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

  • ACS Omega. 2025 Dec 17;10(51):62757-62774. doi: 10.1021/acsomega.5c07593.
Lauren D Stettler  1 ,  Vincent T Kopysciansky  1 ,  Jenna E Poor  1 ,  Gabriela de Lima Menezes  2 ,  Elton VanNoy  1 ,  Guilherme Bastos Alves  3 ,  Blake M Shellenberger  1 ,  Faith Garasich  1 ,  Sylvia Stanell  1 ,  Katyanna Sales Bezerra  3 ,  Jonas Ivan Nobre Oliveira  3 ,  Umberto Laino Fulco  2 ,  Geneive E Henry  1
Affiliations
  • 1. Department of Chemistry, Susquehanna University, 514 University Avenue, Selinsgrove, Pennsylvania 17870, United States.
  • 2. Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal 59078-400, RN, Brazil.
  • 3. Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil.
PMID: 41487228 DOI: 10.1021/acsomega.5c07593
Abstract

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 Mpro 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 Mpro (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 Mpro 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.

Products