Antimalarial, Antitrypanosomal, and Antileishmanial Activities and Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the Linker#
Identifieur interne : 000B50 ( Istex/Corpus ); précédent : 000B49; suivant : 000B51Antimalarial, Antitrypanosomal, and Antileishmanial Activities and Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the Linker#
Auteurs : Sophie Girault ; Philippe Grellier ; Amaya Berecibar ; Louis Maes ; Elisabeth Mouray ; Pascal Lemière ; Marie-Ange Debreu ; Elisabeth Davioud-Charvet ; Christian SergheraertSource :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2000.
Abstract
Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 μM upon MRC-5 cells, one displayed IC50 values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 μM.
Url:
DOI: 10.1021/jm990946n
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ISTEX:D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0Le document en format XML
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EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Debreu, Marie Ange" sort="Debreu, Marie Ange" uniqKey="Debreu M" first="Marie-Ange" last="Debreu">Marie-Ange Debreu</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Sergheraert, Christian" sort="Sergheraert, Christian" uniqKey="Sergheraert C" first="Christian" last="Sergheraert">Christian Sergheraert</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation><affiliation><mods:affiliation> Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 8712 33. E-mail: christian.sergheraert@pasteur-lille.fr.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0</idno><date when="2000" year="2000">2000</date><idno type="doi">10.1021/jm990946n</idno><idno type="url">https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000B50</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000B50</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Antimalarial, Antitrypanosomal, and Antileishmanial Activities and
Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the
Linker<ref type="bib" target="#jm990946nAF10"><hi rend="superscript">#</hi></ref></title><author><name sortKey="Girault, Sophie" sort="Girault, Sophie" uniqKey="Girault S" first="Sophie" last="Girault">Sophie Girault</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Grellier, Philippe" sort="Grellier, Philippe" uniqKey="Grellier P" first="Philippe" last="Grellier">Philippe Grellier</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> CNRS - EP1790.</mods:affiliation></affiliation></author><author><name sortKey="Berecibar, Amaya" sort="Berecibar, Amaya" uniqKey="Berecibar A" first="Amaya" last="Berecibar">Amaya Berecibar</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Maes, Louis" sort="Maes, Louis" uniqKey="Maes L" first="Louis" last="Maes">Louis Maes</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Tibotec.</mods:affiliation></affiliation></author><author><name sortKey="Mouray, Elisabeth" sort="Mouray, Elisabeth" uniqKey="Mouray E" first="Elisabeth" last="Mouray">Elisabeth Mouray</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> CNRS - EP1790.</mods:affiliation></affiliation></author><author><name sortKey="Lemiere, Pascal" sort="Lemiere, Pascal" uniqKey="Lemiere P" first="Pascal" last="Lemière">Pascal Lemière</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Debreu, Marie Ange" sort="Debreu, Marie Ange" uniqKey="Debreu M" first="Marie-Ange" last="Debreu">Marie-Ange Debreu</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation></author><author><name sortKey="Sergheraert, Christian" sort="Sergheraert, Christian" uniqKey="Sergheraert C" first="Christian" last="Sergheraert">Christian Sergheraert</name><affiliation><mods:affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie et Institut Pasteur de Lille.</mods:affiliation></affiliation><affiliation><mods:affiliation> Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 8712 33. E-mail: christian.sergheraert@pasteur-lille.fr.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2000-06-17">2000</date><date when="2000-07-13">2000</date><biblScope unit="vol">43</biblScope><biblScope unit="issue">14</biblScope><biblScope unit="page" from="2646">2646</biblScope><biblScope unit="page" to="2654">2654</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 μM upon MRC-5 cells, one displayed IC50 values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 μM.</div></front></TEI><istex><corpusName>acs</corpusName><keywords><teeft><json:string>cruzi</json:string><json:string>falciparum</json:string><json:string>cytotoxicity</json:string><json:string>brucei</json:string><json:string>bisacridines</json:string><json:string>antimalarial</json:string><json:string>linker</json:string><json:string>parasite</json:string><json:string>macrophage</json:string><json:string>infantum</json:string><json:string>chem</json:string><json:string>side chain</json:string><json:string>bisquinolines</json:string><json:string>bisacridine</json:string><json:string>derivative</json:string><json:string>plasmodium</json:string><json:string>bisacridine derivative</json:string><json:string>acridine</json:string><json:string>bisintercalation</json:string><json:string>trypanosoma</json:string><json:string>chloroquine</json:string><json:string>vacuole</json:string><json:string>medicinal chemistry</json:string><json:string>peritoneal</json:string><json:string>cytotoxic</json:string><json:string>girault</json:string><json:string>erythrocyte</json:string><json:string>plasmodium falciparum</json:string><json:string>piperazine</json:string><json:string>food vacuole</json:string><json:string>cytotoxic effect</json:string><json:string>amino</json:string><json:string>antimalarial activity</json:string><json:string>trypanosoma cruzi</json:string><json:string>parasite nucleus</json:string><json:string>aromatic ring</json:string><json:string>medicinal</json:string><json:string>analogue</json:string><json:string>datum</json:string><json:string>compound</json:string><json:string>efflux mechanism</json:string><json:string>minimal distance</json:string><json:string>falciparum strain</json:string><json:string>high level</json:string><json:string>piperazine derivative</json:string><json:string>further wash</json:string><json:string>mouse primary peritoneal macrophage</json:string><json:string>cruzi epimastigotes</json:string><json:string>polar group</json:string><json:string>trypanothione reductase</json:string><json:string>percent reduction</json:string><json:string>acridine ring</json:string><json:string>similar efficiency</json:string><json:string>other compound</json:string><json:string>trypanosoma brucei</json:string><json:string>confocal microscopy</json:string><json:string>further development</json:string><json:string>spermidine linker</json:string><json:string>high fluorescence</json:string><json:string>propidium iodide</json:string><json:string>single carbon</json:string><json:string>murine muscle cell</json:string><json:string>bifunctional interaction</json:string><json:string>experimental section</json:string><json:string>terminal nitrogen atom</json:string><json:string>antiparasitic activity</json:string><json:string>different degree</json:string><json:string>antitrypanosomal activity</json:string><json:string>potential antitumor agent</json:string><json:string>deprotected analogue</json:string><json:string>succinic anhydride</json:string><json:string>institut pasteur</json:string><json:string>carboxylic acid</json:string><json:string>leishmania infantum</json:string><json:string>display high level</json:string><json:string>base pair</json:string><json:string>murine macrophage</json:string><json:string>trypomastigote form</json:string><json:string>amastigote form</json:string><json:string>total parasite load</json:string><json:string>untreated control culture</json:string><json:string>primary mouse peritoneal macrophage</json:string><json:string>culture slide</json:string><json:string>drug activity</json:string><json:string>strain fcb1r</json:string><json:string>culture medium</json:string><json:string>molecular probe</json:string><json:string>acridine moiety</json:string><json:string>fetal calf serum</json:string><json:string>continuous culture</json:string><json:string>semiautomated microdilution technique</json:string><json:string>chloroquine uptake</json:string><json:string>bifunctional intercalators</json:string><json:string>antitumor activity</json:string><json:string>falciparum fcb1r strain</json:string></teeft></keywords><author><json:item><name>GIRAULT Sophie</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Institut de Biologie et Institut Pasteur de Lille.</json:string></affiliations></json:item><json:item><name>GRELLIER Philippe</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>CNRS - EP1790.</json:string></affiliations></json:item><json:item><name>BERECIBAR Amaya</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string></affiliations></json:item><json:item><name>MAES Louis</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Tibotec.</json:string></affiliations></json:item><json:item><name>MOURAY Elisabeth</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>CNRS - EP1790.</json:string></affiliations></json:item><json:item><name>LEMIèRE Pascal</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Institut de Biologie et Institut Pasteur de Lille.</json:string></affiliations></json:item><json:item><name>DEBREU Marie-Ange</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Institut de Biologie et Institut Pasteur de Lille.</json:string></affiliations></json:item><json:item><name>DAVIOUD-CHARVET Elisabeth</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Institut de Biologie et Institut Pasteur de Lille.</json:string></affiliations></json:item><json:item><name>SERGHERAERT Christian</name><affiliations><json:string>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</json:string><json:string>Institut de Biologie et Institut Pasteur de Lille.</json:string><json:string>Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 8712 33. E-mail: christian.sergheraert@pasteur-lille.fr.</json:string></affiliations></json:item></author><arkIstex>ark:/67375/TPS-GDW43MKP-L</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 μM upon MRC-5 cells, one displayed IC50 values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 μM.</abstract><qualityIndicators><score>8.428</score><pdfWordCount>5898</pdfWordCount><pdfCharCount>38984</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><pdfWordsPerPage>655</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>119</abstractWordCount><abstractCharCount>821</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Antimalarial, Antitrypanosomal, and Antileishmanial Activities and Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the Linker#</title><genre><json:string>research-article</json:string></genre><host><title>Journal of Medicinal Chemistry</title><language><json:string>unknown</json:string></language><issn><json:string>0022-2623</json:string></issn><eissn><json:string>1520-4804</json:string></eissn><volume>43</volume><issue>14</issue><pages><first>2646</first><last>2654</last></pages><genre><json:string>journal</json:string></genre></host><ark><json:string>ark:/67375/TPS-GDW43MKP-L</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - chemistry, medicinal</json:string></wos><scienceMetrix><json:string>1 - natural sciences</json:string><json:string>2 - chemistry</json:string><json:string>3 - medicinal & biomolecular chemistry</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Drug Discovery</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Medicine</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string></inist></categories><publicationDate>2000</publicationDate><copyrightDate>2000</copyrightDate><doi><json:string>10.1021/jm990946n</json:string></doi><id>D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/bundle.zip</uri></json:item><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/fulltext.txt</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Antimalarial, Antitrypanosomal, and Antileishmanial Activities and
Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the
Linker#</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>American Chemical Society</publisher><availability><licence>Copyright © 2000 American Chemical Society</licence><p>American Chemical Society</p></availability><date type="e-published" when="2000-06-17">2000</date><date when="2000-07-13">2000</date><date type="Copyright" when="2000">2000</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main" xml:lang="en">Antimalarial, Antitrypanosomal, and Antileishmanial Activities and
Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the
Linker<ref type="bib" target="#jm990946nAF10"><hi rend="superscript">#</hi></ref></title><author xml:id="author-0000"><persName><surname>Girault</surname><forename type="first">Sophie</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>†</ref><p>
Institut de Biologie et Institut Pasteur de Lille.</p></note></author><author xml:id="author-0001"><persName><surname>Grellier</surname><forename type="first">Philippe</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>‡</ref><p>
CNRS - EP1790.</p></note></author><author xml:id="author-0002"><persName><surname>Berecibar</surname><forename type="first">Amaya</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation></author><author xml:id="author-0003"><persName><surname>Maes</surname><forename type="first">Louis</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>§</ref><p>
Tibotec.</p></note></author><author xml:id="author-0004"><persName><surname>Mouray</surname><forename type="first">Elisabeth</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>‡</ref><p>
CNRS - EP1790.</p></note></author><author xml:id="author-0005"><persName><surname>Lemière</surname><forename type="first">Pascal</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>†</ref><p>
Institut de Biologie et Institut Pasteur de Lille.</p></note></author><author xml:id="author-0006"><persName><surname>Debreu</surname><forename type="first">Marie-Ange</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>†</ref><p>
Institut de Biologie et Institut Pasteur de Lille.</p></note></author><author xml:id="author-0007"><persName><surname>Davioud-Charvet</surname><forename type="first">Elisabeth</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>†</ref><p>
Institut de Biologie et Institut Pasteur de Lille.</p></note></author><author xml:id="author-0008" role="corresp"><persName><surname>Sergheraert</surname><forename type="first">Christian</forename></persName><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</affiliation><note place="foot"><ref>†</ref><p>
Institut de Biologie et Institut Pasteur de Lille.</p></note><affiliation role="corresp"> Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 87 12 33. E-mail: christian.sergheraert@pasteur-lille.fr.</affiliation></author><idno type="istex">D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0</idno><idno type="ark">ark:/67375/TPS-GDW43MKP-L</idno><idno type="DOI">10.1021/jm990946n</idno></analytic><monogr><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="acspubs">jm</idno><idno type="coden">jmcmar</idno><idno type="pISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2000-06-17">2000</date><date when="2000-07-13">2000</date><biblScope unit="vol">43</biblScope><biblScope unit="issue">14</biblScope><biblScope unit="page" from="2646">2646</biblScope><biblScope unit="page" to="2654">2654</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract><graphic url="jm990946nn00001.eps"></graphic><p>Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by
alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and
tested for their in vitro activity upon the erythrocytic stage of<hi rend="italic"> Plasmodium falciparum,</hi>
trypomastigote stage of<hi rend="italic"> Trypanosoma brucei, </hi>and amastigote stage of <hi rend="italic">Trypanosoma cruzi </hi>and
<hi rend="italic">Leishmania infantum</hi> as well as for their cytotoxic effects upon MRC-5 cells. Results clearly
showed the importance of the nature of the linker and of its side chain for antiparasitic activity,
cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at
25 μM upon MRC-5 cells, one displayed IC<hi rend="subscript">50</hi> values ranging from 8 to 18 nM against different
<hi rend="italic">P. falciparum</hi> strains while three others totally inhibited <hi rend="italic">T. </hi><hi rend="italic">brucei</hi> at 1.56 μM.
</p></abstract><textClass ana="subject"><keywords scheme="document-type-name"><term>Article</term></keywords></textClass><langUsage><language ident="zxx"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI></fulltext><metadata><istex:metadataXml wicri:clean="corpus acs not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:document><article article-type="research-article" specific-use="acs2jats-1.1.23" dtd-version="1.1d1"><front><journal-meta><journal-id journal-id-type="acspubs">jm</journal-id><journal-id journal-id-type="coden">jmcmar</journal-id><journal-title-group><journal-title>Journal of Medicinal Chemistry</journal-title><abbrev-journal-title>J. Med. Chem.</abbrev-journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn><publisher><publisher-name>American Chemical Society</publisher-name></publisher><self-uri>pubs.acs.org/jmc</self-uri></journal-meta><article-meta><article-id pub-id-type="doi">10.1021/jm990946n</article-id><article-categories><subj-group subj-group-type="document-type-name"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Antimalarial, Antitrypanosomal, and Antileishmanial Activities and
Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the
Linker<xref rid="jm990946nAF10"><sup>#</sup></xref></article-title></title-group><contrib-group><contrib contrib-type="author"><name name-style="western"><surname>Girault</surname><given-names>Sophie</given-names></name><xref rid="jm990946nAF2"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Grellier</surname><given-names>Philippe</given-names></name><xref rid="jm990946nAF3"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Berecibar</surname><given-names>Amaya</given-names></name></contrib><contrib contrib-type="author"><name name-style="western"><surname>Maes</surname><given-names>Louis</given-names></name><xref rid="jm990946nAF4"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Mouray</surname><given-names>Elisabeth</given-names></name><xref rid="jm990946nAF3"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Lemière</surname><given-names>Pascal</given-names></name><xref rid="jm990946nAF2"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Debreu</surname><given-names>Marie-Ange</given-names></name><xref rid="jm990946nAF2"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Davioud-Charvet</surname><given-names>Elisabeth</given-names></name><xref rid="jm990946nAF2"><sup>†</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>Sergheraert</surname><given-names>Christian</given-names></name><xref rid="jm990946nAF1">*</xref><xref rid="jm990946nAF2"><sup>†</sup></xref></contrib><aff>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,
59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,
61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium
</aff></contrib-group><author-notes><fn id="jm990946nAF2"><label>†</label><p>
Institut de Biologie et Institut Pasteur de Lille.</p></fn><fn id="jm990946nAF3"><label>‡</label><p>
CNRS - EP1790.</p></fn><fn id="jm990946nAF4"><label>§</label><p>
Tibotec.</p></fn><corresp id="jm990946nAF1">
Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 87
12 33. E-mail: christian.sergheraert@pasteur-lille.fr.</corresp></author-notes><pub-date pub-type="epub"><day>17</day><month>06</month><year>2000</year></pub-date><pub-date pub-type="ppub"><day>13</day><month>07</month><year>2000</year></pub-date><volume>43</volume><issue>14</issue><fpage>2646</fpage><lpage>2654</lpage><supplementary-material xlink:href="jm990946n_s.pdf" orientation="portrait" position="float"></supplementary-material><history><date date-type="received"><day>03</day><month>11</month><year>1999</year></date><date date-type="asap"><day>17</day><month>06</month><year>2000</year></date><date date-type="issue-pub"><day>13</day><month>07</month><year>2000</year></date></history><permissions><copyright-statement>Copyright © 2000 American Chemical Society</copyright-statement><copyright-year>2000</copyright-year><copyright-holder>American Chemical Society</copyright-holder></permissions><abstract><graphic content-type="abstract-graphic" xlink:href="jm990946nn00001.eps" orientation="portrait" position="float"></graphic><p>Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by
alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and
tested for their in vitro activity upon the erythrocytic stage of<italic toggle="yes"> Plasmodium falciparum,</italic>
trypomastigote stage of<italic toggle="yes"> Trypanosoma brucei, </italic>and amastigote stage of <italic toggle="yes">Trypanosoma cruzi </italic>and
<italic toggle="yes">Leishmania infantum</italic> as well as for their cytotoxic effects upon MRC-5 cells. Results clearly
showed the importance of the nature of the linker and of its side chain for antiparasitic activity,
cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at
25 μM upon MRC-5 cells, one displayed IC<sub>50</sub> values ranging from 8 to 18 nM against different
<italic toggle="yes">P. falciparum</italic> strains while three others totally inhibited <italic toggle="yes">T. </italic><italic toggle="yes">brucei</italic> at 1.56 μM.
</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>jm990946n</meta-value></custom-meta></custom-meta-group></article-meta><notes id="jm990946nAF10"><label>#</label><p>
Abbreviations: CQ, chloroquine; DAPI, 4,6-diamidino-2-phenylindole; MF, mefloquine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue); PyBrop, bromotris(pyrrolidinophosphonium) hexafluorophosphate.</p></notes><notes id="jm990946nAF6"><label>⊥</label><p>
Present address: Institut de Recherche Jouveinal, Parke-Davis,
3-9 rue de la Loge, 94265 Fresnes Cedex, France.</p></notes></front><body><sec id="d7e235"><title>Introduction</title><p>Malaria, trypanosomiasis, and leishmaniasis are major diseases in developing countries which continue to
infect several hundreds of millions of people and which
are responsible for a mortality rate in excess of 1 million
per year. Present chemotherapies are proving inadequate, are toxic, or are becoming ineffective due to an
increase in resistance. The trivalent arsenical drug
melarsoprol is still widely used against the second stage
of African trypanosomiasis in which <italic toggle="yes">Trypanosoma</italic> <italic toggle="yes">brucei rhodesiense</italic> or <italic toggle="yes">gambiense</italic> has invaded the central
nervous system. The toxicity of this treatment is responsible for the death of approximately 5% of its
recipients. Benznidazole, the only commercial drug still
available for treatment during the chronic stage of
Chagas' disease, is no longer efficient, while its safety
continues to be debated. Against <italic toggle="yes">Leishmania</italic> parasite,
amphotericin B and pentamidine are toxic in therapeutic doses, while resistance to pentavalent antimonials
is increasing. The effectiveness of chloroquine (CQ,
Chart <xref rid="jm990946nc00001"></xref>), the cheap, antimalarial mainstay for more
than 50 years, is also being undermined by the evolution
of resistant parasites.<named-content content-type="bibref-group"><xref rid="jm990946nb00001" ref-type="bibr"></xref>,<xref rid="jm990946nb00002" ref-type="bibr"></xref></named-content> CQ is believed to exert its
activity by inhibiting hemozoin formation in the digestive vacuole of the malaria parasite,<named-content content-type="bibref-group"><xref rid="jm990946nb00003" ref-type="bibr"></xref>,<xref rid="jm990946nb00004" ref-type="bibr"></xref></named-content> though this has
recently been questioned by Ginsburg and co-workers
who have suggested that inhibition of the degradation
of ferriprotoporphyrin IX by glutathione-dependent redox processes could be a second mode of action of CQ.<xref rid="jm990946nb00005" ref-type="bibr"></xref>
Biochemical studies indicate that isolates of the CQ-resistant parasite accumulate less drug in the food
vacuole than their more sensitive counterparts. However, opinion remains divided upon the mechanistic
explanation for the reduction: (1) a rapid CQ efflux
mechanism by CQ-resistant parasites,<xref rid="jm990946nb00006" ref-type="bibr"></xref> (2) an elevated
pH in the food vacuole of the CQ-resistant parasites,<xref rid="jm990946nb00007" ref-type="bibr"></xref>
(3) resistance being linked to a carrier-mediated CQ
uptake,<xref rid="jm990946nb00008" ref-type="bibr"></xref> (4) resistance being linked to a reduced CQ
affinity to ferriprotoporphyrin.<xref rid="jm990946nb00009" ref-type="bibr"></xref> CQ resistance may
involve several mechanisms; however its reversal by
molecules such as verapamil, desipramine, and chlorpromazine suggests that an enhanced CQ efflux by a
multidrug-resistant mechanism may be implicated.<named-content content-type="bibref-group"><xref rid="jm990946nb00006" ref-type="bibr"></xref>,<xref rid="jm990946nb00010" ref-type="bibr"></xref></named-content>
One possibility to overcome this mechanism is to design
quinoline-based drugs which are not recognized by the
proteins involved in drug efflux. In this regard, bulky
bisquinolines were synthesized and suggested to be
extruded with difficulty by a proteinaceous transporter.<xref rid="jm990946nb00011" ref-type="bibr"></xref> They were also discovered to inhibit the growth
of CQ-sensitive and CQ-resistant parasites with similar
efficiency though it was not proved that steric hindrance
was the deciding factor for this.<named-content content-type="bibref-group"><xref rid="jm990946nb00011" ref-type="bibr"></xref>−<xref rid="jm990946nb00012" specific-use="suppress-in-print" ref-type="bibr"></xref><xref rid="jm990946nb00013" specific-use="suppress-in-print" ref-type="bibr"></xref><xref rid="jm990946nb00014" ref-type="bibr"></xref></named-content> Further development of the most promising molecule Ro 47-7737<sup>13</sup>
(Chart <xref rid="jm990946nc00001"></xref>) as that of other bisquinolines, described
earlier, piperaquine, hydroxypiperaquine, and dichloroquinazine,<xref rid="jm990946nb00015" ref-type="bibr"></xref> was suspended for reasons of toxicity.
<fig id="jm990946nc00001" position="float" fig-type="chart" orientation="portrait"><label>1</label><caption><p>Structure of Antimalarial Molecules</p></caption><graphic xlink:href="jm990946nc00001.eps" position="float" orientation="portrait"></graphic></fig></p><p>Acridine derivatives have been considered as potential
antiprotozoal agents, e.g: 9-anilinoacridine topoisomerase
II inhibitors show high levels of antileishmanial and
antitrypanosomal activity.<xref rid="jm990946nb00016" ref-type="bibr"></xref> Furthermore, quinacrine,
the 9-amino-6-chloro-2-methoxyacridine analogue of CQ
(Chart <xref rid="jm990946nc00001"></xref>), which was used clinically before CQ, is still
an approved treatment of giardiasis. Sharing the same
features as a weak diprotic base, it accumulates in the
acidic food vacuole (pH = 5) of <italic toggle="yes">Plasmodium</italic> and
prevents hematin polymerization.<xref rid="jm990946nb00004" ref-type="bibr"></xref> Until now, bisacridines have been poorly studied for their antiparasitic
activity, yet they, along with bisquinolines, may represent an alternative method to avoiding the efflux
mechanism. In addition bisacridines offer the advantage
of being viewed precisely by cellular fluorescence imaging. However, the presence of an acridine moiety in a
molecule can lead to stronger interactions with DNA
and generate cytotoxicity, especially in the case of
bisintercalation. Bisintercalation requires a minimal
distance between the acridine rings. Bis(9-amino-6-chloro-2-methoxyacridines) corresponding to a spermine
or spermidine linker were found to bisintercalate, while
the removal of a single carbon (symmetrical linker
−NH−(CH<sub>2</sub>)<sub>3</sub>−NH−(CH<sub>2</sub>)<sub>3</sub>−NH−) suppressed bisintercalation.<xref rid="jm990946nb00017" ref-type="bibr"></xref> It was also reported that acridine substituents play a role in intercalation and DNA recognition<named-content content-type="bibref-group"><xref rid="jm990946nb00018" ref-type="bibr"></xref>,<xref rid="jm990946nb00019" ref-type="bibr"></xref></named-content>
and that an increase of rigidity can favor binding affinity
in relation to the subsequent decrease of the loss in
entropy.<named-content content-type="bibref-group"><xref rid="jm990946nb00020" ref-type="bibr"></xref>,<xref rid="jm990946nb00021" ref-type="bibr"></xref></named-content> Besides, for unsubstituted bisacridines, an
evolution from monofunctional to bifunctional interaction was found by lengthening the methylene chain from
four carbons to six.<named-content content-type="bibref-group"><xref rid="jm990946nb00019" ref-type="bibr"></xref>,<xref rid="jm990946nb00022" ref-type="bibr"></xref>,<xref rid="jm990946nb00023" ref-type="bibr"></xref></named-content></p><p>We have therefore undertaken the synthesis and an
in vitro antiparasitic activity study upon <italic toggle="yes">Plasmodium
falciparum</italic> of three series of bisacridines in which
aromatic rings are joined by alkanediamines, polyamines,
or polyamines substituted by a side chain (Chart <xref rid="jm990946nc00002"></xref>). In
the latter case, the length of the linker proved unfavorable to bisintercalation, while the nature of the side
chain could contribute to either a diminishing or canceling of the interaction with the phosphate groups of
human DNA and consequently to a decrease of cytotoxicity. Antiparasitic efficacy of these compounds against
<italic toggle="yes">Trypanosoma cruzi</italic>, <italic toggle="yes">Trypanosoma brucei</italic>, and <italic toggle="yes">Leishmania </italic><italic toggle="yes">infantum</italic>, as well as the evaluation of their cytotoxicity, is also reported.
<fig id="jm990946nh00001" position="float" fig-type="scheme" orientation="portrait"><label>1</label><caption><p>Synthesis of Bisacridines<bold>1</bold>−<bold>9</bold><italic toggle="yes"><sup>a</sup></italic><sup></sup></p><p><fn id="d7e389"><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Reagents: K<sub>2</sub>CO<sub>3</sub>, DMF.</p></fn></p></caption><graphic xlink:href="jm990946nh00001.eps" position="float" orientation="portrait"></graphic></fig><fig id="jm990946nc00002" position="float" fig-type="chart" orientation="portrait"><label>2</label><caption><p>Bisacridines of the A, B, and C Series</p></caption><graphic xlink:href="jm990946nc00002.eps" position="float" orientation="portrait"></graphic></fig></p></sec><sec id="d7e412"><title>Chemistry</title><p>In preference to the generally adopted method, employing phenol, as described by Canellakis et al,<xref rid="jm990946nb00024" ref-type="bibr"></xref>
bisacridines <bold>1</bold><bold>−</bold><bold>9</bold> (A and B series, Chart <xref rid="jm990946nc00002"></xref>) were synthesized according to the method described for 4-aminoquinolines preparation,<xref rid="jm990946nb00025" ref-type="bibr"></xref> by reacting polyamines with
3 equiv of 6,9-dichloro-2-methoxyacridine in DMF at
reflux, in the presence of potassium carbonate as an
inorganic base (Scheme <xref rid="jm990946nh00001"></xref>). Chromatography on silica
gel columns was the selected method for purification.
</p><p>In the C series (Chart <xref rid="jm990946nc00002"></xref>), the side chain was fixed by
coupling various carboxylic groups with the central,
secondary amino group of compounds <bold>6</bold><bold>−</bold><bold>8</bold>, using PyBroP reagent.<named-content content-type="bibref-group"><xref rid="jm990946nb00026" ref-type="bibr"></xref>,<xref rid="jm990946nb00027" ref-type="bibr"></xref></named-content> Thus, bisacridines <bold>10</bold><bold>−</bold><bold>25</bold> were synthesized, as shown in Scheme <xref rid="jm990946nh00002"></xref>, by coupling bisacridines
<bold>6</bold><bold>−</bold><bold>8</bold> with appropriate <italic toggle="yes">N</italic>-Boc- and/or <italic toggle="yes">N</italic>-Fmoc-amino
acids. <italic toggle="yes">N</italic>-Boc-amino protecting groups of compounds <bold>10</bold>
and <bold>21 </bold>were removed by treatment with a 1:1 mixture
of TFA/CH<sub>2</sub>Cl<sub>2</sub> to give deprotected analogues <bold>26</bold> and <bold>29,</bold>
respectively (Scheme <xref rid="jm990946nh00002"></xref>). <italic toggle="yes">N</italic>-Fmoc-amino or Fmoc-ester
protecting groups of compounds <bold>19</bold>, <bold>20</bold>, and <bold>25</bold> were
removed by treatment with a 20:80 piperidine/DMF
mixture to give deprotected analogues <bold>27</bold>,<bold> 28,</bold> and <bold>30,</bold>
respectively (Scheme <xref rid="jm990946nh00002"></xref>). Acetyl protection of compound
<bold>23</bold> was removed by treatment with an aqueous solution
of K<sub>2</sub>CO<sub>3</sub> to give deprotected compound <bold>31</bold> (Scheme <xref rid="jm990946nh00002"></xref>).
Thick-layer chromatography was used for purification.
<fig id="jm990946nh00002" position="float" fig-type="scheme" orientation="portrait"><label>2</label><caption><p>Synthesis of Bisacridines<bold>10</bold>−<bold>31</bold><italic toggle="yes"><sup>a</sup></italic><sup></sup></p><p><fn id="d7e542"><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Reagents: (a) PyBrop, DIEA, DMF; (b) TFA/CH<sub>2</sub>Cl<sub>2</sub> (1:1); (c) piperidine/DMF (20:80); (d) K<sub>2</sub>CO<sub>3</sub>, H<sub>2</sub>O, MeOH.</p></fn></p></caption><graphic xlink:href="jm990946nh00002.eps" position="float" orientation="portrait"></graphic></fig></p><p>Compound <bold>32</bold> was synthesized, as shown in Scheme
<xref rid="jm990946nh00003"></xref>, by reaction of bisacridine <bold>6</bold> with succinic anhydride,
while its amide analogue <bold>33</bold> was prepared by treating
compound <bold>32</bold> with ammonium hydrogenocarbonate. The
morpholinoamide derivative <bold>34</bold> was synthesized by
coupling the carboxylic acid <bold>32</bold> with morpholine using
the coupling method described in Scheme <xref rid="jm990946nh00002"></xref>.
<fig id="jm990946nh00003" position="float" fig-type="scheme" orientation="portrait"><label>3</label><caption><p>Synthesis of Bisacridines<bold>32</bold>−<bold>34</bold><italic toggle="yes"><sup>a</sup></italic><sup></sup></p><p><fn id="d7e608"><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Reagents: (a) succinic anhydride, pyridine; (b) Boc<sub>2</sub>O, NH<sub>4</sub>HCO<sub>3</sub>, pyridine, DMF; (c) morpholine, PyBrop, DIEA, DMF.</p></fn></p></caption><graphic xlink:href="jm990946nh00003.eps" position="float" orientation="portrait"></graphic></fig><fig id="jm990946nh00004" position="float" fig-type="scheme" orientation="portrait"><label>4</label><caption><p>Synthesis of Bisacridines<bold>35</bold>−<bold>40</bold><italic toggle="yes"><sup>a</sup></italic><sup></sup></p><p><fn id="d7e644"><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Reagents: 3-chloropropionyl chloride, 1-ethylpiperidine, THF, then R<sub>1</sub>R<sub>2</sub>NH, THF.</p></fn></p></caption><graphic xlink:href="jm990946nh00004.eps" position="float" orientation="portrait"></graphic></fig></p><p>In the case of bisacridines <bold>35</bold><bold>−</bold><bold>40</bold>, fixation of the
amino side chain was accomplished in two steps: the
reaction of secondary amino compound <bold>6</bold> with 3-chloropropionyl chloride, using 1-ethylpiperidine as a base,
followed by substitution of the remaining chloro group
by the appropriate amine (Scheme <xref rid="jm990946nh00004"></xref>).<xref rid="jm990946nb00027" ref-type="bibr"></xref> As a tertiary
amine 1-ethylpiperidine was preferred to pyridine which
was previously reported to lead to a nonconvertible
pyridinium salt.<xref rid="jm990946nb00028" ref-type="bibr"></xref></p></sec><sec id="d7e679"><title>Biological Results</title><p><bold>In Vitro Antimalarial Activity upon </bold><bold><italic toggle="yes">P. falciparum</italic></bold><bold>.</bold> Initially all of the compounds were tested for
their antimalarial activity upon the CQ-resistant strain
FcB1R (IC<sub>50</sub> CQ = 138.6 nM, IC<sub>50</sub> MF = 6.9 nM). In
the A series (Table <xref rid="jm990946nt00001"></xref>), increasing the length of the
alkanediamine linker proved unfavorable toward activity (IC<sub>50</sub> values increased from 16 to 176 nM from 6 to
12 carbons). Values in the B series (Table <xref rid="jm990946nt00001"></xref>), were
consistent regardless of the distance between the nitrogen atoms of the linker (IC<sub>50</sub> around 60 nM), except
for the piperazine derivative <bold>9 </bold>which proved more
efficient (IC<sub>50</sub> = 17 nM). In comparison with all other
compounds of the A and B series, this derivative also
showed a unique and contrasting behavior at the
cellular localization level. In confocal microscopy, while
infected erythrocytes incubated with 10 μM quinacrine
displayed a weak fluorescence associated with the
parasite food vacuole and the erythrocytic and parasitic
membranes (data not shown), a high fluorescence,
associated exclusively with the parasite, was observed
with 1 μM compound <bold>9</bold> (Figure <xref rid="jm990946nf00001"></xref>A). No labeling of the
food vacuole and of the normal or infected erythrocyte
cytosols/membranes was recorded. Fluorescence was
mainly concentrated in structures which colocalized
with propidium iodide or DAPI labeling, suggesting a
concentration of compound <bold>9</bold> in the parasite nuclei (data
not shown). In murine muscle L-6 cells, which were used
as a control, no nuclear labeling was observed; the
fluorescence of compound <bold>9</bold> was only associated with
vesicles (Figure <xref rid="jm990946nf00001"></xref>B), which co-localized with lysosome-specific probe labeling (data not shown). The other
members of the A and B series displayed a specific
parasite labeling similar to that for compound <bold>9</bold> (Figure
<xref rid="jm990946nf00001"></xref>C). However, a weaker fluorescence was associated
with the parasite nucleus while fluorescence was mainly
associated with the parasite cytoplasm. When compared
with compound <bold>9</bold>, the A and B series revealed a marked
difference in L-6 cells localization, showing a diffuse
labeling within the cell cytosol and no concentration in
lysosome-like vesicles (Figure <xref rid="jm990946nf00001"></xref>D).
<fig id="jm990946nf00001" position="float" orientation="portrait"><label>1</label><caption><p>Labeling of<italic toggle="yes">P. falciparum</italic>-infected erythrocytes (A, C) and mouse L-6 cells (B, D) using compounds <bold>9</bold> (A, B) and <bold>1</bold> (C,
D). Infected cultures of <italic toggle="yes">P. </italic><italic toggle="yes">falciparum</italic> were incubated with 1 μM bisacridine derivative and then with 10 μg/mL nonexchangeable
lipid DIL C<sub>18</sub>(3) (see Experimental Section). DIL C<sub>18</sub>(3) permitted the visualization of the membranes of the infected and noninfected
erythrocytes (arrow). Bisacridine derivatives accumulated specifically in the intracellular parasites (arrowhead). Food vacuole
(FV) was not labeled. For compound <bold>9</bold>, a high fluorescence was associated with a structure which colocalized with the parasite
nucleus (N). L-6 cells were only labeled with bisacridine derivatives. Bar scale is in μm. A and B are images of one section, C and
D are 3D reconstructions of a sequential image collection.</p></caption><graphic xlink:href="jm990946nf00001.tif" position="float" orientation="portrait"></graphic></fig><table-wrap id="jm990946nt00001" position="float" orientation="portrait"><label>1</label><caption><p>In Vitro Sensitivity of<italic toggle="yes">P. </italic><italic toggle="yes">f</italic><italic toggle="yes">alciparum</italic> FcB1R Strain to
Bisacridines <bold>1</bold><bold>−</bold><bold>9</bold> (A and B Series)</p></caption><oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="6"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:colspec colnum="6" colname="6"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">molecule</oasis:entry><oasis:entry namest="2" nameend="2">series</oasis:entry><oasis:entry namest="3" nameend="3">central amine</oasis:entry><oasis:entry namest="4" nameend="4"><italic toggle="yes">n</italic></oasis:entry><oasis:entry namest="5" nameend="5"><italic toggle="yes">n</italic>‘</oasis:entry><oasis:entry namest="6" nameend="6">IC<sub>50</sub> (nM)<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>1</bold></oasis:entry><oasis:entry colname="2">A
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4">4
</oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6">18 ± 7<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>2</bold></oasis:entry><oasis:entry colname="2">A
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4">6
</oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6">16 ± 10<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>3</bold></oasis:entry><oasis:entry colname="2">A
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4">8
</oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6">19 ± 10<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>4</bold></oasis:entry><oasis:entry colname="2">A
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4">10
</oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6">57 ± 30<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>5</bold></oasis:entry><oasis:entry colname="2">A
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4">12
</oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6">176 ± 96<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>6</bold></oasis:entry><oasis:entry colname="2">B
</oasis:entry><oasis:entry colname="3">NH
</oasis:entry><oasis:entry colname="4">3
</oasis:entry><oasis:entry colname="5">3
</oasis:entry><oasis:entry colname="6">55 ± 9<italic toggle="yes"><sup>c</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>7</bold></oasis:entry><oasis:entry colname="2">B
</oasis:entry><oasis:entry colname="3">NH
</oasis:entry><oasis:entry colname="4">2
</oasis:entry><oasis:entry colname="5">2
</oasis:entry><oasis:entry colname="6">63 ± 10<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>8</bold></oasis:entry><oasis:entry colname="2">B
</oasis:entry><oasis:entry colname="3">NH
</oasis:entry><oasis:entry colname="4">3
</oasis:entry><oasis:entry colname="5">4
</oasis:entry><oasis:entry colname="6">61 ± 3<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>9</bold></oasis:entry><oasis:entry colname="2">B
</oasis:entry><oasis:entry colname="3">piperazine
</oasis:entry><oasis:entry colname="4">3
</oasis:entry><oasis:entry colname="5">3
</oasis:entry><oasis:entry colname="6">17 ± 10<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> IC<sub>50</sub> CQ = 138.6 ± 8.4 nM; IC<sub>50</sub> MF = 6.9 ± 0.3 nM.<italic toggle="yes"><sup>b</sup></italic><sup>-<italic toggle="yes">d</italic></sup> <italic toggle="yes">n</italic>,
number of experiments: <italic toggle="yes"><sup>b</sup></italic><sup></sup><italic toggle="yes">n</italic> = 3; <italic toggle="yes"><sup>c</sup></italic><sup></sup><italic toggle="yes">n</italic> = 5; <italic toggle="yes"><sup>d</sup></italic><sup></sup><italic toggle="yes">n</italic> = 4.</p></table-wrap-foot></table-wrap></p><p>In the C series (Table <xref rid="jm990946nt00002"></xref>), activity proved to be highly
dependent upon the nature of the Boc- and/or Fmoc-protected amino acid residue fixed to the central nitrogen atom of the linker and upon the distance between
the terminal nitrogen atoms. A high level of activity
(IC<sub>50</sub> values about 30 nM) was observed for the alanine
derivatives <bold>10</bold> and <bold>13</bold> (<italic toggle="yes">n</italic> = <italic toggle="yes">n</italic>‘ = 3), for both enantiomers,
while their analogues <bold>11</bold> (<italic toggle="yes">n</italic> = <italic toggle="yes">n</italic>‘ = 2) and <bold>12</bold> (<italic toggle="yes">n</italic> = 3,
<italic toggle="yes">n</italic>‘ = 4) were less active (IC<sub>50</sub> of 109 and 330 nM,
respectively). <italic toggle="yes">N</italic>-Boc-amino acids with longer hydrophobic side chains, leucine (compound <bold>15</bold>) and valine
(compound <bold>16</bold>), were the most active, while the polarity
of the side chains proved consistently unfavorable since
the protected derivatives <bold>10</bold> and <bold>19</bold><bold>−</bold><bold>25</bold> were more
active than their corresponding deprotected counterparts <bold>26</bold> and <bold>27</bold><bold>−</bold><bold>31</bold>. Also, the succinimide derivative
<bold>33</bold> revealed a better activity than its carboxylic analogue
<bold>32</bold>. Addition of a second amino acid residue (compound
<bold>18</bold>) was unfavorable. Amino derivatives <bold>35</bold><bold>−</bold><bold>40 </bold>displayed IC<sub>50</sub> values between 26 and 91 nM, with the
exception of the piperazine derivative <bold>39 </bold>(IC<sub>50</sub> > 500
nM) which via its terminal nitrogen atom could play the
role of hydrogen-bond donor. In this series, the absence
of a protonable amino group led to the less active
morpholine compound <bold>34</bold>. Five compounds among the
most active upon the CQ-resistant strain FcB1R (compounds <bold>9</bold>, <bold>10</bold>, <bold>13</bold>, <bold>15</bold>, and <bold>16</bold>) were subsequently
evaluated for their efficiency in inhibiting the growth
of seven strains showing different degrees of resistance
to CQ or MF (Table <xref rid="jm990946nt00003"></xref>). An inverse correlation was
observed for compounds <bold>10</bold>, <bold>13</bold>, <bold>15</bold>, and <bold>16</bold>, as recently
reported for bisquinolines by Vennerstrom and co-workers,<xref rid="jm990946nb00029" ref-type="bibr"></xref> the more the parasites appeared resistant to
CQ, the more they seemed sensitive to the compounds
under investigation. On the contrary, piperazine compound <bold>9</bold> displayed quite similar efficiency (IC<sub>50</sub> values
between 8 and 18 nM), whatever the CQ resistance of
the strain. No such correlation was observed with the
resistance to MF.
<table-wrap id="jm990946nt00002" position="float" orientation="portrait"><label>2</label><caption><p>In Vitro Sensitivity of<italic toggle="yes">P. </italic><italic toggle="yes">f</italic><italic toggle="yes">alciparum</italic> FcB1R Strain to
Bisacridines <bold>10</bold><bold>−</bold><bold>40</bold> (C Series)</p></caption><oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="5"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">molecule</oasis:entry><oasis:entry namest="2" nameend="2"><italic toggle="yes">n</italic></oasis:entry><oasis:entry namest="3" nameend="3"><italic toggle="yes">n</italic>‘</oasis:entry><oasis:entry namest="4" nameend="4">R<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry><oasis:entry namest="5" nameend="5">IC<sub>50</sub> (nM)<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>10</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">31 ± 2<italic toggle="yes"><sup>c</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>11</bold></oasis:entry><oasis:entry colname="2">2
</oasis:entry><oasis:entry colname="3">2
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">109 ± 3<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>12</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">4
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">330 ± 59<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>13</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>3 </sub>(<sc>d</sc> enantiomer)
</oasis:entry><oasis:entry colname="5">33 ± 2<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>14</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH<sub>2</sub>-NHBoc
</oasis:entry><oasis:entry colname="5">92 ± 19<italic toggle="yes"><sup>e</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>15</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-CH(CH<sub>3</sub>)<sub>2</sub></oasis:entry><oasis:entry colname="5">27 ± 4<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>16</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH(CH<sub>3</sub>)<sub>2</sub></oasis:entry><oasis:entry colname="5">25 ± 7<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>17</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHFmoc)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">232 ± 85<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>18</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH<sub>2</sub>-NH-CO-CH(NHBoc)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">440<italic toggle="yes"><sup>f</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>19</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-(CH<sub>2</sub>)<sub>4</sub>-NHFmoc
</oasis:entry><oasis:entry colname="5">273 ± 75<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>20</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-NHFmoc
</oasis:entry><oasis:entry colname="5">71 ± 3<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>21</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-NHBoc
</oasis:entry><oasis:entry colname="5">55 ± 3<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>22</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>OBn
</oasis:entry><oasis:entry colname="5">138<italic toggle="yes"><sup>f</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>23</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>OAc
</oasis:entry><oasis:entry colname="5">63 ± 15<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>24</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-COOC<sub>6</sub>H<sub>11</sub></oasis:entry><oasis:entry colname="5">31 ± 4<italic toggle="yes"><sup>c</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>25</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-COOFmoc
</oasis:entry><oasis:entry colname="5">230 ± 16<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>26</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NH<sub>2</sub>)-CH<sub>3</sub></oasis:entry><oasis:entry colname="5">>500<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>27</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-(CH<sub>2</sub>)<sub>4</sub>-NH<sub>2</sub></oasis:entry><oasis:entry colname="5">>500<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>28</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-NH<sub>2</sub></oasis:entry><oasis:entry colname="5">307<italic toggle="yes"><sup>f</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>29</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NH<sub>2</sub>)-CH<sub>2</sub>−NH<sub>2</sub></oasis:entry><oasis:entry colname="5">>500<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>30</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>-COOH
</oasis:entry><oasis:entry colname="5">>500<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>31</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-CH(NHBoc)-CH<sub>2</sub>OH
</oasis:entry><oasis:entry colname="5">247 ± 92<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>32</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-COOH
</oasis:entry><oasis:entry colname="5">270<italic toggle="yes"><sup>f</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>33</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-CONH<sub>2</sub></oasis:entry><oasis:entry colname="5">40 ± 10<italic toggle="yes"><sup>e</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>34</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-CO-morpholine
</oasis:entry><oasis:entry colname="5">436 ± 56<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>35</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-morpholine
</oasis:entry><oasis:entry colname="5">26 ± 2<italic toggle="yes"><sup>e</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>36</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-piperidine
</oasis:entry><oasis:entry colname="5">67 ± 11<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>37</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-pyrrolidine
</oasis:entry><oasis:entry colname="5">91 ± 19<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>38</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-(4-methylpiperazine)
</oasis:entry><oasis:entry colname="5">62 ± 8<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>39</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-piperazine
</oasis:entry><oasis:entry colname="5">>500<italic toggle="yes"><sup>f</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>40</bold></oasis:entry><oasis:entry colname="2">3
</oasis:entry><oasis:entry colname="3">3
</oasis:entry><oasis:entry colname="4">CO-(CH<sub>2</sub>)<sub>2</sub>-NH(CH<sub>3</sub>)<sub>2</sub></oasis:entry><oasis:entry colname="5">39 ± 5<italic toggle="yes"><sup>d</sup></italic><sup></sup></oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Ac, acetyl; Bn, benzyl; Boc, <italic toggle="yes">tert</italic>-butoxycarbonyl; Fmoc, 9-fluorenylmethyloxycarbonyl.<italic toggle="yes"><sup>b</sup></italic><sup></sup> IC<sub>50</sub> CQ = 138.6 ± 8.4 nM; IC<sub>50</sub> MF =
6.9 ± 0.3 nM.<italic toggle="yes"><sup>c</sup></italic><sup>-<italic toggle="yes">f</italic></sup> <italic toggle="yes">n</italic>, number of experiments: <italic toggle="yes"><sup>c</sup></italic><sup></sup><italic toggle="yes">n</italic> = 5; <italic toggle="yes"><sup>d</sup></italic><sup></sup><italic toggle="yes">n</italic> = 3; <italic toggle="yes"><sup>e</sup></italic><sup></sup><italic toggle="yes">n</italic> =
