5-Cyano substituted diarylpyridines as potent HIV-1 NNRTIs: Rational design, synthesis, and activity evaluation.

To develop more potent HIV-1 inhibitors against a variety of NNRTIs-resistant strains, a series of 5-cyano substituted diarylpyridines was designed based on the cocrystal structural analysis. Among them, I-5b showed the greatest potency (EC50 = 5.62-171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC50 values of 9.37 nM, being much superior to that of NVP (EC50 = 5128 nM) and EFV (EC50 = 114 nM) and comparable to that of ETR (EC50 = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT enzyme inhibitory activity (IC50 = 0.094-12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking.