Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.
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.
Li
Xingnan
X
Center for Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.
Vince
Robert
R
D000577:Amides / Q000737:chemistry; D002384:Catalysis; D002614:Chelating Agents / Q000737:chemistry*; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008274:Magnesium / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry; D010848:Picolinic Acids / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D002614:Chelating Agents; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008670:Metals; D010848:Picolinic Acids; D011687:Purines; D011804:Quinolines; D010165:Palladium; D019427:HIV Integrase; C003142:picolinamide; D008274:Magnesium