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 (EC 50 = 5.62–171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC 50 values of 9.37 nM, being much superior to that of NVP (EC 50 = 5128 nM) and EFV (EC 50 = 114 nM) and comparable to that of ETR (EC 50 = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT enzyme inhibitory activity (IC 50 = 0.094–12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking. [Display omitted] • A series of 24 novel 5-cyano substituted diarylpyridines was designed and synthesized. • I-5b showed. • The molecular docking of representative compounds was conducted. [ABSTRACT FROM AUTHOR]