With the aim of developing novel anti-SARS-CoV-2 drugs to address the ongoing evolution and emergence of drug-resistant strains, the reported SARS-CoV-2 M inhibitor was selected as a lead to find novel, highly potent, and broad-spectrum inhibitors. Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, (IC = 1.05 μM), (IC = 1.08 μM), and (IC = 0.154 μM) demonstrated potent SARS-CoV-2 M inhibition comparable to or slightly weaker than . Antiviral activity evaluations revealed that compound exhibited the strongest antiviral activity with an EC value of 0.18 μM, quite comparable to the marketed drug Nirmatrelvir (EC = 0.123 μM) and inferior to (EC = 0.042 μM). Molecular dynamics simulations elucidated the key interactions between compounds , , , and the binding pocket of SARS-CoV-2 M, providing valuable insights into their mechanisms of action. These findings identify compound as a promising lead for anti-SARS-CoV-2 drug development.
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