Chromene-Thiazole Derivatives as Potential SARS-CoV‑2 M^pro Inhibitors: Synthesis and Computational Studies

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• The COVID-19 pandemic necessitates the development of effective antiviral therapies.
• SARS-CoV-2 main protease (M^pro) is a critical target for antiviral drug development due to its essential role in viral replication.

Purpose of the Study:

• To synthesize and evaluate novel chromene-thiazole derivatives as potential inhibitors of SARS-CoV-2 M^pro.
• To investigate the binding interactions and stability of these derivatives with the target enzyme using computational methods.

Main Methods:

• Synthesis of three chromene-thiazole derivatives incorporating benzimidazole, benzothiazole, and phenyl-1,2,4-triazole moieties.
• Characterization using FT-IR, 1H NMR, 13C NMR, and HRMS.
• Computational studies including Density Functional Theory (DFT), molecular docking, molecular dynamics simulations, and QM/MM calculations.

Main Results:

• Docking analyses revealed significant interactions with SARS-CoV-2 M^pro (PDB ID: 6LU7), with affinity scores ranging from -7.5 to -8.4 kcal/mol.
• The phenyl-1,2,4-triazole derivative exhibited the highest docking affinity (-8.4 kcal/mol), comparable to the known inhibitor ML188 (-7.5 kcal/mol).
• Molecular dynamics and QM/MM simulations confirmed the stability of protein-ligand complexes and identified key stabilizing amino acid residues.

Conclusions:

• The synthesized chromene-thiazole derivatives demonstrate significant potential as SARS-CoV-2 M^pro inhibitors.
• Computational modeling supports their efficacy and provides insights into their mechanism of action.
• These compounds represent promising candidates for further development as antiviral agents against SARS-CoV-2.