Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer's Agents.

In continuous efforts to develop anti-Alzheimer's agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound showed multitargeting properties to act as an anti-Alzheimer's agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound inhibits the enzyme with a half-maximal inhibitory concentration (IC) value of 0.78 μM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of against oxidative DNA damage. Compound also showed 53.04% inhibition against Aβ aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound with the enzyme AChE, which showed that the enzyme-ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD cutoff value (50 mg/kg) in comparison to donepezil (LD: 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer's disease (AD).