Discovery of a New Donepezil-like Acetylcholinesterase Inhibitor for Targeting Alzheimer's Disease: Computational Studies with Biological Validation.

Alzheimer's disorder is one of the most common worldwide health problems, and its prevalence continues to increase, thereby straining the healthcare budgets of both developed and developing countries. So far, donepezil is the only Food and Drug Administration-approved dual-binding site inhibitor of acetylcholinesterase (AChE) that can amplify the cholinergic activity and also decrease Aβ aggregation in Alzheimer patients. We report herein a new donepezil-like natural compound derivative (D1) as a convincing AChE inhibitor. The in silico studies suggests that D1 exhibits a dual-binding mode of action and interacts with both the catalytic anionic site and peripheral anionic site (PAS) of human AChE. The biological studies confirm the dual-binding site character of D1 and revealed that D1 not only enhances the acetylcholine levels but also reduces the accumulation of Aβ plaques in Caenorhabditis elegans. In fact, 5 μM D1 was seen more potent in elevating the acetylcholine expression than 25 μM donepezil. While most of the non-cholinergic functions of donepezil, associated with the PAS of AChE, were gradually lost at higher concentrations, D1 was more functional at similar doses. Promisingly, D1 also exerted an agonistic effect on the α7 nicotinic acetylcholine receptor.