Kanwal_2026_Med.Chem.Res_35_425

Single-target ligands have insufficient effectiveness in treating Alzheimers disease (AD), leading to the development of new pharmacological strategies, particularly multi-target-directed ligands (MTDLs) that tackle the multifactorial nature of the impairment. Among these, dual inhibition of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) represents a promising approach for enhancing therapeutic outcomes. Here, analogs of 4-methylbenzyl 5-arylthiophene-2-carboxylates (5a5h) were identified as dual inhibitors of AChE and MAO-B. In vitro evaluations demonstrated that 5a-5d exhibited the most promising inhibition potential towards targeted enzymes (AChE and MAO-B), having IC50 values 0.72 +/- 0.01 microM to 1.69 +/- 0.04 microM for AChE and 0.19 +/- 0.03 microM to 2.69 +/- 0.10 microM for MAO-B. Docking analysis is consistent with the in vitro studies, critically unveiling bindings, commonly hydrogen interactions, pi-Sulphur, pi-pi interaction, pi-alkyl, and alkyl-alkyl ligand and enzyme binding interactions. These results underscore the promise of these dual inhibitors in tackling the complex pathology of AD.