</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jefferson, R" uniqKey="Jefferson R">R. Jefferson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Carroll, M W" uniqKey="Carroll M">M. W. Carroll</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Robertson, M N" uniqKey="Robertson M">M. N. Robertson</name>
</author>
<author><name sortKey="Ylioja, P M" uniqKey="Ylioja P">P. M. Ylioja</name>
</author>
<author><name sortKey="Williamson, A E" uniqKey="Williamson A">A. E. Williamson</name>
</author>
<author><name sortKey="Woelfle, M" uniqKey="Woelfle M">M. Woelfle</name>
</author>
<author><name sortKey="Robins, M" uniqKey="Robins M">M. Robins</name>
</author>
<author><name sortKey="Badiola, K A" uniqKey="Badiola K">K. A. Badiola</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Badiola, K A" uniqKey="Badiola K">K. A. Badiola</name>
</author>
<author><name sortKey="Bird, C" uniqKey="Bird C">C. Bird</name>
</author>
<author><name sortKey="Brocklesby, W S" uniqKey="Brocklesby W">W. S. Brocklesby</name>
</author>
<author><name sortKey="Casson, J" uniqKey="Casson J">J. Casson</name>
</author>
<author><name sortKey="Chapman, R T" uniqKey="Chapman R">R. T. Chapman</name>
</author>
<author><name sortKey="Coles, S J" uniqKey="Coles S">S. J. Coles</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gamo, F J" uniqKey="Gamo F">F.-J. Gamo</name>
</author>
<author><name sortKey="Sanz, L M" uniqKey="Sanz L">L. M. Sanz</name>
</author>
<author><name sortKey="Vidal, J" uniqKey="Vidal J">J. Vidal</name>
</author>
<author><name sortKey="De Cozar, C" uniqKey="De Cozar C">C. de Cozar</name>
</author>
<author><name sortKey="Alvarez, E" uniqKey="Alvarez E">E. Alvarez</name>
</author>
<author><name sortKey="Lavandera, J L" uniqKey="Lavandera J">J.-L. Lavandera</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guiguemde, W A" uniqKey="Guiguemde W">W. A. Guiguemde</name>
</author>
<author><name sortKey="Shelat, A A" uniqKey="Shelat A">A. A. Shelat</name>
</author>
<author><name sortKey="Bouck, D" uniqKey="Bouck D">D. Bouck</name>
</author>
<author><name sortKey="Duffy, S" uniqKey="Duffy S">S. Duffy</name>
</author>
<author><name sortKey="Crowther, G J" uniqKey="Crowther G">G. J. Crowther</name>
</author>
<author><name sortKey="Davis, P H" uniqKey="Davis P">P. H. Davis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Plouffe, D" uniqKey="Plouffe D">D. Plouffe</name>
</author>
<author><name sortKey="Brinker, A" uniqKey="Brinker A">A. Brinker</name>
</author>
<author><name sortKey="Mcnamara, C" uniqKey="Mcnamara C">C. McNamara</name>
</author>
<author><name sortKey="Henson, K" uniqKey="Henson K">K. Henson</name>
</author>
<author><name sortKey="Kato, N" uniqKey="Kato N">N. Kato</name>
</author>
<author><name sortKey="Kuhen, K" uniqKey="Kuhen K">K. Kuhen</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Calder N, F" uniqKey="Calder N F">F. Calderón</name>
</author>
<author><name sortKey="Barros, D" uniqKey="Barros D">D. Barros</name>
</author>
<author><name sortKey="Bueno, J M" uniqKey="Bueno J">J. M. Bueno</name>
</author>
<author><name sortKey="Coter N, J M" uniqKey="Coter N J">J. M. Coterón</name>
</author>
<author><name sortKey="Fernandez, E" uniqKey="Fernandez E">E. Fernández</name>
</author>
<author><name sortKey="Gamo, F J" uniqKey="Gamo F">F. J. Gamo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rueda, L" uniqKey="Rueda L">L. Rueda</name>
</author>
<author><name sortKey="Castellote, I" uniqKey="Castellote I">I. Castellote</name>
</author>
<author><name sortKey="Castro Pichel, J" uniqKey="Castro Pichel J">J. Castro-Pichel</name>
</author>
<author><name sortKey="Chaparro, M J" uniqKey="Chaparro M">M. J. Chaparro</name>
</author>
<author><name sortKey="De La Rosa, J C" uniqKey="De La Rosa J">J. C. de la Rosa</name>
</author>
<author><name sortKey="Garcia Perez, A" uniqKey="Garcia Perez A">A. Garcia-Perez</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sanz, L M" uniqKey="Sanz L">L. M. Sanz</name>
</author>
<author><name sortKey="Jimenez Diaz, M B" uniqKey="Jimenez Diaz M">M. B. Jiménez-Díaz</name>
</author>
<author><name sortKey="Crespo, B" uniqKey="Crespo B">B. Crespo</name>
</author>
<author><name sortKey="De Cozar, C" uniqKey="De Cozar C">C. De-Cozar</name>
</author>
<author><name sortKey="Almela, M J" uniqKey="Almela M">M. J. Almela</name>
</author>
<author><name sortKey="Angulo Barturen, I" uniqKey="Angulo Barturen I">I. Angulo-Barturen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Calder N, F" uniqKey="Calder N F">F. Calderón</name>
</author>
<author><name sortKey="Vidal Mas, J" uniqKey="Vidal Mas J">J. Vidal-Mas</name>
</author>
<author><name sortKey="Burrows, J" uniqKey="Burrows J">J. Burrows</name>
</author>
<author><name sortKey="De La Rosa, J C" uniqKey="De La Rosa J">J. C. de la Rosa</name>
</author>
<author><name sortKey="Jimenez Diaz, M B" uniqKey="Jimenez Diaz M">M. B. Jiménez-Díaz</name>
</author>
<author><name sortKey="Mulet, T" uniqKey="Mulet T">T. Mulet</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Murugesan, D" uniqKey="Murugesan D">D. Murugesan</name>
</author>
<author><name sortKey="Mital, A" uniqKey="Mital A">A. Mital</name>
</author>
<author><name sortKey="Kaiser, M" uniqKey="Kaiser M">M. Kaiser</name>
</author>
<author><name sortKey="Shackleford, D M" uniqKey="Shackleford D">D. M. Shackleford</name>
</author>
<author><name sortKey="Morizzi, J" uniqKey="Morizzi J">J. Morizzi</name>
</author>
<author><name sortKey="Katneni, K" uniqKey="Katneni K">K. Katneni</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Murugesan, D" uniqKey="Murugesan D">D. Murugesan</name>
</author>
<author><name sortKey="Kaiser, M" uniqKey="Kaiser M">M. Kaiser</name>
</author>
<author><name sortKey="White, K L" uniqKey="White K">K. L. White</name>
</author>
<author><name sortKey="Norval, S" uniqKey="Norval S">S. Norval</name>
</author>
<author><name sortKey="Riley, J" uniqKey="Riley J">J. Riley</name>
</author>
<author><name sortKey="Wyatt, P G" uniqKey="Wyatt P">P. G. Wyatt</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Gu, X P" uniqKey="Gu X">X. P. Gu</name>
</author>
<author><name sortKey="Nishida, N" uniqKey="Nishida N">N. Nishida</name>
</author>
<author><name sortKey="Ikeda, I" uniqKey="Ikeda I">I. Ikeda</name>
</author>
<author><name sortKey="Okahara, M" uniqKey="Okahara M">M. Okahara</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chiu, P K" uniqKey="Chiu P">P.-K. Chiu</name>
</author>
<author><name sortKey="Sannes, M P" uniqKey="Sannes M">M. P. Sannes</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ylioja, P M" uniqKey="Ylioja P">P. M. Ylioja</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Avery, V" uniqKey="Avery V">V. Avery</name>
</author>
<author><name sortKey="Baell, J" uniqKey="Baell J">J. Baell</name>
</author>
<author><name sortKey="Batra, S" uniqKey="Batra S">S. Batra</name>
</author>
<author><name sortKey="Burrows, J" uniqKey="Burrows J">J. Burrows</name>
</author>
<author><name sortKey="Bhattacharyya, S" uniqKey="Bhattacharyya S">S. Bhattacharyya</name>
</author>
<author><name sortKey="Calderon, F" uniqKey="Calderon F">F. Calderon</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Ertl, P" uniqKey="Ertl P">P. Ertl</name>
</author>
<author><name sortKey="Patiny, L" uniqKey="Patiny L">L. Patiny</name>
</author>
<author><name sortKey="Sander, T" uniqKey="Sander T">T. Sander</name>
</author>
<author><name sortKey="Rufener, C" uniqKey="Rufener C">C. Rufener</name>
</author>
<author><name sortKey="Zasso, M" uniqKey="Zasso M">M. Zasso</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Swain, C" uniqKey="Swain C">C. Swain</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Swain, C" uniqKey="Swain C">C. Swain</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Avery, V M" uniqKey="Avery V">V. M. Avery</name>
</author>
<author><name sortKey="Bashyam, S" uniqKey="Bashyam S">S. Bashyam</name>
</author>
<author><name sortKey="Burrows, J N" uniqKey="Burrows J">J. N. Burrows</name>
</author>
<author><name sortKey="Duffy, S" uniqKey="Duffy S">S. Duffy</name>
</author>
<author><name sortKey="Papadatos, G" uniqKey="Papadatos G">G. Papadatos</name>
</author>
<author><name sortKey="Puthukkuti, S" uniqKey="Puthukkuti S">S. Puthukkuti</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Bhandari, S V" uniqKey="Bhandari S">S. V. Bhandari</name>
</author>
<author><name sortKey="Bothara, K G" uniqKey="Bothara K">K. G. Bothara</name>
</author>
<author><name sortKey="Patil, A A" uniqKey="Patil A">A. A. Patil</name>
</author>
<author><name sortKey="Chitre, T S" uniqKey="Chitre T">T. S. Chitre</name>
</author>
<author><name sortKey="Sarkate, A P" uniqKey="Sarkate A">A. P. Sarkate</name>
</author>
<author><name sortKey="Gore, S T" uniqKey="Gore S">S. T. Gore</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Urbano, M" uniqKey="Urbano M">M. Urbano</name>
</author>
<author><name sortKey="Guerrero, M" uniqKey="Guerrero M">M. Guerrero</name>
</author>
<author><name sortKey="Velaparthi, S" uniqKey="Velaparthi S">S. Velaparthi</name>
</author>
<author><name sortKey="Crisp, M" uniqKey="Crisp M">M. Crisp</name>
</author>
<author><name sortKey="Chase, P" uniqKey="Chase P">P. Chase</name>
</author>
<author><name sortKey="Hodder, P" uniqKey="Hodder P">P. Hodder</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Singh, T" uniqKey="Singh T">T. Singh</name>
</author>
<author><name sortKey="Sharma, P K" uniqKey="Sharma P">P. K. Sharma</name>
</author>
<author><name sortKey="Mondal, S C" uniqKey="Mondal S">S. C. Mondal</name>
</author>
<author><name sortKey="Kumar, N" uniqKey="Kumar N">N. Kumar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hopkins, A L" uniqKey="Hopkins A">A. L. Hopkins</name>
</author>
<author><name sortKey="Keseru, G M" uniqKey="Keseru G">G. M. Keserü</name>
</author>
<author><name sortKey="Leeson, P D" uniqKey="Leeson P">P. D. Leeson</name>
</author>
<author><name sortKey="Rees, D C" uniqKey="Rees D">D. C. Rees</name>
</author>
<author><name sortKey="Reynolds, C H" uniqKey="Reynolds C">C. H. Reynolds</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Baell, J B" uniqKey="Baell J">J. B. Baell</name>
</author>
<author><name sortKey="Holloway, G A" uniqKey="Holloway G">G. A. Holloway</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Saubern, S" uniqKey="Saubern S">S. Saubern</name>
</author>
<author><name sortKey="Guha, R" uniqKey="Guha R">R. Guha</name>
</author>
<author><name sortKey="Baell, J B" uniqKey="Baell J">J. B. Baell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Baell, J B" uniqKey="Baell J">J. B. Baell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mok, N Y" uniqKey="Mok N">N. Y. Mok</name>
</author>
<author><name sortKey="Maxe, S" uniqKey="Maxe S">S. Maxe</name>
</author>
<author><name sortKey="Brenk, R" uniqKey="Brenk R">R. Brenk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bruns, R F" uniqKey="Bruns R">R. F. Bruns</name>
</author>
<author><name sortKey="Watson, I A" uniqKey="Watson I">I. A. Watson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mendgen, T" uniqKey="Mendgen T">T. Mendgen</name>
</author>
<author><name sortKey="Steuer, C" uniqKey="Steuer C">C. Steuer</name>
</author>
<author><name sortKey="Klein, C D" uniqKey="Klein C">C. D. Klein</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Thorne, N" uniqKey="Thorne N">N. Thorne</name>
</author>
<author><name sortKey="Auld, D S" uniqKey="Auld D">D. S. Auld</name>
</author>
<author><name sortKey="Inglese, J" uniqKey="Inglese J">J. Inglese</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lowe, D" uniqKey="Lowe D">D. Lowe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lowe, D" uniqKey="Lowe D">D. Lowe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Singh, J" uniqKey="Singh J">J. Singh</name>
</author>
<author><name sortKey="Petter, R C" uniqKey="Petter R">R. C. Petter</name>
</author>
<author><name sortKey="Baillie, T A" uniqKey="Baillie T">T. A. Baillie</name>
</author>
<author><name sortKey="Whitty, A" uniqKey="Whitty A">A. Whitty</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Huth, J R" uniqKey="Huth J">J. R. Huth</name>
</author>
<author><name sortKey="Mendoza, R" uniqKey="Mendoza R">R. Mendoza</name>
</author>
<author><name sortKey="Olejniczak, E T" uniqKey="Olejniczak E">E. T. Olejniczak</name>
</author>
<author><name sortKey="Johnson, R W" uniqKey="Johnson R">R. W. Johnson</name>
</author>
<author><name sortKey="Cothron, D A" uniqKey="Cothron D">D. A. Cothron</name>
</author>
<author><name sortKey="Liu, Y" uniqKey="Liu Y">Y. Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ekins, S" uniqKey="Ekins S">S. Ekins</name>
</author>
<author><name sortKey="Williams, A J" uniqKey="Williams A">A. J. Williams</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Todd, M H" uniqKey="Todd M">M. H. Todd</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ylioja, P M" uniqKey="Ylioja P">P. M. Ylioja</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bostrom, J" uniqKey="Bostrom J">J. Boström</name>
</author>
<author><name sortKey="Hogner, A" uniqKey="Hogner A">A. Hogner</name>
</author>
<author><name sortKey="Llinas, A" uniqKey="Llinas A">A. Llinàs</name>
</author>
<author><name sortKey="Wellner, E" uniqKey="Wellner E">E. Wellner</name>
</author>
<author><name sortKey="Plowright, A T" uniqKey="Plowright A">A. T. Plowright</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Olesen, P X0a H" uniqKey="Olesen P">P.
H. Olesen</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Berry, L M" uniqKey="Berry L">L. M. Berry</name>
</author>
<author><name sortKey="Wollenberg, L" uniqKey="Wollenberg L">L. Wollenberg</name>
</author>
<author><name sortKey="Zhao, Z" uniqKey="Zhao Z">Z. Zhao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Danker, T" uniqKey="Danker T">T. Danker</name>
</author>
<author><name sortKey="Moller, C" uniqKey="Moller C">C. Möller</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ruecker, A" uniqKey="Ruecker A">A. Ruecker</name>
</author>
<author><name sortKey="Mathias, D K" uniqKey="Mathias D">D. K. Mathias</name>
</author>
<author><name sortKey="Straschil, U" uniqKey="Straschil U">U. Straschil</name>
</author>
<author><name sortKey="Churcher, T S" uniqKey="Churcher T">T. S. Churcher</name>
</author>
<author><name sortKey="Dinglasan, R R" uniqKey="Dinglasan R">R. R. Dinglasan</name>
</author>
<author><name sortKey="Leroy, D" uniqKey="Leroy D">D. Leroy</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meister, S" uniqKey="Meister S">S. Meister</name>
</author>
<author><name sortKey="Plouffe, D M" uniqKey="Plouffe D">D. M. Plouffe</name>
</author>
<author><name sortKey="Kuhen, K L" uniqKey="Kuhen K">K. L. Kuhen</name>
</author>
<author><name sortKey="Bonamy, G M C" uniqKey="Bonamy G">G. M. C. Bonamy</name>
</author>
<author><name sortKey="Wu, T" uniqKey="Wu T">T. Wu</name>
</author>
<author><name sortKey="Barnes, S W" uniqKey="Barnes S">S. W. Barnes</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lee, A Y" uniqKey="Lee A">A. Y. Lee</name>
</author>
<author><name sortKey="St Onge, R P" uniqKey="St Onge R">R. P. St.Onge</name>
</author>
<author><name sortKey="Proctor, M J" uniqKey="Proctor M">M. J. Proctor</name>
</author>
<author><name sortKey="Wallace, I M" uniqKey="Wallace I">I. M. Wallace</name>
</author>
<author><name sortKey="Nile, A H" uniqKey="Nile A">A. H. Nile</name>
</author>
<author><name sortKey="Spagnuolo, P A" uniqKey="Spagnuolo P">P. A. Spagnuolo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Subramanian, A" uniqKey="Subramanian A">A. Subramanian</name>
</author>
<author><name sortKey="Tamayo, P" uniqKey="Tamayo P">P. Tamayo</name>
</author>
<author><name sortKey="Mootha, V K" uniqKey="Mootha V">V. K. Mootha</name>
</author>
<author><name sortKey="Mukherjee, S" uniqKey="Mukherjee S">S. Mukherjee</name>
</author>
<author><name sortKey="Ebert, B L" uniqKey="Ebert B">B. L. Ebert</name>
</author>
<author><name sortKey="Gillette, M A" uniqKey="Gillette M">M. A. Gillette</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gupta, A P" uniqKey="Gupta A">A. P. Gupta</name>
</author>
<author><name sortKey="Chin, W H" uniqKey="Chin W">W. H. Chin</name>
</author>
<author><name sortKey="Zhu, L" uniqKey="Zhu L">L. Zhu</name>
</author>
<author><name sortKey="Mok, S" uniqKey="Mok S">S. Mok</name>
</author>
<author><name sortKey="Luah, Y H" uniqKey="Luah Y">Y.-H. Luah</name>
</author>
<author><name sortKey="Lim, E H" uniqKey="Lim E">E.-H. Lim</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jiang, L" uniqKey="Jiang L">L. Jiang</name>
</author>
<author><name sortKey="Mu, J" uniqKey="Mu J">J. Mu</name>
</author>
<author><name sortKey="Zhang, Q" uniqKey="Zhang Q">Q. Zhang</name>
</author>
<author><name sortKey="Ni, T" uniqKey="Ni T">T. Ni</name>
</author>
<author><name sortKey="Srinivasan, P" uniqKey="Srinivasan P">P. Srinivasan</name>
</author>
<author><name sortKey="Rayavara, K" uniqKey="Rayavara K">K. Rayavara</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yu, L" uniqKey="Yu L">L. Yu</name>
</author>
<author><name sortKey="Lopez, A" uniqKey="Lopez A">A. Lopez</name>
</author>
<author><name sortKey="Anaflous, A" uniqKey="Anaflous A">A. Anaflous</name>
</author>
<author><name sortKey="El Bali, B" uniqKey="El Bali B">B. El Bali</name>
</author>
<author><name sortKey="Hamal, A" uniqKey="Hamal A">A. Hamal</name>
</author>
<author><name sortKey="Ericson, E" uniqKey="Ericson E">E. Ericson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sanz, L M" uniqKey="Sanz L">L. M. Sanz</name>
</author>
<author><name sortKey="Crespo, B" uniqKey="Crespo B">B. Crespo</name>
</author>
<author><name sortKey="De C Zar, C" uniqKey="De C Zar C">C. De-Cózar</name>
</author>
<author><name sortKey="Ding, X C" uniqKey="Ding X">X. C. Ding</name>
</author>
<author><name sortKey="Llergo, J L" uniqKey="Llergo J">J. L. Llergo</name>
</author>
<author><name sortKey="Burrows, J N" uniqKey="Burrows J">J. N. Burrows</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Prathipati, P" uniqKey="Prathipati P">P. Prathipati</name>
</author>
<author><name sortKey="Ma, N L" uniqKey="Ma N">N. L. Ma</name>
</author>
<author><name sortKey="Manjunatha, U H" uniqKey="Manjunatha U">U. H. Manjunatha</name>
</author>
<author><name sortKey="Bender, A" uniqKey="Bender A">A. Bender</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Koutsoukas, A" uniqKey="Koutsoukas A">A. Koutsoukas</name>
</author>
<author><name sortKey="Simms, B" uniqKey="Simms B">B. Simms</name>
</author>
<author><name sortKey="Kirchmair, J" uniqKey="Kirchmair J">J. Kirchmair</name>
</author>
<author><name sortKey="Bond, P J" uniqKey="Bond P">P. J. Bond</name>
</author>
<author><name sortKey="Whitmore, A V" uniqKey="Whitmore A">A. V. Whitmore</name>
</author>
<author><name sortKey="Zimmer, S" uniqKey="Zimmer S">S. Zimmer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Martinez Jimenez, F" uniqKey="Martinez Jimenez F">F. Martínez-Jiménez</name>
</author>
<author><name sortKey="Papadatos, G" uniqKey="Papadatos G">G. Papadatos</name>
</author>
<author><name sortKey="Yang, L" uniqKey="Yang L">L. Yang</name>
</author>
<author><name sortKey="Wallace, I M" uniqKey="Wallace I">I. M. Wallace</name>
</author>
<author><name sortKey="Kumar, V" uniqKey="Kumar V">V. Kumar</name>
</author>
<author><name sortKey="Pieper, U" uniqKey="Pieper U">U. Pieper</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Baldwin, J" uniqKey="Baldwin J">J. Baldwin</name>
</author>
<author><name sortKey="Farajallah, A M" uniqKey="Farajallah A">A. M. Farajallah</name>
</author>
<author><name sortKey="Malmquist, N A" uniqKey="Malmquist N">N. A. Malmquist</name>
</author>
<author><name sortKey="Rathod, P K" uniqKey="Rathod P">P. K. Rathod</name>
</author>
<author><name sortKey="Phillips, M A" uniqKey="Phillips M">M. A. Phillips</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Spillman, N J" uniqKey="Spillman N">N. J. Spillman</name>
</author>
<author><name sortKey="Allen, R J W" uniqKey="Allen R">R. J. W. Allen</name>
</author>
<author><name sortKey="Mcnamara, C W" uniqKey="Mcnamara C">C. W. McNamara</name>
</author>
<author><name sortKey="Yeung, B K S" uniqKey="Yeung B">B. K. S. Yeung</name>
</author>
<author><name sortKey="Winzeler, E A" uniqKey="Winzeler E">E. A. Winzeler</name>
</author>
<author><name sortKey="Diagana, T T" uniqKey="Diagana T">T. T. Diagana</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="White, N J" uniqKey="White N">N. J. White</name>
</author>
<author><name sortKey="Pukrittayakamee, S" uniqKey="Pukrittayakamee S">S. Pukrittayakamee</name>
</author>
<author><name sortKey="Phyo, A P" uniqKey="Phyo A">A. P. Phyo</name>
</author>
<author><name sortKey="Rueangweerayut, R" uniqKey="Rueangweerayut R">R. Rueangweerayut</name>
</author>
<author><name sortKey="Nosten, F" uniqKey="Nosten F">F. Nosten</name>
</author>
<author><name sortKey="Jittamala, P" uniqKey="Jittamala P">P. Jittamala</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vaidya, A B" uniqKey="Vaidya A">A. B. Vaidya</name>
</author>
<author><name sortKey="Morrisey, J M" uniqKey="Morrisey J">J. M. Morrisey</name>
</author>
<author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z. Zhang</name>
</author>
<author><name sortKey="Das, S" uniqKey="Das S">S. Das</name>
</author>
<author><name sortKey="Daly, T M" uniqKey="Daly T">T. M. Daly</name>
</author>
<author><name sortKey="Otto, T D" uniqKey="Otto T">T. D. Otto</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jimenez Diaz, M B" uniqKey="Jimenez Diaz M">M. B. Jiménez-Díaz</name>
</author>
<author><name sortKey="Ebert, D" uniqKey="Ebert D">D. Ebert</name>
</author>
<author><name sortKey="Salinas, Y" uniqKey="Salinas Y">Y. Salinas</name>
</author>
<author><name sortKey="Pradhan, A" uniqKey="Pradhan A">A. Pradhan</name>
</author>
<author><name sortKey="Lehane, A M" uniqKey="Lehane A">A. M. Lehane</name>
</author>
<author><name sortKey="Myrand Lapierre, M E" uniqKey="Myrand Lapierre M">M.-E. Myrand-Lapierre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Flannery, E L" uniqKey="Flannery E">E. L. Flannery</name>
</author>
<author><name sortKey="Mcnamara, C W" uniqKey="Mcnamara C">C. W. McNamara</name>
</author>
<author><name sortKey="Kim, S W" uniqKey="Kim S">S. W. Kim</name>
</author>
<author><name sortKey="Kato, T S" uniqKey="Kato T">T. S. Kato</name>
</author>
<author><name sortKey="Li, F W" uniqKey="Li F">F.-W. Li</name>
</author>
<author><name sortKey="Teng, C H" uniqKey="Teng C">C. H. Teng</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lehane, A M" uniqKey="Lehane A">A. M. Lehane</name>
</author>
<author><name sortKey="Ridgway, M C" uniqKey="Ridgway M">M. C. Ridgway</name>
</author>
<author><name sortKey="Baker, E" uniqKey="Baker E">E. Baker</name>
</author>
<author><name sortKey="Kirk, K" uniqKey="Kirk K">K. Kirk</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Van Voorhis, W C" uniqKey="Van Voorhis W">W. C. van Voorhis</name>
</author>
<author><name sortKey="Adams, J H" uniqKey="Adams J">J. H. Adams</name>
</author>
<author><name sortKey="Adelfio, R" uniqKey="Adelfio R">R. Adelfio</name>
</author>
<author><name sortKey="Ahyong, V" uniqKey="Ahyong V">V. Ahyong</name>
</author>
<author><name sortKey="Akabas, M H" uniqKey="Akabas M">M. H. Akabas</name>
</author>
