Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs

Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound 1 (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead K-5a2 was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC₅₀) = 3.30 nM) and mutant strain RES056 (EC₅₀ = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, 8a (half maximal inhibitory concentration (IC₅₀) = 0.028 μM) was remarkably superior to that of K-5a2 (IC₅₀ = 0.300 μM) and comparable to that of etravirine (ETR; IC₅₀ = 0.011 μM). Notably, 8a exhibited better druggability than that of K-5a2, including significantly reduced CYP enzymatic inhibitory activity (IC₅₀ > 50 μM), lower human ether-à-go-go related gene (hERG) inhibition (IC₅₀ > 30 μM), and improved metabolic stability (short half-life, T_1/2 = 77.5 min) in vitro.