Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach.

Abstract By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC 50 in the range of 0.78–4.46 μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC 50  = 0.78 μM, SI = 24). In addition, LBD-6 showed moderate activity against L100I mutant (EC 50  = 5.64 μM) and double mutant strain RES056 (EC 50  = 22.24 μM). Preliminary structure–activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization.