A Prodrug Form of a Plasmodium falciparum Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline
Identifieur interne : 000194 ( Istex/Curation ); précédent : 000193; suivant : 000195A Prodrug Form of a Plasmodium falciparum Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline
Auteurs : Elisabeth Davioud-Charvet [Allemagne, États-Unis] ; Sandrine Delarue [Allemagne] ; Christophe Biot [Allemagne] ; Babett Schwöbel [Allemagne] ; Catharina C. Boehme [Allemagne] ; Andreas Müssigbrodt [Allemagne] ; Louis Maes [Allemagne] ; Christian Sergheraert [Allemagne] ; Philippe Grellier [Allemagne] ; R. Heiner Schirmer [Allemagne] ; Katja Becker [Allemagne]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2001.
Abstract
Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED50 values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED50 being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.
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DOI: 10.1021/jm010268g
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>A Prodrug Form of a Plasmodium falciparum Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline</title><author><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation><wicri:noCountry code="no comma"> UMR 8525 CNRS−Université de Lille II-IPL.</wicri:noCountry></affiliation><affiliation wicri:level="2"><mods:affiliation> Present address: College of Pharmacy, University of Michigan,428 Church Street, Ann Arbor, MI 48109-1065.</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea> Present address: College of Pharmacy, University of Michigan,428 Church Street, Ann Arbor</wicri:cityArea></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</mods:affiliation><wicri:noCountry code="no comma"> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</wicri:noCountry></affiliation></author><author><name sortKey="Delarue, Sandrine" sort="Delarue, Sandrine" uniqKey="Delarue S" first="Sandrine" last="Delarue">Sandrine Delarue</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation><wicri:noCountry code="no comma"> UMR 8525 CNRS−Université de Lille II-IPL.</wicri:noCountry></affiliation></author><author><name sortKey="Biot, Christophe" sort="Biot, Christophe" uniqKey="Biot C" first="Christophe" last="Biot">Christophe Biot</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and 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Giessen.</wicri:noCountry></affiliation></author><author><name sortKey="Boehme, Catharina C" sort="Boehme, Catharina C" uniqKey="Boehme C" first="Catharina C." last="Boehme">Catharina C. 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Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Interdisziplinäres Forschungszentrum der Universität Giessen.</mods:affiliation><wicri:noCountry code="no comma"> Interdisziplinäres Forschungszentrum der Universität Giessen.</wicri:noCountry></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation><wicri:noCountry code="no comma"> Biochemie-Zentrum der Universität Heidelberg.</wicri:noCountry></affiliation></author><author><name sortKey="Mussigbrodt, Andreas" sort="Mussigbrodt, Andreas" uniqKey="Mussigbrodt A" first="Andreas" last="Müssigbrodt">Andreas Müssigbrodt</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation><wicri:noCountry code="no comma"> Biochemie-Zentrum der Universität Heidelberg.</wicri:noCountry></affiliation></author><author><name sortKey="Maes, Louis" sort="Maes, Louis" uniqKey="Maes L" first="Louis" last="Maes">Louis Maes</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Tibotec.</mods:affiliation><wicri:noCountry code="no comma"> Tibotec.</wicri:noCountry></affiliation></author><author><name sortKey="Sergheraert, Christian" sort="Sergheraert, Christian" uniqKey="Sergheraert C" first="Christian" last="Sergheraert">Christian Sergheraert</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation><wicri:noCountry code="no comma"> UMR 8525 CNRS−Université de Lille II-IPL.</wicri:noCountry></affiliation></author><author><name sortKey="Grellier, Philippe" sort="Grellier, Philippe" uniqKey="Grellier P" first="Philippe" last="Grellier">Philippe Grellier</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Muséum National d'Histoire Naturelle.</mods:affiliation><wicri:noCountry code="no comma"> Muséum National d'Histoire Naturelle.</wicri:noCountry></affiliation></author><author><name sortKey="Schirmer, R Heiner" sort="Schirmer, R Heiner" uniqKey="Schirmer R" first="R. Heiner" last="Schirmer">R. Heiner Schirmer</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation><wicri:noCountry code="no comma"> Biochemie-Zentrum der Universität Heidelberg.</wicri:noCountry></affiliation></author><author><name sortKey="Becker, Katja" sort="Becker, Katja" uniqKey="Becker K" first="Katja" last="Becker">Katja Becker</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Interdisziplinäres Forschungszentrum der Universität Giessen.</mods:affiliation><wicri:noCountry code="no comma"> Interdisziplinäres Forschungszentrum der Universität Giessen.</wicri:noCountry></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</mods:affiliation><wicri:noCountry code="no comma"> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E43EEA0ED3C756078348A9AE186AEAF4B52291FC</idno><date when="2001" year="2001">2001</date><idno type="doi">10.1021/jm010268g</idno><idno type="url">https://api.istex.fr/ark:/67375/TPS-NQT42VGL-Q/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000194</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000194</idno><idno type="wicri:Area/Istex/Curation">000194</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">A Prodrug Form of a <hi rend="italic">Plasmodium falciparum </hi>Glutathione Reductase Inhibitor
Conjugated with a 4-Anilinoquinoline</title><author><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation></affiliation><affiliation wicri:level="2"><mods:affiliation> Present address: College of Pharmacy, University of Michigan,428 Church Street, Ann Arbor, MI 48109-1065.</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea> Present address: College of Pharmacy, University of Michigan,428 Church Street, Ann Arbor</wicri:cityArea></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</mods:affiliation></affiliation></author><author><name sortKey="Delarue, Sandrine" sort="Delarue, Sandrine" uniqKey="Delarue S" first="Sandrine" last="Delarue">Sandrine Delarue</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation></affiliation></author><author><name sortKey="Biot, Christophe" sort="Biot, Christophe" uniqKey="Biot C" first="Christophe" last="Biot">Christophe Biot</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation></affiliation></author><author><name sortKey="Schwobel, Babett" sort="Schwobel, Babett" uniqKey="Schwobel B" first="Babett" last="Schwöbel">Babett Schwöbel</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Interdisziplinäres Forschungszentrum der Universität Giessen.</mods:affiliation></affiliation></author><author><name sortKey="Boehme, Catharina C" sort="Boehme, Catharina C" uniqKey="Boehme C" first="Catharina C." last="Boehme">Catharina C. Boehme</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Interdisziplinäres Forschungszentrum der Universität Giessen.</mods:affiliation></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation></affiliation></author><author><name sortKey="Mussigbrodt, Andreas" sort="Mussigbrodt, Andreas" uniqKey="Mussigbrodt A" first="Andreas" last="Müssigbrodt">Andreas Müssigbrodt</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation></affiliation></author><author><name sortKey="Maes, Louis" sort="Maes, Louis" uniqKey="Maes L" first="Louis" last="Maes">Louis Maes</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Tibotec.</mods:affiliation></affiliation></author><author><name sortKey="Sergheraert, Christian" sort="Sergheraert, Christian" uniqKey="Sergheraert C" first="Christian" last="Sergheraert">Christian Sergheraert</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> UMR 8525 CNRS−Université de Lille II-IPL.</mods:affiliation></affiliation></author><author><name sortKey="Grellier, Philippe" sort="Grellier, Philippe" uniqKey="Grellier P" first="Philippe" last="Grellier">Philippe Grellier</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Muséum National d'Histoire Naturelle.</mods:affiliation></affiliation></author><author><name sortKey="Schirmer, R Heiner" sort="Schirmer, R Heiner" uniqKey="Schirmer R" first="R. Heiner" last="Schirmer">R. Heiner Schirmer</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation></affiliation></author><author><name sortKey="Becker, Katja" sort="Becker, Katja" uniqKey="Becker K" first="Katja" last="Becker">Katja Becker</name><affiliation wicri:level="1"><mods:affiliation>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>UMR 8525 CNRS−Université Lille II−Institut Pasteur de Lille, Institut de Biologie de Lille, 1 rue du Professeur Calmette,BP447 59021 Lille Cedex, France, Tibotec, L11 Gen. de Wittelaan, B-32800 Mechelen, Belgium, Laboratoire de BiologieParasitaire, Muséum National d'Histoire Naturelle, IFR CNRS 63, 61 rue Buffon, 75005 Paris, France, Biochemie-Zentrumder Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, and InterdisziplinäresForschungszentrum der Universität Giessen, Heinrich Buff-Ring 26-32, D-35392 Giessen</wicri:regionArea></affiliation><affiliation><mods:affiliation> Interdisziplinäres Forschungszentrum der Universität Giessen.</mods:affiliation></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. For E.D.-C.: (phone) +1 (734) 615 1281; (fax) +1 (734) 615 3079; (e-mail)edavioud@umich.edu. For K.B.: (phone) (49) 6419 93 91 20; (fax) (49)6419 93 91 29; (e-mail) becker.katja@gmx.de.</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="2001-10-26">2001</date><date when="2001-11-22">2001</date><biblScope unit="vol">44</biblScope><biblScope unit="issue">24</biblScope><biblScope unit="page" from="4268">4268</biblScope><biblScope unit="page" to="4276">4276</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">Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED50 values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED50 being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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