Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.
Identifieur interne : 003F78 ( Main/Merge ); précédent : 003F77; suivant : 003F79Novel 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 ; Alessandra Roux ; Marino Artico ; Antonio Lavecchia ; Luciana Marinelli ; Ettore Novellino ; Lucia Palmisano ; Mauro Andreotti ; Roberta Amici ; Clementina Maria Galluzzo ; Lucia Nencioni ; Anna Teresa Palamara ; Yves Pommier ; Christophe MarchandSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2006.
Descripteurs français
- KwdFr :
- ADN viral (), Conception de médicament, Cétoacides (), Cétoacides (pharmacologie), Cétoacides (synthèse chimique), Domaine catalytique, Humains, Hydroxy-butyrates (), Hydroxy-butyrates (pharmacologie), Hydroxy-butyrates (synthèse chimique), Inhibiteurs de l'intégrase du VIH (), Inhibiteurs de l'intégrase du VIH (pharmacologie), Inhibiteurs de l'intégrase du VIH (synthèse chimique), Intégrase du VIH (), Intégrase du VIH (métabolisme), Liaison aux protéines, Lignée cellulaire, Modèles moléculaires, Quinolinone (), Quinolinone (pharmacologie), Quinolinone (synthèse chimique), Relation structure-activité, Structure tertiaire des protéines, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- métabolisme : Intégrase du VIH.
- pharmacologie : Cétoacides, Hydroxy-butyrates, Inhibiteurs de l'intégrase du VIH, Quinolinone.
- synthèse chimique : Cétoacides, Hydroxy-butyrates, Inhibiteurs de l'intégrase du VIH, Quinolinone.
- ADN viral, Conception de médicament, Cétoacides, Domaine catalytique, Humains, Hydroxy-butyrates, Inhibiteurs de l'intégrase du VIH, Intégrase du VIH, Liaison aux protéines, Lignée cellulaire, Modèles moléculaires, Quinolinone, Relation structure-activité, Structure tertiaire des protéines, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Catalytic Domain, Cell Line, DNA, Viral (chemistry), Drug Design, HIV Integrase (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (chemistry), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), Humans, Hydroxybutyrates (chemical synthesis), Hydroxybutyrates (chemistry), Hydroxybutyrates (pharmacology), Keto Acids (chemical synthesis), Keto Acids (chemistry), Keto Acids (pharmacology), Models, Molecular, Protein Binding, Protein Structure, Tertiary, Quinolones (chemical synthesis), Quinolones (chemistry), Quinolones (pharmacology), 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 beta-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.
DOI: 10.1021/jm0511583
PubMed: 16539381
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 002309
- to stream PubMed, to step Curation: 002309
- to stream PubMed, to step Checkpoint: 002087
- to stream Ncbi, to step Merge: 001419
- to stream Ncbi, to step Curation: 001419
- to stream Ncbi, to step Checkpoint: 001419
Links to Exploration step
pubmed:16539381Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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><affiliation wicri:level="1"><nlm:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Università di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy. roberto.disanto@uniroma1.it</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Università di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma</wicri:regionArea><wicri:noRegion>I-00185 Roma</wicri:noRegion></affiliation></author><author><name sortKey="Costi, Roberta" sort="Costi, Roberta" uniqKey="Costi R" first="Roberta" last="Costi">Roberta Costi</name></author><author><name sortKey="Roux, Alessandra" sort="Roux, Alessandra" uniqKey="Roux A" first="Alessandra" last="Roux">Alessandra Roux</name></author><author><name sortKey="Artico, Marino" sort="Artico, Marino" uniqKey="Artico M" first="Marino" last="Artico">Marino Artico</name></author><author><name sortKey="Lavecchia, Antonio" sort="Lavecchia, Antonio" uniqKey="Lavecchia A" first="Antonio" last="Lavecchia">Antonio Lavecchia</name></author><author><name sortKey="Marinelli, Luciana" sort="Marinelli, Luciana" uniqKey="Marinelli L" first="Luciana" last="Marinelli">Luciana Marinelli</name></author><author><name sortKey="Novellino, Ettore" sort="Novellino, Ettore" uniqKey="Novellino E" first="Ettore" last="Novellino">Ettore Novellino</name></author><author><name sortKey="Palmisano, Lucia" sort="Palmisano, Lucia" uniqKey="Palmisano L" first="Lucia" last="Palmisano">Lucia Palmisano</name></author><author><name sortKey="Andreotti, Mauro" sort="Andreotti, Mauro" uniqKey="Andreotti M" first="Mauro" last="Andreotti">Mauro Andreotti</name></author><author><name sortKey="Amici, Roberta" sort="Amici, Roberta" uniqKey="Amici R" first="Roberta" last="Amici">Roberta Amici</name></author><author><name sortKey="Galluzzo, Clementina Maria" sort="Galluzzo, Clementina Maria" uniqKey="Galluzzo C" first="Clementina Maria" last="Galluzzo">Clementina Maria Galluzzo</name></author><author><name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name></author><author><name sortKey="Palamara, Anna Teresa" sort="Palamara, Anna Teresa" uniqKey="Palamara A" first="Anna Teresa" last="Palamara">Anna Teresa Palamara</name></author><author><name