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.