Synthesis, molecular modeling, 3D-QSAR and biological evaluation studies of new benzimidazole derivatives as potential MAO-A and MAO-B inhibitors

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 (mu M)= 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 (mu M)= 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 H-1-NMR, C-13-NMR, and HRMS analyzes. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

In this study, a series of new benzimidazole derivatives were designed and synthesized as potential MAO-A and MAO-B inhibitors. The compounds showed promising inhibitory activity against the target enzymes, and their interactions with proteins were investigated through molecular docking and molecular dynamics simulations. The key structural fragments responsible for the inhibition on MAO-A and MAO-B were identified using CoMFA models. ADME calculations indicated good drug-like properties for the compounds. X-ray diffraction analysis and spectroscopic techniques were employed for structural characterization.