SrasV1, Main, Exploration, bibRecord, 004428

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

Identifieur interne : 004428 ( Main/Exploration ); précédent : 004427; suivant : 004429

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

English descriptors

KwdEn :
- Antiviral, Aromatic compound, Bicyclic compound, Binding mode, Carboxylic acid, Catalytic Domain, Cell Line, Chemical synthesis, DNA, Viral (chemistry), Diketone, Drug Design, Enzyme inhibitor, HIV Integrase (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (chemistry), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), HIV-1 virus, Humans, Hydroxyacid, Hydroxybutyrates (chemical synthesis), Hydroxybutyrates (chemistry), Hydroxybutyrates (pharmacology), In vitro, Inhibitor enzyme complex, Keto Acids (chemical synthesis), Keto Acids (chemistry), Keto Acids (pharmacology), Ketoacid, Ketoenol, Mechanism of action, Modeling, Models, Molecular, Molecular model, Nitrogen heterocycle, Nucleotidyltransferases, Protein Binding, Protein Structure, Tertiary, Quinolone derivatives, Quinolones (chemical synthesis), Quinolones (chemistry), Quinolones (pharmacology), Structure activity relation, Structure-Activity Relationship.
MESH :
- chemical , chemical synthesis : HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- chemical , chemistry : DNA, Viral, HIV Integrase, HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- chemical , metabolism : HIV Integrase.
- chemical , pharmacology : HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- drug effects : HIV-1.
- Catalytic Domain, Cell Line, Drug Design, Humans, Models, Molecular, Protein Binding, Protein Structure, Tertiary, Structure-Activity Relationship.

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.

Affiliations:

Le document en format XML

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<author><name sortKey="Novellino, Ettore" sort="Novellino, Ettore" uniqKey="Novellino E" first="Ettore" last="Novellino">Ettore Novellino</name>
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</placeName>
</affiliation>
</author>
<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>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<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>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<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>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>Italie</country>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name>
<affiliation wicri:level="4"><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>
</inist:fA14>
<country>Italie</country>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
<orgName type="university">Université de Rome « La Sapienza »</orgName>
<placeName><settlement type="city">Rome</settlement>
<region type="region" nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<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="4"><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>
</inist:fA14>
<country>Italie</country>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
<orgName type="university">Université de Rome « La Sapienza »</orgName>
<placeName><settlement type="city">Rome</settlement>
<region type="region" nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<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>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Bethesda, Maryland 20892-4255</wicri:noRegion>
</affiliation>
</author>
<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>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Bethesda, Maryland 20892-4255</wicri:noRegion>
</affiliation>
</author>
</analytic>
<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>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><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>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term>
<term>Aromatic compound</term>
<term>Bicyclic compound</term>
<term>Binding mode</term>
<term>Carboxylic acid</term>
<term>Catalytic Domain</term>
<term>Cell Line</term>
<term>Chemical synthesis</term>
<term>DNA, Viral (chemistry)</term>
<term>Diketone</term>
<term>Drug Design</term>
<term>Enzyme inhibitor</term>
<term>HIV Integrase (chemistry)</term>
<term>HIV Integrase (metabolism)</term>
<term>HIV Integrase Inhibitors (chemical synthesis)</term>
<term>HIV Integrase Inhibitors (chemistry)</term>
<term>HIV Integrase Inhibitors (pharmacology)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 virus</term>
<term>Humans</term>
<term>Hydroxyacid</term>
<term>Hydroxybutyrates (chemical synthesis)</term>
<term>Hydroxybutyrates (chemistry)</term>
<term>Hydroxybutyrates (pharmacology)</term>
<term>In vitro</term>
<term>Inhibitor enzyme complex</term>
<term>Keto Acids (chemical synthesis)</term>
<term>Keto Acids (chemistry)</term>
<term>Keto Acids (pharmacology)</term>
<term>Ketoacid</term>
<term>Ketoenol</term>
<term>Mechanism of action</term>
<term>Modeling</term>
<term>Models, Molecular</term>
<term>Molecular model</term>
<term>Nitrogen heterocycle</term>
<term>Nucleotidyltransferases</term>
<term>Protein Binding</term>
<term>Protein Structure, Tertiary</term>
<term>Quinolone derivatives</term>
<term>Quinolones (chemical synthesis)</term>
<term>Quinolones (chemistry)</term>
<term>Quinolones (pharmacology)</term>
<term>Structure activity relation</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ADN viral ()</term>
<term>Conception de médicament</term>
<term>Cétoacides ()</term>
<term>Cétoacides (pharmacologie)</term>
<term>Cétoacides (synthèse chimique)</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Hydroxy-butyrates ()</term>
<term>Hydroxy-butyrates (pharmacologie)</term>
<term>Hydroxy-butyrates (synthèse chimique)</term>
<term>Inhibiteurs de l'intégrase du VIH ()</term>
<term>Inhibiteurs de l'intégrase du VIH (pharmacologie)</term>
<term>Inhibiteurs de l'intégrase du VIH (synthèse chimique)</term>
<term>Intégrase du VIH ()</term>
<term>Intégrase du VIH (métabolisme)</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire</term>
<term>Modèles moléculaires</term>
<term>Quinolinone ()</term>
<term>Quinolinone (pharmacologie)</term>
<term>Quinolinone (synthèse chimique)</term>
<term>Relation structure-activité</term>
<term>Structure tertiaire des protéines</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>HIV Integrase Inhibitors</term>
<term>Hydroxybutyrates</term>
<term>Keto Acids</term>
<term>Quinolones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA, Viral</term>
<term>HIV Integrase</term>
<term>HIV Integrase Inhibitors</term>
<term>Hydroxybutyrates</term>
<term>Keto Acids</term>
<term>Quinolones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Integrase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>HIV Integrase Inhibitors</term>
<term>Hydroxybutyrates</term>
<term>Keto Acids</term>
<term>Quinolones</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Intégrase du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Cétoacides</term>
<term>Hydroxy-butyrates</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Quinolinone</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Cétoacides</term>
<term>Hydroxy-butyrates</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Quinolinone</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term>
<term>Cell Line</term>
<term>Drug Design</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Protein Binding</term>
<term>Protein Structure, Tertiary</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>ADN viral</term>
<term>Conception de médicament</term>
<term>Cétoacide</term>
<term>Cétoacides</term>
<term>Dicétone</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Hydroxy-butyrates</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Intégrase du VIH</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire</term>
<term>Modèles moléculaires</term>
<term>Quinolinone</term>
<term>Relation structure-activité</term>
<term>Structure tertiaire des protéines</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</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>
<term>Hétérocycle azote</term>
<term>Composé bicyclique</term>
<term>Composé aromatique</term>
<term>Modèle moléculaire</term>
<term>Complexe enzyme inhibiteur</term>
<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>
<term>Integrase</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<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>
</front>
</TEI>
<affiliations><list><country><li>Italie</li>
<li>États-Unis</li>
</country>
<region><li>Latium</li>
</region>
<settlement><li>Rome</li>
</settlement>
<orgName><li>Université de Rome « La Sapienza »</li>
</orgName>
</list>
<tree><country name="Italie"><region name="Latium"><name sortKey="Di Santo, Roberto" sort="Di Santo, Roberto" uniqKey="Di Santo R" first="Roberto" last="Di Santo">Roberto Di Santo</name>
</region>
<name sortKey="Amici, Roberta" sort="Amici, Roberta" uniqKey="Amici R" first="Roberta" last="Amici">Roberta Amici</name>
<name sortKey="Andreotti, Mauro" sort="Andreotti, Mauro" uniqKey="Andreotti M" first="Mauro" last="Andreotti">Mauro Andreotti</name>
<name sortKey="Artico, Marino" sort="Artico, Marino" uniqKey="Artico M" first="Marino" last="Artico">Marino Artico</name>
<name sortKey="Costi, Roberta" sort="Costi, Roberta" uniqKey="Costi R" first="Roberta" last="Costi">Roberta Costi</name>
<name sortKey="Galluzzo, Clementina Maria" sort="Galluzzo, Clementina Maria" uniqKey="Galluzzo C" first="Clementina Maria" last="Galluzzo">Clementina Maria Galluzzo</name>
<name sortKey="Lavecchia, Antonio" sort="Lavecchia, Antonio" uniqKey="Lavecchia A" first="Antonio" last="Lavecchia">Antonio Lavecchia</name>
<name sortKey="Marinelli, Luciana" sort="Marinelli, Luciana" uniqKey="Marinelli L" first="Luciana" last="Marinelli">Luciana Marinelli</name>
<name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name>
<name sortKey="Novellino, Ettore" sort="Novellino, Ettore" uniqKey="Novellino E" first="Ettore" last="Novellino">Ettore Novellino</name>
<name sortKey="Palamara, Anna Teresa" sort="Palamara, Anna Teresa" uniqKey="Palamara A" first="Anna Teresa" last="Palamara">Anna Teresa Palamara</name>
<name sortKey="Palmisano, Lucia" sort="Palmisano, Lucia" uniqKey="Palmisano L" first="Lucia" last="Palmisano">Lucia Palmisano</name>
<name sortKey="Roux, Alessandra" sort="Roux, Alessandra" uniqKey="Roux A" first="Alessandra" last="Roux">Alessandra Roux</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Pommier, Yves" sort="Pommier, Yves" uniqKey="Pommier Y" first="Yves" last="Pommier">Yves Pommier</name>
</noRegion>
<name sortKey="Marchand, Christophe" sort="Marchand, Christophe" uniqKey="Marchand C" first="Christophe" last="Marchand">Christophe Marchand</name>
</country>
</tree>
</affiliations>
</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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