<author><name sortKey="Alano, P" uniqKey="Alano P">P. Alano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lowe, D" uniqKey="Lowe D">D. Lowe</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article" xml:lang="EN"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">ACS Cent Sci</journal-id>
<journal-id journal-id-type="iso-abbrev">ACS Cent Sci</journal-id>
<journal-id journal-id-type="publisher-id">oc</journal-id>
<journal-id journal-id-type="coden">acscii</journal-id>
<journal-title-group><journal-title>ACS Central Science</journal-title>
</journal-title-group>
<issn pub-type="ppub">2374-7943</issn>
<issn pub-type="epub">2374-7951</issn>
<publisher><publisher-name>American Chemical Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27800551</article-id>
<article-id pub-id-type="pmc">5084075</article-id>
<article-id pub-id-type="doi">10.1021/acscentsci.6b00086</article-id>
<article-categories><subj-group><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Open Source Drug Discovery: Highly Potent Antimalarial
Compounds Derived from the Tres Cantos Arylpyrroles</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="ath1"><name><surname>Williamson</surname>
<given-names>Alice E.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="notes-2" ref-type="notes">‡</xref>
</contrib>
<contrib contrib-type="author" id="ath2"><name><surname>Ylioja</surname>
<given-names>Paul M.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="notes-2" ref-type="notes">‡</xref>
</contrib>
<contrib contrib-type="author" id="ath3"><name><surname>Robertson</surname>
<given-names>Murray N.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="notes-2" ref-type="notes">‡</xref>
</contrib>
<contrib contrib-type="author" id="ath4"><name><surname>Antonova-Koch</surname>
<given-names>Yevgeniya</given-names>
</name>
<xref rid="aff2" ref-type="aff">§</xref>
</contrib>
<contrib contrib-type="author" id="ath5"><name><surname>Avery</surname>
<given-names>Vicky</given-names>
</name>
<xref rid="aff3" ref-type="aff">∥</xref>
</contrib>
<contrib contrib-type="author" id="ath6"><name><surname>Baell</surname>
<given-names>Jonathan B.</given-names>
</name>
<xref rid="aff4" ref-type="aff">⊥</xref>
</contrib>
<contrib contrib-type="author" id="ath7"><name><surname>Batchu</surname>
<given-names>Harikrishna</given-names>
</name>
<xref rid="aff5" ref-type="aff">#</xref>
</contrib>
<contrib contrib-type="author" id="ath8"><name><surname>Batra</surname>
<given-names>Sanjay</given-names>
</name>
<xref rid="aff5" ref-type="aff">#</xref>
</contrib>
<contrib contrib-type="author" id="ath9"><name><surname>Burrows</surname>
<given-names>Jeremy N.</given-names>
</name>
<xref rid="aff6" ref-type="aff">¶</xref>
</contrib>
<contrib contrib-type="author" id="ath10"><name><surname>Bhattacharyya</surname>
<given-names>Soumya</given-names>
</name>
<xref rid="aff5" ref-type="aff">#</xref>
</contrib>
<contrib contrib-type="author" id="ath11"><name><surname>Calderon</surname>
<given-names>Felix</given-names>
</name>
<xref rid="aff7" ref-type="aff">α</xref>
</contrib>
<contrib contrib-type="author" id="ath12"><name><surname>Charman</surname>
<given-names>Susan A.</given-names>
</name>
<xref rid="aff4" ref-type="aff">⊥</xref>
</contrib>
<contrib contrib-type="author" id="ath13"><name><surname>Clark</surname>
<given-names>Julie</given-names>
</name>
<xref rid="aff8" ref-type="aff">β</xref>
</contrib>
<contrib contrib-type="author" id="ath14"><name><surname>Crespo</surname>
<given-names>Benigno</given-names>
</name>
<xref rid="aff7" ref-type="aff">α</xref>
</contrib>
<contrib contrib-type="author" id="ath15"><name><surname>Dean</surname>
<given-names>Matin</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath16"><name><surname>Debbert</surname>
<given-names>Stefan L.</given-names>
</name>
<xref rid="aff9" ref-type="aff">γ</xref>
</contrib>
<contrib contrib-type="author" id="ath17"><name><surname>Delves</surname>
<given-names>Michael</given-names>
</name>
<xref rid="aff10" ref-type="aff">δ</xref>
</contrib>
<contrib contrib-type="author" id="ath18"><name><surname>Dennis</surname>
<given-names>Adelaide S. M.</given-names>
</name>
<xref rid="aff11" ref-type="aff">ϵ</xref>
</contrib>
<contrib contrib-type="author" id="ath19"><name><surname>Deroose</surname>
<given-names>Frederik</given-names>
</name>
<xref rid="aff12" ref-type="aff">ζ</xref>
</contrib>
<contrib contrib-type="author" id="ath20"><name><surname>Duffy</surname>
<given-names>Sandra</given-names>
</name>
<xref rid="aff3" ref-type="aff">∥</xref>
</contrib>
<contrib contrib-type="author" id="ath21"><name><surname>Fletcher</surname>
<given-names>Sabine</given-names>
</name>
<xref rid="aff3" ref-type="aff">∥</xref>
</contrib>
<contrib contrib-type="author" id="ath22"><name><surname>Giaever</surname>
<given-names>Guri</given-names>
</name>
<xref rid="aff13" ref-type="aff">η</xref>
</contrib>
<contrib contrib-type="author" id="ath23"><name><surname>Hallyburton</surname>
<given-names>Irene</given-names>
</name>
<xref rid="aff14" ref-type="aff">θ</xref>
</contrib>
<contrib contrib-type="author" id="ath24"><name><surname>Gamo</surname>
<given-names>Francisco-Javier</given-names>
</name>
<xref rid="aff7" ref-type="aff">α</xref>
</contrib>
<contrib contrib-type="author" id="ath25"><name><surname>Gebbia</surname>
<given-names>Marinella</given-names>
</name>
<xref rid="aff13" ref-type="aff">η</xref>
</contrib>
<contrib contrib-type="author" id="ath26"><name><surname>Guy</surname>
<given-names>R. Kiplin</given-names>
</name>
<xref rid="aff8" ref-type="aff">β</xref>
</contrib>
<contrib contrib-type="author" id="ath27"><name><surname>Hungerford</surname>
<given-names>Zoe</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath28"><name><surname>Kirk</surname>
<given-names>Kiaran</given-names>
</name>
<xref rid="aff11" ref-type="aff">ϵ</xref>
</contrib>
<contrib contrib-type="author" id="ath29"><name><surname>Lafuente-Monasterio</surname>
<given-names>Maria
J.</given-names>
</name>
<xref rid="aff7" ref-type="aff">α</xref>
</contrib>
<contrib contrib-type="author" id="ath30"><name><surname>Lee</surname>
<given-names>Anna</given-names>
</name>
<xref rid="aff13" ref-type="aff">η</xref>
</contrib>
<contrib contrib-type="author" id="ath31"><name><surname>Meister</surname>
<given-names>Stephan</given-names>
</name>
<xref rid="aff2" ref-type="aff">§</xref>
</contrib>
<contrib contrib-type="author" id="ath32"><name><surname>Nislow</surname>
<given-names>Corey</given-names>
</name>
<xref rid="aff13" ref-type="aff">η</xref>
</contrib>
<contrib contrib-type="author" id="ath33"><name><surname>Overington</surname>
<given-names>John P.</given-names>
</name>
<xref rid="aff15" ref-type="aff">ι</xref>
</contrib>
<contrib contrib-type="author" id="ath34"><name><surname>Papadatos</surname>
<given-names>George</given-names>
</name>
<xref rid="aff15" ref-type="aff">ι</xref>
</contrib>
<contrib contrib-type="author" id="ath35"><name><surname>Patiny</surname>
<given-names>Luc</given-names>
</name>
<xref rid="aff16" ref-type="aff">κ</xref>
</contrib>
<contrib contrib-type="author" id="ath36"><name><surname>Pham</surname>
<given-names>James</given-names>
</name>
<xref rid="aff17" ref-type="aff">λ</xref>
</contrib>
<contrib contrib-type="author" id="ath37"><name><surname>Ralph</surname>
<given-names>Stuart
A.</given-names>
</name>
<xref rid="aff17" ref-type="aff">λ</xref>
</contrib>
<contrib contrib-type="author" id="ath38"><name><surname>Ruecker</surname>
<given-names>Andrea</given-names>
</name>
<xref rid="aff10" ref-type="aff">δ</xref>
</contrib>
<contrib contrib-type="author" id="ath39"><name><surname>Ryan</surname>
<given-names>Eileen</given-names>
</name>
<xref rid="aff4" ref-type="aff">⊥</xref>
</contrib>
<contrib contrib-type="author" id="ath40"><name><surname>Southan</surname>
<given-names>Christopher</given-names>
</name>
<xref rid="aff18" ref-type="aff">μ</xref>
</contrib>
<contrib contrib-type="author" id="ath41"><name><surname>Srivastava</surname>
<given-names>Kumkum</given-names>
</name>
<xref rid="aff5" ref-type="aff">#</xref>
</contrib>
<contrib contrib-type="author" id="ath42"><name><surname>Swain</surname>
<given-names>Chris</given-names>
</name>
<xref rid="aff19" ref-type="aff">ν</xref>
</contrib>
<contrib contrib-type="author" id="ath43"><name><surname>Tarnowski</surname>
<given-names>Matthew
J.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath44"><name><surname>Thomson</surname>
<given-names>Patrick</given-names>
</name>
<xref rid="aff20" ref-type="aff">ξ</xref>
</contrib>
<contrib contrib-type="author" id="ath45"><name><surname>Turner</surname>
<given-names>Peter</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath46"><name><surname>Wallace</surname>
<given-names>Iain M.</given-names>
</name>
<xref rid="aff15" ref-type="aff">ι</xref>
<xref rid="notes-1" ref-type="notes">ο</xref>
</contrib>
<contrib contrib-type="author" id="ath47"><name><surname>Wells</surname>
<given-names>Timothy
N. C.</given-names>
</name>
<xref rid="aff6" ref-type="aff">¶</xref>
</contrib>
<contrib contrib-type="author" id="ath48"><name><surname>White</surname>
<given-names>Karen</given-names>
</name>
<xref rid="aff4" ref-type="aff">⊥</xref>
</contrib>
<contrib contrib-type="author" id="ath49"><name><surname>White</surname>
<given-names>Laura</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath50"><name><surname>Willis</surname>
<given-names>Paul</given-names>
</name>
<xref rid="aff6" ref-type="aff">¶</xref>
</contrib>
<contrib contrib-type="author" id="ath51"><name><surname>Winzeler</surname>
<given-names>Elizabeth A.</given-names>
</name>
<xref rid="aff2" ref-type="aff">§</xref>
</contrib>
<contrib contrib-type="author" id="ath52"><name><surname>Wittlin</surname>
<given-names>Sergio</given-names>
</name>
<xref rid="aff21" ref-type="aff">π</xref>
</contrib>
<contrib contrib-type="author" corresp="yes" id="ath53"><name><surname>Todd</surname>
<given-names>Matthew H.</given-names>
</name>
<xref rid="cor1" ref-type="other">*</xref>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="notes-2" ref-type="notes">‡</xref>
</contrib>
<aff id="aff1"><label>†</label>
School of Chemistry,<institution>The University of Sydney</institution>
, Sydney, New South Wales 2006,<country>Australia</country>
</aff>
<aff id="aff2"><label>§</label>
Department of Pediatrics, Pharmacology & Drug Development,<institution>University of California San Diego</institution>
, 9500 Gilman Drive, La Jolla, California 92093,<country>United States</country>
</aff>
<aff id="aff3"><label>∥</label>
Discovery Biology, Eskitis Institute for Drug Discovery,<institution>Griffith University</institution>
, Nathan, Queensland 4111,<country>Australia</country>
</aff>
<aff id="aff4"><label>⊥</label>
Monash Institute of Pharmaceutical Sciences,<institution>Monash University</institution>
, 381 Royal Parade, Parkville, Victoria 3052,<country>Australia</country>
</aff>
<aff id="aff5"><label>#</label>
<institution>CSIR-Central Drug Research Institute</institution>
, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031,<country>India</country>
</aff>
<aff id="aff6"><label>¶</label>
<institution>Medicines for Malaria Venture</institution>
, PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15,<country>Switzerland</country>
</aff>
<aff id="aff7"><label>α</label>
Tres Cantos Medicines Development Campus, Diseases of the Developing World,<institution>GlaxoSmithKline</institution>
, Severo Ochoa 2, 28760 Tres Cantos,<country>Spain</country>
</aff>
<aff id="aff8"><label>β</label>
Department of Chemical Biology & Therapeutics,<institution>St. Jude Children’s Research Hospital</institution>
, MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,<country>United States</country>
</aff>
<aff id="aff9"><label>γ</label>
Department of Chemistry,<institution>Lawrence University</institution>
, 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911,<country>United States</country>
</aff>
<aff id="aff10"><label>δ</label>
Department of Life Sciences,<institution>Imperial College London</institution>
, South Kensington, London SW7 2AZ,<country>U.K.</country>
</aff>
<aff id="aff11"><label>ϵ</label>
Research School of Biology,<institution>The Australian National University</institution>
, Canberra, ACT 2601,<country>Australia</country>
</aff>
<aff id="aff12"><label>ζ</label>
<institution>Asclepia Outsourcing Solutions</institution>
, Damvalleistraat 49, B-9070 Destelbergen,<country>Belgium</country>
</aff>
<aff id="aff13"><label>η</label>
Donnelly Centre for Cellular and Biomolecular Research,<institution>University of Toronto</institution>
, 160 College Street, Toronto, Ontario M5S 3E1,<country>Canada</country>
</aff>
<aff id="aff14"><label>θ</label>
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery,<institution>University of Dundee</institution>
, Dundee, DD1 5EH,<country>U.K.</country>
</aff>
<aff id="aff15"><label>ι</label>
<institution>European Molecular Biology Laboratory—European Bioinformatics Institute</institution>
, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD,<country>U.K.</country>
</aff>
<aff id="aff16"><label>κ</label>
Institute of Chemical Sciences and Engineering (ISIC),<institution>Ecole Polytechnique Fédérale de Lausanne (EPFL)</institution>
, Lausanne 1015,<country>Switzerland</country>
</aff>
<aff id="aff17"><label>λ</label>
Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute,<institution>The University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</aff>
<aff id="aff18"><label>μ</label>
IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences,<institution>University of Edinburgh</institution>
, Edinburgh, EH8 9XD,<country>U.K.</country>
</aff>
<aff id="aff19"><label>ν</label>
<institution>Cambridge MedChem Consulting</institution>
, 8 Mangers Lane, Duxford, Cambridge CB22 4RN,<country>U.K.</country>
</aff>
<aff id="aff20"><label>ξ</label>
School of Chemistry,<institution>The University of Edinburgh</institution>
, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ,<country>U.K.</country>
</aff>
<aff id="aff21"><label>π</label>
<institution>Swiss Tropical and Public Health Institute</institution>
, Socinstrasse 57, 4051 Basel,<country>Switzerland</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
E-mail: <email>matthew.todd@sydney.edu.au</email>
, <email>@mattoddchem</email>
.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>14</day>
<month>09</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><day>26</day>
<month>10</month>
<year>2016</year>
</pub-date>
<volume>2</volume>
<issue>10</issue>
<fpage>687</fpage>
<lpage>701</lpage>
<history><date date-type="received"><day>31</day>
<month>05</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 American Chemical Society</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>American Chemical Society</copyright-holder>
<license><license-p>This is an open access article published under a Creative Commons Attribution (CC-BY) <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html">License</ext-link>
, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.</license-p>
</license>
</permissions>
<abstract><p content-type="toc-graphic"><graphic xlink:href="oc-2016-000863_0009" id="ab-d31e657"></graphic>
</p>
<p>The
development of new antimalarial compounds remains a pivotal part of
the strategy for malaria elimination. Recent large-scale phenotypic
screens have provided a wealth of potential starting points for hit-to-lead
campaigns. One such public set is explored, employing an open source
research mechanism in which all data and ideas were shared in real
time, anyone was able to participate, and patents were not sought.
One chemical subseries was found to exhibit oral activity but contained
a labile ester that could not be replaced without loss of activity,
and the original hit exhibited remarkable sensitivity to minor structural
change. A second subseries displayed high potency, including activity
within gametocyte and liver stage assays, but at the cost of low solubility.
As an open source research project, unexplored avenues are clearly
identified and may be explored further by the community; new findings
may be cumulatively added to the present work.</p>
</abstract>
<abstract abstract-type="short"><p>Starting from hits identified by a pharmaceutical company, new antimalarials
have been discovered using an “open source” approach
that discloses data in real time and eschews secrecy.</p>
</abstract>
<custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name>
<meta-value>oc6b00086</meta-value>
</custom-meta>
<custom-meta><meta-name>document-id-new-14</meta-name>
<meta-value>oc-2016-000863</meta-value>
</custom-meta>
<custom-meta><meta-name>ccc-price</meta-name>
<meta-value></meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec id="sec1"><title>Introduction</title>
<p>Malaria remains one of the world’s
most deadly diseases. There were an estimated 214 million cases of
malaria in 2015, including around 438,000 deaths of which the majority,
tragically, were young children.<sup><xref ref-type="bibr" rid="ref1">1</xref>
</sup>
Besides
the threat to human health, there is significant economic and social
impact on the affected communities with malaria costing Africa billions
of dollars <italic>per annum</italic>
in direct losses and even more
when considering lost economic growth.<sup><xref ref-type="bibr" rid="ref2">2</xref>
,<xref ref-type="bibr" rid="ref3">3</xref>
</sup>
</p>
<p>The continual
threat of drug resistance has led to the World Health Organization
(WHO) recommending that all treatments should only be used in combination;
artemisinin combination therapies (ACTs) comprising an artemisinin
derivative and a 4-aminoquinoline or amino alcohol currently represent
the front line. However, the inevitable reports of resistance or tolerance,
in the form of increased parasite clearance times, have already appeared.<sup><xref ref-type="bibr" rid="ref4">4</xref>
−<xref ref-type="bibr" rid="ref6">6</xref>
</sup>
Loss of the artemisinin class of drugs is a terrifying scenario
that requires urgent risk mitigation. Apart from the introduction
of the ACTs, no viable new drug for malaria has entered the market
in the past 15 years, and the recent results of the Mosquirix vaccine
phase III trials showed 18–36% efficacy depending on patient
age and other factors.<sup><xref ref-type="bibr" rid="ref7">7</xref>
,<xref ref-type="bibr" rid="ref8">8</xref>
</sup>
New chemical series that can replace
and complement the ACTs are urgently needed and are being sought by
a combination of academic and industrial groups, sometimes in collaboration
with nongovernmental organizations (NGOs).<sup><xref ref-type="bibr" rid="ref9">9</xref>
−<xref ref-type="bibr" rid="ref11">11</xref>
</sup>
Of particular
interest are lead candidates with differentiated activity profiles,
ideally targeting gametocyte or liver stage parasites in addition
to blood stages.<sup><xref ref-type="bibr" rid="ref12">12</xref>
−<xref ref-type="bibr" rid="ref15">15</xref>
</sup>
</p>
<p>The ability of the pharmaceutical industry to provide new
medicines cost-effectively is diminishing.<sup><xref ref-type="bibr" rid="ref16">16</xref>
</sup>
The industry acknowledges that lack of innovation is a problem.<sup><xref ref-type="bibr" rid="ref17">17</xref>
</sup>
Pharma is responsible for the creation of most
marketed drugs, yet many of these are arguably not innovative; in
contrast academia and the biotech industry generate more innovative
leads, but many are orphan drugs.<sup><xref ref-type="bibr" rid="ref18">18</xref>
</sup>
Such
challenges disproportionately affect research into new medicines for
tropical diseases, which would inevitably generate a slim profit margin
unlikely to recoup the necessary expenses of research and development.<sup><xref ref-type="bibr" rid="ref19">19</xref>
</sup>
</p>
<p>The weak status of many drug development
pipelines in the pharmaceutical industry is driving the exploration
of alternative models. The current model of drug discovery, whether
in academia<sup><xref ref-type="bibr" rid="ref20">20</xref>
</sup>
or industry, can generally
be characterized by secrecy and an underlying profit motive.<sup><xref ref-type="bibr" rid="ref21">21</xref>
</sup>
In the area of tropical diseases there are significant
philanthropic efforts being made by many companies in providing treatments<sup><xref ref-type="bibr" rid="ref22">22</xref>
</sup>
and engaging in drug development<sup><xref ref-type="bibr" rid="ref23">23</xref>
</sup>
but also in conducting not-for-profit research.<sup><xref ref-type="bibr" rid="ref24">24</xref>
,<xref ref-type="bibr" rid="ref25">25</xref>
</sup>
There have been calls for greater sharing of data in the NTD field,<sup><xref ref-type="bibr" rid="ref26">26</xref>
,<xref ref-type="bibr" rid="ref27">27</xref>
</sup>
including the development of patent pools<sup><xref ref-type="bibr" rid="ref28">28</xref>
</sup>
and new Product Development Partnerships.<sup><xref ref-type="bibr" rid="ref29">29</xref>
</sup>
Repositioning of existing drugs is seen as a possible general strategy
for the development of new antimalarials, even though the challenges
of such an approach are clear.<sup><xref ref-type="bibr" rid="ref30">30</xref>
</sup>
There
has been much recent discussion of the need for “Open Innovation”,
a term with a nebulous definition but typically describing a range
of ideas from the sharing of data in a precompetitive environment
through to competitions that allow organizations to bring in the best
external ideas to complement in-house research but for which there
is no requirement for any collaboration.<sup><xref ref-type="bibr" rid="ref31">31</xref>
</sup>
</p>
<p>A model that has been mooted,<sup><xref ref-type="bibr" rid="ref32">32</xref>
−<xref ref-type="bibr" rid="ref38">38</xref>
</sup>
but never properly implemented and evaluated, is drug discovery
and development where all data and ideas are freely shared, there
are no barriers to participation, and there are no patents—so-called
“Open Source” Drug Discovery. The requirement for total
sharing of data as well as workflows in drug discovery and development
(i.e., the experimental science, as opposed to the software used in
the project<sup><xref ref-type="bibr" rid="ref39">39</xref>
</sup>
) would mirror the same practices
in open source software development—a model that has created
robust and successful products in widespread use and formed the foundation
of major industries as well as spawning for-profit open source software
companies. It was shown recently that the opening up of a laboratory-based
chemical research project to unrestricted participation by anyone
accelerated the research because experts unknown to the core team
were able to join the project and solve transient project needs.<sup><xref ref-type="bibr" rid="ref36">36</xref>
</sup>
That project involved the discovery of a new
synthetic route to a known compound, specifically the active enantiomer
of the drug of choice for the treatment of schistosomiasis, praziquantel.<sup><xref ref-type="bibr" rid="ref40">40</xref>
</sup>
The project benefited from the open sharing
of chemical data and procedures on the Internet, i.e., using the Internet
as a medium that facilitated collaboration and peer review where participants
could influence the direction of the research before it occurred,
rather than use the online content merely as an information resource.
