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

Abstract 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.