Structure-based discovery of novel diarylpyrimidines as potent and selective Non-Nucleoside reverse transcriptase inhibitors: From CH(CN)-Biphenyl-Diarylpyrimidines to CNNH2-Biphenyl-Diarylpyrimidines.

In order to enhance the anti-HIV-1 potency and selectivity of the previously reported compound 3 (EC50 = 27 nM, SI = 1361), a series of novel biphenyl-diarylpyrimidine derivatives were developed by employing structure-based drug design strategy. Among these derivatives, compound M44 demonstrated the most potent inhibitory activity against wild-type (WT) HIV-1 as well as five drug-resistant mutants (EC50 = 5-148 nM), which were 5-173 times more potent than that of 3 (EC50 = 27-9810 nM). Furthermore, this analogue exhibited approximately 11-fold lower cytotoxicity (CC50 = 54 μM) than that of etravirine and rilpivirine. Concurrently, it possessed an improved selectivity index (SI) of 10995. Additionally, compound M44 was characterized by favorable metabolic stability in human plasma and human liver microsomes. No acute toxicity or organ damage was observed at a dose of 2 g/kg. Overall, M44 represents a highly promising lead compound that warrants further optimization efforts to identify potential anti-HIV-1 drug candidates.