Investigation, scaffold hopping of novel donepezil-based compounds as anti-Alzhiemer’s agents: synthesis, in-silico and pharmacological evaluations

Alzheimer’s disease (AD) is a multifaceted neurodegenerative condition. The pathogenesis of AD is highly intricate and the disease is apparent in the aged population ~ 50–70 years old. Even after > 100 years of research, the root origin of AD and its pathogenesis is unclear, complex and multifaceted. Herein, we have designed and synthesized 9 novel molecules with three different heterocyclic scaffolds namely pyrrolidone-2-one, quinoline & indoline-2-one to imitate and explore the novel chemical space around donepezil. The synthesized molecules were evaluated for their potential as anti-Alzheimer’s agents through in-vitro and in-vivo studies in appropriate animal models. To further understand their interaction with acetylcholinesterase enzyme (AChE), extra-precision docking, and molecular dynamics simulation studies were carried out. As the number of compounds was limited to thoroughly explore the structure–activity relationship, atom-based 3D-quantitative structure–activity relationships (QSAR) studies were carried out to get more insights. All the designed compounds were found to inhibit AChE with IC 50 in the micromolar range. From pyrrolidone-2-one series, 6-chloro-N-(1-(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)pyridine-3-sulfonamide ( 9 ), 2-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline ( 18 ) from quinoline series and N-(1-benzylpiperidin-4-yl)-2-(2-oxoindolin-3-yl)acetamide ( 23 ) from indolin-2-one series inhibited AChE with an IC 50 value of 0.01 µM. Based on other biochemical studies like lipid peroxidation, reduced glutathione, superoxide dismutase, catalase, nitrite, and behavioural studies (Morris water maze), compound 9 was found to be a potent AChE inhibitor which can be further explored as a lead molecule to design more potent and effective anti-Alzheimer’s agents.