Conformationally restrained carbazolone-containing α,γ-diketo acids as inhibitors of HIV integrase Original Research Article

Since α,γ-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 α,γ-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 α,γ-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.