SrasV1, PascalFrancis, Curation, bibRecord, 000514

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors : Design, synthesis, biological activities, and mechanism of action

Identifieur interne : 000514 ( PascalFrancis/Curation ); précédent : 000513; suivant : 000515

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors : Design, synthesis, biological activities, and mechanism of action

Auteurs : Roberto Di Santo [Italie] ; Roberta Costi [Italie] ; Alessandra Roux [Italie] ; Marino Artico [Italie] ; Antonio Lavecchia [Italie] ; Luciana Marinelli [Italie] ; Ettore Novellino [Italie] ; Lucia Palmisano [Italie] ; Mauro Andreotti [Italie] ; Roberta Amici [Italie] ; Clementina Maria Galluzzo [Italie] ; Lucia Nencioni [Italie] ; Anna Teresa Palamara [Italie] ; Yves Pommier [États-Unis] ; Christophe Marchand [États-Unis]

Source :

Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2006.

RBID : Pascal:06-0380365

Descripteurs français

Pascal (Inist)
- Cétoacide, Dicétone, Virus HIV1, Synthèse chimique, Relation structure activité, Mécanisme action, Quinolone dérivé, Cétoénol, Hydroxyacide, Acide carboxylique, Hétérocycle azote, Composé bicyclique, Composé aromatique, Modèle moléculaire, Complexe enzyme inhibiteur, Mode liaison, In vitro, Inhibiteur enzyme, Antiviral, Modélisation, Nucleotidyltransferases, Inhibiteur integrase, Quinoléine-3,6-dibut-2-énoïque acide(1-benzyl-1,4-dihydro-α-hydroxy-γ,γ,4-trioxo), Integrase.

English descriptors

KwdEn :
- Antiviral, Aromatic compound, Bicyclic compound, Binding mode, Carboxylic acid, Chemical synthesis, Diketone, Enzyme inhibitor, HIV-1 virus, Hydroxyacid, In vitro, Inhibitor enzyme complex, Ketoacid, Ketoenol, Mechanism of action, Modeling, Molecular model, Nitrogen heterocycle, Nucleotidyltransferases, Quinolone derivatives, Structure activity relation.

Abstract

The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the /3-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.

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C01	`01`		`ENG`	@0 The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the /3-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.
C02	`01`	`X`		`@0 002B02S05`
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C03	`03`	`X`	`FRE`	`@0 Virus HIV1 @2 NW @5 03`
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C03	`05`	`X`	`FRE`	`@0 Relation structure activité @5 05`
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C03	`05`	`X`	`SPA`	`@0 Relación estructura actividad @5 05`
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C03	`07`	`X`	`FRE`	`@0 Quinolone dérivé @5 07`
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C07	`01`	`X`	`FRE`	`@0 Virus immunodéficience humaine @2 NW`
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C07	`06`	`X`	`FRE`	`@0 Enzyme @2 FE`
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N21				`@1 254`

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Le document en format XML

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<author><name sortKey="Palmisano, Lucia" sort="Palmisano, Lucia" uniqKey="Palmisano L" first="Lucia" last="Palmisano">Lucia Palmisano</name>
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<author><name sortKey="Amici, Roberta" sort="Amici, Roberta" uniqKey="Amici R" first="Roberta" last="Amici">Roberta Amici</name>
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<author><name sortKey="Galluzzo, Clementina Maria" sort="Galluzzo, Clementina Maria" uniqKey="Galluzzo C" first="Clementina Maria" last="Galluzzo">Clementina Maria Galluzzo</name>
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<author><name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name>
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<author><name sortKey="Palamara, Anna Teresa" sort="Palamara, Anna Teresa" uniqKey="Palamara A" first="Anna Teresa" last="Palamara">Anna Teresa Palamara</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Istituto cli Microbiologia, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
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<author><name sortKey="Pommier, Yves" sort="Pommier, Yves" uniqKey="Pommier Y" first="Yves" last="Pommier">Yves Pommier</name>
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<author><name sortKey="Marchand, Christophe" sort="Marchand, Christophe" uniqKey="Marchand C" first="Christophe" last="Marchand">Christophe Marchand</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute Building 37. Room 5068, National Institutes of Health</s1>
<s2>Bethesda, Maryland 20892-4255</s2>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors : Design, synthesis, biological activities, and mechanism of action</title>
<author><name sortKey="Di Santo, Roberto" sort="Di Santo, Roberto" uniqKey="Di Santo R" first="Roberto" last="Di Santo">Roberto Di Santo</name>
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<author><name sortKey="Costi, Roberta" sort="Costi, Roberta" uniqKey="Costi R" first="Roberta" last="Costi">Roberta Costi</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimenio di Studi Farmaceutici, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
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<author><name sortKey="Roux, Alessandra" sort="Roux, Alessandra" uniqKey="Roux A" first="Alessandra" last="Roux">Alessandra Roux</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimenio di Studi Farmaceutici, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
<s2>00185 Roma</s2>
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<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Artico, Marino" sort="Artico, Marino" uniqKey="Artico M" first="Marino" last="Artico">Marino Artico</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimenio di Studi Farmaceutici, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
<s2>00185 Roma</s2>
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<sZ>1 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Lavecchia, Antonio" sort="Lavecchia, Antonio" uniqKey="Lavecchia A" first="Antonio" last="Lavecchia">Antonio Lavecchia</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", via D. Montesano 49</s1>
<s2>80131 Napoli</s2>
<s3>ITA</s3>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Marinelli, Luciana" sort="Marinelli, Luciana" uniqKey="Marinelli L" first="Luciana" last="Marinelli">Luciana Marinelli</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", via D. Montesano 49</s1>
<s2>80131 Napoli</s2>
<s3>ITA</s3>
<sZ>5 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Novellino, Ettore" sort="Novellino, Ettore" uniqKey="Novellino E" first="Ettore" last="Novellino">Ettore Novellino</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", via D. Montesano 49</s1>
<s2>80131 Napoli</s2>
<s3>ITA</s3>
<sZ>5 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Palmisano, Lucia" sort="Palmisano, Lucia" uniqKey="Palmisano L" first="Lucia" last="Palmisano">Lucia Palmisano</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299</s1>
<s2>00161 Roma</s2>
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<sZ>8 aut.</sZ>
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<author><name sortKey="Andreotti, Mauro" sort="Andreotti, Mauro" uniqKey="Andreotti M" first="Mauro" last="Andreotti">Mauro Andreotti</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299</s1>
<s2>00161 Roma</s2>
<s3>ITA</s3>
<sZ>8 aut.</sZ>
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<author><name sortKey="Amici, Roberta" sort="Amici, Roberta" uniqKey="Amici R" first="Roberta" last="Amici">Roberta Amici</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299</s1>
<s2>00161 Roma</s2>
<s3>ITA</s3>
<sZ>8 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Galluzzo, Clementina Maria" sort="Galluzzo, Clementina Maria" uniqKey="Galluzzo C" first="Clementina Maria" last="Galluzzo">Clementina Maria Galluzzo</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299</s1>
<s2>00161 Roma</s2>
<s3>ITA</s3>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Istituto cli Microbiologia, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
<s2>00185 Roma</s2>
<s3>ITA</s3>
<sZ>12 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Palamara, Anna Teresa" sort="Palamara, Anna Teresa" uniqKey="Palamara A" first="Anna Teresa" last="Palamara">Anna Teresa Palamara</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Istituto cli Microbiologia, Università di Roma "La Sapienza", P. le A. Moro 5</s1>
<s2>00185 Roma</s2>
<s3>ITA</s3>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
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<country>Italie</country>
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<author><name sortKey="Pommier, Yves" sort="Pommier, Yves" uniqKey="Pommier Y" first="Yves" last="Pommier">Yves Pommier</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute Building 37. Room 5068, National Institutes of Health</s1>
<s2>Bethesda, Maryland 20892-4255</s2>
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<sZ>14 aut.</sZ>
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<country>États-Unis</country>
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<author><name sortKey="Marchand, Christophe" sort="Marchand, Christophe" uniqKey="Marchand C" first="Christophe" last="Marchand">Christophe Marchand</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute Building 37. Room 5068, National Institutes of Health</s1>
<s2>Bethesda, Maryland 20892-4255</s2>
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<sZ>14 aut.</sZ>
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<series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date when="2006">2006</date>
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<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
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<idno type="ISSN">0022-2623</idno>
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<term>Aromatic compound</term>
<term>Bicyclic compound</term>
<term>Binding mode</term>
<term>Carboxylic acid</term>
<term>Chemical synthesis</term>
<term>Diketone</term>
<term>Enzyme inhibitor</term>
<term>HIV-1 virus</term>
<term>Hydroxyacid</term>
<term>In vitro</term>
<term>Inhibitor enzyme complex</term>
<term>Ketoacid</term>
<term>Ketoenol</term>
<term>Mechanism of action</term>
<term>Modeling</term>
<term>Molecular model</term>
<term>Nitrogen heterocycle</term>
<term>Nucleotidyltransferases</term>
<term>Quinolone derivatives</term>
<term>Structure activity relation</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Cétoacide</term>
<term>Dicétone</term>
<term>Virus HIV1</term>
<term>Synthèse chimique</term>
<term>Relation structure activité</term>
<term>Mécanisme action</term>
<term>Quinolone dérivé</term>
<term>Cétoénol</term>
<term>Hydroxyacide</term>
<term>Acide carboxylique</term>
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<term>Composé bicyclique</term>
<term>Composé aromatique</term>
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<term>Mode liaison</term>
<term>In vitro</term>
<term>Inhibiteur enzyme</term>
<term>Antiviral</term>
<term>Modélisation</term>
<term>Nucleotidyltransferases</term>
<term>Inhibiteur integrase</term>
<term>Quinoléine-3,6-dibut-2-énoïque acide(1-benzyl-1,4-dihydro-α-hydroxy-γ,γ,4-trioxo)</term>
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<front><div type="abstract" xml:lang="en">The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the /3-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.</div>
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<s3>ITA</s3>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
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<fA14 i1="05"><s1>Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute Building 37. Room 5068, National Institutes of Health</s1>
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<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA"><s0>Compuesto bicíclico</s0>
<s5>12</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE"><s0>Composé aromatique</s0>
<s5>13</s5>
</fC03>
<fC03 i1="13" i2="X" l="ENG"><s0>Aromatic compound</s0>
<s5>13</s5>
</fC03>
<fC03 i1="13" i2="X" l="SPA"><s0>Compuesto aromático</s0>
<s5>13</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE"><s0>Modèle moléculaire</s0>
<s5>14</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG"><s0>Molecular model</s0>
<s5>14</s5>
</fC03>
<fC03 i1="14" i2="X" l="SPA"><s0>Modelo molecular</s0>
<s5>14</s5>
</fC03>
<fC03 i1="15" i2="X" l="FRE"><s0>Complexe enzyme inhibiteur</s0>
<s5>15</s5>
</fC03>
<fC03 i1="15" i2="X" l="ENG"><s0>Inhibitor enzyme complex</s0>
<s5>15</s5>
</fC03>
<fC03 i1="15" i2="X" l="SPA"><s0>Complejo enzima inhibidor</s0>
<s5>15</s5>
</fC03>
<fC03 i1="16" i2="X" l="FRE"><s0>Mode liaison</s0>
<s5>16</s5>
</fC03>
<fC03 i1="16" i2="X" l="ENG"><s0>Binding mode</s0>
<s5>16</s5>
</fC03>
<fC03 i1="16" i2="X" l="SPA"><s0>Modo de enlace</s0>
<s5>16</s5>
</fC03>
<fC03 i1="17" i2="X" l="FRE"><s0>In vitro</s0>
<s5>17</s5>
</fC03>
<fC03 i1="17" i2="X" l="ENG"><s0>In vitro</s0>
<s5>17</s5>
</fC03>
<fC03 i1="17" i2="X" l="SPA"><s0>In vitro</s0>
<s5>17</s5>
</fC03>
<fC03 i1="18" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0>
<s5>32</s5>
</fC03>
<fC03 i1="18" i2="X" l="ENG"><s0>Enzyme inhibitor</s0>
<s5>32</s5>
</fC03>
<fC03 i1="18" i2="X" l="SPA"><s0>Inhibidor enzima</s0>
<s5>32</s5>
</fC03>
<fC03 i1="19" i2="X" l="FRE"><s0>Antiviral</s0>
<s5>33</s5>
</fC03>
<fC03 i1="19" i2="X" l="ENG"><s0>Antiviral</s0>
<s5>33</s5>
</fC03>
<fC03 i1="19" i2="X" l="SPA"><s0>Antiviral</s0>
<s5>33</s5>
</fC03>
<fC03 i1="20" i2="X" l="FRE"><s0>Modélisation</s0>
<s5>34</s5>
</fC03>
<fC03 i1="20" i2="X" l="ENG"><s0>Modeling</s0>
<s5>34</s5>
</fC03>
<fC03 i1="20" i2="X" l="SPA"><s0>Modelización</s0>
<s5>34</s5>
</fC03>
<fC03 i1="21" i2="X" l="FRE"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
<s5>35</s5>
</fC03>
<fC03 i1="21" i2="X" l="ENG"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
<s5>35</s5>
</fC03>
<fC03 i1="21" i2="X" l="SPA"><s0>Nucleotidyltransferases</s0>
<s2>FE</s2>
<s5>35</s5>
</fC03>
<fC03 i1="22" i2="X" l="FRE"><s0>Inhibiteur integrase</s0>
<s4>INC</s4>
<s5>76</s5>
</fC03>
<fC03 i1="23" i2="X" l="FRE"><s0>Quinoléine-3,6-dibut-2-énoïque acide(1-benzyl-1,4-dihydro-α-hydroxy-γ,γ,4-trioxo)</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>77</s5>
</fC03>
<fC03 i1="24" i2="X" l="FRE"><s0>Integrase</s0>
<s4>INC</s4>
<s5>91</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Virus immunodéficience humaine</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Human immunodeficiency virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Human immunodeficiency virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Transferases</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Enzyme</s0>
<s2>FE</s2>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Enzima</s0>
<s2>FE</s2>
</fC07>
<fN21><s1>254</s1>
</fN21>
</pA>
</standard>
</inist>
</record>

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Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors : Design, synthesis, biological activities, and mechanism of action

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors : Design, synthesis, biological activities, and mechanism of action

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