Several other initiatives have leveraged the advantage of open online
discussion of chemical data and results generated by others.<sup><xref ref-type="bibr" rid="ref41">41</xref>
−<xref ref-type="bibr" rid="ref43">43</xref>
</sup>
</p>
<p>The present work extends this idea to the identification of
novel bioactive compounds. A previous demonstration of an open drug
discovery cycle was shown by the Usefulchem project, which found four
micromolar hits from a small product library after <italic>in silico</italic>
target prediction and docking.<sup><xref ref-type="bibr" rid="ref44">44</xref>
</sup>
The
Open Source Drug Discovery project in India has carried out a crowdsourcing
project for annotation of the <italic>Mycobacterium tuberculosis</italic>
genome.<sup><xref ref-type="bibr" rid="ref45">45</xref>
−<xref ref-type="bibr" rid="ref47">47</xref>
</sup>
In the field of biotechnology the CAMBIA organization
used patents to enforce a code of conduct based on the open sharing
of technologies, in that experimental tools could be freely used,
provided no further patents were taken to restrict the use of those
tools by others.<sup><xref ref-type="bibr" rid="ref48">48</xref>
</sup>
</p>
<p>The “open
source” moniker is not merely semantic and distinguishes such
projects from other “open” ventures in several important
regards,<sup><xref ref-type="bibr" rid="ref38">38</xref>
</sup>
described by the six laws that
governed the operation of the present project (<xref rid="fig1" ref-type="fig">Figure <xref rid="fig1" ref-type="fig">1</xref>
</xref>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S1</ext-link>
).<sup><xref ref-type="bibr" rid="ref49">49</xref>
</sup>
Crucially, the research <italic>process</italic>
(i.e., strategic discussions, issues involving doubt) takes place
in the public domain. The Creative Commons license covering project
content ensures free reuse of all content including for commercial
purposes (CC-BY),<sup><xref ref-type="bibr" rid="ref50">50</xref>
</sup>
and uses a free or
open source composite technical platform that has recently been reviewed.<sup><xref ref-type="bibr" rid="ref51">51</xref>
,<xref ref-type="bibr" rid="ref52">52</xref>
</sup>
</p>
<fig id="fig1" position="float"><label>Figure 1</label>
<caption><p>Six
laws of open research governing the present project.</p>
</caption>
<graphic xlink:href="oc-2016-000863_0001" id="gr1" position="float"></graphic>
</fig>
<p>In recent years, teams led by Novartis, St. Jude’s
Children’s Research Hospital, and GlaxoSmithKline (GSK) Tres
Cantos have released large data sets of antimalarial compounds derived
from phenotypic high throughput screening (HTS) campaigns.<sup><xref ref-type="bibr" rid="ref53">53</xref>
−<xref ref-type="bibr" rid="ref56">56</xref>
</sup>
The GSK Tres Cantos Antimalarial (TCAMS) data set contained 13,533
filtered hits which were subsequently prioritized and grouped to provide
numerous starting points for other research groups;<sup><xref ref-type="bibr" rid="ref57">57</xref>
</sup>
all of these 47 scaffolds have been explored either internally
by GSK, by independent groups, or in collaboration between GSK and
academic groups. GSK themselves have published evaluations of two
of these priority series, the cyclopropyl carboxamides<sup><xref ref-type="bibr" rid="ref58">58</xref>
,<xref ref-type="bibr" rid="ref59">59</xref>
</sup>
and an indoline series.<sup><xref ref-type="bibr" rid="ref60">60</xref>
</sup>
No further
optimization work has been performed by GSK on these two series due
to the inherent risks identified. The original GSK data set was used
to identify starting points for the present campaign, resulting in
the selection of TCMDC-123812 (OSM-S-5, <xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
A) and its 4-aminoantipyrine derivative TCMDC-123794
(OSM-S-6) because of their attractive physicochemical properties,
such as low logP and molecular weight, coupled with promising bioactivity
and therefore presumed high ligand efficiency. (Compound numbering
in this paper is based on the original project numbering, rather than
a renumbering for this paper, allowing simpler cross-correlation between
this paper and the live Web sites. The convention used is Open Source
Malaria (OSM)-first letter of city in which compound was first made
(e.g., S = Sydney)-incremental integer. Batch numbers are included
in internal project numbering schemes.) A number of compounds in the
original TCAMS set<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
featured the arylpyrrole
core with alternative head groups lacking the ester linkage (<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
B). TCMDC-123563
was discounted (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S2</ext-link>
)<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
as it represented a singleton and contained an unfavorable
ketone linkage. A cluster of related compounds, the 2-iminothiazolidin-4-ones
(the “near neighbors”, NN), was targeted because the
members (including TCMDC-124103, -125697, and -125698) possessed promising
activities without the ester, and indicated tolerance to variation
elsewhere in the structure. While this work was being written up for
publication, Gilbert et al. published details of a series of pyrrolones
(identified through an unpublished screen performed by the World Health
Organization Special Programme for Research and Training in Tropical
Diseases (WHO-TDR) but also identified in the Novartis antimalarial
data set<sup><xref ref-type="bibr" rid="ref55">55</xref>
</sup>
) that have some structural similarities
to the NN compounds (i.e., an arylpyrrole joined through a double
bond to a different heterocycle), and comparisons will be drawn below
with this series.<sup><xref ref-type="bibr" rid="ref62">62</xref>
,<xref ref-type="bibr" rid="ref63">63</xref>
</sup>
</p>
<fig id="fig2" position="float"><label>Figure 2</label>
<caption><p>(A) Arylpyrrole hits from the TCAMS data
set. (B) Selected “near neighbors” (NN) from the TCAMS
data set. Activities quoted are vs 3D7. Not shown: related NN compounds
TCMDC-124456 (680 nM) and TCMDC-125659 (237 nM). (XC<sub>50</sub>
=
approximate IC<sub>50</sub>
value.<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
)</p>
</caption>
<graphic xlink:href="oc-2016-000863_0002" id="gr2" position="float"></graphic>
</fig>
<p>It was important to resynthesize
the original hit compounds (<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
A) to confirm their activity with authentic samples
prior to beginning a hit to lead campaign where the NN compounds would
act as a potential backup subseries.</p>
</sec>
<sec id="sec2"><title>Results and Discussion</title>
<sec id="sec2.1"><title>Resynthesis of Original
Hits and Their Putative Prodrug Fragments</title>
<p>The synthetic approaches
to any molecule in this paper may be found in full in the relevant
electronic laboratory notebook<sup><xref ref-type="bibr" rid="ref64">64</xref>
</sup>
and are
summarized in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
(Chemical Protocols; figures with the prefix “SC”
may be found therein).</p>
<p>The two original GSK hits (OSM-S-5 and
-6) were successfully resynthesized via a novel pyrrole acid (OSM-S-4, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC1</ext-link>
) that was prepared via a Paal–Knorr
cyclization of the relevant aniline and ethyl 2-acetyl-4-oxopentanoate.<sup><xref ref-type="bibr" rid="ref65">65</xref>
,<xref ref-type="bibr" rid="ref66">66</xref>
</sup>
This approach was found to be superior to an alternative method
involving initial synthesis of the unfunctionalized <italic>N</italic>
-arylpyrrole, followed by conversion to the corresponding aldehyde
with a Vilsmeier–Haack reaction (a procedure that was improved
through a community suggestion (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S3</ext-link>
)<sup><xref ref-type="bibr" rid="ref67">67</xref>
</sup>
) and then oxidation to a carboxylic
acid, because the pyrrole aldehyde was found to be remarkably resilient
to a range of oxidants. (An alternative route using a Friedel–Crafts
acylation between the unsubstituted pyrrole and ethyl chloroformate,
suggested in an e-mail from the community, gave only starting material
in two attempts.)</p>
<p>To confirm the promise of the two starting
points OSM-S-5 and -6, they were evaluated against 3D7 (drug-sensitive)
and K1 (chloroquine resistant) strains of <italic>Plasmodium falciparum</italic>
in a whole cell assay and against HEK-293 cells as a cytotoxicity
marker (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB1</ext-link>
, Biological Protocols;
tables with the prefix “SB” may be found in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
). Biological data may
be browsed in a static data set taken as a snapshot for this paper
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_002.xls">Data Sets S1</ext-link>
(Excel), <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_003.zip">S2</ext-link>
(SDF)), online in a database constructed through periodic
batch uploads,<sup><xref ref-type="bibr" rid="ref68">68</xref>
</sup>
or in a “living
database” to which may be added future data;<sup><xref ref-type="bibr" rid="ref69">69</xref>
</sup>
the latter may be visualized in a web browser<sup><xref ref-type="bibr" rid="ref70">70</xref>
</sup>
using an open source system that was recently
deployed in the Wikipedia Chemical Structure Explorer,<sup><xref ref-type="bibr" rid="ref71">71</xref>
</sup>
or the data may be downloaded and visualized
offline with proprietary (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S4</ext-link>
)<sup><xref ref-type="bibr" rid="ref72">72</xref>
</sup>
or open source (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S5</ext-link>
)<sup><xref ref-type="bibr" rid="ref73">73</xref>
</sup>
tools). The evaluation was performed
in three different institutions using different assays and widely
employed controls; controls are important to assess reproducibility
and interassay variability<sup><xref ref-type="bibr" rid="ref74">74</xref>
</sup>
but also to
minimize possible bias in evaluating compounds where there are pre-existing
data from other researchers already in the public domain (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S6</ext-link>
).<sup><xref ref-type="bibr" rid="ref75">75</xref>
</sup>
The
tests confirmed that the original compounds TCMDC-123812 (OSM-S-5)
and TCMDC-123794 (OSM-S-6) are potent (300–500 nM range), although
slightly less than previously reported (IC<sub>50</sub>
of ca. 330
and 54 nM respectively from a colorimetric LDH assay over 72 h<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
) with low associated cytotoxicities and similar
efficacy against 3D7 and K1 strains. The stability of the ester linker
under biologically relevant conditions was expected to be poor, so
the aldehyde, ethyl ester, and carboxylic acid 4-fluoropyrroles made
en route to these compounds were evaluated as potentially active fragments
but were found to exhibit relatively low activity, suggesting that
the parent compounds do not act as prodrugs in this way (similar inactivity
was observed for the 4-H, 4-Me, and 4-CF<sub>3</sub>
aldehydes, esters,
and acid fragments) (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_004.xls">Data Sets S3</ext-link>
–<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_006.xls">S5</ext-link>
).</p>
<sec id="sec2.1.1"><title>Amide Analogues of the Original Hits</title>
<p>Replacement of the ester with a hydrolytically more stable amide
was undertaken through synthesis of eight derivatives (<xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref>
</xref>
), most of which were obtained
through SOCl<sub>2</sub>
-mediated conversion of acid OSM-S-4 to the
acid chloride. Compound OSM-S-16 served as a control lacking the pyrrole
moiety, OSM-S-8 served as a truncated “des-glycinyl”
analogue, and the importance of amide methylation was explored with
compounds OSM-S-59 and -93. In addition, the six most relevant commercially
available compounds were purchased (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC2</ext-link>
). (For more on strategies for selecting compounds for commercial
acquisition, colloquially known as “SAR by catalog”,
see the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S2</ext-link>
and the component files referred to therein).)</p>
<fig id="fig3" position="float"><label>Figure 3</label>
<caption><p>Synthesized
amide analogues. Synthetic details and structures of purchased compounds
may be found in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
. All compounds were found to possess low activity (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB2</ext-link>
).</p>
</caption>
<graphic xlink:href="oc-2016-000863_0003" id="gr3" position="float"></graphic>
</fig>
<p>The conversion of ester
to amide resulted in essentially total loss of biological activity
in all cases (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB2</ext-link>
), even for the
analogues involving minimal changes (OSM-S-19 and OSM-S-21), so the
amide series was not explored further.</p>
</sec>
<sec id="sec2.1.2"><title>The Alternative “Near
Neighbor” 2-Iminothiazolidinones</title>
<p>In parallel with
the initial evaluation of the amide analogues, a number of NN analogues
were synthesized (<xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref>
</xref>
), typically from a Vilsmeier–Haack oxidation of the
relevant pyrrole to the corresponding aldehyde and then condensation
with the appropriate 2-iminothiazolidin-4-one (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC3</ext-link>
).<sup><xref ref-type="bibr" rid="ref76">76</xref>
−<xref ref-type="bibr" rid="ref78">78</xref>
</sup>
While double bond geometry was undefined for the
original hits, Z-geometry was established here by X-ray crystallography
on four compounds and therefore assumed more broadly for the series
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC4</ext-link>
). Given the low predicted solubility
of these NN compounds, several were generated with lower clogP values
and submitted for biological testing (OSM-S-109 through -115, OSM-S-108,
and OSM-S-138), alongside analogues synthesized and submitted by an
independent undergraduate laboratory cohort: OSM-A-1 through -4 and
resyntheses of OSM-S-37 and -111.</p>
<fig id="fig4" position="float"><label>Figure 4</label>
<caption><p>Near neighbor compounds biologically evaluated. Raw data
may be found in <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB3</ext-link>
.</p>
</caption>
<graphic xlink:href="oc-2016-000863_0004" id="gr4" position="float"></graphic>
</fig>
<p>Many compounds in the NN series
showed high potencies (shown schematically in <xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref>
</xref>
; raw data in <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB3</ext-link>
), with several found to be more active than the original TCAMS hits.
The compounds exhibited low associated cytotoxicity. The aryl component
of the pyrrole moiety was moderately tolerant to changes (though small
changes could result in large changes in activity, exemplified by
the 4-F and 3-F isomers), while the thiazolidinone component was found
to be more sensitive. Incorporation of cyclopentyl, phenyl, and acetyl
components was tolerated, but the methylenenitrile group was not.
Replacement of the arylpyrrole moiety with a phenyl resulted in loss
of activity.</p>
<p>While high potency was obtained with several members
of the NN series, this was achieved at the cost of high calculated
lipophilicity with many compounds in this series exhibiting calculated
logP values of 5 or more and correspondingly poor lipophilic efficiency
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figures S15 and S16</ext-link>
).<sup><xref ref-type="bibr" rid="ref79">79</xref>
</sup>
Solubility was a challenge in several of the assays examining
these compounds. Those compounds with more polar groups on the constituent
aromatic rings suffered a drop in potency, but the pyridinyl analogue
OSM-S-51 (calculated LogP = 1.8) provides a possible future line of
inquiry for the community. A lipophilicity/potency trend was also
generally seen in the pyrrolone series,<sup><xref ref-type="bibr" rid="ref62">62</xref>
</sup>
though potency was seen for several compounds containing a substituted
piperidine ring in place of the <italic>N</italic>
-aryl group.<sup><xref ref-type="bibr" rid="ref63">63</xref>
</sup>
</p>
<p>The open nature of the project enabled
regular consultation with the wider medicinal chemistry community
in real time, i.e., where community input could influence the direction
of the research. An important contribution to the project from outside
the core experimental team (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S17</ext-link>
)<sup><xref ref-type="bibr" rid="ref80">80</xref>
</sup>
was discussion of whether the most potent members
of the NN series were pan assay interference compounds (PAINS), i.e.,
compounds frequently appearing as hits in high throughput screens
yet which do not exhibit a straightforward “drug-like”
interaction with a biological target.<sup><xref ref-type="bibr" rid="ref81">81</xref>
</sup>
The OSM compounds were run through the KNIME PAINS filter,<sup><xref ref-type="bibr" rid="ref82">82</xref>
,<xref ref-type="bibr" rid="ref83">83</xref>
</sup>
and both the 2-imino-4-thiazolidinone and arylpyrrole components
of these compounds were flagged as potential PAINS, with the proposed
cause of the interference of the former being the thiazolidinone <italic>exo</italic>
-double bond acting as a Michael acceptor, though it
has been noted that this core is much more problematic in rhodanines
than in their 2-imino counterparts.<sup><xref ref-type="bibr" rid="ref84">84</xref>
</sup>
The
topic of PAINS has been the subject of extensive recent discussion
in papers<sup><xref ref-type="bibr" rid="ref84">84</xref>
−<xref ref-type="bibr" rid="ref88">88</xref>
</sup>
and in online communities (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figures S18 and S19</ext-link>
).<sup><xref ref-type="bibr" rid="ref89">89</xref>
,<xref ref-type="bibr" rid="ref90">90</xref>
</sup>
Although most concern has centered on rhodanines,
any related structure could be problematic if it contains a potentially
reactive conjugated <italic>exo</italic>
-double bond. In the area
of chemotherapeutic and antiparasitic agents, such motifs may still
be present in viable leads.<sup><xref ref-type="bibr" rid="ref84">84</xref>
</sup>
The negative
view of rhodanine derivatives in the medicinal chemistry community
is generally derived from academic reports and patents where positive
assay hits have been reported without adequate evaluation of SAR or
elucidation of the mode of action. A complicating factor, often not
considered, is that PAINS are defined on the basis of results from
target-based screens, where one would not link a cellular readout
to the target if nonspecific protein reactivity were possible.<sup><xref ref-type="bibr" rid="ref84">84</xref>
</sup>
Conversely, a covalent modifier from a cellular
screen may still be useful as a probe under some circumstances.<sup><xref ref-type="bibr" rid="ref91">91</xref>
</sup>
The present compounds may not be problematically
reactive and may still be progression candidates for the following
reasons: (1) The parent hit compounds (TCMDC-123812 (OSM-S-5) and
-123974 (OSM-S-6), <xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
) were shown not to be “promiscuous” frequent
hitters in the original GSK data;<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
(2)
the assay data described above show that the relevant 2-imino-4-thiazolidinone
fragment was inactive on its own (OSM-S-55, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB3</ext-link>
, entry 30), and (3) preliminary experimental controls were
performed to assess the reactivity of the <italic>exo</italic>
double
bond (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC5</ext-link>
) that showed no reactivity
of the exocyclic double bond to hydrogenation or the addition of hydride
or a thiol in model cases. Yet it was noted that these compounds not
only are closely related to known PAINS but also fail by ALARM NMR
filtering, which is designed to detect known protein-reactive cores.<sup><xref ref-type="bibr" rid="ref92">92</xref>
−<xref ref-type="bibr" rid="ref94">94</xref>
</sup>
Ultimately, the authorship team adopted varying positions. Overall,
given the poor physical properties of these compounds and the extensive
additional work that would be needed to fully mitigate the series
risks, and encouraged by one of us (J.B.B.) to move away from PAINS-like
structures, the team decided not to further pursue this subseries.</p>
<p>Poor solubility with excessive lipophilicity may not just impart
poor pharmacokinetic properties but also drive nonspecific protein
reactivity through hydrophobic burial that may not be picked up in <italic>in vitro</italic>
assays. The emphasis for this series moved toward
analogues that promised improved solubility. As with all key strategic
decision points in this open source project, discussion of possible
structures took place in an online public consultation.<sup><xref ref-type="bibr" rid="ref95">95</xref>
</sup>
The meeting recalibrated the project focus with
selection of the next synthetic compounds and agreement on which commercially
available analogues to purchase and evaluate (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S24</ext-link>
).<sup><xref ref-type="bibr" rid="ref96">96</xref>
</sup>
This community consultation
confirmed ethers, amines, sulfonamides, oxadiazoles, and substituted
ester analogues of the original arylpyrrole hits as the most valuable
targets (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S25</ext-link>
).<sup><xref ref-type="bibr" rid="ref97">97</xref>
</sup>
Synthesis of a shortlist of such analogues was planned
and undertaken by whomever wished to do so (half of the ten top-ranked
synthetic shortlist were ultimately made; synthetic planning assistance
was received <italic>gratis</italic>
from the private sector (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Texts S6 and S7</ext-link>
), and the most relevant commercially available compounds
were purchased and evaluated. GSK assessed the proposed compounds
and confirmed (publicly) that none of the molecules had previously
been evaluated for antimalarial activity as part of the TCAMS screen.</p>
</sec>
<sec id="sec2.1.3"><title>Analogues in the Arylpyrrole Series</title>
<p>Several analogue series
of the original arylpyrroles were synthesized and evaluated (<xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref>
</xref>
, raw data in each
case may be found in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
).</p>
<fig id="fig5" position="float"><label>Figure 5</label>
<caption><p>Analogues evaluated in the main arylpyrrole series.</p>
</caption>
<graphic xlink:href="oc-2016-000863_0005" id="gr5" position="float"></graphic>
</fig>
<sec id="sec2.1.3.1"><title>Ethers</title>
<p>One of the most promising
proposed analogues was the ether OSM-S-236. A number of approaches
have failed to generate the desired product, attributed to the instability
of either the arylpyrrole alcohol starting material OSM-S-11 (which
decomposed on silica and when stored under inert conditions at 2 °C)
or (if formed) the desired product itself (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC6</ext-link>
). The synthesis of this compound was abandoned, given that
similar side reactivity may be seen <italic>in vivo</italic>
, although
such reactivity could be mitigated through the use of more electron-deficient
pyrroles.</p>
</sec>
<sec id="sec2.1.3.2"><title>Amines</title>
<p>Four amine analogues (OSM-S-58,
-60, -94, and -95) were successfully prepared by reductive alkylation
of the relevant pyrrole aldehyde, and three additional amine analogues
were purchased (OSM-S-88 to -90, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC7</ext-link>
). All were found to be inactive. The synthesized structures were
found to be prone to decomposition under ambient conditions.</p>
</sec>
<sec id="sec2.1.3.3"><title>Modified
Esters</title>
<p>In an attempt to decrease the hydrolytic lability
of the ester, methyl groups were introduced adjacent to this functional
group (OSM-S-116 and -68) (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC8</ext-link>
).
To assess the influence of introducing methyl groups to the terminal
amide, analogues OSM-S-82 and OSM-S-91 were purchased. All compounds
were found to exhibit low potency (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB4</ext-link>
), further suggesting that minor structural changes to the potent
TCAMS hit compounds reduce activity.</p>
</sec>
<sec id="sec2.1.3.4"><title>Ketones</title>
<p>Friedel–Crafts
acylation of a pyrrole precursor with succinic anhydride and subsequent
amidation provided three ketone analogues (OSM-S-98, -102, and -103, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC9</ext-link>
) that were found to exhibit essentially
zero potency, with only OSM-S-103 showing any activity at higher concentrations.</p>
</sec>
<sec id="sec2.1.3.5"><title>Sulfonamides</title>
<p>Three sulfonamide analogues (OSM-E-1 to -3)
were synthetically derived directly from the relevant arylpyrrole
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC10</ext-link>
) and were also found to lack
potency.</p>
</sec>
<sec id="sec2.1.3.6"><title>Pyrazoles</title>
<p>Two pyrazole analogues
(OSM-S-57 and -92) were synthesized (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC11</ext-link>
) and evaluated to assess the impact of modifying the arylpyrrole
core. Both compounds were found to be inactive; the fluoro analogue
of OSM-S-57 was thus not synthesized. A related heterocycle alteration
was also found to be detrimental to the literature pyrrolone series.<sup><xref ref-type="bibr" rid="ref62">62</xref>
</sup>
</p>
</sec>
<sec id="sec2.1.3.7"><title>Oxazoles</title>
<p>The oxazole analogue OSM-S-105
was prepared from the carboxylic acid of the corresponding arylpyrazole,
though the analogous sequence for the parent arylpyrrole series could
not be completed (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC12</ext-link>
). This compound
and several of the synthetic precursors were evaluated and all found
to be inactive.</p>
</sec>
<sec id="sec2.1.3.8"><title>Triazoles</title>
<p>The triazole analogue
OSM-E-8 was synthesized via a Cu(I)-catalyzed cycloaddition reaction
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure SC13</ext-link>
) and evaluated alongside four
synthetic precursors and side products, but all compounds were found
to be inactive.</p>
</sec>
</sec>
</sec>
<sec id="sec2.2"><title>Synthetic Threads That Remain Open</title>
<p>Several synthetic targets for this series remain open (<xref rid="fig6" ref-type="fig">Figure <xref rid="fig6" ref-type="fig">6</xref>
</xref>
) such as the ether compound
OSM-S-236 (though it seems likely that this compound will be unstable)
and the oxazole OSM-S-246. The oxadiazole shown was proposed, and
preliminary experiments toward its synthesis were performed (see precursor
OSM-S-269 in the project laboratory notebooks for further details).<sup><xref ref-type="bibr" rid="ref64">64</xref>
</sup>
The oxadiazole is a common replacement for carbonyl
containing compounds in hit to lead campaigns,<sup><xref ref-type="bibr" rid="ref98">98</xref>
</sup>
and so it was reasoned that the inclusion of this heterocycle
might have favorable consequences for drug metabolism, though a commercial
oxadiazole analogue (OSM-S-85, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
) had been found to be inactive, leading to the synthetic effort
toward the oxadiazole being downgraded. The tolerance of the NN set
to the introduction of the pyridine in OSM-S-51 (<xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref>
</xref>
) could be explored further
as a means to increase solubility in that cluster, and a pendant substituted
piperidine was found to lead to several potent compounds in the pyrrolone
series that possesses some structural similarities to the NN series.<sup><xref ref-type="bibr" rid="ref63">63</xref>
</sup>
Indeed variation of the aromatic group in the
arylpyrrole series was not explored given the intractability of substituting
the ester: given the tight SAR, low solubility, and poor metabolic
stability observed for the series, the project viewed the probabilities
of success as limited and so did not pursue these targets.</p>
<fig id="fig6" position="float"><label>Figure 6</label>
<caption><p>Three targets
that remain open for synthetic inquiry.</p>
</caption>
<graphic xlink:href="oc-2016-000863_0006" id="gr6" position="float"></graphic>
</fig>
<p><italic>In silico</italic>
pharmacophore modeling has to
date proven ineffective at high-confidence analogue prediction, but
this remains an open challenge<sup><xref ref-type="bibr" rid="ref99">99</xref>
</sup>
to which
others may contribute given the data set available.<sup><xref ref-type="bibr" rid="ref68">68</xref>
,<xref ref-type="bibr" rid="ref69">69</xref>
</sup>
Some preliminary results suggesting a common feature map for the
arylpyrrole and NN subseries were of particular interest and could
be explored with the more substantial bioactivity data now available.</p>
<p>Along these lines, an automated bioisosteric replacement analysis<sup><xref ref-type="bibr" rid="ref100">100</xref>
</sup>
was performed for the NN series (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S8</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_020.zip">Data Set S19</ext-link>
) focusing on replacement of the pyrrole phenyl substituent, and
output suggestions were generated for potent compound OSM-S-35 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figures S27–S30</ext-link>
); these may be explored
in the future.</p>
<p>All these structures are available for investigation
by the community, building on the unsuccessful attempts detailed in
the online laboratory notebooks. It is hoped that the sharing of negative
synthetic data in this way (16 attempts in the case of the ether OSM-S-236)
will lead to a faster completion of syntheses of analogues in the
future since prior attempts are not “orphaned” in undisclosed
or unpublished notebooks. Participants in future work may be physically
located anywhere; they are requested (but not obligated) to operate
open source (unrestricted sharing of all data and ideas) to avoid
wasteful duplication of effort. The results, whether substantial or
incremental, may be added to the series wiki.<sup><xref ref-type="bibr" rid="ref101">101</xref>
</sup>
However, it is important to acknowledge the limitations
of the series identified to date, meaning further analogue synthesis
undertaken by the community in the absence of better knowledge of
the biological target is likely to be unproductive.</p>
</sec>
<sec id="sec2.3"><title>Advanced Biological
Evaluation</title>
<p>To assess further the attractiveness of this class
of compounds, attention was focused on the most potent of the newly
discovered analogues and the original hits. Given that the compounds
arose from a phenotypic assay, no mechanism of action (MoA) was known,
and preliminary investigations described below were designed to probe
this, with a view to minimizing any potential MoA overlap with other
compounds already in development.</p>
<sec id="sec2.3.1"><title>Metabolic and Solubility
Assays</title>
<p>The two original GSK hits (OSM-S-5 and -6) and six
NN compounds were evaluated for their kinetic solubility in phosphate
buffer and their metabolic stability in human liver microsomes (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB5</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_021.zip">Data Sets S20</ext-link>
and <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_022.xls">S21</ext-link>
). Both the arylpyrrole esters
showed good solubility, but showed degradation in microsomes even
in the absence of cofactors for cytochrome P450 and glucuronidation
enzymes (NADPH and UDPGA, respectively) suggesting degradation by
nonspecific enzymes. The iminothiazolidinone (NN) compounds showed
generally low rates of metabolic degradation but at a cost of very
low solubility (a general feature also of the literature pyrrolone
series<sup><xref ref-type="bibr" rid="ref62">62</xref>
</sup>
that displayed typically higher
rates of metabolic clearance).</p>
</sec>
<sec id="sec2.3.2"><title>Oral Efficacy in Mice</title>
<p>Representative compounds from both subseries were evaluated in
an oral <italic>in vivo</italic>
mouse trial (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_023.xls">Data Set S22</ext-link>
). The original starting points OSM-S-5 and -6
(<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
) were chosen
along with NN representative OSM-S-35 (<xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref>
</xref>
). All three compounds were found to be inactive <italic>in vivo</italic>
in <italic>Plasmodium berghei</italic>
ANKA infected
mice at 50 mg/kg after 4 days po. It is plausible that at least some
of the arylpyrrole ester compounds would be degraded by general hydrolysis
during absorption, and this could explain their inactivity in the
mouse model despite their more favorable (although still high) cLogP
values. Analysis of the plasma samples from the trial with OSM-S-5
showed that the compound was indeed orally available, but concentrations
in the blood were above the EC<sub>50</sub>
for only approximately
4 h (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_024.xls">Data Set S23</ext-link>
). The same compound
was evaluated for stability in human and mouse plasma and found to
be susceptible to hydrolysis (<italic>t</italic>
<sub>1/2</sub>
114
min), but it was stable in human plasma with no measurable loss after
240 min (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_025.xls">Data Set S24</ext-link>
). Esterase activity
is higher in rodents than in other species,<sup><xref ref-type="bibr" rid="ref102">102</xref>
</sup>
as confirmed by using <italic>p</italic>
-nitrophenol acetate as
a control compound in this assay. By way of comparison, the literature
pyrrolone series had also exhibited low oral bioavailability that
likely resulted from a combination of low solubility and significant
metabolic clearance.<sup><xref ref-type="bibr" rid="ref62">62</xref>
,<xref ref-type="bibr" rid="ref63">63</xref>
</sup>
</p>
<p>A metabolite identification
and glutathione trapping experiment was carried out on OSM-S-35 in
the presence of metabolic activation (human microsomes, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_026.xls">Data Set S25</ext-link>
). A number of metabolites were
detected, mainly oxygenated species (mono-, bis-, and trioxygenated
metabolites) with the predominant metabolite (based on peak area and
assuming similar response factors for each metabolite) arising from
likely hydroxylation of the pyrrole substituted benzene. In the presence
of glutathione ethyl ester (GSH-EE), weak signals for adducts were
observed for both parent compound and mono- and bisoxygenated metabolites.
In the case of the parent compound, the GSH-EE adduct was observed
both in the presence and in the absence of metabolic activation. Further
characterization of the adducts was precluded by the very weak MS/MS
spectra; however, the detection of adducts suggests that the formation
of reactive species cannot be ruled out.</p>
</sec>
<sec id="sec2.3.3"><title>hERG Liability</title>
<p>There is increasing awareness of the importance for drug candidates
of inhibition of hERG (the human <italic>ether-à-go-go</italic>
-related gene ion channel), which is sensitive to blockade by many
drug-like structures. Such blockage has led to a number of prominent
postmarketing withdrawals.<sup><xref ref-type="bibr" rid="ref103">103</xref>
</sup>
Regulators
are sensitive to any hERG activity, and a hERG counterscreen is often
now run early in hit characterization and series prioritization. Compounds
OSM-S-5 and OSM-S-35 were shown not to suffer from significant hERG
activity (IC<sub>50</sub>
> 33 μM vs 0.7 μM for control
compound quinidine), implying that the original ester and NN class
of compounds are not likely to exhibit undesirable cardiac side effects
later in development (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_027.xls">Data Set S26</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S11</ext-link>
).</p>
</sec>
<sec id="sec2.3.4"><title>Late Stage Gametocyte Assay</title>
<p>There are relatively few compounds effective against the gametocyte
stage of the parasite,<sup><xref ref-type="bibr" rid="ref12">12</xref>
,<xref ref-type="bibr" rid="ref13">13</xref>
</sup>
though such compounds are important
in the prevention of disease transmission. Four compounds found to
be active in the asexual assay were evaluated against late stage (IV–V)
gametocytes. The results (<xref rid="tbl1" ref-type="other">Table <xref rid="tbl1" ref-type="other">1</xref>
</xref>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_028.xls">Data Sets S27</ext-link>
and <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_029.xls">S28</ext-link>
) indicated that the NN compounds OSM-S-38
and OSM-S-39 exhibited highly promising IC<sub>50</sub>
values of
4 nM and 2.6 nM respectively, comparable to the activities of artemisinin
and artesunate. Compound OSM-S-9 also showed good activity while one
of the original hit compounds (OSM-S-5) exhibited low levels of activity.
Several compounds evaluated were found to lead to an unusual parasite
morphology that may be indicative of a slow-acting mechanism of action
(Supporting Information, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_028.xls">late stage gametocyte assays 1</ext-link>
and <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_029.xls">2</ext-link>
).</p>
<table-wrap id="tbl1" position="float"><label>Table 1</label>
<caption><title>Potency vs Late Stage Gametocytes for Selected Compounds</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="left"></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">OSM-S-</th>
<th style="border:none;" align="center">late stage GAM<xref rid="t1fn1" ref-type="table-fn">a</xref>
(nM)</th>
</tr>
</thead>
<tbody><tr><td style="border:none;" align="left">5</td>
<td style="border:none;" align="left">75% at 60 μM</td>
</tr>
<tr><td style="border:none;" align="left">9</td>
<td style="border:none;" align="left">28</td>
</tr>
<tr><td style="border:none;" align="left">38</td>
<td style="border:none;" align="left">4</td>
</tr>
<tr><td style="border:none;" align="left">39</td>
<td style="border:none;" align="left">2.6</td>
</tr>
<tr><td style="border:none;" align="left">111<xref rid="t1fn2" ref-type="table-fn">b</xref>
</td>
<td style="border:none;" align="left">686</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1fn1"><label>a</label>
<p><ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_028.xls">Data Set S27</ext-link>
.</p>
</fn>
<fn id="t1fn2"><label>b</label>
<p>Value for this compound taken from <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_029.xls">Data Set S28</ext-link>
. Controls: see the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>When the compounds were evaluated
in a dual gamete formation assay (DGFA)<sup><xref ref-type="bibr" rid="ref104">104</xref>
</sup>
to evaluate separately the susceptibilities of male and female mature
stage V gametocytes to both the hit ester (OSM-S-5) and a selection
of NN compounds, it was found that all compounds possessed low activity
at 1 μM against both sexes (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S10</ext-link>
). The discrepancy in the data arising from these two gametocyte
assays may arise from the slightly different cell biology assayed
(stage IV/V gametocytes vs stage V mature gametocytes) or most likely
is a function of the relative compound exposure times (96 h vs 24
h).</p>
</sec>
<sec id="sec2.3.5"><title>Liver Stage</title>
<p>Liver
stage activity is strategically important in antimalarial drug discovery
because compounds that block development of exoerythrocytic parasite
stages in hepatic cells often prove to have causal prophylactic activity
in animal models.<sup><xref ref-type="bibr" rid="ref14">14</xref>
,<xref ref-type="bibr" rid="ref105">105</xref>
</sup>
Three compounds (original hit
OSM-S-5 and the NN compounds OSM-S-38 and -111) were assessed for
their activity against sporozoites in liver cells (vs atovaquone as
positive control) and displayed varying potencies (<xref rid="tbl2" ref-type="other">Table <xref rid="tbl2" ref-type="other">2</xref>
</xref>
; <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_030.xls">Data Sets S29</ext-link>
–<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_032.xls">31</ext-link>
; <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S31</ext-link>
) that track with blood stage potency.
Of particular note is the striking potency of the nontoxic compound
OSM-S-38, which may at this level provide protection from malaria
to people who have been treated with the compound after an infectious
bite. Given the similarity observed in the possible mode of action
(see <xref rid="sec2.3.6" ref-type="other">next section</xref>
), it is unclear why
the arylpyrrole compound OSM-S-5 should exhibit such low levels of
activity in the present assay vs the NN compounds. Possible explanations
include differential solubility or stability; the level of cytotoxicity
observed for OSM-S-5 suggests that the liver stage potency is probably
just a generic toxic effect.</p>
<table-wrap id="tbl2" position="float"><label>Table 2</label>
<caption><title>Liver and Blood Stage
Potencies for Selected Compounds</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">OSM-S-</th>
<th style="border:none;" align="center"><italic>P. berghei</italic>
IC<sub>50</sub>
(nM)</th>
<th style="border:none;" align="center">cytotoxicity (HepG2, IC<sub>50</sub>
, nM)</th>
<th style="border:none;" align="center">blood stage potency (3D7, nM)</th>
</tr>
</thead>
<tbody><tr><td style="border:none;" align="left">5<xref rid="t2fn1" ref-type="table-fn">a</xref>
,<xref rid="t2fn5" ref-type="table-fn">b</xref>
</td>
<td style="border:none;" align="left">24000, 14000</td>
<td style="border:none;" align="left">9800, 18000</td>
<td style="border:none;" align="left">502<xref rid="t2fn3" ref-type="table-fn">c</xref>
</td>
</tr>
<tr><td style="border:none;" align="left">38<xref rid="t2fn1" ref-type="table-fn">a</xref>
,<xref rid="t2fn5" ref-type="table-fn">b</xref>
</td>
<td style="border:none;" align="left">19, 13</td>
<td style="border:none;" align="left">>50000</td>
<td style="border:none;" align="left">79<xref rid="t2fn4" ref-type="table-fn">d</xref>
</td>
</tr>
<tr><td style="border:none;" align="left">111<xref rid="t2fn2" ref-type="table-fn">e</xref>
</td>
<td style="border:none;" align="left">350</td>
<td style="border:none;" align="left">4400</td>
<td style="border:none;" align="left">147<xref rid="t2fn4" ref-type="table-fn">d</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t2fn1"><label>a</label>
<p><ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_031.xls">Data Set S30</ext-link>
.</p>
</fn>
<fn id="t2fn5"><label>b</label>
<p><ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_032.xls">Data Set S31</ext-link>
.</p>
</fn>
<fn id="t2fn3"><label>c</label>
<p>See <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB1</ext-link>
.</p>
</fn>
<fn id="t2fn4"><label>d</label>
<p>See <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Table SB3</ext-link>
.</p>
</fn>
<fn id="t2fn2"><label>e</label>
<p><ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_030.xls">Data Set S29</ext-link>
; <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S31</ext-link>
, liver stage potency curve.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="sec2.3.6"><title>Mode of Action</title>
<p>As with most phenotypic hit to lead projects,
the activity assays were carried out on whole parasites, giving a
more realistic measure of activity than enzyme-based assays at the
expense of an unknown mode of action. To predict the mode of action
of the members of these series, eight representative active compounds
(structures in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
) across both subseries were evaluated in a yeast-based genetic sensitivity
Hip Hop assay<sup><xref ref-type="bibr" rid="ref106">106</xref>
,<xref ref-type="bibr" rid="ref107">107</xref>
</sup>
that seeks mutations that result
in enhanced compound potency, i.e., to identify any sensitive biological
processes. The most potent compounds (OSM-S-39 and -51) showed enrichments
for processes involved in chromatin remodeling and DNA repair. Indeed,
inspection of the rank ordered genes for all compounds showed a preponderance
of genes for diverse components of chromatin architecture, remodeling,
and post-translational modification of chromatin proteins. These results
are consistent with a perturbation of chromatin condensation with
predicted follow-on effects on gene expression. Several groups have
highlighted apparent plasticity of global gene expression in the malaria
parasite which is manifested as a complex program of histone modification.<sup><xref ref-type="bibr" rid="ref108">108</xref>
,<xref ref-type="bibr" rid="ref109">109</xref>
</sup>
To attempt to gain additional insight into genome wide screens,
we compared the data from several OSM compounds to a data set of 3200
similar genome wide screens to identify the 10 most similar profiles
for each of these OSM analogues. This provided clear concordance between
these results and screens for other compounds, for OSM-S-39 (danthron,
an anthraquinone derivative, as well as artemisinin), OSM-S-51 (the
antineoplastics mitoxanthrone and mitomycin C), and OSM-S-9 (the antiarrhythmic
agent DTBHQ). Taken together, these data point to a global dysregulation
of chromatin architecture and suggest that further bioinformatics
analysis both within the hip-hop data set and to orthologous data
sets may be informative. The finding that the profile of the compounds
is similar to that of known antimalarials (e.g., artemisinin) is provocative
and warrants consideration. While it is formally possible that the
predicted mechanism of select OSM compounds is similar to that of
artemisinin, in our experience the degree of concordance we see between
the OSM compounds and artemisinin suggests that the OSM compounds
perturb a similar, but distinct, cellular target or pathway. This
observation is consistent with our recent observation that, in a compendium
of 3200 chemogenomic screens, the majority of compounds fell into ∼45
cellular response classes.<sup><xref ref-type="bibr" rid="ref106">106</xref>
</sup>
Our finding
that different compounds from the same series have different profiles
is also compelling and is consistent with previously published work
demonstrating that single atom changes within a compound class can
produce distinct cellular responses, which we attribute to small differences
in compound structure resulting in significant fitness differences.<sup><xref ref-type="bibr" rid="ref110">110</xref>
</sup>
In order to derive experimental evidence for
possible differences in mode of action, a parasite reduction ratio
(PRR, generically “rate of killing”)<sup><xref ref-type="bibr" rid="ref111">111</xref>
</sup>
assay was run for six of these compounds (across both arylpyrrole
and NN series) even though this assay is not a direct measure of differences
in gene expression. The results (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S1, Figure S37</ext-link>
) suggest a common mechanism of action between the subseries
and one that is distinct from artemisinin, which has previously exhibited
a substantially faster killing profile. It remains a possibility that
the <italic>in vivo</italic>
target and/or impact on gene expression
of the compounds in the arylpyrrole/near neighbor series are distinct
and yet they still share a common mode of action, but this was not
investigated further here.</p>
<p>The potency of the near neighbor
set led to an <italic>in silico</italic>
target prediction study being
performed on OSM-S-39 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S11</ext-link>
). The method
employed a naive Bayes statistical model identifying molecular structural
features of small molecules with protein targets, using the ChEMBL
database. Similar statistical approaches based on known activities
of compounds have been successfully applied to identify targets of
antitubercular compounds.<sup><xref ref-type="bibr" rid="ref112">112</xref>
−<xref ref-type="bibr" rid="ref114">114</xref>
</sup>
A total of 1,287 proteins were
included for which at least 50 active compounds were known with activities
<10 μM, with the other compounds in the database comprising
the inactives. After the OSM compounds were scored against each target,
the scores obtained were standardized by comparison with scores obtained
through comparison with a random set of >10K compounds. The prediction
list was culled for proteins relevant to malaria (3D7 proteome), and
the analysis gave as the most likely candidate targets, in order of
significance, carboxy-terminal domain RNA polymerase II polypeptide
A small phosphatase 1 (Q8I3U9), dihydroorotate dehydrogenase (DHODH,
Q08210), SUMO-activating enzyme subunit 2 (Q8I553) and 1 (Q8IHS2),
and cyclin-dependent kinase 1 (P61075). To kick-start the process
of exploring these predictions, this compound and 24 others representative
of both the hit compounds were evaluated in an experimental assay
for DHODH inhibition (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_037.xls">Data Set S36</ext-link>
; <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Text S14</ext-link>
) vs two positive control compounds (TCMDC-125840
and -123822) known to inhibit this enzyme.<sup><xref ref-type="bibr" rid="ref115">115</xref>
</sup>
None of the compounds exhibited any activity, strongly suggesting
that this is not the target for either subseries of compounds. A line
of inquiry remaining open is the equivalent assays against the other
targets identified in the <italic>in silico</italic>
prediction.</p>
<p>Involvement of PfATP4, a putative plasma membrane ion pump, in the
mechanism of action was ruled out. The relevant experiments measure
the effect of a compound on the cytosolic [Na<sup>+</sup>
] ([Na<sup>+</sup>
]<sub>i</sub>
) in isolated (trophozoite-stage) parasites preloaded
with the Na<sup>+</sup>
-sensitive fluorescent indicator SBFI. PfATP4
is important since it is the proposed target of the antimalarial compound
KAE609<sup><xref ref-type="bibr" rid="ref116">116</xref>
</sup>
that has recently successfully
completed phase 2 trials,<sup><xref ref-type="bibr" rid="ref117">117</xref>
</sup>
as well as
that of a pyrazoleamide<sup><xref ref-type="bibr" rid="ref118">118</xref>
</sup>
a dihydroisoquinolone
((+)-SJ-733),<sup><xref ref-type="bibr" rid="ref119">119</xref>
</sup>
various aminopyrazoles,<sup><xref ref-type="bibr" rid="ref120">120</xref>
</sup>
28 of the 400 potent antiplasmodial compounds
comprising the MMV Malaria Box,<sup><xref ref-type="bibr" rid="ref121">121</xref>
</sup>
and
a triazolopyrazine series being investigated by the Open Source Malaria
Consortium.<sup><xref ref-type="bibr" rid="ref122">122</xref>
</sup>
All of these compounds cause
an immediate increase in parasite [Na<sup>+</sup>
]<sub>i</sub>
on
addition to isolated parasites. Here, several compounds across both
subseries were tested at 1 μM for their effect on [Na<sup>+</sup>
]<sub>i</sub>
in saponin-isolated SBFI-loaded trophozoite stage 3D7
parasites.<sup><xref ref-type="bibr" rid="ref116">116</xref>
</sup>
In each case there was no
significant effect on [Na<sup>+</sup>
]<sub>i</sub>
, consistent with
PfATP4 not being the relevant biological target of this compound class
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_038.xls">Data Set S37</ext-link>
; <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S38</ext-link>
).</p>
</sec>
</sec>
</sec>
<sec id="sec3"><title>Conclusions</title>
<p>The public deposition
of novel antimalarial hits from phenotypic whole-cell assays has had
a significant effect on worldwide antimalarial drug discovery by providing
an embarrassment of riches for the early stages of discovery. The
plethora of alternative structures available for investigation has
ultimately led to the series described in this paper being “parked”
in favor of other possible avenues of inquiry. Interestingly the “stop”
decision was straightforward to make in part because the decisions
taken communally in the project had to be justifiable to all onlookers.
The time taken to reach the stop decision in this case was probably
slightly longer than would be expected from a traditionally structured
project because certain contributions were not paid for or grant-supported,
necessitating a lower priority than core interests of the contributing
laboratories.</p>
<p>Both subseries investigated have members with
major strengths, including potency with low molecular weight and significant
late stage gametocyte and liver-stage activity coupled with low toxicity
and low levels of activity in the hERG assay. Indeed, OSM-S-5 is bioavailable.
Many of the most obvious structural changes to the hits, in several
cases changes of a single atom, led to total loss, rather than moderation,
of biological activity, known colloquially as “activity cliffs”
(<xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref>
</xref>
). In the
case of the ester-containing hit OSM-S-5, the ester was likely the
key metabolic liability but could not be replaced with other common
isosteres without loss of activity, yet (in the mouse model, at least)
was found to be too short-lived in plasma to be taken on further.
Other minor changes remote from the ester were also found to result
in a precipitous decrease in potency. The “near neighbor”
analogue set displayed impressive potency coupled with low cytotoxicity
but alongside low solubility that could not easily be engineered out
through side chain modifications.</p>
<fig id="fig7" position="float"><label>Figure 7</label>
<caption><p>Sensitivity of the initial hit OSM-S-5
to minor structural changes.</p>
</caption>
<graphic xlink:href="oc-2016-000863_0007" id="gr7" position="float"></graphic>
</fig>
<p>The emergence of large amounts of open data in the field
of drug discovery for malaria makes it straightforward to search for
new ways forward in a project where a stop decision has been made.
A similarity network map was generated for the most potent compound
identified (OSM-S-39, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_039.zip">Data Set S38</ext-link>
, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S39</ext-link>
) that identifies those compounds most
similar in structure known to the open databases (<xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref>
</xref>
). Some of these are now represented
in the MMV Malaria Box,<sup><xref ref-type="bibr" rid="ref123">123</xref>
</sup>
making simpler
their investigation by other groups. A portion of this map is represented,
alongside the structures and potencies of the closest neighbors in
the map. While it is clear from this analysis that OSM-S-39 remains
the most potent compound identified in this class, exploration of
the neighboring structures in such open data sets may identify a way
forward for this series that could suggest unexplored strategies to
increase solubility with a realistic chance of maintaining potency,
such as the potential scaffold-hop to the triazine TCMDC-125770. (One
of the compounds shown from the Novartis screen, GNF-Pf-5137/1137,
is from the same series as the published pyrrolones.<sup><xref ref-type="bibr" rid="ref62">62</xref>
</sup>
) The recommended way forward, rather than further analogue
synthesis in the present series, is to pursue clarity in the mechanisms
of action of such series using, for example, generation of resistance
coupled with genomic sequencing, or pull-down studies. Subsequent
screening might then establish better starting points from related
structures (informed by what has already been tried via comparison
with network maps) against the relevant target.</p>
<fig id="fig8" position="float"><label>Figure 8</label>
<caption><p>Closest neighbors of
OSM-S-39. (Left) Portion of a network similarity map generated for
OSM-S-39 (coded as batch ZYH-72 in the figure) using methods described
in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Supporting Information</ext-link>
. (Right)
The structures (stereochemistry assumed) and potencies (3D7, range
if multiple values reported) of the most similar compounds in the
ChEMBL database (v13) (key to compound sources: red = GSK TCAMS, blue
= Novartis, green = St. Jude’s).</p>
</caption>
<graphic xlink:href="oc-2016-000863_0008" id="gr8" position="float"></graphic>
</fig>
<p>One of the unique features of this project, the open source
research method, ensures that the unexplored lines of inquiry remain
open alongside the attendant data posted online that makes it straightforward
for others to resume any portion of the research project as fully
fledged participants, with access to both positive and negative data,
details of all procedures as they were carried out (to aid reproducibility),
and anecdotal insight into project loose ends that are easy to explore.
The machine-readability of the present project (for example the use
of cheminformatic strings in the online electronic lab notebook) permits
an unusually straightforward link between a high throughput screening
result in a public database and a “live” research project
that has investigated that compound.</p>
<p>Contributions to this project
arose from disparate sources: (i) core government/NGO/foundation support,
via both direct grant support and in-kind contributions (it is likely
that direct support from public/philanthropic funds will always be
needed as part of any open source drug discovery campaign); (ii) additional
compound synthesis by undergraduate or postgraduate university students,
either individually or as part of crowdsourced classes; (iii) expertise
and advice emerging from the wider online community, both solicited
and spontaneous; and (iv) additional laboratory contributions from
other specialist centers, such as academic laboratories with block
grants or pharmaceutical companies. These sources have considerable
potential and can be mobilized further. For example, the time of researchers
in major organizations (pharmaceutical companies, universities, CROs)
could be contributed via policies that allow staff to work part-time
on their own projects mimicking the <italic>pro bono</italic>
system
of the major law firms; such policies have been sporadically adopted
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">Figure S40</ext-link>
)<sup><xref ref-type="bibr" rid="ref124">124</xref>
</sup>
and are a component of the GSK Tres Cantos research campus that
kick-started and then supported the work described in this paper.
In cases where resources are not forthcoming, direct payment (e.g.,
generated through crowdsourcing) could be awarded via competition,
as occurred in this paper to create the graphical abstract. Each situation
in the diverse base of support for an open source project will be
different, and may be driven by appropriate selfless and selfish motives
(e.g., contribution to a public health project vs securing publication
authorship). Besides the transparency and completeness of the data
arising from the research, this experiment with open source drug discovery
made clear some of the advantages of this way of working: the breadth
of people and expertise arising from “external” sources
that were contributed rather than actively solicited, such as successful
compound synthesis by federated groups of graduate and undergraduate
students, or the analysis of data obtained by others. Allowing participation
by “strangers” introduces costs, such as the time required
by a “core” team to maintain the project status, data,
and methodology to allow meaningful contributions (in particular a
real-time data set making clear the series SAR). We predict that tools
and practices will arise to make easier some of these challenges,
as open source methods in drug discovery and development become more
widely adopted.</p>
</sec>
</body>
<back><notes id="notes-4" notes-type="si"><title>Supporting Information Available</title>
<p>The Supporting
Information is available free of charge on the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org">ACS Publications website</ext-link>
at
DOI: <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/abs/10.1021/acscentsci.6b00086">10.1021/acscentsci.6b00086</ext-link>
.<list id="silist" list-type="simple"><list-item><p>Complete electronic laboratory notebooks, images
of NMR spectra for novel compounds, and archived snapshots of OSM
wiki pages are available from The University of Sydney eScholarship
Repository at <uri xlink:href="http://hdl.handle.net/2123/14132">http://hdl.handle.net/2123/14132</uri>
, <uri xlink:href="http://hdl.handle.net/2123/14123">http://hdl.handle.net/2123/14123</uri>
, and <uri xlink:href="http://hdl.handle.net/2123/15389">http://hdl.handle.net/2123/15389</uri>
, respectively.</p>
</list-item>
<list-item><p>Chemical and biological
protocols, other text-based files, and screengrabs (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_001.pdf">PDF</ext-link>
)</p>
</list-item>
<list-item><p>All molecules (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_002.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>All molecules
in SDF format (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_003.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Ralph assay 1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_004.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from GSK assay
1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_005.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency
data from Avery assay 1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_006.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Similarity network data for Tres Cantos series in Cytoscape
format (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_007.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Map of purchaseable compounds around OSM-S-35 in Cytoscape format
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_008.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Potency
data from Ralph assay 2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_009.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from GSK assay 2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_010.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Avery
assay 2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_011.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Avery assay 3a (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_012.pdf">PDF</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Avery assay 3b (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_013.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>X-ray structural
information for OSM-S-35, -42, -54, and -9 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_014.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Avery assay 5 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_015.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data
from Guy assay (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_016.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Avery assay 3c (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_017.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Dundee
assay 1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_018.pdf">PDF</ext-link>
)</p>
</list-item>
<list-item><p>Potency data from Dundee assay 2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_019.pdf">PDF</ext-link>
)</p>
</list-item>
<list-item><p>Bioisostere analysis in Cytoscape
format (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_020.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Solubility and microsomal stability data for OSM-S-5, -6, -9, -10,
-37, -38, -39, and -54 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_021.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Solubility and microsomal stability data for OSM-S-111
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_022.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Data
from oral <italic>in vivo</italic>
<italic>P. berghei</italic>
mouse
trial for compounds OSM-S-5, -6, and -35 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_023.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Pharmacokinetic data from oral <italic>in vivo</italic>
<italic>P. berghei</italic>
mouse trial (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_024.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Human and
mouse plasma stability data for OSM-S-5 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_025.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Metabolite identification assay data
for OSM-S-35 in human liver microsomes (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_026.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>hERG assay data for compounds OSM-S-5
and -35 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_027.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Avery late stage gametocyte assay 1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_028.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Avery late stage gametocyte assay
2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_029.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>UCSD
liver stage assay 1 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_030.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>UCSD liver stage assay 2 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_031.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>UCSD liver stage assay 3 (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_032.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Nislow gene
set enrichment analysis data (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_033.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Nislow gene set enrichment analysis data,
Spotfire format (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_034.zip">ZIP</ext-link>
)</p>
</list-item>
<list-item><p>Nislow gene set
enrichment analysis data (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_035.pdf">PDF</ext-link>
)</p>
</list-item>
<list-item><p>Nislow fitness defect scores for all deletion
strains (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_036.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Data from GSK DHODH assay (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_037.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Data from Kirk ion regulation assay (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_038.xls">XLS</ext-link>
)</p>
</list-item>
<list-item><p>Similarity
map surrounding OSM-S-39 in Cytoscape format (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00086/suppl_file/oc6b00086_si_039.zip">ZIP</ext-link>
)</p>
</list-item>
</list>
</p>
</notes>
<sec sec-type="supplementary-material"><title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="sifile1"><media xlink:href="oc6b00086_si_001.pdf"><caption><p>oc6b00086_si_001.pdf</p>
</caption>
</media>
</supplementary-material>
<supplementary-material content-type="local-data" id="sifile2"><media xlink:href="oc6b00086_si_002.xls"><caption><p>oc6b00086_si_002.xls</p>
</caption>
</media>
</supplementary-material>
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</caption>
</media>
</supplementary-material>
<supplementary-material content-type="local-data" id="sifile4"><media xlink:href="oc6b00086_si_004.xls"><caption><p>oc6b00086_si_004.xls</p>
</caption>
</media>
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</caption>
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</caption>
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</caption>
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</caption>
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</caption>
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</caption>
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</sec>
<notes id="notes-1"><title>Author Present Address</title>
<p><sup>ο</sup>
I.M.W.:
Merck Research Laboratories, 470 Atlantic Ave, Boston, MA 02210, United States.</p>
</notes>
<notes id="notes-2"><title>Author Contributions</title>
<p><sup>‡</sup>
The authorship
list for this paper is alphabetical aside from the bookenders: the
corresponding author is shown last, and the first three authors performed
the majority of the experimental work.</p>
</notes>
<notes id="notes-3" notes-type="funding-statement"><p>Medicines for Malaria Venture (MMV),
the Australian Research Council (LP120100552, LP120200557), the Australian
National Health and Medical Research Council (Project Grant 1042272).
G.P. and J.P.O. were supported by EMBL Member States and MMV. The
characterization by NMR spectroscopy of compounds from Lawrence University
was made possible by the National Science Foundation (CHE-0923473).
C.S. was supported by Wellcome Trust Biomedical Resources Grant 099156/Z/12/Z.</p>
</notes>
<notes id="NOTES-d90e2372-autogenerated" notes-type="conflict-of-interest"><p>The authors declare
no competing financial interest.</p>
</notes>
<ack><title>Acknowledgments</title>
<p>We would like
to thank the Labtrove team at the University of Southampton led by
Professor Jeremy Frey, OpenWetWare for hosting the OSM wiki, and
publicly available platforms such as Twitter, G+, Facebook, and Github
that have helped in the wider dissemination required for live research
projects. We thank Michael Robins for ongoing technical support of
the online project components. OSM-A-1 through -A-4 were synthesized
by undergraduate organic chemistry students at Lawrence University;
in particular, the work of Shay Albrecht, Margaret Brickner, Patrick
Doughty, Joshua Graber, Sarah Gunby, Briana Harter, Alexander Hurlburt,
Jake Johengen, Sarah Prophet, Greta Schmitt, Chad Skaer, and Konstantinos
Vlachos is acknowledged. Dr. Colin Campbell (The University of Edinburgh)
is thanked for provision of laboratory resources and time, as is the
University of Edinburgh for funding (to P.T.). The Australian Red
Cross Blood Service is thanked for the provision of blood (to K.K.
and V.A.). The authors wish to thank Prof. David Fidock (Columbia
University, NY) for the provision of the NF54 transgenic parasite
expressing GFP linked to the early expressed gametocyte specific protein,
Pfs16. Miscellaneous project inputs were gratefully received from William Jackson (Creative Chemistry), Egon Willighagen (Maastricht University), Martine Keenan (Epichem), Darren Dressen (Los Altos High School), Robert Snell (The University of Cambridge, now Charterhouse School) and Joie Garfunkel (Merck). For their generous time and insights, we thank the other (sometimes anonymous) online contributors. We thank Viputheshwar Sitaraman
(Draw Science) for creating the graphical abstract as part of a competition
for this purpose. We thank Ginger Taylor for creating The Synaptic
Leap website, which hosted much of the early activity in the project.
We would like to thank student volunteers (Min Kyung Chong, Jun Ki
Hong, Martina Yousif, Sebastien Dath) for help with online data
entry.</p>
</ack>
<ref-list><title>References</title>
<ref id="ref1"><mixed-citation publication-type="weblink" id="cit1"><collab>WHO</collab>
. World Malaria Report <bold>2015</bold>
, <uri xlink:href="http://www.who.int/malaria/publications/world-malaria-report-2015/en/">http://www.who.int/malaria/publications/world-malaria-report-2015/en/</uri>
, accessed March 15, 2016.</mixed-citation>
</ref>
<ref id="ref2"><mixed-citation publication-type="book" id="cit2"><person-group person-group-type="allauthors"><name><surname>Snow</surname>
<given-names>R. W.</given-names>
</name>
; <name><surname>Craig</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Newton</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Steketee</surname>
<given-names>R.</given-names>
</name>
</person-group>
<source>The Public Health Burden
of Plasmodium falciparum Malaria in Africa: Deriving the Numbers</source>
; <publisher-name>Fogarty International Centre, National Institutes
of Health</publisher-name>
: <publisher-loc>Bethesda, MD</publisher-loc>
, <year>2010</year>
, <fpage>1</fpage>
–<lpage>81</lpage>
.</mixed-citation>
</ref>
<ref id="ref3"><mixed-citation publication-type="weblink" id="cit3">The
Global Malaria Action Plan, Geneva, <bold>2008</bold>
, <uri xlink:href="http://www.rollbackmalaria.org/microsites/gmap/">http://www.rollbackmalaria.org/microsites/gmap/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref4"><mixed-citation publication-type="journal" id="cit4"><name><surname>Carrara</surname>
<given-names>V.
I.</given-names>
</name>
; <name><surname>Zwang</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Ashley</surname>
<given-names>E. A.</given-names>
</name>
; <name><surname>Price</surname>
<given-names>R. N.</given-names>
</name>
; <name><surname>Stepniewska</surname>
<given-names>K.</given-names>
</name>
; <name><surname>Barends</surname>
<given-names>M.</given-names>
</name>
; et al. <article-title>Changes in the treatment responses to artesunate-mefloquine
on the northwestern border of Thailand during 13 years of continuous
deployment</article-title>
. <source>PLoS One</source>
<year>2009</year>
, <volume>4</volume>
, <fpage>e4551</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pone.0004551</pub-id>
.<pub-id pub-id-type="pmid">19234601</pub-id>
</mixed-citation>
</ref>
<ref id="ref5"><mixed-citation publication-type="journal" id="cit5"><name><surname>Dondorp</surname>
<given-names>A. M.</given-names>
</name>
; <name><surname>Nosten</surname>
<given-names>F.</given-names>
</name>
; <name><surname>Yi</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Das</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Phyo</surname>
<given-names>A. P.</given-names>
</name>
; <name><surname>Tarning</surname>
<given-names>J.</given-names>
</name>
; et al. <article-title>Artemisinin resistance
in <italic>Plasmodium falciparum</italic>
malaria</article-title>
. <source>N. Engl. J. Med.</source>
<year>2009</year>
, <volume>361</volume>
, <fpage>455</fpage>
–<lpage>467</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMoa0808859</pub-id>
.<pub-id pub-id-type="pmid">19641202</pub-id>
</mixed-citation>
</ref>
<ref id="ref6"><mixed-citation publication-type="journal" id="cit6"><name><surname>Phyo</surname>
<given-names>A. P.</given-names>
</name>
; <name><surname>Nkhoma</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Stepniewska</surname>
<given-names>K.</given-names>
</name>
; <name><surname>Ashley</surname>
<given-names>E. A.</given-names>
</name>
; <name><surname>Nair</surname>
<given-names>S.</given-names>
</name>
; <name><surname>McGready</surname>
<given-names>R.</given-names>
</name>
; et al. <article-title>Emergence of artemisinin-resistant malaria
on the western border of Thailand: a longitudinal study</article-title>
. <source>Lancet</source>
<year>2012</year>
, <volume>379</volume>
, <fpage>1960</fpage>
–<lpage>1966</lpage>
<pub-id pub-id-type="doi">10.1016/S0140-6736(12)60484-X</pub-id>
.<pub-id pub-id-type="pmid">22484134</pub-id>
</mixed-citation>
</ref>
<ref id="ref7"><mixed-citation publication-type="journal" id="cit7"><article-title>Efficacy and safety of RTS,S/AS01 malaria vaccine with
or without a booster dose in infants and children in Africa: final
results of a phase 3, individually randomized, controlled trial</article-title>
. <source>Lancet</source>
<year>2015</year>
, <volume>386</volume>
, <fpage>31</fpage>
–<lpage>45</lpage>
<pub-id pub-id-type="doi">10.1016/S0140-6736(15)60721-8</pub-id>
.<pub-id pub-id-type="pmid">25913272</pub-id>
</mixed-citation>
</ref>
<ref id="ref8"><mixed-citation publication-type="journal" id="cit8"><name><surname>Olotu</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Fegan</surname>
<given-names>G.</given-names>
</name>
; <name><surname>Wambua</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Nyangweso</surname>
<given-names>G.</given-names>
</name>
; <name><surname>Awuondo</surname>
<given-names>K. O.</given-names>
</name>
; <name><surname>Leach</surname>
<given-names>A.</given-names>
</name>
; et al. <article-title>Four-year efficacy of
RTS,S/AS01E and its interaction with malaria exposure</article-title>
. <source>N. Engl. J. Med.</source>
<year>2013</year>
, <volume>368</volume>
, <fpage>1111</fpage>
–<lpage>1120</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMoa1207564</pub-id>
.<pub-id pub-id-type="pmid">23514288</pub-id>
</mixed-citation>
</ref>
<ref id="ref9"><mixed-citation publication-type="journal" id="cit9"><name><surname>Wells</surname>
<given-names>T. N. C.</given-names>
</name>
; <name><surname>van Huijsduijnen</surname>
<given-names>R. H.</given-names>
</name>
; <name><surname>Van Voorhis</surname>
<given-names>W. C.</given-names>
</name>
<article-title>Malaria
medicines: a glass half full?</article-title>
. <source>Nat. Rev. Drug
Discovery</source>
<year>2015</year>
, <volume>14</volume>
, <fpage>424</fpage>
–<lpage>442</lpage>
<pub-id pub-id-type="doi">10.1038/nrd4573</pub-id>
.<pub-id pub-id-type="pmid">26000721</pub-id>
</mixed-citation>
</ref>
<ref id="ref10"><mixed-citation publication-type="journal" id="cit10"><name><surname>Flannery</surname>
<given-names>E.
L.</given-names>
</name>
; <name><surname>Chatterjee</surname>
<given-names>A. K.</given-names>
</name>
; <name><surname>Winzeler</surname>
<given-names>E. A.</given-names>
</name>
<article-title>Antimalarial drug discovery – approaches and
progress towards new medicines</article-title>
. <source>Nat. Rev. Microbiol.</source>
<year>2013</year>
, <volume>11</volume>
, <fpage>849</fpage>
–<lpage>862</lpage>
<pub-id pub-id-type="doi">10.1038/nrmicro3138</pub-id>
.<pub-id pub-id-type="pmid">24217412</pub-id>
</mixed-citation>
</ref>
<ref id="ref11"><mixed-citation publication-type="journal" id="cit11"><name><surname>Burrows</surname>
<given-names>J. N.</given-names>
</name>
; <name><surname>Elliott</surname>
<given-names>R. L.</given-names>
</name>
; <name><surname>Kaneko</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Mowbray</surname>
<given-names>C. E.</given-names>
</name>
; <name><surname>Waterson</surname>
<given-names>D.</given-names>
</name>
<article-title>The role of modern drug discovery
in the fight against neglected and tropical diseases</article-title>
. <source>MedChemComm</source>
<year>2014</year>
, <volume>5</volume>
, <fpage>688</fpage>
–<lpage>700</lpage>
<pub-id pub-id-type="doi">10.1039/c4md00011k</pub-id>
.</mixed-citation>
</ref>
<ref id="ref12"><mixed-citation publication-type="journal" id="cit12"><name><surname>Peatey</surname>
<given-names>C. L.</given-names>
</name>
; <name><surname>Leroy</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Gardiner</surname>
<given-names>D. L.</given-names>
</name>
; <name><surname>Trenholme</surname>
<given-names>K. R.</given-names>
</name>
<article-title>Anti-malarial
drugs: how effective are they against <italic>Plasmodium falciparum</italic>
gametocytes?</article-title>
. <source>Malar. J.</source>
<year>2012</year>
, <volume>11</volume>
, <fpage>34</fpage>
<pub-id pub-id-type="doi">10.1186/1475-2875-11-34</pub-id>
.<pub-id pub-id-type="pmid">22305482</pub-id>
</mixed-citation>
</ref>
<ref id="ref13"><mixed-citation publication-type="journal" id="cit13"><name><surname>Duffy</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Avery</surname>
<given-names>V. M.</given-names>
</name>
<article-title>Identification of inhibitors of <italic>Plasmodium
falciparum</italic>
gametocyte development</article-title>
. <source>Malar. J.</source>
<year>2013</year>
, <volume>12</volume>
, <fpage>408</fpage>
<pub-id pub-id-type="doi">10.1186/1475-2875-12-408</pub-id>
.<pub-id pub-id-type="pmid">24206914</pub-id>
</mixed-citation>
</ref>
<ref id="ref14"><mixed-citation publication-type="journal" id="cit14"><name><surname>McNamara</surname>
<given-names>C. W.</given-names>
</name>
; <name><surname>Lee</surname>
<given-names>M. C. S.</given-names>
</name>
; <name><surname>Lim</surname>
<given-names>C. S.</given-names>
</name>
; <name><surname>Lim</surname>
<given-names>S. H.</given-names>
</name>
; <name><surname>Roland</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Nagle</surname>
<given-names>A.</given-names>
</name>
; et al. <article-title>Targeting <italic>Plasmodium</italic>
PI(4)K to eliminate malaria</article-title>
. <source>Nature</source>
<year>2013</year>
, <volume>504</volume>
, <fpage>248</fpage>
–<lpage>253</lpage>
<pub-id pub-id-type="doi">10.1038/nature12782</pub-id>
.<pub-id pub-id-type="pmid">24284631</pub-id>
</mixed-citation>
</ref>
<ref id="ref15"><mixed-citation publication-type="journal" id="cit15"><name><surname>Dembélé</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Franetich</surname>
<given-names>J.-F.</given-names>
</name>
; <name><surname>Lorthiois</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Gego</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Zeeman</surname>
<given-names>A.-M.</given-names>
</name>
; <name><surname>Kocken</surname>
<given-names>C. H. M.</given-names>
</name>
; et al. <article-title>Persistence and activation of malaria hypnozoites
in long-term primary hepatocyte cultures</article-title>
. <source>Nat.
Med.</source>
<year>2014</year>
, <volume>20</volume>
, <fpage>307</fpage>
–<lpage>312</lpage>
<pub-id pub-id-type="doi">10.1038/nm.3461</pub-id>
.<pub-id pub-id-type="pmid">24509527</pub-id>
</mixed-citation>
</ref>
<ref id="ref16"><mixed-citation publication-type="journal" id="cit16"><name><surname>Scannell</surname>
<given-names>J.
W.</given-names>
</name>
; <name><surname>Blanckley</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Boldon</surname>
<given-names>H.</given-names>
</name>
; <name><surname>Warrington</surname>
<given-names>B.</given-names>
</name>
<article-title>Diagnosing the decline in pharmaceutical
R&D efficiency</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2012</year>
, <volume>11</volume>
, <fpage>191</fpage>
–<lpage>200</lpage>
<pub-id pub-id-type="doi">10.1038/nrd3681</pub-id>
.<pub-id pub-id-type="pmid">22378269</pub-id>
</mixed-citation>
</ref>
<ref id="ref17"><mixed-citation publication-type="journal" id="cit17"><name><surname>Paul</surname>
<given-names>S. M.</given-names>
</name>
; <name><surname>Mytelka</surname>
<given-names>D. S.</given-names>
</name>
; <name><surname>Dunwiddie</surname>
<given-names>C. T.</given-names>
</name>
; <name><surname>Persinger</surname>
<given-names>C. C.</given-names>
</name>
; <name><surname>Munos</surname>
<given-names>B. H.</given-names>
</name>
; <name><surname>Lindborg</surname>
<given-names>S. R.</given-names>
</name>
; et al. <article-title>How
to improve R&D productivity: the pharmaceutical industry’s
grand challenge</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2010</year>
, <volume>9</volume>
, <fpage>203</fpage>
–<lpage>214</lpage>
<pub-id pub-id-type="doi">10.1038/nrd3078</pub-id>
.<pub-id pub-id-type="pmid">20168317</pub-id>
</mixed-citation>
</ref>
<ref id="ref18"><mixed-citation publication-type="journal" id="cit18"><name><surname>Kneller</surname>
<given-names>R.</given-names>
</name>
<article-title>The importance of new companies for
drug discovery: origins of a decade of new drugs</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2010</year>
, <volume>9</volume>
, <fpage>867</fpage>
–<lpage>882</lpage>
<pub-id pub-id-type="doi">10.1038/nrd3251</pub-id>
.<pub-id pub-id-type="pmid">21031002</pub-id>
</mixed-citation>
</ref>
<ref id="ref19"><mixed-citation publication-type="weblink" id="cit19">The 10/90
Report on Health Research 1999, <source>Global Forum for Health Research</source>
, <bold>1999</bold>
, <uri xlink:href="http://www.css.ethz.ch/content/specialinterest/gess/cis/center-for-securities-studies/en/services/digital-library/publications/publication.html/20437">http://www.css.ethz.ch/content/specialinterest/gess/cis/center-for-securities-studies/en/services/digital-library/publications/publication.html/20437</uri>
, accessed Aug 9, 2016.</mixed-citation>
</ref>
<ref id="ref20"><mixed-citation publication-type="journal" id="cit20"><name><surname>Jorgensen</surname>
<given-names>W. L.</given-names>
</name>
<article-title>Challenges for academic
drug discovery</article-title>
. <source>Angew. Chem., Int. Ed.</source>
<year>2012</year>
, <volume>51</volume>
, <fpage>11680</fpage>
–<lpage>11684</lpage>
<pub-id pub-id-type="doi">10.1002/anie.201204625</pub-id>
.</mixed-citation>
</ref>
<ref id="ref21"><mixed-citation publication-type="journal" id="cit21"><name><surname>Lezaun</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Montgomery</surname>
<given-names>C. M.</given-names>
</name>
<article-title>The pharmaceutical
commons. Sharing and exclusion in global health drug development</article-title>
. <source>Sci. Technol. Hum. Val.</source>
<year>2015</year>
, <volume>40</volume>
, <fpage>3</fpage>
–<lpage>29</lpage>
<pub-id pub-id-type="doi">10.1177/0162243914542349</pub-id>
.</mixed-citation>
</ref>
<ref id="ref22"><mixed-citation publication-type="weblink" id="cit22">Uniting to Combat Neglected Tropical Diseases, <uri xlink:href="http://www.unitingtocombatntds.org">http://www.unitingtocombatntds.org</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref23"><mixed-citation publication-type="weblink" id="cit23">Institute of One World Health,
now the PATH drug development program, <uri xlink:href="http://sites.path.org/drugdevelopment/">http://sites.path.org/drugdevelopment/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref24"><mixed-citation publication-type="weblink" id="cit24">Novartis Institutes for Biomedical
Research, <uri xlink:href="https://www.nibr.com/our-research/institutes/novartis-institute-tropical-diseases">https://www.nibr.com/our-research/institutes/novartis-institute-tropical-diseases</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref25"><mixed-citation publication-type="weblink" id="cit25">Tres Cantos OpenLab Foundation, <uri xlink:href="http://www.openlabfoundation.org/">http://www.openlabfoundation.org/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref26"><mixed-citation publication-type="journal" id="cit26"><name><surname>Hopkins</surname>
<given-names>A. L.</given-names>
</name>
; <name><surname>Witty</surname>
<given-names>M. J.</given-names>
</name>
; <name><surname>Nwaka</surname>
<given-names>S.</given-names>
</name>
<article-title>Neglected diseases.
Mission possible</article-title>
. <source>Nature</source>
<year>2007</year>
, <volume>449</volume>
, <fpage>166</fpage>
–<lpage>169</lpage>
<pub-id pub-id-type="doi">10.1038/449166a</pub-id>
.<pub-id pub-id-type="pmid">17851512</pub-id>
</mixed-citation>
</ref>
<ref id="ref27"><mixed-citation publication-type="journal" id="cit27"><name><surname>Ortí</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Carbajo</surname>
<given-names>R. J.</given-names>
</name>
; <name><surname>Pieper</surname>
<given-names>U.</given-names>
</name>
; <name><surname>Eswar</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Maurer</surname>
<given-names>S. M.</given-names>
</name>
; <name><surname>Rai</surname>
<given-names>A. K.</given-names>
</name>
; et al. <article-title>A kernel
for the Tropical Disease Initiative</article-title>
. <source>Nat. Biotechnol.</source>
<year>2009</year>
, <volume>27</volume>
, <fpage>320</fpage>
–<lpage>321</lpage>
<pub-id pub-id-type="doi">10.1038/nbt0409-320</pub-id>
.<pub-id pub-id-type="pmid">19352362</pub-id>
</mixed-citation>
</ref>
<ref id="ref28"><mixed-citation publication-type="weblink" id="cit28">World Intellectual Property Office Re:Search, <uri xlink:href="http://www.wipo.int/research/en/">http://www.wipo.int/research/en/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref29"><mixed-citation publication-type="journal" id="cit29"><name><surname>Jakobsen</surname>
<given-names>P.
H.</given-names>
</name>
; <name><surname>Wang</surname>
<given-names>M.-W.</given-names>
</name>
; <name><surname>Nwaka</surname>
<given-names>S.</given-names>
</name>
<article-title>Innovative partnerships for drug discovery against neglected diseases</article-title>
. <source>PLoS Neglected Trop. Dis.</source>
<year>2011</year>
, <volume>5</volume>
, <fpage>e1221</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pntd.0001221</pub-id>
.</mixed-citation>
</ref>
<ref id="ref30"><mixed-citation publication-type="journal" id="cit30"><name><surname>Lotharius</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Gamo-Benito</surname>
<given-names>F. J.</given-names>
</name>
; <name><surname>Angulo-Barturen</surname>
<given-names>I.</given-names>
</name>
; <name><surname>Clark</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Connelly</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Ferrer-Bazaga</surname>
<given-names>S.</given-names>
</name>
; et al. <article-title>Repositioning: the fast track to new anti-malarial medicines?</article-title>
. <source>Malar. J.</source>
<year>2014</year>
, <volume>13</volume>
, <fpage>143</fpage>
<pub-id pub-id-type="doi">10.1186/1475-2875-13-143</pub-id>
.<pub-id pub-id-type="pmid">24731288</pub-id>
</mixed-citation>
</ref>
<ref id="ref31"><mixed-citation publication-type="journal" id="cit31"><name><surname>Hunter</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Stephens</surname>
<given-names>S.</given-names>
</name>
<article-title>Is open innovation
the way forward for big pharma?</article-title>
. <source>Nat. Rev. Drug
Discovery</source>
<year>2010</year>
, <volume>9</volume>
, <fpage>87</fpage>
–<lpage>88</lpage>
<pub-id pub-id-type="doi">10.1038/nrd3099</pub-id>
.</mixed-citation>
</ref>
<ref id="ref32"><mixed-citation publication-type="journal" id="cit32"><name><surname>Maurer</surname>
<given-names>S.
M.</given-names>
</name>
; <name><surname>Rai</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Sali</surname>
<given-names>A.</given-names>
</name>
<article-title>Finding cures for tropical diseases: is open source an answer?</article-title>
. <source>PLoS Med.</source>
<year>2004</year>
, <volume>1</volume>
, <fpage>e56</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pmed.0010056</pub-id>
.<pub-id pub-id-type="pmid">15630466</pub-id>
</mixed-citation>
</ref>
<ref id="ref33"><mixed-citation publication-type="journal" id="cit33"><name><surname>Munos</surname>
<given-names>B.</given-names>
</name>
<article-title>Can open-source R&D reinvigorate
drug research?</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2006</year>
, <volume>5</volume>
, <fpage>723</fpage>
–<lpage>729</lpage>
<pub-id pub-id-type="doi">10.1038/nrd2131</pub-id>
.<pub-id pub-id-type="pmid">16915233</pub-id>
</mixed-citation>
</ref>
<ref id="ref34"><mixed-citation publication-type="journal" id="cit34"><name><surname>Singh</surname>
<given-names>S.</given-names>
</name>
<article-title>India takes an open source approach
to drug discovery</article-title>
. <source>Cell</source>
<year>2008</year>
, <volume>133</volume>
, <fpage>201</fpage>
–<lpage>203</lpage>
<pub-id pub-id-type="doi">10.1016/j.cell.2008.04.003</pub-id>
.<pub-id pub-id-type="pmid">18423188</pub-id>
</mixed-citation>
</ref>
<ref id="ref35"><mixed-citation publication-type="journal" id="cit35"><name><surname>Munos</surname>
<given-names>B.</given-names>
</name>
<article-title>Can open-source drug R&D repower
pharmaceutical innovation?</article-title>
. <source>Clin. Pharmacol.
Ther.</source>
<year>2010</year>
, <volume>87</volume>
, <fpage>534</fpage>
–<lpage>536</lpage>
<pub-id pub-id-type="doi">10.1038/clpt.2010.26</pub-id>
.<pub-id pub-id-type="pmid">20407458</pub-id>
</mixed-citation>
</ref>
<ref id="ref36"><mixed-citation publication-type="journal" id="cit36"><name><surname>Woelfle</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Olliaro</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
<article-title>Open science is a research accelerator</article-title>
. <source>Nat. Chem.</source>
<year>2011</year>
, <volume>3</volume>
, <fpage>745</fpage>
–<lpage>748</lpage>
<pub-id pub-id-type="doi">10.1038/nchem.1149</pub-id>
.<pub-id pub-id-type="pmid">21941234</pub-id>
</mixed-citation>
</ref>
<ref id="ref37"><mixed-citation publication-type="journal" id="cit37"><name><surname>Ortí</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Carbajo</surname>
<given-names>R. J.</given-names>
</name>
; <name><surname>Pieper</surname>
<given-names>U.</given-names>
</name>
; <name><surname>Eswar</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Maurer</surname>
<given-names>S. M.</given-names>
</name>
; <name><surname>Rai</surname>
<given-names>A. K.</given-names>
</name>
; et al. <article-title>A kernel for open source drug discovery in tropical
diseases</article-title>
. <source>PLoS Neglected Trop. Dis.</source>
<year>2009</year>
, <volume>3</volume>
, <fpage>e418</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pntd.0000418</pub-id>
.</mixed-citation>
</ref>
<ref id="ref38"><mixed-citation publication-type="journal" id="cit38"><name><surname>Årdal</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Alstadsæter</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Røttingen</surname>
<given-names>J. A.</given-names>
</name>
<article-title>Common characteristics of open source software development
and applicability for drug discovery: a systematic review</article-title>
. <source>Health Res. Policy Syst.</source>
<year>2011</year>
, <volume>9</volume>
, <fpage>36</fpage>
<pub-id pub-id-type="doi">10.1186/1478-4505-9-36</pub-id>
.<pub-id pub-id-type="pmid">21955914</pub-id>
</mixed-citation>
</ref>
<ref id="ref39"><mixed-citation publication-type="journal" id="cit39"><name><surname>DeLano</surname>
<given-names>W. L.</given-names>
</name>
<article-title>The case
for open-source software in drug discovery</article-title>
. <source>Drug Discovery Today</source>
<year>2005</year>
, <volume>10</volume>
, <fpage>213</fpage>
–<lpage>217</lpage>
<pub-id pub-id-type="doi">10.1016/S1359-6446(04)03363-X</pub-id>
.<pub-id pub-id-type="pmid">15708536</pub-id>
</mixed-citation>
</ref>
<ref id="ref40"><mixed-citation publication-type="journal" id="cit40"><name><surname>Woelfle</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Seerden</surname>
<given-names>J.-P.</given-names>
</name>
; <name><surname>de Gooijer</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Pouwer</surname>
<given-names>K.</given-names>
</name>
; <name><surname>Olliaro</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
<article-title>Resolution of praziquantel</article-title>
. <source>PLoS Neglected Trop. Dis.</source>
<year>2011</year>
, <volume>5</volume>
, <fpage>e1260</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pntd.0001260</pub-id>
.</mixed-citation>
</ref>
<ref id="ref41"><mixed-citation publication-type="weblink" id="cit41">Org Prep Daily, <uri xlink:href="https://orgprepdaily.wordpress.com/">https://orgprepdaily.wordpress.com/</uri>
, accessed
Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref42"><mixed-citation publication-type="weblink" id="cit42">ChemSpider Synthetic Pages, <uri xlink:href="http://cssp.chemspider.com/">http://cssp.chemspider.com/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref43"><mixed-citation publication-type="journal" id="cit43"><name><surname>Reaves</surname>
<given-names>M. L.</given-names>
</name>
; <name><surname>Sinha</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Rabinowitz</surname>
<given-names>J. D.</given-names>
</name>
; <name><surname>Kruglyak</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Redfield</surname>
<given-names>R. J.</given-names>
</name>
<article-title>Absence
of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells</article-title>
. <source>Science</source>
<year>2012</year>
, <volume>337</volume>
, <fpage>470</fpage>
–<lpage>473</lpage>
<pub-id pub-id-type="doi">10.1126/science.1219861</pub-id>
.<pub-id pub-id-type="pmid">22773140</pub-id>
</mixed-citation>
</ref>
<ref id="ref44"><mixed-citation publication-type="weblink" id="cit44">The UsefulChem
Project, <uri xlink:href="http://usefulchem.wikispaces.com/">http://usefulchem.wikispaces.com/</uri>
, accessed Dec
8, 2015.</mixed-citation>
</ref>
<ref id="ref45"><mixed-citation publication-type="weblink" id="cit45">Indian OSDD Project, <uri xlink:href="http://www.osdd.net/">http://www.osdd.net/</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref46"><mixed-citation publication-type="journal" id="cit46"><name><surname>Anand</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Sankaran</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Mukherjee</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Yeturu</surname>
<given-names>K.</given-names>
</name>
; <name><surname>Laskowski</surname>
<given-names>R.</given-names>
</name>
; <name><surname>Bhardwaj</surname>
<given-names>A.</given-names>
</name>
; et al. <article-title>Structural
annotation of <italic>Mycobacterium tuberculosis</italic>
proteome</article-title>
. <source>PLoS One</source>
<year>2011</year>
, <volume>6</volume>
, <fpage>e27044</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pone.0027044</pub-id>
.<pub-id pub-id-type="pmid">22073123</pub-id>
</mixed-citation>
</ref>
<ref id="ref47"><mixed-citation publication-type="journal" id="cit47"><name><surname>Bhardwaj</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Scaria</surname>
<given-names>V.</given-names>
</name>
; <name><surname>Raghava</surname>
<given-names>G. P. S.</given-names>
</name>
; <name><surname>Lynn</surname>
<given-names>A. M.</given-names>
</name>
; <name><surname>Chandra</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Banerjee</surname>
<given-names>S.</given-names>
</name>
; et al. <article-title>Open source drug discovery – a new paradigm
of collaborative research in tuberculosis drug development</article-title>
. <source>Tuberculosis</source>
<year>2011</year>
, <volume>91</volume>
, <fpage>479</fpage>
–<lpage>486</lpage>
<pub-id pub-id-type="doi">10.1016/j.tube.2011.06.004</pub-id>
.<pub-id pub-id-type="pmid">21782516</pub-id>
</mixed-citation>
</ref>
<ref id="ref48"><mixed-citation publication-type="journal" id="cit48"><name><surname>Jefferson</surname>
<given-names>R.</given-names>
</name>
<article-title>Science as social enterprise: The CAMBIA BiOS Initiative</article-title>
. <source>Innovations: Technology, Governance, Globalization</source>
<year>2006</year>
, <volume>1</volume>
, <fpage>13</fpage>
–<lpage>44</lpage>
<pub-id pub-id-type="doi">10.1162/itgg.2006.1.4.13</pub-id>
.</mixed-citation>
</ref>
<ref id="ref49"><mixed-citation publication-type="weblink" id="cit49"><person-group><name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
</person-group>
<article-title>Open source
drug discovery for malaria</article-title>
. <source>Synaptic Leap</source>
<year>2011</year>
, <fpage>Node 343</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/343">http://www.thesynapticleap.org/node/343</uri>
.</mixed-citation>
</ref>
<ref id="ref50"><mixed-citation publication-type="journal" id="cit50"><name><surname>Carroll</surname>
<given-names>M. W.</given-names>
</name>
<article-title>Creative commons and the openness
of open access</article-title>
. <source>N. Engl. J. Med.</source>
<year>2013</year>
, <volume>368</volume>
, <fpage>789</fpage>
–<lpage>791</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMp1300040</pub-id>
.<pub-id pub-id-type="pmid">23445090</pub-id>
</mixed-citation>
</ref>
<ref id="ref51"><mixed-citation publication-type="journal" id="cit51"><name><surname>Robertson</surname>
<given-names>M. N.</given-names>
</name>
; <name><surname>Ylioja</surname>
<given-names>P. M.</given-names>
</name>
; <name><surname>Williamson</surname>
<given-names>A. E.</given-names>
</name>
; <name><surname>Woelfle</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Robins</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Badiola</surname>
<given-names>K. A.</given-names>
</name>
; et al. <article-title>Open
source drug discovery - a limited tutorial</article-title>
. <source>Parasitology</source>
<year>2014</year>
, <volume>141</volume>
, <fpage>148</fpage>
–<lpage>157</lpage>
<pub-id pub-id-type="doi">10.1017/S0031182013001121</pub-id>
.<pub-id pub-id-type="pmid">23985301</pub-id>
</mixed-citation>
</ref>
<ref id="ref52"><mixed-citation publication-type="journal" id="cit52"><name><surname>Badiola</surname>
<given-names>K. A.</given-names>
</name>
; <name><surname>Bird</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Brocklesby</surname>
<given-names>W. S.</given-names>
</name>
; <name><surname>Casson</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Chapman</surname>
<given-names>R. T.</given-names>
</name>
; <name><surname>Coles</surname>
<given-names>S. J.</given-names>
</name>
; et al. <article-title>Experiences
with a researcher-centric ELN</article-title>
. <source>Chem. Sci.</source>
<year>2015</year>
, <volume>6</volume>
, <fpage>1614</fpage>
–<lpage>1629</lpage>
<pub-id pub-id-type="doi">10.1039/C4SC02128B</pub-id>
.</mixed-citation>
</ref>
<ref id="ref53"><mixed-citation publication-type="journal" id="cit53"><name><surname>Gamo</surname>
<given-names>F.-J.</given-names>
</name>
; <name><surname>Sanz</surname>
<given-names>L. M.</given-names>
</name>
; <name><surname>Vidal</surname>
<given-names>J.</given-names>
</name>
; <name><surname>de Cozar</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Alvarez</surname>
<given-names>E.</given-names>
</name>
; <name><surname>Lavandera</surname>
<given-names>J.-L.</given-names>
</name>
; et al. <article-title>Thousands of chemical starting points for antimalarial lead identification</article-title>
. <source>Nature</source>
<year>2010</year>
, <volume>465</volume>
, <fpage>305</fpage>
–<lpage>310</lpage>
<pub-id pub-id-type="doi">10.1038/nature09107</pub-id>
.<pub-id pub-id-type="pmid">20485427</pub-id>
</mixed-citation>
</ref>
<ref id="ref54"><mixed-citation publication-type="journal" id="cit54"><name><surname>Guiguemde</surname>
<given-names>W. A.</given-names>
</name>
; <name><surname>Shelat</surname>
<given-names>A. A.</given-names>
</name>
; <name><surname>Bouck</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Duffy</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Crowther</surname>
<given-names>G. J.</given-names>
</name>
; <name><surname>Davis</surname>
<given-names>P. H.</given-names>
</name>
; et al. <article-title>Chemical genetics of <italic>Plasmodium falciparum</italic>
</article-title>
. <source>Nature</source>
<year>2010</year>
, <volume>465</volume>
, <fpage>311</fpage>
–<lpage>315</lpage>
<pub-id pub-id-type="doi">10.1038/nature09099</pub-id>
.<pub-id pub-id-type="pmid">20485428</pub-id>
</mixed-citation>
</ref>
<ref id="ref55"><mixed-citation publication-type="journal" id="cit55"><name><surname>Plouffe</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Brinker</surname>
<given-names>A.</given-names>
</name>
; <name><surname>McNamara</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Henson</surname>
<given-names>K.</given-names>
</name>
; <name><surname>Kato</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Kuhen</surname>
<given-names>K.</given-names>
</name>
; et al. <article-title><italic>In silico</italic>
activity profiling reveals
the mechanism of action of antimalarials discovered in a high-throughput
screen</article-title>
. <source>Proc. Natl. Acad. Sci. U. S. A.</source>
<year>2008</year>
, <volume>105</volume>
, <fpage>9059</fpage>
–<lpage>9064</lpage>
<pub-id pub-id-type="doi">10.1073/pnas.0802982105</pub-id>
.<pub-id pub-id-type="pmid">18579783</pub-id>
</mixed-citation>
</ref>
<ref id="ref56"><mixed-citation publication-type="weblink" id="cit56">ChEMBL Neglected Tropical Disease Archive, <uri xlink:href="http://www.ebi.ac.uk/chemblntd">http://www.ebi.ac.uk/chemblntd</uri>
.</mixed-citation>
</ref>
<ref id="ref57"><mixed-citation publication-type="journal" id="cit57"><name><surname>Calderón</surname>
<given-names>F.</given-names>
</name>
; <name><surname>Barros</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Bueno</surname>
<given-names>J. M.</given-names>
</name>
; <name><surname>Coterón</surname>
<given-names>J. M.</given-names>
</name>
; <name><surname>Fernández</surname>
<given-names>E.</given-names>
</name>
; <name><surname>Gamo</surname>
<given-names>F. J.</given-names>
</name>
; et al. <article-title>An
invitation to open innovation in malaria drug discovery: 47 quality
starting points from the TCAMS</article-title>
. <source>ACS Med. Chem.
