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 4b 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 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC50) value of 0.78 mu M and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against A beta(1-42) aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b 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 LD50 cutoff value (50 mg/kg) in comparison to donepezil (LD50: 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 4b 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 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer's disease (AD).

Automated summary

In this study, a series of multitargeting molecules were rationally designed and synthesized to develop anti-Alzheimer's agents. Compound 4b showed multitargeting properties as an effective and well-tolerated anti-Alzheimer's agent in vivo. It exhibited acetylcholinesterase inhibition, DNA protection against oxidative damage, and inhibition of A beta(1-42) aggregations. Molecular dynamics simulations confirmed the stability of the compound with the enzyme. In animal experiments, compound 4b and donepezil both significantly improved memory. The study suggests that compound 4b, designed based on the structural features of donepezil, has potential as an alternative therapeutic for Alzheimer's disease.