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 (S)-4a, a series of halomethylene-linked biphenyl-DAPYs were developed. Enantioselectivity studies of the most promising 5m suggested that the (S)-enantiomer was more potent than its (R)-counterpart and racemate. The optimal (S)-5m exhibited remarkable antiviral activity toward wild-type HIV-1 and single mutant strains (EC50 = 3.7-231 nM). Notably, this compound possessed 32-fold lower cytotoxicity and a 13-fold higher selectivity index (CC50 > 288 μM, SI > 78,125) than those of (S)-4a. In vitro metabolic stability assays demonstrated that (S)-5m had good stability in human plasma and human liver microsomes. Besides, no apparent inhibition of CYP or hERG was observed. More importantly, (S)-5m was characterized by favorable in vivo safety properties (LD50 > 2 g/kg) and significantly improved PK profiles (F = 49.5%, T1/2 = 13.86 h). These findings provided insights for the design of novel NNRTIs for HIV treatment.