Novel Indole-Based Cinnamate Derivatives Show Potential as Broad-Spectrum Antivirals Against COVID-19

Strategic Insights -

Researchers from the University of Milan have made significant strides in the development of a novel series of indole-based ethyl cinnamate derivatives that have shown promising results in inhibiting the SARS-CoV-2 Main Protease (M) and human cathepsins, essential enzymes involved in viral replication and entry. These findings suggest that these multitarget inhibitors may be effective in reducing the risk of resistance associated with single-target agents and highlight their potential in the context of pandemic preparedness.

Key Takeaways:

  • The study reports the synthesis and biological evaluation of a novel series of indole-based ethyl cinnamate derivatives designed as multitarget inhibitors of both SARS-CoV-2 Main Protease (M) and human cathepsin, namely CatL and CatS.
  • Enzymatic assays showed that several compounds exert significant inhibition on multiple targets, with the tert-leucine (Tle) residue at P2 position of these (pseudo)dipeptides playing a critical role in multitarget enzyme inhibition and antiviral activity.
  • Time-of-drug-addition experiments revealed that compound 12 primarily inhibited viral entry by targeting CatL, while compound 20 affected both entry and post-entry stages of hCoV replication cycle due to its dual-inhibitory activity against both CatL and M.
  • The research concluded that the demonstrated effectiveness of Tle-containing indole-based cinnamates as broad-spectrum antivirals highlights their potential in the context of pandemic preparedness.
  • The study's findings support the development of multitarget inhibitors as promising antivirals able to inhibit both a- and b-coronavirus, reducing the risk of resistance associated with single-target agents.

Statistics:

  • Twelve compounds (12, 20, and 3) restricted viral replication with high selectivity values (SI = 98, 56, and 101, respectively) against representative a- (hCoV-229E) and b-coronavirus (hCoV-OC43).
  • The most effective compounds (12 and 20) exhibited inhibition of viral replication with efficacies (EC) of 4.09 M for hCoV-OC43, 0.77 M for hCoV-229E, 6.68 M for hCoV-OC43, and 0.62 M for hCoV-229E.

Sources:

  • Bioorganic & Medicinal Chemistry, 2025;128:118258
  • Synthesis and multitarget inhibitory effect of indole-based ethyl cinnamate derivatives against SARS-CoV-2 Mpro and cathepsins for broad-spectrum anti-coronavirus activity
  • University of Milan Reports Findings in COVID-19 (Synthesis and multitarget inhibitory effect of indole-based ethyl cinnamate derivatives against SARS-CoV-2 Mpro and cathepsins for broad-spectrum anti-coronavirus activity). Chemicals & Chemistry. June 13, 2025; p 14.