title: Conformationally restrained carbazolone-containing alpha,gamma-diketo acids as inhibitors of HIV integrase.
abstract: Since alpha,gamma-diketo acid (DKA) compounds were identified as potent and selective inhibitors for HIV integrase, numerous structural modification studies have been carried out to search for a clinical candidate as a supplement for the highly active antiretroviral therapy regimen. Due to the lack of structural information on inhibitor-integrase interactions, a comprehensive structure-activity relationship study is necessary. Most of the reported modification studies on the key alpha,gamma-diketo acid pharmacophore focused on substituting the carboxylate moiety with its bioisosteres or other electron-pair bearing heterocycles. We were interested in studying the conformation and geometry of the central diketo moiety. A series of carbazolone-containing alpha,gamma-diketo acids were designed and synthesized by applying conformational restraint onto the open-chain form of the diketo acid. These compounds showed anti-integrase activity in the low micromolar range, and integrase assay results indicated that the geometry of the diketo acid moiety is crucial to potency. Carbazol-1-one containing DKA analogs (7-8) showed a 2- to 3-fold increase in activity compared with those of carbazol-4-one containing DKA analogs (5 and 6). Alkylation of carbazol-4-one DKA nitrogen (6a-c) led to a loss of activity, suggesting this nitrogen atom may directly interact with the active site of integrase. The halogens (7b-d) and para-fluorobenzyl substituents (8a-d) on carbazol-1-one ring had little effect on potency.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, and Center for Drug Design, Academic Health Center, University of Minnesota, 8-123A WDH, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
authors.forename: Xingnan
authors.initials: X
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
mesh_terms: D000215:Acylation; D002227:Carbazoles / Q000737:chemistry*; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase