Investigation of Parkinson’s Disease: Synthesis, <i>In Vitro</i> and <i>In Silico</i> Screening of Imidazopyridine-Derived Thiadiazole-Bearing Benzimidazole Scaffolds as Effective MAO-A and MAO-B Inhibitors

With the increasing prevalence of neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) are rapidly emerging as promising candidates for their treatment. In this context, we have synthesized a series of novel imidazopyridine-derived thiadiazole-bearing benzimidazole compounds as potential MAO-A and MAO-B inhibitors. These compounds were structurally elucidated by 1 H NMR, [Formula: see text]C NMR and Mass analysis. Most of the compounds displayed good inhibition in the range of (IC[Formula: see text]value 23.30 ± 2.70 − 57.80 ± 6.60 [Formula: see text]M for hMAO-A and 23.60 ± 1.90 − 59.70 ± 6.80 [Formula: see text]M) in comparison of reference drugs toloxatone (IC[Formula: see text]34.50 ± 3.20 [Formula: see text]M) and Lazabemide (IC[Formula: see text]39.90 ± 4.40 [Formula: see text]M), respectively. Compounds 11, 8, 2, 10 and 7 demonstrated IC[Formula: see text] 23.30 ± 2.70 − 29.40 ± 3.70 [Formula: see text]M against MAO-A and IC[Formula: see text] 23.60 ± 1.90 − 30.30 ± 3.30 against MAO-B, indicating significant activity compared to the standard inhibitors. Additionally, molecular docking analysis was performed to predict the binding modes of the newly synthesized derivatives with the MAO-A and MAO-B enzymes. The docking results were aligned well with the findings from the in vitro studies, exhibiting hydrogen bonding, [Formula: see text]-donor hydrogen bond, [Formula: see text]–[Formula: see text]-T-shaped, [Formula: see text]–[Formula: see text]-stacking, [Formula: see text]-alkyl, [Formula: see text]-anion, [Formula: see text]-sigma, [Formula: see text]-sulfur and halogen (fluorine) interactions, further supporting their potential as effective enzyme inhibitors.