Arora_2025_Mol.Divers__

Acetylcholinesterase inhibitors (AChEIs) are essential in the treatment of neurodegenerative disorders like Alzheimer's disease, as they prevent the breakdown of acetylcholine, thereby enhancing cognitive function. This review provides a comprehensive analysis of the structural motifs and mechanisms governing AChEI pharmacological activity, with a focus on medicinal chemistry strategies to enhance potency, selectivity, and pharmacokinetic properties. Beginning with the physiological role of acetylcholinesterase in neurological disorders, the review explores the historical evolution of AChEIs and highlights key structural interactions with catalytic, peripheral anionic, and allosteric binding sites. Advances in computational modeling, virtual screening, and structure-based drug design are discussed, alongside emerging approaches, such as multi-target-directed ligands and prodrugs. Additionally, the significance of natural products and drug repurposing in identifying novel AChEI scaffolds is emphasized, contributing to chemical diversity and innovation in drug discovery. By integrating computational tools, expansive chemical libraries, and innovative design strategies, this review identifies promising directions for developing effective AChEIs. These advancements hold great potential in addressing the multifaceted nature of neurodegenerative diseases and improving therapeutic interventions.