Lett.</source>
<year>2011</year>
, <volume>2</volume>
, <fpage>741</fpage>
–<lpage>746</lpage>
<pub-id pub-id-type="doi">10.1021/ml200135p</pub-id>
.<pub-id pub-id-type="pmid">24900261</pub-id>
</mixed-citation>
</ref>
<ref id="ref58"><mixed-citation publication-type="journal" id="cit58"><name><surname>Rueda</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Castellote</surname>
<given-names>I.</given-names>
</name>
; <name><surname>Castro-Pichel</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Chaparro</surname>
<given-names>M. J.</given-names>
</name>
; <name><surname>de la Rosa</surname>
<given-names>J. C.</given-names>
</name>
; <name><surname>Garcia-Perez</surname>
<given-names>A.</given-names>
</name>
; et al. <article-title>Cyclopropyl carboxamides: a new oral antimalarial
series derived from the Tres Cantos anti-malarial set (TCAMS)</article-title>
. <source>ACS Med. Chem. Lett.</source>
<year>2011</year>
, <volume>2</volume>
, <fpage>840</fpage>
–<lpage>844</lpage>
<pub-id pub-id-type="doi">10.1021/ml2001517</pub-id>
.<pub-id pub-id-type="pmid">24900273</pub-id>
</mixed-citation>
</ref>
<ref id="ref59"><mixed-citation publication-type="journal" id="cit59"><name><surname>Sanz</surname>
<given-names>L. M.</given-names>
</name>
; <name><surname>Jiménez-Díaz</surname>
<given-names>M. B.</given-names>
</name>
; <name><surname>Crespo</surname>
<given-names>B.</given-names>
</name>
; <name><surname>De-Cozar</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Almela</surname>
<given-names>M. J.</given-names>
</name>
; <name><surname>Angulo-Barturen</surname>
<given-names>I.</given-names>
</name>
; et al. <article-title>Cyclopropyl carboxamides,
a chemically novel class of antimalarial agents identified in a phenotypic
screen</article-title>
. <source>Antimicrob. Agents Chemother.</source>
<year>2011</year>
, <volume>55</volume>
, <fpage>5740</fpage>
–<lpage>5745</lpage>
<pub-id pub-id-type="doi">10.1128/AAC.05188-11</pub-id>
.<pub-id pub-id-type="pmid">21968362</pub-id>
</mixed-citation>
</ref>
<ref id="ref60"><mixed-citation publication-type="journal" id="cit60"><name><surname>Calderón</surname>
<given-names>F.</given-names>
</name>
; <name><surname>Vidal-Mas</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Burrows</surname>
<given-names>J.</given-names>
</name>
; <name><surname>de la Rosa</surname>
<given-names>J. C.</given-names>
</name>
; <name><surname>Jiménez-Díaz</surname>
<given-names>M. B.</given-names>
</name>
; <name><surname>Mulet</surname>
<given-names>T.</given-names>
</name>
; et al. <article-title>A divergent SAR study allows optimization of a potent
5-HT<sub>2c</sub>
inhibitor to a promising antimalarial scaffold</article-title>
. <source>ACS Med. Chem. Lett.</source>
<year>2012</year>
, <volume>3</volume>
, <fpage>373</fpage>
–<lpage>377</lpage>
<pub-id pub-id-type="doi">10.1021/ml300008j</pub-id>
.<pub-id pub-id-type="pmid">24900481</pub-id>
</mixed-citation>
</ref>
<ref id="ref61"><mixed-citation publication-type="weblink" id="cit61"><person-group><name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
</person-group>
<article-title>Known near neighbors of initial Tres Cantos leads</article-title>
. <source>Synaptic Leap</source>
<year>2011</year>
, <fpage>Node 349</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/349">http://www.thesynapticleap.org/node/349</uri>
.</mixed-citation>
</ref>
<ref id="ref62"><mixed-citation publication-type="journal" id="cit62"><name><surname>Murugesan</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Mital</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Kaiser</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Shackleford</surname>
<given-names>D. M.</given-names>
</name>
; <name><surname>Morizzi</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Katneni</surname>
<given-names>K.</given-names>
</name>
; et al. <article-title>Discovery and structure-activity
relationships of pyrrolone antimalarials</article-title>
. <source>J.
Med. Chem.</source>
<year>2013</year>
, <volume>56</volume>
, <fpage>2975</fpage>
–<lpage>2990</lpage>
<pub-id pub-id-type="doi">10.1021/jm400009c</pub-id>
.<pub-id pub-id-type="pmid">23517371</pub-id>
</mixed-citation>
</ref>
<ref id="ref63"><mixed-citation publication-type="journal" id="cit63"><name><surname>Murugesan</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Kaiser</surname>
<given-names>M.</given-names>
</name>
; <name><surname>White</surname>
<given-names>K. L.</given-names>
</name>
; <name><surname>Norval</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Riley</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Wyatt</surname>
<given-names>P. G.</given-names>
</name>
; et al. <article-title>Structure-activity relationship studies of pyrrolone antimalarial
agents</article-title>
. <source>ChemMedChem</source>
<year>2013</year>
, <volume>8</volume>
, <fpage>1537</fpage>
–<lpage>1544</lpage>
<pub-id pub-id-type="doi">10.1002/cmdc.201300177</pub-id>
.<pub-id pub-id-type="pmid">23918316</pub-id>
</mixed-citation>
</ref>
<ref id="ref64"><mixed-citation publication-type="weblink" id="cit64">Relevant Open Source Malaria electronic laboratory notebooks, <uri xlink:href="http://malaria.ourexperiment.org/">http://malaria.ourexperiment.org/</uri>
, available offline at <uri xlink:href="http://hdl.handle.net/2123/14132">http://hdl.handle.net/2123/14132</uri>
.</mixed-citation>
</ref>
<ref id="ref65"><mixed-citation publication-type="journal" id="cit65"><name><surname>Gu</surname>
<given-names>X. P.</given-names>
</name>
; <name><surname>Nishida</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Ikeda</surname>
<given-names>I.</given-names>
</name>
; <name><surname>Okahara</surname>
<given-names>M.</given-names>
</name>
<article-title>2-(Chloromethyl)-3,5-dioxahex-1-ene.
An effective acetonylating reagent</article-title>
. <source>J. Org.
Chem.</source>
<year>1987</year>
, <volume>52</volume>
, <fpage>3192</fpage>
–<lpage>3196</lpage>
<pub-id pub-id-type="doi">10.1021/jo00391a003</pub-id>
.</mixed-citation>
</ref>
<ref id="ref66"><mixed-citation publication-type="journal" id="cit66"><name><surname>Chiu</surname>
<given-names>P.-K.</given-names>
</name>
; <name><surname>Sannes</surname>
<given-names>M. P.</given-names>
</name>
<article-title>The synthesis and chemistry of azolenines. Part 18.
Preparation of 3-ethoxycarbonyl-3<italic>H</italic>
-pyrroles <italic>via</italic>
the Paal-Knorr reaction, and sigmatropic rearrangements
involving competitive ester migrations to C-2, C-4 and N</article-title>
. <source>Tetrahedron</source>
<year>1990</year>
, <volume>46</volume>
, <fpage>3439</fpage>
–<lpage>3456</lpage>
<pub-id pub-id-type="doi">10.1016/S0040-4020(01)81514-3</pub-id>
.</mixed-citation>
</ref>
<ref id="ref67"><mixed-citation publication-type="weblink" id="cit67"><person-group><name><surname>Ylioja</surname>
<given-names>P. M.</given-names>
</name>
</person-group>
<article-title>Proposed resynthesis
strategy for TCMDC-123812 and TCMDC-123794</article-title>
. <source>Synaptic Leap</source>
<year>2011</year>
, <fpage>Node 344</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/344">http://www.thesynapticleap.org/node/344</uri>
.</mixed-citation>
</ref>
<ref id="ref68"><mixed-citation publication-type="weblink" id="cit68"><person-group person-group-type="allauthors"><name><surname>Avery</surname>
<given-names>V.</given-names>
</name>
; <name><surname>Baell</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Batra</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Burrows</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Bhattacharyya</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Calderon</surname>
<given-names>F.</given-names>
</name>
</person-group>
; et al. <source>Open Source Malaria deposition
1: screening of compounds synthesized and sourced by the OSDDMalaria
Consortium against Plasmodium falciparum and measurement of cytotoxicity</source>
. <year>2013</year>
, <uri xlink:href="https://www.ebi.ac.uk/chembl/malaria/doc/inspect/CHEMBL2113921">https://www.ebi.ac.uk/chembl/malaria/doc/inspect/CHEMBL2113921</uri>
. DOI: <pub-id pub-id-type="doi">10.6019/CHEMBL2113921</pub-id>
.</mixed-citation>
</ref>
<ref id="ref69"><mixed-citation publication-type="weblink" id="cit69">Open Source
Malaria Master Compound List, <uri xlink:href="http://tinyurl.com/OSM-Compounds">http://tinyurl.com/OSM-Compounds</uri>
, accessed Nov 23, 2015.</mixed-citation>
</ref>
<ref id="ref70"><mixed-citation publication-type="weblink" id="cit70">ChemInfo Malaria Hub, Open Source
Malaria Series 1, <uri xlink:href="http://malaria.cheminfo.org/Display_data.html?series=1">http://malaria.cheminfo.org/Display_data.html?series=1</uri>
, accessed Nov 23, 2015.</mixed-citation>
</ref>
<ref id="ref71"><mixed-citation publication-type="journal" id="cit71"><name><surname>Ertl</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Patiny</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Sander</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Rufener</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Zasso</surname>
<given-names>M.</given-names>
</name>
<article-title>Wikipedia chemical structure explorer:
substructure and similarity searching of molecules from Wikipedia</article-title>
. <source>J. Cheminf.</source>
<year>2015</year>
, <volume>7</volume>
, <fpage>10</fpage>
<pub-id pub-id-type="doi">10.1186/s13321-015-0061-y</pub-id>
.</mixed-citation>
</ref>
<ref id="ref72"><mixed-citation publication-type="weblink" id="cit72"><person-group person-group-type="allauthors"><name><surname>Swain</surname>
<given-names>C.</given-names>
</name>
</person-group>
<article-title>Importing Open Source Malaria project data</article-title>
, <uri xlink:href="http://macinchem.org/reviews/vortex/tut26/scripting_vortex26.php">http://macinchem.org/reviews/vortex/tut26/scripting_vortex26.php</uri>
, <bold>2015</bold>
, accessed Nov 23, 2015.</mixed-citation>
</ref>
<ref id="ref73"><mixed-citation publication-type="weblink" id="cit73"><person-group person-group-type="allauthors"><name><surname>Swain</surname>
<given-names>C.</given-names>
</name>
</person-group>
Accessing Open Source Malaria
data using an iPython notebook, <bold>2015</bold>
, <uri xlink:href="http://www.macinchem.org/reviews/osm/osmipython.php">http://www.macinchem.org/reviews/osm/osmipython.php</uri>
, accessed Nov 23, 2015.</mixed-citation>
</ref>
<ref id="ref74"><mixed-citation publication-type="journal" id="cit74"><name><surname>Avery</surname>
<given-names>V. M.</given-names>
</name>
; <name><surname>Bashyam</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Burrows</surname>
<given-names>J. N.</given-names>
</name>
; <name><surname>Duffy</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Papadatos</surname>
<given-names>G.</given-names>
</name>
; <name><surname>Puthukkuti</surname>
<given-names>S.</given-names>
</name>
; et al. <article-title>Screening and hit evaluation of a chemical library against blood-stage <italic>Plasmodium falciparum</italic>
</article-title>
. <source>Malar. J.</source>
<year>2014</year>
, <volume>13</volume>
, <fpage>190</fpage>
<pub-id pub-id-type="doi">10.1186/1475-2875-13-190</pub-id>
.<pub-id pub-id-type="pmid">24886460</pub-id>
</mixed-citation>
</ref>
<ref id="ref75"><mixed-citation publication-type="weblink" id="cit75">Open Source Malaria Google+ Community, <uri xlink:href="https://plus.google.com/114702323662314783325/posts/Pma1Ddk2XCy">https://plus.google.com/114702323662314783325/posts/Pma1Ddk2XCy</uri>
, <bold>2012</bold>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref76"><mixed-citation publication-type="journal" id="cit76"><name><surname>Bhandari</surname>
<given-names>S. V.</given-names>
</name>
; <name><surname>Bothara</surname>
<given-names>K. G.</given-names>
</name>
; <name><surname>Patil</surname>
<given-names>A. A.</given-names>
</name>
; <name><surname>Chitre</surname>
<given-names>T. S.</given-names>
</name>
; <name><surname>Sarkate</surname>
<given-names>A. P.</given-names>
</name>
; <name><surname>Gore</surname>
<given-names>S. T.</given-names>
</name>
; et al. <article-title>Design, synthesis and pharmacological screening of
novel antihypertensive agents using hybrid approach</article-title>
. <source>Bioorg. Med. Chem.</source>
<year>2009</year>
, <volume>17</volume>
, <fpage>390</fpage>
–<lpage>400</lpage>
<pub-id pub-id-type="doi">10.1016/j.bmc.2008.10.032</pub-id>
.<pub-id pub-id-type="pmid">19036593</pub-id>
</mixed-citation>
</ref>
<ref id="ref77"><mixed-citation publication-type="journal" id="cit77"><name><surname>Urbano</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Guerrero</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Velaparthi</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Crisp</surname>
<given-names>M.</given-names>
</name>
; <name><surname>Chase</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Hodder</surname>
<given-names>P.</given-names>
</name>
; et al. <article-title>Discovery,
synthesis and SAR analysis of novel selective small molecule S1P<sub>4</sub>
-R agonists based on a (2<italic>Z</italic>
,5<italic>Z</italic>
)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one
chemotype</article-title>
. <source>Bioorg. Med. Chem. Lett.</source>
<year>2011</year>
, <volume>21</volume>
, <fpage>6739</fpage>
–<lpage>6745</lpage>
<pub-id pub-id-type="doi">10.1016/j.bmcl.2011.09.049</pub-id>
.<pub-id pub-id-type="pmid">21982495</pub-id>
</mixed-citation>
</ref>
<ref id="ref78"><mixed-citation publication-type="journal" id="cit78"><name><surname>Singh</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Sharma</surname>
<given-names>P. K.</given-names>
</name>
; <name><surname>Mondal</surname>
<given-names>S. C.</given-names>
</name>
; <name><surname>Kumar</surname>
<given-names>N.</given-names>
</name>
<article-title>Difference in rate of reaction of some thiazolidinone derivatives
with synthesis and spectral characterization</article-title>
. <source>J. Adv. Sci. Res.</source>
<year>2011</year>
, <volume>2</volume>
, <fpage>58</fpage>
–<lpage>61</lpage>
.</mixed-citation>
</ref>
<ref id="ref79"><mixed-citation publication-type="journal" id="cit79"><name><surname>Hopkins</surname>
<given-names>A. L.</given-names>
</name>
; <name><surname>Keserü</surname>
<given-names>G. M.</given-names>
</name>
; <name><surname>Leeson</surname>
<given-names>P. D.</given-names>
</name>
; <name><surname>Rees</surname>
<given-names>D. C.</given-names>
</name>
; <name><surname>Reynolds</surname>
<given-names>C. H.</given-names>
</name>
<article-title>The role
of ligand efficiency metrics in drug discovery</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2014</year>
, <volume>13</volume>
, <fpage>105</fpage>
–<lpage>121</lpage>
<pub-id pub-id-type="doi">10.1038/nrd4163</pub-id>
.<pub-id pub-id-type="pmid">24481311</pub-id>
</mixed-citation>
</ref>
<ref id="ref80"><mixed-citation publication-type="weblink" id="cit80"><person-group><name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
</person-group>
<article-title>Biological results for first set of compounds</article-title>
. <source>Synaptic Leap</source>
<year>2012</year>
, <fpage>Node 367</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/367">http://www.thesynapticleap.org/node/367</uri>
.</mixed-citation>
</ref>
<ref id="ref81"><mixed-citation publication-type="journal" id="cit81"><name><surname>Baell</surname>
<given-names>J. B.</given-names>
</name>
; <name><surname>Holloway</surname>
<given-names>G. A.</given-names>
</name>
<article-title>New substructure filters for removal of Pan Assay Interference
Compounds (PAINS) from screening libraries and for their exclusion
in bioassays</article-title>
. <source>J. Med. Chem.</source>
<year>2010</year>
, <volume>53</volume>
, <fpage>2719</fpage>
–<lpage>2740</lpage>
<pub-id pub-id-type="doi">10.1021/jm901137j</pub-id>
.<pub-id pub-id-type="pmid">20131845</pub-id>
</mixed-citation>
</ref>
<ref id="ref82"><mixed-citation publication-type="weblink" id="cit82">KNIME: <uri xlink:href="https://www.knime.org/">https://www.knime.org/</uri>
, accessed Dec
8, 2015.</mixed-citation>
</ref>
<ref id="ref83"><mixed-citation publication-type="journal" id="cit83"><name><surname>Saubern</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Guha</surname>
<given-names>R.</given-names>
</name>
; <name><surname>Baell</surname>
<given-names>J. B.</given-names>
</name>
<article-title>KNIME workflow
to assess PAINS filters in SMARTS format. Comparison of RDKit and
Indigo cheminformatics libraries</article-title>
. <source>Mol. Inf.</source>
<year>2011</year>
, <volume>30</volume>
, <fpage>847</fpage>
–<lpage>850</lpage>
<pub-id pub-id-type="doi">10.1002/minf.201100076</pub-id>
.</mixed-citation>
</ref>
<ref id="ref84"><mixed-citation publication-type="journal" id="cit84"><name><surname>Baell</surname>
<given-names>J. B.</given-names>
</name>
<article-title>Observations on screening-based research
and some concerning trends in the literature</article-title>
. <source>Future Med. Chem.</source>
<year>2010</year>
, <volume>2</volume>
, <fpage>1529</fpage>
–<lpage>1546</lpage>
<pub-id pub-id-type="doi">10.4155/fmc.10.237</pub-id>
.<pub-id pub-id-type="pmid">21426147</pub-id>
</mixed-citation>
</ref>
<ref id="ref85"><mixed-citation publication-type="journal" id="cit85"><name><surname>Mok</surname>
<given-names>N. Y.</given-names>
</name>
; <name><surname>Maxe</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Brenk</surname>
<given-names>R.</given-names>
</name>
<article-title>Locating sweet spots for screening
hits and evaluating pan-assay interference filters from the performance
analysis of two lead-like libraries</article-title>
. <source>J. Chem.
Inf. Model.</source>
<year>2013</year>
, <volume>53</volume>
, <fpage>534</fpage>
–<lpage>544</lpage>
<pub-id pub-id-type="doi">10.1021/ci300382f</pub-id>
.<pub-id pub-id-type="pmid">23451880</pub-id>
</mixed-citation>
</ref>
<ref id="ref86"><mixed-citation publication-type="journal" id="cit86"><name><surname>Bruns</surname>
<given-names>R. F.</given-names>
</name>
; <name><surname>Watson</surname>
<given-names>I. A.</given-names>
</name>
<article-title>Rules for identifying
potentially reactive or promiscuous compounds</article-title>
. <source>J. Med. Chem.</source>
<year>2012</year>
, <volume>55</volume>
, <fpage>9763</fpage>
–<lpage>9772</lpage>
<pub-id pub-id-type="doi">10.1021/jm301008n</pub-id>
.<pub-id pub-id-type="pmid">23061697</pub-id>
</mixed-citation>
</ref>
<ref id="ref87"><mixed-citation publication-type="journal" id="cit87"><name><surname>Mendgen</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Steuer</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Klein</surname>
<given-names>C. D.</given-names>
</name>
<article-title>Privileged scaffolds or promiscuous
binders: a comparative study on rhodanines and related heterocycles
in medicinal chemistry</article-title>
. <source>J. Med. Chem.</source>
<year>2012</year>
, <volume>55</volume>
, <fpage>743</fpage>
–<lpage>753</lpage>
<pub-id pub-id-type="doi">10.1021/jm201243p</pub-id>
.<pub-id pub-id-type="pmid">22077389</pub-id>
</mixed-citation>
</ref>
<ref id="ref88"><mixed-citation publication-type="journal" id="cit88"><name><surname>Thorne</surname>
<given-names>N.</given-names>
</name>
; <name><surname>Auld</surname>
<given-names>D. S.</given-names>
</name>
; <name><surname>Inglese</surname>
<given-names>J.</given-names>
</name>
<article-title>Apparent activity
in high-throughput screening: origins of compound-dependent assay
interference</article-title>
. <source>Curr. Opin. Chem. Biol.</source>
<year>2010</year>
, <volume>14</volume>
, <fpage>315</fpage>
–<lpage>324</lpage>
<pub-id pub-id-type="doi">10.1016/j.cbpa.2010.03.020</pub-id>
.<pub-id pub-id-type="pmid">20417149</pub-id>
</mixed-citation>
</ref>
<ref id="ref89"><mixed-citation publication-type="weblink" id="cit89"><person-group person-group-type="allauthors"><name><surname>Lowe</surname>
<given-names>D.</given-names>
</name>
</person-group>
<article-title>Polluting the literature with PAINs</article-title>
. <source>In the
Pipeline</source>
, <year>2010</year>
, <uri xlink:href="http://blogs.sciencemag.org/pipeline/archives/2010/02/08/polluting_the_literature_with_pains">http://blogs.sciencemag.org/pipeline/archives/2010/02/08/polluting_the_literature_with_pains</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref90"><mixed-citation publication-type="weblink" id="cit90"><person-group person-group-type="allauthors"><name><surname>Lowe</surname>
<given-names>D.</given-names>
</name>
</person-group>
<article-title>PAINS go mainstream</article-title>
, <source>In the Pipeline</source>
, <year>2014</year>
, <uri xlink:href="http://blogs.sciencemag.org/pipeline/archives/2014/09/26/pains_go_mainstream">http://blogs.sciencemag.org/pipeline/archives/2014/09/26/pains_go_mainstream</uri>
, accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref91"><mixed-citation publication-type="journal" id="cit91"><name><surname>Singh</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Petter</surname>
<given-names>R. C.</given-names>
</name>
; <name><surname>Baillie</surname>
<given-names>T. A.</given-names>
</name>
; <name><surname>Whitty</surname>
<given-names>A.</given-names>
</name>
<article-title>The resurgence of covalent drugs</article-title>
. <source>Nat. Rev. Drug Discovery</source>
<year>2011</year>
, <volume>10</volume>
, <fpage>307</fpage>
–<lpage>317</lpage>
<pub-id pub-id-type="doi">10.1038/nrd3410</pub-id>
.<pub-id pub-id-type="pmid">21455239</pub-id>
</mixed-citation>
</ref>
<ref id="ref92"><mixed-citation publication-type="weblink" id="cit92">SmartsFilter, <uri xlink:href="http://pasilla.health.unm.edu/tomcat/biocomp/smartsfilter">http://pasilla.health.unm.edu/tomcat/biocomp/smartsfilter</uri>
,
accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref93"><mixed-citation publication-type="journal" id="cit93"><name><surname>Huth</surname>
<given-names>J. R.</given-names>
</name>
; <name><surname>Mendoza</surname>
<given-names>R.</given-names>
</name>
; <name><surname>Olejniczak</surname>
<given-names>E. T.</given-names>
</name>
; <name><surname>Johnson</surname>
<given-names>R. W.</given-names>
</name>
; <name><surname>Cothron</surname>
<given-names>D. A.</given-names>
</name>
; <name><surname>Liu</surname>
<given-names>Y.</given-names>
</name>
; et al. <article-title>ALARM
NMR: a rapid and robust experimental method to detect reactive false
positives in biochemical screens</article-title>
. <source>J. Am. Chem.
