Computational design, synthesis and biological evaluation of novel pyridinone derivatives as NNRTIs

Abstract

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 pi-pi 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.