The emergence of resistance against first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) necessitates the development of novel scaffolds with improved antiviral efficacy. In this study, a series of pyridinone derivatives were designed and synthesized as potential NNRTIs. The antiviral evaluation against wild-type HIV-1 in MT-4 cells revealed that most of the compounds displayed limited or no activity, often accompanied by cytotoxic effects. However, two derivatives, 4e and 4i, demonstrated remarkable inhibition of HIV-1 replication, with 4i exhibiting low-nanomolar potency against HIV-1 (EC50 = 5.3 nM), having almost one half of the Rilpivirine activity. Molecular docking confirmed critical hydrogen bonding interactions with Lys103 and π–π stacking with Trp229 and Tyr181, while 300 ns molecular dynamics simulations verified the stability of the compound-enzyme complexes. Collectively, these findings highlight the pyridinone scaffold, particularly compound 4i, as a promising lead for further optimization toward next-generation NNRTIs.
Movahednia et al. (Sat,) studied this question.