LAUSR

This study describes the synthesis, pharmacological evaluation, including acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibition, amyloid beta (Aβ) antiaggregation, and neuroprotective effects, as well as molecular modeling of novel 2-(4-substituted phenyl)-1H-benzimidazole derivatives. These derivatives were synthesized by cyclization of o-phenylenediamines with sodium hydroxy(4-substituted phenyl)methanesulfonate salts. In vitro studies indicated that the most of the target compounds showed remarkable inhibitory activity against BChE (IC50: 13.60–95.44 µM). Among them, 3d and 3g-i also exhibited high selectivity (SI ≥ 35.7) for BChE with IC50 values 39.56, 13.60, 14.45, and 15.15 µM, respectively. According to the molecular modeling studies, it may be assumed that the compounds are able to reach the catalytic site of BChE but not that of AChE. The compounds showing BChE inhibitory effects were subsequently examined for their Aβ-antiaggregating and neuroprotective activities. Among the compounds, 3d inhibited the Aβ1–40 aggregation and demonstrated significant neuroprotection against H2O2-induced and Aβ1–40-induced cell death. Collectively, compound 3d showed the best multifunctional activity (BChE; IC50 = 39.56 µM, SI > 126; Aβ self-mediated aggregation; 67.78% at 100 μM; H2O2-induced cytotoxicity with cell viability of 98% and Aβ1-40-induced cytotoxicity with cell viability of 127%). All these results suggested that 2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazole (compound 3d) could be a promising multi-target lead candidate against Alzheimer’s disease.