Halogenation-Driven Discovery of Halomethylene-Biphenyl-Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Safety and PK Profiles.

To improve the safety and PK profiles of our previously established ()-, a series of halomethylene-linked biphenyl-DAPYs were developed. Enantioselectivity studies of the most promising suggested that the ()-enantiomer was more potent than its ()-counterpart and racemate. The optimal ()- exhibited remarkable antiviral activity toward wild-type HIV-1 and single mutant strains (EC = 3.7-231 nM). Notably, this compound possessed 32-fold lower cytotoxicity and a 13-fold higher selectivity index (CC > 288 μM, SI > 78,125) than those of ()-. In vitro metabolic stability assays demonstrated that ()- had good stability in human plasma and human liver microsomes. Besides, no apparent inhibition of CYP or hERG was observed. More importantly, ()- was characterized by favorable in vivo safety properties (LD > 2 g/kg) and significantly improved PK profiles ( = 49.5%, = 13.86 h). These findings provided insights for the design of novel NNRTIs for HIV treatment.