Design, synthesis, and anti-SARS-CoV-2 activity of vilazodone derivatives as METTL3 inhibitors.

During the COVID-19 pandemic, the substantial global health burden imposed by SARS-CoV-2 and its variants-driven by high transmissibility, virulence, and frequent mutations-has highlighted the urgent need for broad-spectrum antiviral agents as a key component of pandemic preparedness. In our preliminary screening, vilazodone was identified as an inhibitor of SARS-CoV-2 replication via targeting the METTL3 protein. Building on this finding, a total of 33 vilazodone derivatives were designed and synthesized in the present study to enhance antiviral potency and improve the selectivity index. Among these derivatives, compound D4 exhibited the most potent anti-SARS-CoV-2 activity, surpassing that of the positive control remdesivir. Its potent antiviral efficacy and favorable therapeutic index provide an important basis for antiviral drug development. However, its moderate binding to METTL3 and weak inhibitory activity suggest that its antiviral activity may be mediated through targets other than METTL3. Although this finding poses a challenge to the METTL3-targeting strategy, it also opens up new research directions for further dissecting the mechanism of action of this compound and exploring its potential targets.