Soc.</source>
<year>2005</year>
, <volume>127</volume>
, <fpage>217</fpage>
–<lpage>224</lpage>
<pub-id pub-id-type="doi">10.1021/ja0455547</pub-id>
.<pub-id pub-id-type="pmid">15631471</pub-id>
</mixed-citation>
</ref>
<ref id="ref94"><mixed-citation publication-type="journal" id="cit94"><name><surname>Ekins</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Williams</surname>
<given-names>A. J.</given-names>
</name>
<article-title>When pharmaceutical
companies publish large datasets: an abundance of riches or fool’s
gold?</article-title>
. <source>Drug Discovery Today</source>
<year>2010</year>
, <volume>15</volume>
, <fpage>812</fpage>
–<lpage>815</lpage>
<pub-id pub-id-type="doi">10.1016/j.drudis.2010.08.010</pub-id>
.<pub-id pub-id-type="pmid">20732447</pub-id>
</mixed-citation>
</ref>
<ref id="ref95"><mixed-citation publication-type="weblink" id="cit95">OSM Consortium, <article-title>OSDD Malaria public consultation
1</article-title>
, <year>2012</year>
, <uri xlink:href="https://www.youtube.com/watch?v=ooM8kuo14Bg">https://www.youtube.com/watch?v=ooM8kuo14Bg</uri>
, accessed Dec 8, 2015, available for download from The University
of Sydney eScholarship Repository at <uri xlink:href="http://hdl.handle.net/2123/14110">http://hdl.handle.net/2123/14110</uri>
.</mixed-citation>
</ref>
<ref id="ref96"><mixed-citation publication-type="weblink" id="cit96"><person-group><name><surname>Todd</surname>
<given-names>M. H.</given-names>
</name>
</person-group>
<article-title>Desired compounds
consultation phase 2</article-title>
. <source>Synaptic Leap</source>
<year>2012</year>
, <fpage>Node 412</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/412">http://www.thesynapticleap.org/node/412</uri>
.</mixed-citation>
</ref>
<ref id="ref97"><mixed-citation publication-type="weblink" id="cit97"><person-group><name><surname>Ylioja</surname>
<given-names>P. M.</given-names>
</name>
</person-group>
<article-title>Consultation
outcome</article-title>
. <source>Synaptic Leap</source>
<year>2012</year>
, <fpage>Node 416</fpage>
. <uri xlink:href="http://www.thesynapticleap.org/node/416">http://www.thesynapticleap.org/node/416</uri>
.</mixed-citation>
</ref>
<ref id="ref98"><mixed-citation publication-type="journal" id="cit98"><name><surname>Boström</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Hogner</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Llinàs</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Wellner</surname>
<given-names>E.</given-names>
</name>
; <name><surname>Plowright</surname>
<given-names>A. T.</given-names>
</name>
<article-title>Oxadiazoles in medicinal chemistry</article-title>
. <source>J. Med. Chem.</source>
<year>2012</year>
, <volume>55</volume>
, <fpage>1817</fpage>
–<lpage>1830</lpage>
<pub-id pub-id-type="doi">10.1021/jm2013248</pub-id>
.<pub-id pub-id-type="pmid">22185670</pub-id>
</mixed-citation>
</ref>
<ref id="ref99"><mixed-citation publication-type="weblink" id="cit99">OSM electronic
laboratory notebook, pharmacophore modelling of OSM compounds: <uri xlink:href="http://malaria.ourexperiment.org/pharmacophore_modelling_">http://malaria.ourexperiment.org/pharmacophore_modelling_</uri>
,
accessed Dec 8, 2015.</mixed-citation>
</ref>
<ref id="ref100"><mixed-citation publication-type="journal" id="cit100"><name><surname>Olesen</surname>
<given-names>P.
H.</given-names>
</name>
<article-title>The use of bioisosteric
groups in lead optimization</article-title>
. <source>Curr. Opin. Drug
Discovery Dev.</source>
<year>2001</year>
, <volume>4</volume>
, <fpage>471</fpage>
–<lpage>478</lpage>
.</mixed-citation>
</ref>
<ref id="ref101"><mixed-citation publication-type="weblink" id="cit101">Open Source Malaria Wiki, GSK
Arylpyrrole Series: <uri xlink:href="http://openwetware.org/wiki/OpenSourceMalaria:GSK_Arylpyrrole_Series">http://openwetware.org/wiki/OpenSourceMalaria:GSK_Arylpyrrole_Series</uri>
, accessed Dec 8, 2015. (Snapshot available for download at The University
of Sydney eScholarship Repository at <uri xlink:href="http://hdl.handle.net/2123/15389">http://hdl.handle.net/2123/15389</uri>
).</mixed-citation>
</ref>
<ref id="ref102"><mixed-citation publication-type="journal" id="cit102"><name><surname>Berry</surname>
<given-names>L. M.</given-names>
</name>
; <name><surname>Wollenberg</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Zhao</surname>
<given-names>Z.</given-names>
</name>
<article-title>Esterase activities in the blood, liver and intestine of several
preclinical species and humans</article-title>
. <source>Drug Metab.
Lett.</source>
<year>2009</year>
, <volume>3</volume>
, <fpage>70</fpage>
–<lpage>77</lpage>
<pub-id pub-id-type="doi">10.2174/187231209788654081</pub-id>
.<pub-id pub-id-type="pmid">19601867</pub-id>
</mixed-citation>
</ref>
<ref id="ref103"><mixed-citation publication-type="journal" id="cit103"><name><surname>Danker</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Möller</surname>
<given-names>C.</given-names>
</name>
<article-title>Early identification of hERG liability in drug discovery
programs by automated patch clamp</article-title>
. <source>Front. Pharmacol.</source>
<year>2014</year>
, <pub-id pub-id-type="doi">10.3389/fphar.2014.00203</pub-id>
.</mixed-citation>
</ref>
<ref id="ref104"><mixed-citation publication-type="journal" id="cit104"><name><surname>Ruecker</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Mathias</surname>
<given-names>D. K.</given-names>
</name>
; <name><surname>Straschil</surname>
<given-names>U.</given-names>
</name>
; <name><surname>Churcher</surname>
<given-names>T. S.</given-names>
</name>
; <name><surname>Dinglasan</surname>
<given-names>R. R.</given-names>
</name>
; <name><surname>Leroy</surname>
<given-names>D.</given-names>
</name>
; et al. <article-title>A male and female gametocyte functional viability assay
to identify biologically relevant malaria transmission-blocking drugs</article-title>
. <source>Antimicrob. Agents Chemother.</source>
<year>2014</year>
, <volume>58</volume>
, <fpage>7292</fpage>
–<lpage>7302</lpage>
<pub-id pub-id-type="doi">10.1128/AAC.03666-14</pub-id>
.<pub-id pub-id-type="pmid">25267664</pub-id>
</mixed-citation>
</ref>
<ref id="ref105"><mixed-citation publication-type="journal" id="cit105"><name><surname>Meister</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Plouffe</surname>
<given-names>D. M.</given-names>
</name>
; <name><surname>Kuhen</surname>
<given-names>K. L.</given-names>
</name>
; <name><surname>Bonamy</surname>
<given-names>G. M. C.</given-names>
</name>
; <name><surname>Wu</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Barnes</surname>
<given-names>S. W.</given-names>
</name>
; et al. <article-title>Imaging
of <italic>Plasmodium</italic>
liver stages to drive next-generation
antimalarial drug discovery</article-title>
. <source>Science</source>
<year>2011</year>
, <volume>334</volume>
, <fpage>1372</fpage>
–<lpage>1377</lpage>
<pub-id pub-id-type="doi">10.1126/science.1211936</pub-id>
.<pub-id pub-id-type="pmid">22096101</pub-id>
</mixed-citation>
</ref>
<ref id="ref106"><mixed-citation publication-type="journal" id="cit106"><name><surname>Lee</surname>
<given-names>A. Y.</given-names>
</name>
; <name><surname>St.Onge</surname>
<given-names>R. P.</given-names>
</name>
; <name><surname>Proctor</surname>
<given-names>M. J.</given-names>
</name>
; <name><surname>Wallace</surname>
<given-names>I. M.</given-names>
</name>
; <name><surname>Nile</surname>
<given-names>A. H.</given-names>
</name>
; <name><surname>Spagnuolo</surname>
<given-names>P. A.</given-names>
</name>
; et al. <article-title>Mapping the cellular response to small molecules using chemogenomic
fitness signatures</article-title>
. <source>Science</source>
<year>2014</year>
, <volume>344</volume>
, <fpage>208</fpage>
–<lpage>211</lpage>
<pub-id pub-id-type="doi">10.1126/science.1250217</pub-id>
.<pub-id pub-id-type="pmid">24723613</pub-id>
</mixed-citation>
</ref>
<ref id="ref107"><mixed-citation publication-type="journal" id="cit107"><name><surname>Subramanian</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Tamayo</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Mootha</surname>
<given-names>V. K.</given-names>
</name>
; <name><surname>Mukherjee</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Ebert</surname>
<given-names>B. L.</given-names>
</name>
; <name><surname>Gillette</surname>
<given-names>M. A.</given-names>
</name>
; et al. <article-title>Gene
set enrichment analysis: a knowledge-based approach for interpreting
genome-wide expression profiles</article-title>
. <source>Proc. Natl.
Acad. Sci. U. S. A.</source>
<year>2005</year>
, <volume>102</volume>
, <fpage>15545</fpage>
–<lpage>15550</lpage>
<pub-id pub-id-type="doi">10.1073/pnas.0506580102</pub-id>
.<pub-id pub-id-type="pmid">16199517</pub-id>
</mixed-citation>
</ref>
<ref id="ref108"><mixed-citation publication-type="journal" id="cit108"><name><surname>Gupta</surname>
<given-names>A. P.</given-names>
</name>
; <name><surname>Chin</surname>
<given-names>W. H.</given-names>
</name>
; <name><surname>Zhu</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Mok</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Luah</surname>
<given-names>Y.-H.</given-names>
</name>
; <name><surname>Lim</surname>
<given-names>E.-H.</given-names>
</name>
; et al. <article-title>Dynamic epigenetic regulation
of gene expression during the life cycle of malaria parasite <italic>Plasmodium falciparum</italic>
</article-title>
. <source>PLoS Pathog.</source>
<year>2013</year>
, <volume>9</volume>
, <fpage>e1003170</fpage>
<pub-id pub-id-type="doi">10.1371/journal.ppat.1003170</pub-id>
.<pub-id pub-id-type="pmid">23468622</pub-id>
</mixed-citation>
</ref>
<ref id="ref109"><mixed-citation publication-type="journal" id="cit109"><name><surname>Jiang</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Mu</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Zhang</surname>
<given-names>Q.</given-names>
</name>
; <name><surname>Ni</surname>
<given-names>T.</given-names>
</name>
; <name><surname>Srinivasan</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Rayavara</surname>
<given-names>K.</given-names>
</name>
; et al. <article-title>PfSETvs methylation
of histone H3K36 represses virulence genes in <italic>Plasmodium falciparum</italic>
</article-title>
. <source>Nature</source>
<year>2013</year>
, <volume>499</volume>
, <fpage>223</fpage>
–<lpage>227</lpage>
<pub-id pub-id-type="doi">10.1038/nature12361</pub-id>
.<pub-id pub-id-type="pmid">23823717</pub-id>
</mixed-citation>
</ref>
<ref id="ref110"><mixed-citation publication-type="journal" id="cit110"><name><surname>Yu</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Lopez</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Anaflous</surname>
<given-names>A.</given-names>
</name>
; <name><surname>El Bali</surname>
<given-names>B.</given-names>
</name>
; <name><surname>Hamal</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Ericson</surname>
<given-names>E.</given-names>
</name>
; et al. <article-title>Chemical-genetic profiling of imidazo[1,2-<italic>a</italic>
]pyridines and – pyrimidines reveals target pathways conserved
between yeast and human cells</article-title>
. <source>PLoS Genet.</source>
<year>2008</year>
, <volume>4</volume>
, <fpage>e1000284</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pgen.1000284</pub-id>
.<pub-id pub-id-type="pmid">19043571</pub-id>
</mixed-citation>
</ref>
<ref id="ref111"><mixed-citation publication-type="journal" id="cit111"><name><surname>Sanz</surname>
<given-names>L. M.</given-names>
</name>
; <name><surname>Crespo</surname>
<given-names>B.</given-names>
</name>
; <name><surname>De-Cózar</surname>
<given-names>C.</given-names>
</name>
; <name><surname>Ding</surname>
<given-names>X. C.</given-names>
</name>
; <name><surname>Llergo</surname>
<given-names>J. L.</given-names>
</name>
; <name><surname>Burrows</surname>
<given-names>J. N.</given-names>
</name>
; et al. <article-title><italic>P. falciparum in vitro</italic>
killing rates allow to discriminate
between different antimalarial mode-of-action</article-title>
. <source>PLoS One</source>
<year>2012</year>
, <volume>7</volume>
, <fpage>e30949</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pone.0030949</pub-id>
.<pub-id pub-id-type="pmid">22383983</pub-id>
</mixed-citation>
</ref>
<ref id="ref112"><mixed-citation publication-type="journal" id="cit112"><name><surname>Prathipati</surname>
<given-names>P.</given-names>
</name>
; <name><surname>Ma</surname>
<given-names>N. L.</given-names>
</name>
; <name><surname>Manjunatha</surname>
<given-names>U. H.</given-names>
</name>
; <name><surname>Bender</surname>
<given-names>A.</given-names>
</name>
<article-title>Fishing the target of antitubercular compounds: <italic>in silico</italic>
target deconvolution model development and validation</article-title>
. <source>J. Proteome Res.</source>
<year>2009</year>
, <volume>8</volume>
, <fpage>2788</fpage>
–<lpage>2798</lpage>
<pub-id pub-id-type="doi">10.1021/pr8010843</pub-id>
.<pub-id pub-id-type="pmid">19301903</pub-id>
</mixed-citation>
</ref>
<ref id="ref113"><mixed-citation publication-type="journal" id="cit113"><name><surname>Koutsoukas</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Simms</surname>
<given-names>B.</given-names>
</name>
; <name><surname>Kirchmair</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Bond</surname>
<given-names>P. J.</given-names>
</name>
; <name><surname>Whitmore</surname>
<given-names>A. V.</given-names>
</name>
; <name><surname>Zimmer</surname>
<given-names>S.</given-names>
</name>
; et al. <article-title>From <italic>in silico</italic>
target prediction to
multi-target drug design: current databases, methods and applications</article-title>
. <source>J. Proteomics</source>
<year>2011</year>
, <volume>74</volume>
, <fpage>2554</fpage>
–<lpage>2574</lpage>
<pub-id pub-id-type="doi">10.1016/j.jprot.2011.05.011</pub-id>
.<pub-id pub-id-type="pmid">21621023</pub-id>
</mixed-citation>
</ref>
<ref id="ref114"><mixed-citation publication-type="journal" id="cit114"><name><surname>Martínez-Jiménez</surname>
<given-names>F.</given-names>
</name>
; <name><surname>Papadatos</surname>
<given-names>G.</given-names>
</name>
; <name><surname>Yang</surname>
<given-names>L.</given-names>
</name>
; <name><surname>Wallace</surname>
<given-names>I. M.</given-names>
</name>
; <name><surname>Kumar</surname>
<given-names>V.</given-names>
</name>
; <name><surname>Pieper</surname>
<given-names>U.</given-names>
</name>
; et al. <article-title>Target prediction for an open access set of compounds active against <italic>Mycobacterium tuberculosis</italic>
</article-title>
. <source>PLoS Comput.
Biol.</source>
<year>2013</year>
, <volume>9</volume>
, <fpage>e1003253</fpage>
<pub-id pub-id-type="doi">10.1371/journal.pcbi.1003253</pub-id>
.<pub-id pub-id-type="pmid">24098102</pub-id>
</mixed-citation>
</ref>
<ref id="ref115"><mixed-citation publication-type="journal" id="cit115"><name><surname>Baldwin</surname>
<given-names>J.</given-names>
</name>
; <name><surname>Farajallah</surname>
<given-names>A. M.</given-names>
</name>
; <name><surname>Malmquist</surname>
<given-names>N. A.</given-names>
</name>
; <name><surname>Rathod</surname>
<given-names>P. K.</given-names>
</name>
; <name><surname>Phillips</surname>
<given-names>M. A.</given-names>
</name>
<article-title>Malarial dihydroorotate
dehydrogenase: substrate and inhibitor specificity</article-title>
. <source>J. Biol. Chem.</source>
<year>2002</year>
, <volume>277</volume>
, <fpage>41827</fpage>
–<lpage>41834</lpage>
<pub-id pub-id-type="doi">10.1074/jbc.M206854200</pub-id>
.<pub-id pub-id-type="pmid">12189151</pub-id>
</mixed-citation>
</ref>
<ref id="ref116"><mixed-citation publication-type="journal" id="cit116"><name><surname>Spillman</surname>
<given-names>N. J.</given-names>
</name>
; <name><surname>Allen</surname>
<given-names>R. J. W.</given-names>
</name>
; <name><surname>McNamara</surname>
<given-names>C. W.</given-names>
</name>
; <name><surname>Yeung</surname>
<given-names>B. K. S.</given-names>
</name>
; <name><surname>Winzeler</surname>
<given-names>E. A.</given-names>
</name>
; <name><surname>Diagana</surname>
<given-names>T. T.</given-names>
</name>
; et al. <article-title>Na<sup>+</sup>
regulation
in the malaria parasite <italic>Plasmodium falciparum</italic>
involves
the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials</article-title>
. <source>Cell Host Microbe</source>
<year>2013</year>
, <volume>13</volume>
, <fpage>227</fpage>
–<lpage>237</lpage>
<pub-id pub-id-type="doi">10.1016/j.chom.2012.12.006</pub-id>
.<pub-id pub-id-type="pmid">23414762</pub-id>
</mixed-citation>
</ref>
<ref id="ref117"><mixed-citation publication-type="journal" id="cit117"><name><surname>White</surname>
<given-names>N. J.</given-names>
</name>
; <name><surname>Pukrittayakamee</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Phyo</surname>
<given-names>A. P.</given-names>
</name>
; <name><surname>Rueangweerayut</surname>
<given-names>R.</given-names>
</name>
; <name><surname>Nosten</surname>
<given-names>F.</given-names>
</name>
; <name><surname>Jittamala</surname>
<given-names>P.</given-names>
</name>
; et al. <article-title>Spiroindolone KAE609
for falciparum and vivax malaria</article-title>
. <source>N. Engl. J.
Med.</source>
<year>2014</year>
, <volume>371</volume>
, <fpage>403</fpage>
–<lpage>410</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMoa1315860</pub-id>
.<pub-id pub-id-type="pmid">25075833</pub-id>
</mixed-citation>
</ref>
<ref id="ref118"><mixed-citation publication-type="journal" id="cit118"><name><surname>Vaidya</surname>
<given-names>A. B.</given-names>
</name>
; <name><surname>Morrisey</surname>
<given-names>J. M.</given-names>
</name>
; <name><surname>Zhang</surname>
<given-names>Z.</given-names>
</name>
; <name><surname>Das</surname>
<given-names>S.</given-names>
</name>
; <name><surname>Daly</surname>
<given-names>T. M.</given-names>
</name>
; <name><surname>Otto</surname>
<given-names>T. D.</given-names>
</name>
; et al. <article-title>Pyrazoleamide compounds are potent antimalarials that
target Na<sup>+</sup>
homeostasis in intraerythrocytic <italic>Plasmodium
falciparum</italic>
</article-title>
. <source>Nat. Commun.</source>
<year>2014</year>
, <volume>5</volume>
, <fpage>5521</fpage>
<pub-id pub-id-type="doi">10.1038/ncomms6521</pub-id>
.<pub-id pub-id-type="pmid">25422853</pub-id>
</mixed-citation>
</ref>
<ref id="ref119"><mixed-citation publication-type="journal" id="cit119"><name><surname>Jiménez-Díaz</surname>
<given-names>M. B.</given-names>
</name>
; <name><surname>Ebert</surname>
<given-names>D.</given-names>
</name>
; <name><surname>Salinas</surname>
<given-names>Y.</given-names>
</name>
; <name><surname>Pradhan</surname>
<given-names>A.</given-names>
</name>
; <name><surname>Lehane</surname>
<given-names>A. M.</given-names>
</name>
; <name><surname>Myrand-Lapierre</surname>
<given-names>M.-E.</given-names>
</name>
; et al. <article-title>+)-SJ733, a clinical candidate for malaria that acts through ATP4
to induce rapid host-mediated clearance of <italic>Plasmodium</italic>
</article-title>
. <source>Proc. Natl. Acad. Sci. U. S. A.</source>
<year>2014</year>
, <volume>111</volume>
, <fpage>E5455</fpage>
–<lpage>E5462</lpage>
<pub-id pub-id-type="doi">10.1073/pnas.1414221111</pub-id>
.<pub-id pub-id-type="pmid">25453091</pub-id>
</mixed-citation>
</ref>
<ref id="ref120"><mixed-citation publication-type="journal" id="cit120"><name><surname>Flannery</surname>
<given-names>E. L.</given-names>
</name>
; <name><surname>McNamara</surname>
<given-names>C. W.</given-names>
</name>
; <name><surname>Kim</surname>
<given-names>S. W.</given-names>
</name>
; <name><surname>Kato</surname>
<given-names>T. S.</given-names>
</name>
; <name><surname>Li</surname>
<given-names>F.-W.</given-names>
</name>
; <name><surname>Teng</surname>
<given-names>C. H.</given-names>
</name>
; et al. <article-title>Mutations
in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance
to both aminopyrazole and spiroindolone antimalarials</article-title>
. <source>ACS Chem. Biol.</source>
<year>2015</year>
, <volume>10</volume>
, <fpage>413</fpage>
–<lpage>420</lpage>
<pub-id pub-id-type="doi">10.1021/cb500616x</pub-id>
.<pub-id pub-id-type="pmid">25322084</pub-id>
</mixed-citation>
</ref>
<ref id="ref121"><mixed-citation publication-type="journal" id="cit121"><name><surname>Lehane</surname>
<given-names>A. M.</given-names>
</name>
; <name><surname>Ridgway</surname>
<given-names>M. C.</given-names>
</name>
; <name><surname>Baker</surname>
<given-names>E.</given-names>
</name>
; <name><surname>Kirk</surname>
<given-names>K.</given-names>
</name>
<article-title>Diverse chemotypes
disrupt ion homeostasis in the malaria parasite</article-title>
. <source>Mol. Microbiol.</source>
<year>2014</year>
, <volume>94</volume>
, <fpage>327</fpage>
–<lpage>339</lpage>
<pub-id pub-id-type="doi">10.1111/mmi.12765</pub-id>
.<pub-id pub-id-type="pmid">25145582</pub-id>
</mixed-citation>
</ref>
<ref id="ref122"><mixed-citation publication-type="weblink" id="cit122">Open Source
Malaria Wiki, Triazolopyrazine (TP) Series: <uri xlink:href="http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series">http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series</uri>
, accessed Dec 8, 2015. (Snapshot available for download at The University
of Sydney eScholarship Repository at <uri xlink:href="http://hdl.handle.net/2123/15389">http://hdl.handle.net/2123/15389</uri>
).</mixed-citation>
</ref>
<ref id="ref123"><mixed-citation publication-type="journal" id="cit123"><name><surname>van Voorhis</surname>
<given-names>W. C.</given-names>
</name>
; <name><surname>Adams</surname>
<given-names>J. H.</given-names>
</name>
; <name><surname>Adelfio</surname>
<given-names>R.</given-names>
</name>
; <name><surname>Ahyong</surname>
<given-names>V.</given-names>
</name>
; <name><surname>Akabas</surname>
<given-names>M. H.</given-names>
</name>
; <name><surname>Alano</surname>
<given-names>P.</given-names>
</name>
; et al. <article-title>Open source
drug discovery with the malaria box compound collection for neglected
diseases and beyond</article-title>
. <source>PLoS Pathog.</source>
<year>2016</year>
, <volume>12</volume>
, <fpage>e1005763</fpage>
<pub-id pub-id-type="doi">10.1371/journal.ppat.1005763</pub-id>
.<pub-id pub-id-type="pmid">27467575</pub-id>
</mixed-citation>
</ref>
<ref id="ref124"><mixed-citation publication-type="weblink" id="cit124"><person-group person-group-type="allauthors"><name><surname>Lowe</surname>
<given-names>D.</given-names>
</name>
</person-group>
<article-title>Company time for your own ideas, or not?</article-title>
<source>In the Pipeline</source>
, <year>2016</year>
<uri xlink:href="http://blogs.sciencemag.org/pipeline/archives/2016/07/21/company-time-for-your-own-ideas-or-not">http://blogs.sciencemag.org/pipeline/archives/2016/07/21/company-time-for-your-own-ideas-or-not</uri>
, accessed July 25, 2016.</mixed-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>
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