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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans</title><author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name><affiliation><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff></affiliation></author><author><name sortKey="Menard, Didier" sort="Menard, Didier" uniqKey="Menard D" first="Didier" last="Menard">Didier Menard</name><affiliation><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff></affiliation></author><author><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name><affiliation><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff></affiliation></author><author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name><affiliation><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff></affiliation></author><author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name><affiliation><nlm:aff id="aff6">Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</nlm:aff></affiliation></author><author><name sortKey="Jimenez Diaz, Maria Belen" sort="Jimenez Diaz, Maria Belen" uniqKey="Jimenez Diaz M" first="María Belén" last="Jiménez-Díaz">María Belén Jiménez-Díaz</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Angulo Barturen, I Igo" sort="Angulo Barturen, I Igo" uniqKey="Angulo Barturen I" first="I Igo" last="Angulo-Barturen">I Igo Angulo-Barturen</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Martinez, Maria Santos" sort="Martinez, Maria Santos" uniqKey="Martinez M" first="María Santos" last="Martínez">María Santos Martínez</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Sanz, Laura M" sort="Sanz, Laura M" uniqKey="Sanz L" first="Laura M." last="Sanz">Laura M. Sanz</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</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="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</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="aff9">Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff10">University of Basel, Basel, Switzerland</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="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</nlm:aff></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name><affiliation><nlm:aff id="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</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="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J." last="Delves">Michael J. Delves</name><affiliation><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Sinden, Robert E" sort="Sinden, Robert E" uniqKey="Sinden R" first="Robert E." last="Sinden">Robert E. Sinden</name><affiliation><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25421480</idno><idno type="pmc">4335868</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335868</idno><idno type="RBID">PMC:4335868</idno><idno type="doi">10.1128/AAC.04419-14</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001740</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001740</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans</title><author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name><affiliation><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff></affiliation></author><author><name sortKey="Menard, Didier" sort="Menard, Didier" uniqKey="Menard D" first="Didier" last="Menard">Didier Menard</name><affiliation><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff></affiliation></author><author><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name><affiliation><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff></affiliation></author><author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name><affiliation><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff></affiliation></author><author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name><affiliation><nlm:aff id="aff6">Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</nlm:aff></affiliation></author><author><name sortKey="Jimenez Diaz, Maria Belen" sort="Jimenez Diaz, Maria Belen" uniqKey="Jimenez Diaz M" first="María Belén" last="Jiménez-Díaz">María Belén Jiménez-Díaz</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Angulo Barturen, I Igo" sort="Angulo Barturen, I Igo" uniqKey="Angulo Barturen I" first="I Igo" last="Angulo-Barturen">I Igo Angulo-Barturen</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Martinez, Maria Santos" sort="Martinez, Maria Santos" uniqKey="Martinez M" first="María Santos" last="Martínez">María Santos Martínez</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Sanz, Laura M" sort="Sanz, Laura M" uniqKey="Sanz L" first="Laura M." last="Sanz">Laura M. Sanz</name><affiliation><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</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="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</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="aff9">Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland</nlm:aff></affiliation><affiliation><nlm:aff id="aff10">University of Basel, Basel, Switzerland</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="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</nlm:aff></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name><affiliation><nlm:aff id="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</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="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J." last="Delves">Michael J. Delves</name><affiliation><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Sinden, Robert E" sort="Sinden, Robert E" uniqKey="Sinden R" first="Robert E." last="Sinden">Robert E. Sinden</name><affiliation><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><affiliation><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff></affiliation></author></analytic><series><title level="j">Antimicrobial Agents and Chemotherapy</title><idno type="ISSN">0066-4804</idno><idno type="eISSN">1098-6596</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising <italic>in vitro</italic> parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for <italic>in vitro</italic> and <italic>in vivo</italic> efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent <italic>in vitro</italic> activity, with 50% inhibitory concentrations (IC<sub>50</sub>s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory <named-content content-type="genus-species">Plasmodium falciparum</named-content> isolates. Activities against <italic>ex vivo</italic> clinical isolates of both <named-content content-type="genus-species">P. falciparum</named-content> and <named-content content-type="genus-species">Plasmodium vivax</named-content> were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in <italic>in vivo</italic> mouse models of <named-content content-type="genus-species">Plasmodium berghei</named-content> and <named-content content-type="genus-species">P. falciparum</named-content> infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Antimicrob Agents Chemother</journal-id><journal-id journal-id-type="iso-abbrev">Antimicrob. Agents Chemother</journal-id><journal-id journal-id-type="hwp">aac</journal-id><journal-id journal-id-type="pmc">aac</journal-id><journal-id journal-id-type="publisher-id">AAC</journal-id><journal-title-group><journal-title>Antimicrobial Agents and Chemotherapy</journal-title></journal-title-group><issn