4; <italic toggle="yes"><sup>f</sup></italic><sup></sup><italic toggle="yes">n</italic> = 2.</p></table-wrap-foot></table-wrap><table-wrap id="jm990946nt00003" position="float" orientation="portrait"><label>3</label><caption><p>Efficiency of Five of the Most Active Compounds against FcB1R, To Inhibit Growth of Parasites Expressing Different Degrees of Resistance to CQ</p></caption><oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="8"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:colspec colnum="6" colname="6"></oasis:colspec><oasis:colspec colnum="7" colname="7"></oasis:colspec><oasis:colspec colnum="8" colname="8"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry colname="1"></oasis:entry><oasis:entry namest="2" nameend="8">IC<sub>50 </sub>(nM)<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry namest="1" nameend="1"><italic toggle="yes">P. falciparum</italic>
strain</oasis:entry><oasis:entry namest="2" nameend="2">CQ</oasis:entry><oasis:entry namest="3" nameend="3">MF</oasis:entry><oasis:entry namest="4" nameend="4"><bold>9</bold></oasis:entry><oasis:entry namest="5" nameend="5"><bold>10</bold></oasis:entry><oasis:entry namest="6" nameend="6"><bold>13</bold></oasis:entry><oasis:entry namest="7" nameend="7"><bold>15</bold></oasis:entry><oasis:entry namest="8" nameend="8"><bold>16</bold></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">3D7
</oasis:entry><oasis:entry colname="2">20 ± 4
</oasis:entry><oasis:entry colname="3">40 ± 10
</oasis:entry><oasis:entry colname="4">13 ± 3
</oasis:entry><oasis:entry colname="5">22 ± 10
</oasis:entry><oasis:entry colname="6">57 ± 6
</oasis:entry><oasis:entry colname="7">48 ± 6
</oasis:entry><oasis:entry colname="8">49 ± 10
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">F32a
</oasis:entry><oasis:entry colname="2">22 ± 2
</oasis:entry><oasis:entry colname="3">62 ± 6
</oasis:entry><oasis:entry colname="4">8 ± 2
</oasis:entry><oasis:entry colname="5">66 ± 5
</oasis:entry><oasis:entry colname="6">89 ± 11
</oasis:entry><oasis:entry colname="7">52 ± 4
</oasis:entry><oasis:entry colname="8">57 ± 2
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">GP1
</oasis:entry><oasis:entry colname="2">39 ± 2
</oasis:entry><oasis:entry colname="3">17 ± 3
</oasis:entry><oasis:entry colname="4">11 ± 5
</oasis:entry><oasis:entry colname="5">35 ± 12
</oasis:entry><oasis:entry colname="6">66 ± 5
</oasis:entry><oasis:entry colname="7">63 ± 6
</oasis:entry><oasis:entry colname="8">83 ± 6
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">FCR3
</oasis:entry><oasis:entry colname="2">102 ± 6
</oasis:entry><oasis:entry colname="3">36 ± 15
</oasis:entry><oasis:entry colname="4">18 ± 6
</oasis:entry><oasis:entry colname="5">nd<italic toggle="yes"><sup>b </sup></italic><sup></sup></oasis:entry><oasis:entry colname="6">32 ± 8
</oasis:entry><oasis:entry colname="7">17 ± 6
</oasis:entry><oasis:entry colname="8">22 ± 8
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">FCM29
</oasis:entry><oasis:entry colname="2">216 ± 25
</oasis:entry><oasis:entry colname="3">8 ± 3
</oasis:entry><oasis:entry colname="4">13 ± 6
</oasis:entry><oasis:entry colname="5">11 ± 4
</oasis:entry><oasis:entry colname="6">11 ± 4
</oasis:entry><oasis:entry colname="7">13 ± 5
</oasis:entry><oasis:entry colname="8">16 ± 6
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">W2
</oasis:entry><oasis:entry colname="2">219 ± 16
</oasis:entry><oasis:entry colname="3">30 ± 3
</oasis:entry><oasis:entry colname="4">12 ± 2
</oasis:entry><oasis:entry colname="5">10 ± 5
</oasis:entry><oasis:entry colname="6">18 ± 8
</oasis:entry><oasis:entry colname="7">15 ± 7
</oasis:entry><oasis:entry colname="8">40 ± 11
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">K1
</oasis:entry><oasis:entry colname="2">267 ± 42
</oasis:entry><oasis:entry colname="3">12 ± 1
</oasis:entry><oasis:entry colname="4">16 ± 5
</oasis:entry><oasis:entry colname="5">12 ± 2
</oasis:entry><oasis:entry colname="6">23 ± 5
</oasis:entry><oasis:entry colname="7">14 ± 7
</oasis:entry><oasis:entry colname="8">36 ± 6</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> Parasites were considered resistant to CQ for IC<sub>50</sub> > 100 nM. IC<sub>50</sub> values are the mean ± standard deviation of three independent
experiments.<italic toggle="yes"><sup>b</sup></italic><sup></sup> nd, not determined.</p></table-wrap-foot></table-wrap></p><p><bold>In Vitro Antitrypanosomal Activity upon </bold><bold><italic toggle="yes">T.
cruzi</italic></bold><bold>, </bold><bold><italic toggle="yes">T. brucei</italic></bold><bold>, and </bold><bold><italic toggle="yes">L. </italic></bold><bold><italic toggle="yes">infantum</italic></bold><bold>.</bold> Compounds of the
series A and B (Table <xref rid="jm990946nt00004"></xref>), with the exception of the
piperazine derivative <bold>9</bold> and to a lesser extent compounds <bold>4</bold> and <bold>5</bold>, were found to be very cytotoxic upon
human diploid embryonic lung cells (MRC-5 cells) and
upon mouse primary peritoneal macrophages used in
the <italic toggle="yes">T. cruzi</italic> and <italic toggle="yes">L. infantum</italic> tests as well as upon <italic toggle="yes">T.
brucei</italic> which is known to be highly sensitive to toxic
molecules. In confocal imaging of <italic toggle="yes">T. </italic><italic toggle="yes">cruzi</italic> epimastigotes,
compound <bold>9</bold> was found to be mainly associated with a
structure which colocalized with kinetoplast DNA (Figure <xref rid="jm990946nf00002"></xref>), while compound <bold>1</bold> displayed a more diffuse
fluorescence associated with both the kinetoplast and
the cytosol (data not shown).
<fig id="jm990946nf00002" position="float" orientation="portrait"><label>2</label><caption><p>Labeling of<italic toggle="yes">T. cruzi</italic> epimastigotes with compound
<bold>9</bold>: A, phase contrast; B, labeling with 1 μM compound <bold>9.
</bold>Fluorescence was mainly associated with a structure which
colocalized with kinetoplast DNA (K). Bar = 3 μm.</p></caption><graphic xlink:href="jm990946nf00002.tif" position="float" orientation="portrait"></graphic></fig></p><p>In the C series (Table <xref rid="jm990946nt00005"></xref>), only five compounds (<bold>25</bold>,
<bold>29</bold><bold>−</bold><bold>32</bold>) were devoid of cytotoxicity toward MRC-5 cells
and mouse macrophages. Four of these molecules possess a polar group (amine, alcohol, or carboxylic acid)
in the side chain linked to the spacer. They were highly
active against <italic toggle="yes">T. brucei</italic> (IC<sub>50</sub> < 1.56 μM or close to 1.56
μM for compound <bold>29</bold>) and only displayed a marginal
activity against <italic toggle="yes">P. falciparum</italic>, <italic toggle="yes">T. cruzi, </italic>and<italic toggle="yes"> L. infantum.
</italic>Compound <bold>29</bold> inhibited trypanothione reductase (TR)
from <italic toggle="yes">T. cruzi</italic> (IC<sub>50</sub> = 20 μM), while IC<sub>50</sub> values for the
other compounds were equal or superior to 50 μM in
the presence of 50 μM trypanothione disulfide (data not
shown); this result was not really surprising since
compound <bold>29</bold> displays the structural requirements for
TR recognition, e.g. the presence of aromatic rings and
of a protonable side chain.<named-content content-type="bibref-group"><xref rid="jm990946nb00027" ref-type="bibr"></xref>,<xref rid="jm990946nb00028" ref-type="bibr"></xref></named-content><table-wrap id="jm990946nt00004" position="float" orientation="portrait"><label>4</label><caption><p>In Vitro Cytotoxicity of Compounds<bold>1</bold><bold>−</bold><bold>9</bold> upon MRC-5 Cells and in Vitro Activities toward Trypomastigote Forms of <italic toggle="yes">T.
</italic><italic toggle="yes">b</italic><italic toggle="yes">rucei </italic>and Amastigote Forms of <italic toggle="yes">T. </italic><italic toggle="yes">c</italic><italic toggle="yes">ruzi</italic> and <italic toggle="yes">L. </italic><italic toggle="yes">i</italic><italic toggle="yes">nfantum</italic></p></caption><oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="17"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:colspec colnum="6" colname="6"></oasis:colspec><oasis:colspec colnum="7" colname="7"></oasis:colspec><oasis:colspec colnum="8" colname="8"></oasis:colspec><oasis:colspec colnum="9" colname="9"></oasis:colspec><oasis:colspec colnum="10" colname="10"></oasis:colspec><oasis:colspec colnum="11" colname="11"></oasis:colspec><oasis:colspec colnum="12" colname="12"></oasis:colspec><oasis:colspec colnum="13" colname="13"></oasis:colspec><oasis:colspec colnum="14" colname="14"></oasis:colspec><oasis:colspec colnum="15" colname="15"></oasis:colspec><oasis:colspec colnum="16" colname="16"></oasis:colspec><oasis:colspec colnum="17" colname="17"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">molecule</oasis:entry><oasis:entry namest="2" nameend="5">cytotoxicity (%)</oasis:entry><oasis:entry namest="6" nameend="9"><italic toggle="yes">T. brucei</italic> (%)</oasis:entry><oasis:entry namest="10" nameend="13"><italic toggle="yes">T. cruzi</italic> (%)<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry><oasis:entry namest="14" nameend="17"><italic toggle="yes">L. infantum</italic> (%)<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry namest="1" nameend="1">concn (μM)</oasis:entry><oasis:entry namest="2" nameend="2">25</oasis:entry><oasis:entry namest="3" nameend="3">12.5</oasis:entry><oasis:entry namest="4" nameend="4">6.25</oasis:entry><oasis:entry namest="5" nameend="5">3.13</oasis:entry><oasis:entry namest="6" nameend="6">12.5</oasis:entry><oasis:entry namest="7" nameend="7">6.25</oasis:entry><oasis:entry namest="8" nameend="8">3.13</oasis:entry><oasis:entry namest="9" nameend="9">1.56</oasis:entry><oasis:entry namest="10" nameend="10">12.5</oasis:entry><oasis:entry namest="11" nameend="11">6.25</oasis:entry><oasis:entry namest="12" nameend="12">3.13</oasis:entry><oasis:entry namest="13" nameend="13">1.56</oasis:entry><oasis:entry namest="14" nameend="14">12.5</oasis:entry><oasis:entry namest="15" nameend="15">6.25</oasis:entry><oasis:entry namest="16" nameend="16">3.13</oasis:entry><oasis:entry namest="17" nameend="17">1.56
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>1</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">90
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>2</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">90
</oasis:entry><oasis:entry colname="4">80
</oasis:entry><oasis:entry colname="5">20
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">99
</oasis:entry><oasis:entry colname="9">90
</oasis:entry><oasis:entry colname="10">70
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">40
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>3</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">20
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">98
</oasis:entry><oasis:entry colname="12">90
</oasis:entry><oasis:entry colname="13">70
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">95
</oasis:entry><oasis:entry colname="16">90
</oasis:entry><oasis:entry colname="17">70
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>4</bold></oasis:entry><oasis:entry colname="2">90
</oasis:entry><oasis:entry colname="3">80
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">99
</oasis:entry><oasis:entry colname="11">70
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">90
</oasis:entry><oasis:entry colname="16">70
</oasis:entry><oasis:entry colname="17">20
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>5</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">20
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">70
</oasis:entry><oasis:entry colname="10">90
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">80
</oasis:entry><oasis:entry colname="16">40
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>6</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">60
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">40
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>7</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">T
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>8</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">T
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>9</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">90
</oasis:entry><oasis:entry colname="8">80
</oasis:entry><oasis:entry colname="9">60
</oasis:entry><oasis:entry colname="10">0
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup><oasis:tgroup cols="11"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:colspec colnum="6" colname="6"></oasis:colspec><oasis:colspec colnum="7" colname="7"></oasis:colspec><oasis:colspec colnum="8" colname="8"></oasis:colspec><oasis:colspec colnum="9" colname="9"></oasis:colspec><oasis:colspec colnum="10" colname="10"></oasis:colspec><oasis:colspec colnum="11" colname="11"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry colname="1">Mel<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry><oasis:entry namest="1" nameend="4">CC<sub>50 </sub>= 12.5 μM
</oasis:entry><oasis:entry namest="1" nameend="4">IC<sub>50 </sub>= 200 nM
</oasis:entry><oasis:entry colname="4"></oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6"></oasis:entry><oasis:entry colname="7"></oasis:entry><oasis:entry colname="8"></oasis:entry><oasis:entry colname="9"></oasis:entry><oasis:entry colname="10"></oasis:entry><oasis:entry colname="11"></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">Benz<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry><oasis:entry namest="1" nameend="4">CC<sub>50 </sub>> 50 μM
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4"></oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6"></oasis:entry><oasis:entry namest="1" nameend="4">IC<sub>50 </sub>= 3130 nM
</oasis:entry><oasis:entry colname="8"></oasis:entry><oasis:entry colname="9"></oasis:entry><oasis:entry colname="10"></oasis:entry><oasis:entry colname="11"></oasis:entry></oasis:row><oasis:row><oasis:entry colname="1">Amp B<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry><oasis:entry namest="1" nameend="4">CC<sub>50 </sub>= 25 μM
</oasis:entry><oasis:entry colname="3"></oasis:entry><oasis:entry colname="4"></oasis:entry><oasis:entry colname="5"></oasis:entry><oasis:entry colname="6"></oasis:entry><oasis:entry colname="7"></oasis:entry><oasis:entry colname="8"></oasis:entry><oasis:entry colname="9"></oasis:entry><oasis:entry colname="10"></oasis:entry><oasis:entry namest="1" nameend="4">IC<sub>50 </sub>= 50 nM</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> T, toxic upon mouse primary peritoneal macrophages used in the test.<italic toggle="yes"><sup>b</sup></italic><sup></sup> Mel, melarsoprol; Benz, benznidazole; Amp B, amphotericin
B. These reference drugs are included in each primary in vitro screening batch.</p></table-wrap-foot></table-wrap><table-wrap id="jm990946nt00005" position="float" orientation="portrait"><label>5</label><caption><p>In Vitro Cytotoxicity of Compounds<bold>10</bold><bold>−</bold><bold>40</bold> upon MRC-5 Cells and in Vitro Activities toward Trypomastigote Forms of <italic toggle="yes">T.
</italic><italic toggle="yes">b</italic><italic toggle="yes">rucei </italic>and Amastigote Forms of <italic toggle="yes">T. </italic><italic toggle="yes">c</italic><italic toggle="yes">ruzi</italic> and <italic toggle="yes">L. </italic><italic toggle="yes">i</italic><italic toggle="yes">nfantum</italic></p></caption><oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="17"><oasis:colspec colnum="1" colname="1"></oasis:colspec><oasis:colspec colnum="2" colname="2"></oasis:colspec><oasis:colspec colnum="3" colname="3"></oasis:colspec><oasis:colspec colnum="4" colname="4"></oasis:colspec><oasis:colspec colnum="5" colname="5"></oasis:colspec><oasis:colspec colnum="6" colname="6"></oasis:colspec><oasis:colspec colnum="7" colname="7"></oasis:colspec><oasis:colspec colnum="8" colname="8"></oasis:colspec><oasis:colspec colnum="9" colname="9"></oasis:colspec><oasis:colspec colnum="10" colname="10"></oasis:colspec><oasis:colspec colnum="11" colname="11"></oasis:colspec><oasis:colspec colnum="12" colname="12"></oasis:colspec><oasis:colspec colnum="13" colname="13"></oasis:colspec><oasis:colspec colnum="14" colname="14"></oasis:colspec><oasis:colspec colnum="15" colname="15"></oasis:colspec><oasis:colspec colnum="16" colname="16"></oasis:colspec><oasis:colspec colnum="17" colname="17"></oasis:colspec><oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">molecule</oasis:entry><oasis:entry namest="2" nameend="5">cytotoxicity (%)</oasis:entry><oasis:entry namest="6" nameend="9"><italic toggle="yes">T. brucei</italic> (%)<italic toggle="yes"><sup>a</sup></italic><sup></sup></oasis:entry><oasis:entry namest="10" nameend="13"><italic toggle="yes">T. cruzi</italic> (%)<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry><oasis:entry namest="14" nameend="17"><italic toggle="yes">L. infantum</italic> (%)<italic toggle="yes"><sup>b</sup></italic><sup></sup></oasis:entry></oasis:row><oasis:row><oasis:entry namest="1" nameend="1">concn (μM)</oasis:entry><oasis:entry namest="2" nameend="2">25</oasis:entry><oasis:entry namest="3" nameend="3">12.5</oasis:entry><oasis:entry namest="4" nameend="4">6.25</oasis:entry><oasis:entry namest="5" nameend="5">3.13</oasis:entry><oasis:entry namest="6" nameend="6">12.5</oasis:entry><oasis:entry namest="7" nameend="7">6.25</oasis:entry><oasis:entry namest="8" nameend="8">3.13</oasis:entry><oasis:entry namest="9" nameend="9">1.56</oasis:entry><oasis:entry namest="10" nameend="10">12.5</oasis:entry><oasis:entry namest="11" nameend="11">6.25</oasis:entry><oasis:entry namest="12" nameend="12">3.13</oasis:entry><oasis:entry namest="13" nameend="13">1.56</oasis:entry><oasis:entry namest="14" nameend="14">12.5</oasis:entry><oasis:entry namest="15" nameend="15">6.25</oasis:entry><oasis:entry namest="16" nameend="16">3.13</oasis:entry><oasis:entry namest="17" nameend="17">1.56
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>10</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">90
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">95
</oasis:entry><oasis:entry colname="16">60
</oasis:entry><oasis:entry colname="17">40
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>11</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">99
</oasis:entry><oasis:entry colname="10">60
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">90
</oasis:entry><oasis:entry colname="15">60
</oasis:entry><oasis:entry colname="16">20
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>12</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">90
</oasis:entry><oasis:entry colname="11">70
</oasis:entry><oasis:entry colname="12">20
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">70
</oasis:entry><oasis:entry colname="15">40
</oasis:entry><oasis:entry colname="16">20
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>13</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">84
</oasis:entry><oasis:entry colname="4">84
</oasis:entry><oasis:entry colname="5">81
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">95
</oasis:entry><oasis:entry colname="13">60
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">99
</oasis:entry><oasis:entry colname="17">95
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>14</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">20
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">80
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">80
</oasis:entry><oasis:entry colname="15">60
</oasis:entry><oasis:entry colname="16">40
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>15</bold></oasis:entry><oasis:entry colname="2">55
</oasis:entry><oasis:entry colname="3">49
</oasis:entry><oasis:entry colname="4">47
</oasis:entry><oasis:entry colname="5">42
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">80
</oasis:entry><oasis:entry colname="13">40
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">95
</oasis:entry><oasis:entry colname="17">90
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>16</bold></oasis:entry><oasis:entry colname="2">60
</oasis:entry><oasis:entry colname="3">59
</oasis:entry><oasis:entry colname="4">54
</oasis:entry><oasis:entry colname="5">43
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">90
</oasis:entry><oasis:entry colname="13">70
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">99
</oasis:entry><oasis:entry colname="17">95
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>17</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">40
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>18</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">71
</oasis:entry><oasis:entry colname="4">41
</oasis:entry><oasis:entry colname="5">31
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>19</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">90
</oasis:entry><oasis:entry colname="4">80
</oasis:entry><oasis:entry colname="5">20
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">80
</oasis:entry><oasis:entry colname="12">20
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">40
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>20</bold></oasis:entry><oasis:entry colname="2">68
</oasis:entry><oasis:entry colname="3">60
</oasis:entry><oasis:entry colname="4">57
</oasis:entry><oasis:entry colname="5">55
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">90
</oasis:entry><oasis:entry colname="12">20
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">95
</oasis:entry><oasis:entry colname="16">70
</oasis:entry><oasis:entry colname="17">20
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>21</bold></oasis:entry><oasis:entry colname="2">70
</oasis:entry><oasis:entry colname="3">50
</oasis:entry><oasis:entry colname="4">48
</oasis:entry><oasis:entry colname="5">43
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">80
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">99
</oasis:entry><oasis:entry colname="16">95
</oasis:entry><oasis:entry colname="17">80
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>22</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">80
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">90
</oasis:entry><oasis:entry colname="16">70
</oasis:entry><oasis:entry colname="17">40
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>23</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">90
</oasis:entry><oasis:entry colname="4">40
</oasis:entry><oasis:entry colname="5">20
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">70
</oasis:entry><oasis:entry colname="11">40
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">90
</oasis:entry><oasis:entry colname="15">80
</oasis:entry><oasis:entry colname="16">60
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>24</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">40
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">98
</oasis:entry><oasis:entry colname="11">70
</oasis:entry><oasis:entry colname="12">20
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">80
</oasis:entry><oasis:entry colname="16">60
</oasis:entry><oasis:entry colname="17">20
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>25</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">40
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">20
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>26</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">40
</oasis:entry><oasis:entry colname="5">20
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">0
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>27</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">40
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">99
</oasis:entry><oasis:entry colname="11">90
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">40
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>28</bold></oasis:entry><oasis:entry colname="2">39
</oasis:entry><oasis:entry colname="3">37
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">99
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">40
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>29</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">90
</oasis:entry><oasis:entry colname="8">60
</oasis:entry><oasis:entry colname="9">20
</oasis:entry><oasis:entry colname="10">0
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>30</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">80
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>31</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">80
</oasis:entry><oasis:entry colname="11">20
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">40
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>32</bold></oasis:entry><oasis:entry colname="2">0
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">95
</oasis:entry><oasis:entry colname="8">80
</oasis:entry><oasis:entry colname="9">60
</oasis:entry><oasis:entry colname="10">0
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>33</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">100
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">95
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>34</bold></oasis:entry><oasis:entry colname="2">60
</oasis:entry><oasis:entry colname="3">20
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">60
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">0
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>35</bold></oasis:entry><oasis:entry colname="2">100
</oasis:entry><oasis:entry colname="3">100
</oasis:entry><oasis:entry colname="4">100
</oasis:entry><oasis:entry colname="5">80
</oasis:entry><oasis:entry colname="6">100
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">60
</oasis:entry><oasis:entry colname="13">40
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>36</bold></oasis:entry><oasis:entry colname="2">78
</oasis:entry><oasis:entry colname="3">71
</oasis:entry><oasis:entry colname="4">57
</oasis:entry><oasis:entry colname="5">42
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">40
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>37</bold></oasis:entry><oasis:entry colname="2">76
</oasis:entry><oasis:entry colname="3">65
</oasis:entry><oasis:entry colname="4">39
</oasis:entry><oasis:entry colname="5">37
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>38</bold></oasis:entry><oasis:entry colname="2">80
</oasis:entry><oasis:entry colname="3">74
</oasis:entry><oasis:entry colname="4">57
</oasis:entry><oasis:entry colname="5">40
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>39</bold></oasis:entry><oasis:entry colname="2">15
</oasis:entry><oasis:entry colname="3">0
</oasis:entry><oasis:entry colname="4">0
</oasis:entry><oasis:entry colname="5">0
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">99
</oasis:entry><oasis:entry colname="9">95
</oasis:entry><oasis:entry colname="10">90
</oasis:entry><oasis:entry colname="11">0
</oasis:entry><oasis:entry colname="12">0
</oasis:entry><oasis:entry colname="13">0
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">0
</oasis:entry><oasis:entry colname="16">0
</oasis:entry><oasis:entry colname="17">0
</oasis:entry></oasis:row><oasis:row><oasis:entry colname="1"><bold>40</bold></oasis:entry><oasis:entry colname="2">54
</oasis:entry><oasis:entry colname="3">40
</oasis:entry><oasis:entry colname="4">39
</oasis:entry><oasis:entry colname="5">30
</oasis:entry><oasis:entry colname="6">nd
</oasis:entry><oasis:entry colname="7">100
</oasis:entry><oasis:entry colname="8">100
</oasis:entry><oasis:entry colname="9">100
</oasis:entry><oasis:entry colname="10">T
</oasis:entry><oasis:entry colname="11">T
</oasis:entry><oasis:entry colname="12">T
</oasis:entry><oasis:entry colname="13">40
</oasis:entry><oasis:entry colname="14">T
</oasis:entry><oasis:entry colname="15">T
</oasis:entry><oasis:entry colname="16">T
</oasis:entry><oasis:entry colname="17">T</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><p><italic toggle="yes"><sup>a</sup></italic><sup></sup> nd, not determined.<italic toggle="yes"><sup>b</sup></italic><sup></sup> T, toxic upon mouse primary peritoneal macrophages used in the test.</p></table-wrap-foot></table-wrap></p></sec><sec id="d7e4207"><title>Discussion</title><p>Bisquinolines were used to overcome CQ resistance
since they were likely to be extruded with difficulty by
a proteinaceous transporter.<xref rid="jm990946nb00011" ref-type="bibr"></xref> They were also discovered
to inhibit the growth of CQ-sensitive and CQ-resistant
parasites. However, further development was suspended
for reasons of toxicity. Monoacridine derivatives were
reported to display high levels of antileishmanial and
antitrypanosomal activity<sup>16</sup> while quinacrine, the acridine analogue of CQ, was in clinical use before CQ.
