5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
Identifieur interne : 001F31 ( Main/Exploration ); précédent : 001F30; suivant : 001F325-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
Auteurs : Christophe Biot [Allemagne, France] ; Holger Bauer [Allemagne] ; R. Heiner Schirmer [Allemagne] ; Elisabeth Davioud-Charvet [Allemagne, France]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2004.
Abstract
Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2‘-(3‘-methyl)-1‘,4‘-naphthoquinolyl] hexanoic acid M5 asan inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M5 action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M5 by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M5 and the bioisoteric tetrazole T4. The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.
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DOI: 10.1021/jm0497545
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Roosevelt,B-1050 Brussels, Belgium, UMR 8525 CNRS-Université Lille II-Institut Pasteur de Lille, Institut de Biologie de Lille,1 rue du Professor Calmette, BP447 59021 Lille Cedex, France, and Biochemie-Zentrum der Universität Heidelberg,Im Neuenheimer Feld 504, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country><wicri:regionArea> To whom correspondence should be addressed. E.D.-C.: tel, +49-6221-54-4188; fax, +49-6221-54-5586; e-mail, elisabeth.davioud@gmx.de.C.B.: tel, (33) 03 20 43 48 93; fax, (33) 03 20 43 65 85; e-mail</wicri:regionArea><wicri:noRegion>(33) 03 20 43 65 85; e-mail</wicri:noRegion><wicri:noRegion>(33) 03 20 43 65 85; e-mail</wicri:noRegion></affiliation></author><author><name sortKey="Bauer, Holger" sort="Bauer, Holger" uniqKey="Bauer H" first="Holger" last="Bauer">Holger Bauer</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bioinformatique Génomique et Structurale, CP 165/61, Université Libre de Bruxelles, 50 Av. F. D. Roosevelt,B-1050 Brussels, Belgium, UMR 8525 CNRS-Université Lille II-Institut Pasteur de Lille, Institut de Biologie de Lille,1 rue du Professor Calmette, BP447 59021 Lille Cedex, France, and Biochemie-Zentrum der Universität Heidelberg,Im Neuenheimer Feld 504, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea> Delegate (E.D.-C.) and Fellow (H.B.) of Centre National de laRecherche Scientifique, France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:regionArea><wicri:noRegion>France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:noRegion><wicri:noRegion>France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Schirmer, R Heiner" sort="Schirmer, R Heiner" uniqKey="Schirmer R" first="R. 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Roosevelt,B-1050 Brussels, Belgium, UMR 8525 CNRS-Université Lille II-Institut Pasteur de Lille, Institut de Biologie de Lille,1 rue du Professor Calmette, BP447 59021 Lille Cedex, France, and Biochemie-Zentrum der Universität Heidelberg,Im Neuenheimer Feld 504, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea> Delegate (E.D.-C.) and Fellow (H.B.) of Centre National de laRecherche Scientifique, France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:regionArea><wicri:noRegion>France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:noRegion><wicri:noRegion>France in the frame of a French−Germancooperation with the University of Heidelberg</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country><wicri:regionArea> To whom correspondence should be addressed. E.D.-C.: tel, +49-6221-54-4188; fax, +49-6221-54-5586; e-mail, elisabeth.davioud@gmx.de.C.B.: tel, (33) 03 20 43 48 93; fax, (33) 03 20 43 65 85; e-mail</wicri:regionArea><wicri:noRegion>(33) 03 20 43 65 85; e-mail</wicri:noRegion><wicri:noRegion>(33) 03 20 43 65 85; e-mail</wicri:noRegion></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="2004-10-26">2004</date><date when="2004-11-18">2004</date><biblScope unit="vol">47</biblScope><biblScope unit="issue">24</biblScope><biblScope unit="page" from="5972">5972</biblScope><biblScope unit="page" to="5983">5983</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">Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2‘-(3‘-methyl)-1‘,4‘-naphthoquinolyl] hexanoic acid M5 asan inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M5 action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M5 by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M5 and the bioisoteric tetrazole T4. The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li></region><settlement><li>Heidelberg</li></settlement><orgName><li>Université libre de Bruxelles</li></orgName></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Biot, Christophe" sort="Biot, Christophe" uniqKey="Biot C" first="Christophe" last="Biot">Christophe Biot</name></region><name sortKey="Bauer, Holger" sort="Bauer, Holger" uniqKey="Bauer H" first="Holger" last="Bauer">Holger Bauer</name><name sortKey="Bauer, Holger" sort="Bauer, Holger" uniqKey="Bauer H" first="Holger" last="Bauer">Holger Bauer</name><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><name sortKey="Davioud Charvet, Elisabeth" sort="Davioud Charvet, Elisabeth" uniqKey="Davioud Charvet E" first="Elisabeth" last="Davioud-Charvet">Elisabeth Davioud-Charvet</name><name sortKey="Schirmer, R Heiner" sort="Schirmer, R Heiner" uniqKey="Schirmer R" first="R. 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