pub-type="ppub">0066-4804</issn><issn pub-type="epub">1098-6596</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25421480</article-id><article-id pub-id-type="pmc">4335868</article-id><article-id pub-id-type="publisher-id">04419-14</article-id><article-id pub-id-type="doi">10.1128/AAC.04419-14</article-id><article-categories><subj-group subj-group-type="heading"><subject>Experimental Therapeutics</subject></subj-group></article-categories><title-group><article-title>Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans</article-title><alt-title alt-title-type="running-head">Antimalarial Histone Methyltransferase Inhibitors</alt-title><alt-title alt-title-type="short-authors">Malmquist et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-2822-8245</contrib-id><name><surname>Malmquist</surname><given-names>Nicholas A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sundriyal</surname><given-names>Sandeep</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Caron</surname><given-names>Joachim</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Patty</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Witkowski</surname><given-names>Benoit</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Menard</surname><given-names>Didier</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Suwanarusk</surname><given-names>Rossarin</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Renia</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nosten</surname><given-names>Francois</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jiménez-Díaz</surname><given-names>María Belén</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Angulo-Barturen</surname><given-names>Iñigo</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martínez</surname><given-names>María Santos</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ferrer</surname><given-names>Santiago</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sanz</surname><given-names>Laura M.</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gamo</surname><given-names>Francisco-Javier</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wittlin</surname><given-names>Sergio</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref><xref ref-type="aff" rid="aff10"><sup>j</sup></xref></contrib><contrib contrib-type="author"><name><surname>Duffy</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="aff11"><sup>k</sup></xref></contrib><contrib contrib-type="author"><name><surname>Avery</surname><given-names>Vicky M.</given-names></name><xref ref-type="aff" rid="aff11"><sup>k</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ruecker</surname><given-names>Andrea</given-names></name><xref ref-type="aff" rid="aff12"><sup>l</sup></xref></contrib><contrib contrib-type="author"><name><surname>Delves</surname><given-names>Michael J.</given-names></name><xref ref-type="aff" rid="aff12"><sup>l</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sinden</surname><given-names>Robert E.</given-names></name><xref ref-type="aff" rid="aff12"><sup>l</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fuchter</surname><given-names>Matthew J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Scherf</surname><given-names>Artur</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><aff id="aff1"><label>a</label>Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</aff><aff id="aff2"><label>b</label>Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</aff><aff id="aff3"><label>c</label>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</aff><aff id="aff4"><label>d</label>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</aff><aff id="aff5"><label>e</label>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</aff><aff id="aff6"><label>f</label>Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</aff><aff id="aff7"><label>g</label>Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</aff><aff id="aff8"><label>h</label>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</aff><aff id="aff9"><label>i</label>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland</aff><aff id="aff10"><label>j</label>University of Basel, Basel, Switzerland</aff><aff id="aff11"><label>k</label>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</aff><aff id="aff12"><label>l</label>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</aff></contrib-group><author-notes><corresp id="cor1">Address correspondence to Nicholas A. Malmquist, <email>nicholas.malmquist@pasteur.fr</email>, or Artur Scherf, <email>artur.scherf@pasteur.fr</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Malmquist NA, Sundriyal S, Caron J, Chen P, Witkowski B, Menard D, Suwanarusk R, Renia L, Nosten F, Jiménez-Díaz MB, Angulo-Barturen I, Martínez MS, Ferrer S, Sanz LM, Gamo F-J, Wittlin S, Duffy S, Avery VM, Ruecker A, Delves MJ, Sinden RE, Fuchter MJ, Scherf A. 2015. Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans. Antimicrob Agents Chemother 59:950–959. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/AAC.04419-14">10.1128/AAC.04419-14</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>24</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>27</day><month>1</month><year>2015</year></pub-date><pub-date pub-type="ppub"><month>2</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>27</day><month>1</month><year>2015</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>59</volume><issue>2</issue><fpage>950</fpage><lpage>959</lpage><history><date date-type="received"><day>1</day><month>10</month><year>2014</year></date><date date-type="rev-request"><day>12</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>20</day><month>11</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder><license license-type="open-access"><license-p>The authors have paid a fee to allow immediate free access to this article.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zac00215000950.pdf"></self-uri><abstract><p>Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising <italic>in vitro</italic> parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for <italic>in vitro</italic> and <italic>in vivo</italic> efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent <italic>in vitro</italic> activity, with 50% inhibitory concentrations (IC<sub>50</sub>s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory <named-content content-type="genus-species">Plasmodium falciparum</named-content> isolates. Activities against <italic>ex vivo</italic> clinical isolates of both <named-content content-type="genus-species">P. falciparum</named-content> and <named-content content-type="genus-species">Plasmodium vivax</named-content> were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in <italic>in vivo</italic> mouse models of <named-content content-type="genus-species">Plasmodium berghei</named-content> and <named-content content-type="genus-species">P. falciparum</named-content> infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.</p></abstract><counts><fig-count count="6"></fig-count><table-count count="3"></table-count><equation-count count="0"></equation-count><ref-count count="39"></ref-count><page-count count="10"></page-count><word-count count="8773"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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