Bisacridines could constitute an alternative to bisquinolines and avoid the efflux mechanism related to CQ
resistance. Compared with bisquinolines, bisacridines
are sterically more hindering, yet they have similar p<italic toggle="yes">K</italic><sub>a</sub>
values (p<italic toggle="yes">K</italic><sub>a</sub> of acridine rings = 6.5) which permit
ionization and consequent accumulation in the food
vacuole of <italic toggle="yes">Plasmodium</italic>. However their potential interaction with DNA is greater, especially in the case of
bisintercalation which can generate cytotoxicity. Bisintercalation requires a minimal distance between the
acridine rings, different if the “excluded site model”<named-content content-type="bibref-group"><xref rid="jm990946nb00030" ref-type="bibr"></xref>,<xref rid="jm990946nb00031" ref-type="bibr"></xref></named-content>
(two aromatic rings have to be separated by at least two
base pairs) is observed: ≥10.2 Å or not (two aromatic
rings on either side of a base pair): ≥6.8 Å. These
minimal distances were compared by Le Pecq and co-workers, with the distances calculated for bis(9-amino-6-chloro-2-methoxyacridines) bound with amino linkers.<xref rid="jm990946nb00017" ref-type="bibr"></xref> Compounds corresponding to a spermine or
spermidine linker displayed distances respectively of
16.1 and 11.2 Å and were found to bisintercalate, while
the removal of a single carbon (symmetical linker
−NH−(CH<sub>2</sub>)<sub>3</sub>−NH−(CH<sub>2</sub>)<sub>3</sub>−NH−) reduced the distance
to 9.9 Å and suppressed bisintercalation. The latter
named linker was therefore introduced into the majority
of compounds <bold>10</bold><bold>−</bold><bold>40</bold> and was substituted by a variety
of side chains in order to decrease possible interaction
with DNA. Bisacridines <bold>1</bold><bold>−</bold><bold>9</bold>, differing by the length,
the nature of the linker, and the absence of a side chain,
were also prepared and studied in comparison.
</p><p>For compounds <bold>1</bold><bold>−</bold><bold>9</bold>, no clear relationship appears
between potential bisintercalation and cytotoxic effects
upon MRC-5 cells. Among the compounds unable to
bisintercalate (compounds <bold>1</bold>, <bold>6</bold>, and <bold>7</bold>), cytotoxicity of <bold>1
</bold>upon MRC-5 cells cannot be related to a definite target
since this compound shows a diffuse labeling in murine
L-6 cell cytosol (Figure <xref rid="jm990946nf00001"></xref>D) while that of <bold>6 </bold>and<bold> 7</bold> might
be explained by the possible inhibition of the polyamine
metabolism.<xref rid="jm990946nb00032" ref-type="bibr"></xref> With compounds capable of bisintercalation (<bold>2</bold><bold>−</bold><bold>5</bold> and <bold>8</bold><bold>−</bold><bold>9</bold>), surprisingly no localization in the
nucleus of murine L-6 cells was observed by confocal
analysis. As with compound <bold>1</bold>, a diffuse labeling of the
cytoplasm was observed for compounds <bold>2</bold><bold>−</bold><bold>5</bold> and <bold>8</bold>, in
contrast to mepacrine which accumulated in the nucleus
(data not shown). Compounds <bold>4</bold> and <bold>5</bold> displayed the
lowest cytotoxic effects upon MRC-5 cells, while an
absence of cytotoxicity was noted for compound <bold>9</bold>. This
difference in cytotoxicity could reflect differences in their
cellular distribution. In fact, introduction of a piperazine
leads to the capture of compound <bold>9</bold> in lysosome-like
vesicules of L-6 cells (Figure <xref rid="jm990946nf00001"></xref>B). The high level of
activity of compound <bold>9</bold> upon <italic toggle="yes">P. </italic><italic toggle="yes">falciparum</italic> could result
from its greater accumulation in the parasite nucleus
(Figure <xref rid="jm990946nf00001"></xref>A) and its bisintercalating properties. The
difference in composition of plasmodial and mammalian
DNA may contribute to such a sizable accumulation.<named-content content-type="bibref-group"><xref rid="jm990946nb00033" ref-type="bibr"></xref>,<xref rid="jm990946nb00034" ref-type="bibr"></xref></named-content>
However, cytoplasmic labeling in the parasite was also
observed for compound <bold>9</bold>, as well as for compounds <bold>2</bold><bold>−</bold><bold>5
</bold>and <bold>8</bold>, suggesting that these compounds might also
interfere with cytoplasmic targets.
</p><p>Each of the compounds <bold>1</bold><bold>−</bold><bold>8</bold> shows a high level of
activity upon <italic toggle="yes">T. brucei</italic>, yet none of which can be
retained due to their toxicity found upon murine macrophages and of the known sensitivity of <italic toggle="yes">T. brucei</italic> to
toxic compounds. Therapeutic indexes of compounds <bold>4</bold>
and <bold>5</bold> proved to be too weak for potential drug use in
large numbers of patients benefitting only from a
minimal medical supervision. Thus from series A and
B, compound <bold>9</bold> is the sole representative worthy of note
as a trypanocidal lead and especially as an antimalarial
lead whose interest is enhanced by its consistent efficiency whatever the CQ sensitivity of the strain tested
(Table <xref rid="jm990946nt00003"></xref>).
</p><p>With the exception of <bold>11</bold> and <bold>12</bold>, compounds <bold>10</bold><bold>−</bold><bold>40</bold>
are derived from compound <bold>6</bold> with their side chain
bound by an amide bond. As expected, the nature of
their respective side chains had a strong influence on
both cytotoxicity and activity against parasites. When
bisacridines <bold>10</bold><bold>−</bold><bold>40</bold> were compared with starting compound <bold>6</bold>, a global decrease in cytotoxic effects upon
MRC-5 cells was observed while activity upon macrophages remained high. Only compounds <bold>25 </bold>and<bold> 29</bold><bold>−</bold><bold>32</bold>
cause no or low levels of cytotoxicity upon both cell lines,
and from among them, four include the presence of a
polar group (alcohol, amino, or carboxylic). The relative
polarity of this group renders likely a decreased cellular
availability that would be responsible for this low
cytotoxicity and also for the weak activity against all
parasites, with the exception of <italic toggle="yes">T. brucei</italic>. <italic toggle="yes">T. brucei</italic>
differs from <italic toggle="yes">P. falciparum</italic>, <italic toggle="yes">T. </italic><italic toggle="yes">cruzi</italic>, and <italic toggle="yes">L. infantum</italic>
by an extracellular growth that confers differences in
biochemical pathways, especially in polyamine metabolism.<xref rid="jm990946nb00035" ref-type="bibr"></xref> Trypanothione reductase from <italic toggle="yes">T. cruzi</italic>, which
is inhibited by compound <bold>29</bold> (IC<sub>50</sub> = 20 μM), cannot be
retained as the target since this compound is totally
inactive upon <italic toggle="yes">T. cruzi. </italic>Compounds <bold>10</bold>, <bold>13</bold>, and <bold>15</bold><bold>−</bold><bold>16</bold>
display high levels of activity upon <italic toggle="yes">T. cruzi </italic>and <italic toggle="yes">L.
</italic><italic toggle="yes">infantum </italic>at 1.56 μM. They also show an intriguing
inverse correlation toward <italic toggle="yes">P. </italic><italic toggle="yes">falciparum</italic> growth inhibition for the seven strains studied and varying in their
sensitivity to CQ. This might suggest either the presence of more sensitive target(s) in CQ-resistant parasites compared with CQ-sensitive ones or a higher
accumulation inside the CQ-resistant parasites due to
mechanism(s) which might be involved in CQ resistance.
However, interest in these four compounds is rendered
questionable by their cytotoxic effects upon MRC-5 cells
and macrophages.
</p></sec><sec id="d7e4492"><title>Conclusions</title><p>From the hypothesis that bulky structures are extruded with difficulty by CQ-resistant strains of <italic toggle="yes">P.
falciparum,</italic> a series of bisacridine derivatives (aliphatic
di-, tri-, and tetramine) was prepared. A side chain with
a variety of amino acid residues was attached to the
polyamine linker, both to improve the weak solubility
of this type of compound and to reduce the possible
interaction with human DNA. The introduction of a
piperazine moiety to the linker led to a unique behavior: a strong and selective activity upon <italic toggle="yes">Plasmodium,</italic>
a localization outside of the food vacuole and associated
mainly with the parasite nucleus along with a total
absence of cytotoxic effects upon MRC-5 cells and
murine macrophages. Although no structure−activity
relationship was evident in the C series with respect to
bisintercalation, the presence of a polar group in the
side chain attached to the linker afforded a reduction
in antimalarial activity while favoring a specific activity
upon <italic toggle="yes">T</italic>. <italic toggle="yes">brucei.</italic></p><p>Compounds <bold>9</bold>, <bold>25</bold>, <bold>30</bold>, and <bold>31</bold>, which satisfy both of
the conditions required for antiparasitic drugs, e.g.
safety and low cost, can be considered as good, new lead
structures against <italic toggle="yes">P. falciparum</italic> and <italic toggle="yes">T. brucei.</italic></p></sec><sec id="d7e4530"><title>Experimental Section</title><p><bold>In Vitro </bold><bold><italic toggle="yes">P. falciparum</italic></bold><bold> Culture and Drug Assays.</bold> <italic toggle="yes">P.
falciparum</italic> strains were maintained in continuous culture on
human erythrocytes as described by Trager and Jensen.<xref rid="jm990946nb00036" ref-type="bibr"></xref> In
vitro antiplasmodial activity was determined using a modification of the semiautomated microdilution technique of Desjardins et al.<xref rid="jm990946nb00037" ref-type="bibr"></xref> <italic toggle="yes">P. falciparum</italic> CQ-sensitive (3D7/unknown origin,
F32a/Tanzania, GP1/Thailand), moderately CQ-resistant (FCR3/Gambia), and CQ-resistant (FcB1R/Colombia, FCM29/Cameroun, K1/Thailand, W2/Indochina) strains were used in
sensitivity testing. FcB1R, F32a, GP1, and FCM29 were
strains obtained by limit dilution. Stock solutions of chloroquine diphosphate and test compounds were prepared in
sterile distilled water and DMSO, respectively. Drug solutions
were serially diluted with culture medium and added to
asynchronous parasite cultures (0.5% parasitemia and 1% final
hematocrite) in 96-well plates for 24 h, at 37 °C, prior to the
addition of 0.5 μCi of [<sup>3</sup>H]hypoxanthine (1−5 Ci/mmol; Amersham, Les Ulis, France) per well, for 24 h. The growth
inhibition for each drug concentration was determined by a
relative comparison of the radioactivity incorporated in the
treated culture with that in the control culture (without drug)
maintained on the same plate. The concentration causing 50%
inhibition (IC<sub>50</sub>) was obtained from the drug concentration−response curve, and the results are expressed as the mean
determined from several independent experiments. The DMSO
concentration never exceeded 0.1% and did not inhibit the
parasite growth.
</p><p><bold>Cytotoxicity Test upon MRC-5 Cells. </bold>A human diploid
embryonic lung cell line (MRC-5, Bio-Whittaker 72211D) and
primary peritoneal mouse macrophages were used to assess
the cytotoxicity for host cells. The peritoneal macrophages were
collected from the peritoneal cavity 48 h after stimulation with
potato starch and seeded in 96-well microplates at 30 000 cells/well. MRC-5 cells were seeded at 5 000 cells/well. After 24 h,
the cells were washed and 2-fold dilutions of the drug were
added in 200 μL of standard culture medium (RPMI + 5%
FCS). The final DMSO concentration in the culture remained
below 0.5%. The cultures were incubated with four concentrations of compounds (25, 12.5, 6.25, and 3.13 μM) at 37 °C in
5% CO<sub>2</sub>−95% air for 7 days. Untreated cultures were included
as controls. For MRC-5 cells, the cytotoxicity was determined
using the colorimetric MTT assay<xref rid="jm990946nb00038" ref-type="bibr"></xref> and scored as a percent
(%) reduction of absorption at 540 nm of treated cultures
versus untreated control cultures. For macrophages, scoring
was performed microscopically.
</p><p><bold>In Vitro Activity against </bold><bold><italic toggle="yes">T. brucei</italic></bold><bold> Trypomastigotes.
</bold>Bloodstream forms of <italic toggle="yes">T. brucei</italic> were cultivated in HMI-9
medium.<xref rid="jm990946nb00039" ref-type="bibr"></xref> In a 96-well microplate, 10 000 hemoflagellates
were incubated at different drug concentrations (12.5, 6.25,
3.13, and 1.56 μM) for 4 days. Parasite multiplication was
measured colorimetrically (490 nm) following addition of MTT,
which converts to an aqueous soluble, formazan product.<xref rid="jm990946nb00038" ref-type="bibr"></xref></p><p><bold>In Vitro Activity against Intracellular </bold><bold><italic toggle="yes">T. cruzi</italic></bold><bold> Amastigotes. </bold>Primary mouse peritoneal macrophages were seeded in
96-well microplates at 30 000 cells/well. After 24 h, about
10 0000 trypomastigotes of <italic toggle="yes">T. cruzi</italic> were added per well
together with 2-fold dilutions of the drug. The cultures were
incubated at 37 °C in 5% CO<sub>2</sub>−95% air for 4 days. Following
fixation in methanol and Giemsa staining, the drug activity
was semiquantitatively scored as a percent (%) reduction of
the total parasite load (free trypomastigotes and intracellular
amastigotes) compared with untreated control cultures. Scoring was performed microscopically.
</p><p><bold>In Vitro Activity against Intracellular </bold><bold><italic toggle="yes">L. infantum</italic></bold><bold>
Amastigotes.</bold> Primary mouse peritoneal macrophages were
seeded in 16-well Lab-Tek culture slides at 30 000 cells/well.
After 24 h, amastigotes of <italic toggle="yes">L. infantum</italic> (derived from the spleen
of an infected donor animal) were added at an infection ratio
of 10/1 together with 2-fold dilutions of the drug. The cultures
were incubated at 37 °C in 5% CO<sub>2</sub>−95% air for 7 days.
Treatment of uninfected control cultures was also included to
determine a selectivity index. Drug activity was semiquantitatively scored as a percent (%) reduction of the total parasite
load or the number of infected macrophages in Wright stained
preparations. Scoring was performed microscopically.
</p><p><bold>Confocal Microscopy.</bold> <italic toggle="yes">P. falciparum</italic>-infected red blood
cells were maintained for 1 h under normal culture conditions,
at 37 °C, in the presence of 1 μM bisacridine derivative.
Following two washes (2000<italic toggle="yes">g</italic>, 5 min), cells were incubated in
culture medium without serum for 15 min in the presence of
10 μg/mL DIL C<sub>18</sub>(3) (1,1‘-dioctadecyl-3,3,3‘,3‘-tetramethylindocarbocyanine perchlorate; Molecular Probes, Inc., Eugene,
OR). After three further washes, cells were mounted on poly-<sc>l</sc>-lysine-coated slides and immediately observed using a confocal laser scanning microscope (MRC 1024, Bio-Rad). In some
experiments, following incubation with a bisacridine derivative, cells were fixed with 2% (v/v) formaldehyde in phosphate-buffered saline (PBS), washed twice, and incubated for 15 min
with 20 μg/mL propidium iodide or 2 μg/mL DAPI (Sigma).
Cells were observed after two further washes; no difference
in labeling with bisacridine derivatives was noted between
either living or fixed cells, or cells not incubated with DIL C<sub>18</sub>(3). For the labeling with mepacrine, infected erythrocytes
were incubated with 10 μM drug for 1 h, washed twice, and
immediately observed. Murine muscle L-6 cells were grown
in 8-well Lab-Tek culture slides (Nunc, Inc., Naperville, IL)
in DMEM supplemented with 5% (v/v) fetal calf serum, at 37
°C, in 5% CO<sub>2</sub>−95% air. Cells were incubated for 1 h in the
presence of 1 μM bisacridine derivative and washed three
times prior to observation. For double-labeling experiments
using a lysosome-specific probe, cells were incubated simultaneously with a bisacridine derivative and LysoTracker Red
DND-99 diluted according to the manufacturer's recommendations (Molecular Probes). <italic toggle="yes">T. cruzi</italic> epimastigotes (Y strain) were
maintained and grown in liver infusion medium, containing
10% (v/v) fetal calf serum, at 28 °C.<xref rid="jm990946nb00040" ref-type="bibr"></xref> Cells were washed twice
in PBS and incubated with 1 μM bisacridine derivative in PBS,
for 1 h. After three washes with PBS, cells were fixed with
1% (v/v) formaldehyde in PBS and incubated for 15 min with
2 μg/mL DAPI. Cells were observed following three further
washes.
</p><p><bold>Assays for TR Inhibition.</bold> Recombinant <italic toggle="yes">T. cruzi</italic> trypanothione reductase was produced from the SG5 <italic toggle="yes">Escherichia coli</italic>
strain with the overproducing expression vector pIBITczTR.
TR activity was measured at 21 °C in 0.02 M Hepes buffer,
pH 7.25, containing 0.15 M KCl, 1 mM EDTA, and 0.2 mM
NADPH with an enzyme concentration of 0.02 U mL<sup>-1</sup>. The
reaction was promoted by the addition of the enzyme, and the
subsequent NADPH oxidation was followed at 340 nm. IC<sub>50</sub>
of the different compounds was evaluated in the presence of
50 μM T(S)<sub>2</sub> and 1% DMSO.
</p></sec></body><back><ack><title>Acknowledgments</title><p>We express our thanks to Gérard Montagne for NMR experiments, Valérie Landry
for IC<sub>50</sub> measurements upon TR, and Dr. Steve Brooks
and Sandrine Delarue for proofreading. This work was
supported by CNRS (GDR 1077, EP CNRS 1790, UMR
CNRS 8525) and Université de Lille II.
</p></ack><notes notes-type="si"><sec id="d7e4682"><title><ext-link xlink:href="/doi/suppl/10.1021%2Fjm990946n">Supporting Information Available</ext-link></title><p>Details of chemical
procedures and analytical data. This material is available free
of charge via the Internet at <uri xlink:href="http://pubs.acs.org">http://pubs.acs.org</uri>.
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Sao Paulo</source><year>1964</year><volume>6</volume><fpage>63</fpage><lpage>100</lpage></element-citation></ref></ref-list></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Antimalarial, Antitrypanosomal, and Antileishmanial Activities and Cytotoxicity of Bis(9-amino-6-chloro-2-methoxyacridines): Influence of the Linker#</title></titleInfo><name type="personal"><namePart type="family">GIRAULT</namePart><namePart type="given">Sophie</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">GRELLIER</namePart><namePart type="given">Philippe</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> CNRS - EP1790.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">BERECIBAR</namePart><namePart type="given">Amaya</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">MAES</namePart><namePart type="given">Louis</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Tibotec.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">MOURAY</namePart><namePart type="given">Elisabeth</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> CNRS - EP1790.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">LEMIèRE</namePart><namePart type="given">Pascal</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">DEBREU</namePart><namePart type="given">Marie-Ange</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">DAVIOUD-CHARVET</namePart><namePart type="given">Elisabeth</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="family">SERGHERAERT</namePart><namePart type="given">Christian</namePart><affiliation>UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447,59021 Lille, France, Muséum National d'Histoire Naturelle, Biologie et Evolution des Parasites, CNRS - EP1790,61 rue Buffon, 75005 Paris, France, and Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium</affiliation><affiliation> Institut de Biologie et Institut Pasteur de Lille.</affiliation><affiliation> Corresponding author. Tel: (33) 3 20 87 12 11. Fax: (33) 3 20 8712 33. E-mail: christian.sergheraert@pasteur-lille.fr.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>American Chemical Society</publisher><dateCreated encoding="w3cdtf">2000-06-17</dateCreated><dateIssued encoding="w3cdtf">2000-07-13</dateIssued><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><note type="footnote" ID="jm990946nAF10"> Abbreviations: CQ, chloroquine; DAPI, 4,6-diamidino-2-phenylindole; MF, mefloquine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue); PyBrop, bromotris(pyrrolidinophosphonium) hexafluorophosphate.</note><note type="footnote" ID="jm990946nAF6"> Present address: Institut de Recherche Jouveinal, Parke-Davis, 3-9 rue de la Loge, 94265 Fresnes Cedex, France.</note><abstract>Forty bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties are joined by alkanediamines, polyamines, or polyamines substituted by a side chain, were synthesized and tested for their in vitro activity upon the erythrocytic stage of Plasmodium falciparum, trypomastigote stage of Trypanosoma brucei, and amastigote stage of Trypanosoma cruzi and Leishmania infantum as well as for their cytotoxic effects upon MRC-5 cells. Results clearly showed the importance of the nature of the linker and of its side chain for antiparasitic activity, cytotoxicity, and cellular localization. Among several compounds devoid of cytotoxic effects at 25 μM upon MRC-5 cells, one displayed IC50 values ranging from 8 to 18 nM against different P. falciparum strains while three others totally inhibited T. brucei at 1.56 μM.</abstract><note type="footnote" ID="jm990946nAF10"> Abbreviations: CQ, chloroquine; DAPI, 4,6-diamidino-2-phenylindole; MF, mefloquine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (thiazolyl blue); PyBrop, bromotris(pyrrolidinophosphonium) hexafluorophosphate.</note><note type="footnote" ID="jm990946nAF6"> Present address: Institut de Recherche Jouveinal, Parke-Davis, 3-9 rue de la Loge, 94265 Fresnes Cedex, France.</note><relatedItem type="host"><titleInfo><title>Journal of Medicinal Chemistry</title></titleInfo><titleInfo type="abbreviated"><title>J. Med. Chem.</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-2623</identifier><identifier type="eISSN">1520-4804</identifier><identifier type="acspubs">jm</identifier><identifier type="coden">JMCMAR</identifier><identifier type="uri">pubs.acs.org/jmc</identifier><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>43</number></detail><detail type="issue"><caption>no.</caption><number>14</number></detail><extent unit="pages"><start>2646</start><end>2654</end></extent></part></relatedItem><identifier type="istex">D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0</identifier><identifier type="ark">ark:/67375/TPS-GDW43MKP-L</identifier><identifier type="DOI">10.1021/jm990946n</identifier><accessCondition type="use and reproduction" contentType="restricted">Copyright © 2000 American Chemical Society</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-X5HBJWF8-J">ACS</recordContentSource><recordOrigin>Copyright © 2000 American Chemical Society</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/record.json</uri></json:item></metadata><annexes><json:item><extension>eps</extension><original>true</original><mimetype>image/x-eps</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/annexes.eps</uri></json:item><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-GDW43MKP-L/annexes.jpeg</uri></json:item><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/D2AAC6B3D985D89F2FCF2ED09FF72A07FFFD56E0/annexes/tiff</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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