Computational Design and Assessment of Bi-Heterocyclic Donepezil Derivatives as Enhanced Acetylcholinesterase Inhibitors

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, is characterized by cognitive decline and neuronal death. Acetylcholinesterase (AChE) remains a primary therapeutic target, with donepezil as a widely used drug. However, its limited efficacy prompts the search for improved derivatives. This raises a key question: Can structural modifications to donepezil lead to analogues with improved therapeutic potential against AD? In this study, novel donepezil analogues are designed by replacing its indanone moiety with bi-heterocyclic scaffolds to enhance binding affinity, pharmacokinetic properties, and anti-AD activity. Molecular docking is used to identify compounds with favorable AChE interactions, followed by pharmacokinetic profiling for drug-likeness and blood–brain barrier permeability. Molecular dynamics simulations further evaluate binding stability and free energy. Among the designed compounds, AS3 (indole-based), AS4 (benzofuran-based), and AS8 (coumarin-based) showed enhanced AChE affinity and stable interactions compared to donepezil. AS4 exhibited the highest binding affinity, while AS8 demonstrated superior reactivity and chemical stability. Additionally, a new compound is designed by modifying both the indanone and piperidine moieties and introducing fluorine functionalization on the benzyl group. This compound demonstrated significantly improved binding affinity toward AChE, highlighting a promising new scaffold for further development.