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

Three chromene-thiazole derivatives bearing benzimidazole, benzothiazole, and phenyl-1,2,4-triazole moieties were synthesized and evaluated for their potential as SARS-CoV-2 M^pro inhibitors. The derivatives were characterized by various spectroscopic and spectrometric methods: FT-IR, ¹H NMR, ¹³C NMR, HRMS. Density functional theory (DFT) at the B3LYP/6-311++G-(3df,3pd) level was used to calculate the optimized structures of the derivatives and determine their electronic properties. Molecular docking analyses of the derivatives with SARS-CoV-2 M^pro (PDB ID: 6LU7) indicate significant interactions, with docking affinity scores ranging from -7.5 kcal/mol for the benzothiazole derivative to -8.4 kcal/mol for the phenyl-1,2,4-triazole derivative. These docking scores are comparable to or better than those of ML188 (-7.5 kcal/mol), a potent SARS-CoV-2 M^pro inhibitor, indicating the inhibitory potential of these derivatives. Molecular dynamics simulations and QM/MM calculations of the derivatives confirmed the stability of the protein-ligand interactions, and highlighted the key amino acid residues involved in stabilization.