Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a triazole tail occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02-1.77 mu M. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB)= 0.020 mu M, EC50(E138K)= 0.015 mu M, CC50= 40.15 mu M), PYrrolidin-1-ylmethanone (3b8, EC50(IIIB)= 0.020 mu M, EC50(E138K)= 0.014 mu M, CC50 = 58.09 mu M) and morpholinomethanone (3b9, EC50(IIIB)= 0.020 mu M, EC50(E138K) = 0.027 mu M, CC50 = 180.90 mu M) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed. (C) 2018 Elsevier Masson SAS. All rights reserved.