5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
Identifieur interne : 000A31 ( Istex/Corpus ); précédent : 000A30; suivant : 000A325-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
Auteurs : Christophe Biot ; Holger Bauer ; R. Heiner Schirmer ; Elisabeth Davioud-CharvetSource :
- 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.
Url:
DOI: 10.1021/jm0497545
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ISTEX:C9C87D4357E24AFC2F532515535998AE3A5034F9Le document en format XML
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Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials</title><author><name sortKey="Biot, Christophe" sort="Biot, Christophe" uniqKey="Biot C" first="Christophe" last="Biot">Christophe Biot</name><affiliation><mods:affiliation>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, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation> Université Libre de Bruxelles.</mods:affiliation></affiliation><affiliation><mods:affiliation> 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,christophe.biot@ensc-lille.fr.</mods:affiliation></affiliation></author><author><name sortKey="Bauer, Holger" sort="Bauer, Holger" uniqKey="Bauer H" first="Holger" last="Bauer">Holger Bauer</name><affiliation><mods:affiliation>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, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie de Lille.</mods:affiliation></affiliation><affiliation><mods:affiliation> 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, Germany.</mods:affiliation></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</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><mods:affiliation>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, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</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>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, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation> Institut de Biologie de Lille.</mods:affiliation></affiliation><affiliation><mods:affiliation> 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, Germany.</mods:affiliation></affiliation><affiliation><mods:affiliation> Biochemie-Zentrum der Universität Heidelberg.</mods:affiliation></affiliation><affiliation><mods:affiliation> 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,christophe.biot@ensc-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="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><istex><corpusName>acs</corpusName><keywords><teeft><json:string>falciparum</json:string><json:string>glutathione</json:string><json:string>reductase</json:string><json:string>gssg</json:string><json:string>nadph</json:string><json:string>mmol</json:string><json:string>carboxylic</json:string><json:string>antimalarial</json:string><json:string>ester</json:string><json:string>uncompetitive</json:string><json:string>naphthoquinone</json:string><json:string>tetrazole</json:string><json:string>tetrazoles</json:string><json:string>chem</json:string><json:string>plasmodium</json:string><json:string>hplc</json:string><json:string>nadp</json:string><json:string>moiety</json:string><json:string>inhibitor</json:string><json:string>menadione</json:string><json:string>medicinal chemistry</json:string><json:string>disulfide</json:string><json:string>cdcl3</json:string><json:string>glutathione reductase</json:string><json:string>methylene</json:string><json:string>schirmer</json:string><json:string>equiv</json:string><json:string>chloroquine</json:string><json:string>biot</json:string><json:string>methylene blue</json:string><json:string>acidic</json:string><json:string>carboxylic acid</json:string><json:string>prodrugs</json:string><json:string>parasite</json:string><json:string>assay</json:string><json:string>biochem</json:string><json:string>redox</json:string><json:string>uncompetitive inhibition</json:string><json:string>trypanothione</json:string><json:string>trypanosoma</json:string><json:string>nucleosil</json:string><json:string>dmso</json:string><json:string>aminoester</json:string><json:string>room temperature</json:string><json:string>medicinal</json:string><json:string>molecular electrostatic potential</json:string><json:string>human glutathione reductase</json:string><json:string>parent carboxylic acid</json:string><json:string>amide</json:string><json:string>antimalarial activity</json:string><json:string>glutathione disulfide</json:string><json:string>binding site</json:string><json:string>naphthoquinone moiety</json:string><json:string>datum</json:string><json:string>heidelberg</json:string><json:string>molecular volume</json:string><json:string>blood cell</json:string><json:string>electronic profile</json:string><json:string>antiplasmodial activity</json:string><json:string>uncompetitive inhibitor</json:string><json:string>parasitic enzyme</json:string><json:string>weak base</json:string><json:string>potent inhibitor</json:string><json:string>ester bond</json:string><json:string>glutathione reductase inhibitor</json:string><json:string>subversive substrate</json:string><json:string>gssg reduction</json:string><json:string>heidelberg university</json:string><json:string>exogenous nadp</json:string><json:string>derivative</json:string><json:string>homo</json:string><json:string>ligand</json:string><json:string>antimalarial action</json:string><json:string>charge distribution</json:string><json:string>binary complex</json:string><json:string>previous observation</json:string><json:string>naphthoquinone reductase activity</json:string><json:string>human cell line</json:string><json:string>falciparum glutathione reductase</json:string><json:string>dixon plot</json:string><json:string>crystal structure</json:string><json:string>optimized geometry</json:string><json:string>deprotonated form</json:string><json:string>acidic compartment</json:string><json:string>same range</json:string><json:string>ternary complex</json:string><json:string>inhibition type</json:string><json:string>tetrazole moiety</json:string><json:string>gssg concentration</json:string><json:string>mass spectrum</json:string><json:string>plasmodium falciparum</json:string><json:string>kinetic study</json:string><json:string>human enzyme</json:string><json:string>dimer interface</json:string><json:string>yellow solid</json:string><json:string>malarial parasite plasmodium falciparum</json:string><json:string>amide bond</json:string><json:string>inhibition</json:string><json:string>enzyme</json:string></teeft></keywords><author><json:item><name>BIOT Christophe</name><affiliations><json:string>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, Germany</json:string><json:string>Université Libre de Bruxelles.</json:string><json:string>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,christophe.biot@ensc-lille.fr.</json:string></affiliations></json:item><json:item><name>BAUER Holger</name><affiliations><json:string>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, Germany</json:string><json:string>Institut de Biologie de Lille.</json:string><json:string>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, Germany.</json:string><json:string>Biochemie-Zentrum der Universität Heidelberg.</json:string></affiliations></json:item><json:item><name>SCHIRMER R. Heiner</name><affiliations><json:string>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, Germany</json:string><json:string>Biochemie-Zentrum der Universität Heidelberg.</json:string></affiliations></json:item><json:item><name>DAVIOUD-CHARVET Elisabeth</name><affiliations><json:string>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, Germany</json:string><json:string>Institut de Biologie de Lille.</json:string><json:string>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, Germany.</json:string><json:string>Biochemie-Zentrum der Universität Heidelberg.</json:string><json:string>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,christophe.biot@ensc-lille.fr.</json:string></affiliations></json:item></author><arkIstex>ark:/67375/TPS-X9C19PQL-5</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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. 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Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials</title><author xml:id="author-0000" role="corresp"><persName><surname>Biot</surname><forename type="first">Christophe</forename></persName><affiliation>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, Germany
</affiliation><note place="foot"><ref>†</ref><p>
Université Libre de Bruxelles.</p></note><affiliation role="corresp"> 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, christophe.biot@ensc-lille.fr.</affiliation></author><author xml:id="author-0001"><persName><surname>Bauer</surname><forename type="first">Holger</forename></persName><affiliation>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, Germany
</affiliation><note place="foot"><ref>‡</ref><p>
Institut de Biologie de Lille.</p></note><note place="foot"><ref>§</ref><p>
Delegate (E.D.-C.) and Fellow (H.B.) of Centre National de la
Recherche Scientifique, France in the frame of a French−German
cooperation with the University of Heidelberg, Germany.</p></note><note place="foot"><ref>‖</ref><p>
Biochemie-Zentrum der Universität Heidelberg.</p></note></author><author xml:id="author-0002"><persName><surname>Schirmer</surname><forename type="first">R. Heiner</forename></persName><affiliation>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, Germany
</affiliation><note place="foot"><ref>‖</ref><p>
Biochemie-Zentrum der Universität Heidelberg.</p></note></author><author xml:id="author-0003" role="corresp"><persName><surname>Davioud-Charvet</surname><forename type="first">Elisabeth</forename></persName><affiliation>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, Germany
</affiliation><note place="foot"><ref>‡</ref><p>
Institut de Biologie de Lille.</p></note><note place="foot"><ref>§</ref><p>
Delegate (E.D.-C.) and Fellow (H.B.) of Centre National de la
Recherche Scientifique, France in the frame of a French−German
cooperation with the University of Heidelberg, Germany.</p></note><note place="foot"><ref>‖</ref><p>
Biochemie-Zentrum der Universität Heidelberg.</p></note><affiliation role="corresp"> 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, christophe.biot@ensc-lille.fr.</affiliation></author><idno type="istex">C9C87D4357E24AFC2F532515535998AE3A5034F9</idno><idno type="ark">ark:/67375/TPS-X9C19PQL-5</idno><idno type="DOI">10.1021/jm0497545</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="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></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract><graphic url="jm0497545n00001.tif"></graphic><p><hi rend="italic">Plasmodium</hi> 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 <hi rend="italic">Plasmodium falciparum</hi> 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 <hi rend="bold">M</hi><hi rend="bold"><hi rend="subscript">5</hi></hi> asan inhibitor of the parasitic enzyme. As
reported here, revisiting the mechanism of <hi rend="bold">M</hi><hi rend="bold"><hi rend="subscript">5</hi></hi> action revealed an uncompetitive inhibition
type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic
function of <hi rend="bold">M</hi><hi rend="bold"><hi rend="subscript">5</hi></hi> 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 <hi rend="bold">M</hi><hi rend="bold"><hi rend="subscript">5</hi></hi> and the bioisoteric
tetrazole <hi rend="bold">T</hi><hi rend="bold"><hi rend="subscript">4</hi></hi>. The potential binding site of these molecules is discussed in light of the recently
solved crystallographic structure of <hi rend="italic">P. falciparum</hi> enzyme.
</p></abstract><textClass ana="subject"><keywords scheme="document-type-name"><term>Article</term></keywords></textClass><langUsage><language ident="zxx"></language></langUsage></profileDesc><revisionDesc><change xml:id="refBibs-istex" who="#ISTEX-API" when="2019-08-1">References added</change></revisionDesc></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-2.0.3"><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/jm0497545</article-id><article-categories><subj-group subj-group-type="document-type-name"><subject>Article</subject></subj-group></article-categories><title-group><article-title>5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and
Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Biot</surname><given-names>Christophe</given-names></name><xref rid="jm0497545AF1">*</xref><xref rid="jm0497545AF2">†</xref></contrib><contrib contrib-type="author"><name><surname>Bauer</surname><given-names>Holger</given-names></name><xref rid="jm0497545AF3">‡</xref><xref rid="jm0497545AF4">§</xref><xref rid="jm0497545AF5">‖</xref></contrib><contrib contrib-type="author"><name><surname>Schirmer</surname><given-names>R. Heiner</given-names></name><xref rid="jm0497545AF5">‖</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Davioud-Charvet</surname><given-names>Elisabeth</given-names></name><xref rid="jm0497545AF1">*</xref><xref rid="jm0497545AF3">‡</xref><xref rid="jm0497545AF4">§</xref><xref rid="jm0497545AF5">‖</xref></contrib><aff>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, Germany
</aff></contrib-group><author-notes><corresp id="jm0497545AF1">
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,
christophe.biot@ensc-lille.fr.</corresp><fn id="jm0497545AF2"><label>†</label><p>
Université Libre de Bruxelles.</p></fn><fn id="jm0497545AF3"><label>‡</label><p>
Institut de Biologie de Lille.</p></fn><fn id="jm0497545AF4"><label>§</label><p>
Delegate (E.D.-C.) and Fellow (H.B.) of Centre National de la
Recherche Scientifique, France in the frame of a French−German
cooperation with the University of Heidelberg, Germany.</p></fn><fn id="jm0497545AF5"><label>‖</label><p>
Biochemie-Zentrum der Universität Heidelberg.</p></fn></author-notes><pub-date pub-type="epub"><day>26</day><month>10</month><year>2004</year></pub-date><pub-date pub-type="ppub"><day>18</day><month>11</month><year>2004</year></pub-date><volume>47</volume><issue>24</issue><fpage>5972</fpage><lpage>5983</lpage><history><date date-type="received"><day>30</day><month>03</month><year>2004</year></date><date date-type="asap"><day>26</day><month>10</month><year>2004</year></date><date date-type="issue-pub"><day>18</day><month>11</month><year>2004</year></date></history><permissions><copyright-statement>Copyright © 2004 American Chemical Society</copyright-statement><copyright-year>2004</copyright-year><copyright-holder>American Chemical Society</copyright-holder></permissions><abstract><graphic content-type="abstract-graphic" xlink:href="jm0497545n00001.tif"></graphic><p><italic>Plasmodium</italic> 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 <italic>Plasmodium falciparum</italic> 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 <bold>M</bold><bold><sub>5</sub></bold> as<bold></bold>an inhibitor of the parasitic enzyme. As
reported here, revisiting the mechanism of <bold>M</bold><bold><sub>5</sub></bold> action revealed an uncompetitive inhibition
type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic
function of <bold>M</bold><bold><sub>5</sub></bold> 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 <bold>M</bold><bold><sub>5</sub></bold> and the bioisoteric
tetrazole <bold>T</bold><bold><sub>4</sub></bold>. The potential binding site of these molecules is discussed in light of the recently
solved crystallographic structure of <italic>P. falciparum</italic> enzyme.
</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>jm0497545</meta-value></custom-meta></custom-meta-group></article-meta></front><body></body><back></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="family">BIOT</namePart><namePart type="given">Christophe</namePart><affiliation>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, Germany</affiliation><affiliation> Université Libre de Bruxelles.</affiliation><affiliation> 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,christophe.biot@ensc-lille.fr.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">BAUER</namePart><namePart type="given">Holger</namePart><affiliation>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, Germany</affiliation><affiliation> Institut de Biologie de Lille.</affiliation><affiliation> 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, Germany.</affiliation><affiliation> Biochemie-Zentrum der Universität Heidelberg.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">SCHIRMER</namePart><namePart type="given">R. Heiner</namePart><affiliation>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, Germany</affiliation><affiliation> Biochemie-Zentrum der Universität Heidelberg.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="family">DAVIOUD-CHARVET</namePart><namePart type="given">Elisabeth</namePart><affiliation>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, Germany</affiliation><affiliation> Institut de Biologie de Lille.</affiliation><affiliation> 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, Germany.</affiliation><affiliation> Biochemie-Zentrum der Universität Heidelberg.</affiliation><affiliation> 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,christophe.biot@ensc-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">2004-10-26</dateCreated><dateIssued encoding="w3cdtf">2004-11-18</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><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.</abstract><relatedItem type="host"><titleInfo><title>Journal of Medicinal Chemistry</title></titleInfo><titleInfo type="abbreviated"><title>J. Med. 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