Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of <i>o/p</i>‐propoxyphenylsubstituted‐1<i>H</i>‐benzimidazole derivatives

Abstract

Abstract This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o ‐ and p ‐(3‐substitutedethoxyphenyl)‐1 H ‐benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC 50 values of 0.14 and 0.22 μM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH‐SY5Y cells exposed to H 2 O 2 . Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H 2 O 2 ‐induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi‐target‐directed ligands against Alzheimer's disease.