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-<i>d</i>]pyrimidine compound <b>1</b> (<b>K-5a2</b>) 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 <b>K-5a2</b> was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that <b>8a</b> 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, <b>8a</b> (half maximal inhibitory concentration (IC₅₀) = 0.028 μM) was remarkably superior to that of <b>K-5a2</b> (IC₅₀ = 0.300 μM) and comparable to that of etravirine (ETR; IC₅₀ = 0.011 μM). Notably, <b>8a</b> exhibited better druggability than that of <b>K-5a2</b>, 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, <i>T</i>_1/2 = 77.5 min) <i>in vitro</i>.