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Conformationally restrained carbazolone-containing alpha,gamma-diketo acids as inhibitors of HIV integrase.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2006 May 01; Vol. 14 (9), pp. 2942-55. Date of Electronic Publication: 2006 Jan 04. - Publication Year :
- 2006
-
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.
- Subjects :
- Acylation
Drug Design
HIV Integrase Inhibitors chemical synthesis
Keto Acids chemical synthesis
Molecular Structure
Structure-Activity Relationship
Carbazoles chemistry
HIV Integrase metabolism
HIV Integrase Inhibitors chemistry
HIV Integrase Inhibitors pharmacology
Keto Acids chemistry
Keto Acids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 14
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16386908
- Full Text :
- https://doi.org/10.1016/j.bmc.2005.12.013