In this study, new 1-ethyl-2-substituted-5-(methylsulfonyl)-1H-benzimidazole derivatives were designed and synthesized as computer-aided potential MAO-A and -B inhibitors. Compounds E6 and E10 were found more active than reference compound moclobemide with IC50 (µM)= 0.096 ± 0.003 and 0.150 ± 0.006 against MAO-A, respectively. Compound E5, on the other hand, exhibited an activity close to the reference selegiline with IC50 (µM)= 0.045 ± 0.002 against MAO-B. The compounds were identified as potential inhibitors by molecular docking method and the protein-ligand interactions of compounds E5, E6, and E10 were described. The stability of the ligand of the MAO-B-E5 complex at the active site was revealed by molecular dynamics simulation. Comparative Molecular Field Analysis (CoMFA) models have been developed to identify the key structural fragments that allow inhibition on MAO-A and -B. The theoretical ADME calculations of the compounds were made, and it was found that they comply with the limiting rules. For detailed elucidation of compound structures, X-ray diffraction analysis of E4 compound was performed, as well as 1H-NMR, 13C-NMR, and HRMS analyzes.
- Molecular dynamics
- X-ray diffraction