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<p>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, <b>4e</b> and <b>4i</b>, demonstrated remarkable inhibition of HIV-1 replication, with <b>4i</b> exhibiting low-nanomolar potency against HIV-1 (EC<sub>50</sub> = 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 <b>4i</b>, as a promising lead for further optimization toward next-generation NNRTIs.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Niloofar Movahednia,
  • Ali Ramazani,
  • Afshin fassihi,
  • Pouria Shirvani,
  • Dominique Schols

摘要

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.