sortKey="Pommier, Yves" sort="Pommier, Yves" uniqKey="Pommier Y" first="Yves" last="Pommier">Yves Pommier</name></author><author><name sortKey="Marchand, Christophe" sort="Marchand, Christophe" uniqKey="Marchand C" first="Christophe" last="Marchand">Christophe Marchand</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2006">2006</date><idno type="RBID">pubmed:16539381</idno><idno type="pmid">16539381</idno><idno type="doi">10.1021/jm0511583</idno><idno type="wicri:Area/PubMed/Corpus">002309</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002309</idno><idno type="wicri:Area/PubMed/Curation">002309</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002309</idno><idno type="wicri:Area/PubMed/Checkpoint">002087</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002087</idno><idno type="wicri:Area/Ncbi/Merge">001419</idno><idno type="wicri:Area/Ncbi/Curation">001419</idno><idno type="wicri:Area/Ncbi/Checkpoint">001419</idno><idno type="wicri:doubleKey">0022-2623:2006:Di Santo R:novel:bifunctional:quinolonyl</idno><idno type="wicri:Area/Main/Merge">003F78</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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><affiliation wicri:level="1"><nlm:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Università di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy. roberto.disanto@uniroma1.it</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Università di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma</wicri:regionArea><wicri:noRegion>I-00185 Roma</wicri:noRegion></affiliation></author><author><name sortKey="Costi, Roberta" sort="Costi, Roberta" uniqKey="Costi R" first="Roberta" last="Costi">Roberta Costi</name></author><author><name sortKey="Roux, Alessandra" sort="Roux, Alessandra" uniqKey="Roux A" first="Alessandra" last="Roux">Alessandra Roux</name></author><author><name sortKey="Artico, Marino" sort="Artico, Marino" uniqKey="Artico M" first="Marino" last="Artico">Marino Artico</name></author><author><name sortKey="Lavecchia, Antonio" sort="Lavecchia, Antonio" uniqKey="Lavecchia A" first="Antonio" last="Lavecchia">Antonio Lavecchia</name></author><author><name sortKey="Marinelli, Luciana" sort="Marinelli, Luciana" uniqKey="Marinelli L" first="Luciana" last="Marinelli">Luciana Marinelli</name></author><author><name sortKey="Novellino, Ettore" sort="Novellino, Ettore" uniqKey="Novellino E" first="Ettore" last="Novellino">Ettore Novellino</name></author><author><name sortKey="Palmisano, Lucia" sort="Palmisano, Lucia" uniqKey="Palmisano L" first="Lucia" last="Palmisano">Lucia Palmisano</name></author><author><name sortKey="Andreotti, Mauro" sort="Andreotti, Mauro" uniqKey="Andreotti M" first="Mauro" last="Andreotti">Mauro Andreotti</name></author><author><name sortKey="Amici, Roberta" sort="Amici, Roberta" uniqKey="Amici R" first="Roberta" last="Amici">Roberta Amici</name></author><author><name sortKey="Galluzzo, Clementina Maria" sort="Galluzzo, Clementina Maria" uniqKey="Galluzzo C" first="Clementina Maria" last="Galluzzo">Clementina Maria Galluzzo</name></author><author><name sortKey="Nencioni, Lucia" sort="Nencioni, Lucia" uniqKey="Nencioni L" first="Lucia" last="Nencioni">Lucia Nencioni</name></author><author><name sortKey="Palamara, Anna Teresa" sort="Palamara, Anna Teresa" uniqKey="Palamara A" first="Anna Teresa" last="Palamara">Anna Teresa Palamara</name></author><author><name sortKey="Pommier, Yves" sort="Pommier, Yves" uniqKey="Pommier Y" first="Yves" last="Pommier">Yves Pommier</name></author><author><name sortKey="Marchand, Christophe" sort="Marchand, Christophe" uniqKey="Marchand C" first="Christophe" last="Marchand">Christophe Marchand</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Catalytic Domain</term><term>Cell Line</term><term>DNA, Viral (chemistry)</term><term>Drug Design</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>Humans</term><term>Hydroxybutyrates (chemical synthesis)</term><term>Hydroxybutyrates (chemistry)</term><term>Hydroxybutyrates (pharmacology)</term><term>Keto Acids (chemical synthesis)</term><term>Keto Acids (chemistry)</term><term>Keto Acids (pharmacology)</term><term>Models, Molecular</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Quinolones (chemical synthesis)</term><term>Quinolones (chemistry)</term><term>Quinolones (pharmacology)</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="MESH" xml:lang="fr"><term>ADN viral</term><term>Conception de médicament</term><term>Cétoacides</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></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 beta-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></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 003F78 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Merge/biblio.hfd -nk 003F78 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Main
|étape= Merge
|type= RBID
|clé= pubmed:16539381
|texte= Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Merge/RBID.i -Sk "pubmed:16539381" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Merge/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |