Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.
Identifieur interne : 002217 ( PubMed/Curation ); précédent : 002216; suivant : 002218Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.
Auteurs : Xingnan Li [États-Unis] ; Robert VinceSource :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2006.
Descripteurs français
- KwdFr :
- Acides picoliniques (), Amides (), Catalyse, Chélateurs (), Cétoacides (), Cétoacides (pharmacologie), Cétoacides (synthèse chimique), Humains, Inhibiteurs de l'intégrase du VIH (pharmacologie), Inhibiteurs de l'intégrase du VIH (synthèse chimique), Intégrase du VIH (métabolisme), Magnésium (), Métaux (), Palladium (), Purines (pharmacologie), Purines (synthèse chimique), Quinoléines (), Relation structure-activité, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- métabolisme : Intégrase du VIH.
- pharmacologie : Cétoacides, Inhibiteurs de l'intégrase du VIH, Purines.
- synthèse chimique : Cétoacides, Inhibiteurs de l'intégrase du VIH, Purines.
- Acides picoliniques, Amides, Catalyse, Chélateurs, Cétoacides, Humains, Magnésium, Métaux, Palladium, Quinoléines, Relation structure-activité, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Amides (chemistry), Catalysis, Chelating Agents (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), Humans, Keto Acids (chemical synthesis), Keto Acids (chemistry), Keto Acids (pharmacology), Magnesium (chemistry), Metals (chemistry), Palladium (chemistry), Picolinic Acids (chemistry), Purines (chemical synthesis), Purines (pharmacology), Quinolines (chemistry), Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : HIV Integrase Inhibitors, Keto Acids, Purines.
- chemical , chemistry : Amides, Chelating Agents, Keto Acids, Magnesium, Metals, Palladium, Picolinic Acids, Quinolines.
- chemical , metabolism : HIV Integrase.
- chemical , pharmacology : HIV Integrase Inhibitors, Keto Acids, Purines.
- drug effects : HIV-1.
- Catalysis, Humans, Structure-Activity Relationship.
Abstract
Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.
DOI: 10.1016/j.bmc.2006.04.011
PubMed: 16753300
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pubmed:16753300Le document en format XML
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<term>HIV Integrase Inhibitors (chemical synthesis)</term>
<term>HIV Integrase Inhibitors (pharmacology)</term>
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<front><div type="abstract" xml:lang="en">Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.</div>
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<Abstract><AbstractText>Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.</AbstractText>
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