Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy.

Abstract

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with ICvalues of 0.31&#xa0;&#xb1;&#xa0;0.04&#xa0;&#x3bc;M and 1.85&#xa0;&#xb1;&#xa0;0.05&#xa0;&#x3bc;M, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300&#xa0;mg/kg) and AlCl(150&#xa0;mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75&#xa0;mg/kg and 1.5&#xa0;mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p&#xa0;<&#xa0;0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56&#xa0;&#xb1;&#xa0;0.10-fold and 1.71&#xa0;&#xb1;&#xa0;1.76-fold), APP (1.96&#xa0;&#xb1;&#xa0;0.17-fold and 3.39&#xa0;&#xb1;&#xa0;0.139-fold), BACE1 (1.92&#xa0;&#xb1;&#xa0;0.10-fold and 2.59&#xa0;&#xb1;&#xa0;0.04-fold), TNF&#x3b1; (2.16&#xa0;&#xb1;&#xa0;0.21-fold and 3.35&#xa0;&#xb1;&#xa0;0.17-fold), IL-1&#x3b1; (1.86&#xa0;&#xb1;&#xa0;0.236-fold and 2.56&#xa0;&#xb1;&#xa0;0.15-fold), and IL-1&#x3b2; (1.58&#xa0;&#xb1;&#xa0;1.82-fold and 2.32&#xa0;&#xb1;&#xa0;0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.