Neuroprotective plant-derived compounds via their anti-cholinesterase activity: Therapeutic potential in Alzheimer's disease

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, with cholinergic dysfunction representing a central pathological feature. Current cholinesterase inhibitor therapies offer only modest symptomatic relief and are frequently limited by adverse effects, underscoring the urgent need for safer, multi-targeted treatment strategies. This review comprehensively explores the therapeutic potential of plant-derived compounds as anti-cholinesterase agents for AD, along with detailing the pathophysiological role of the cholinergic system, including the shifting importance from acetylcholinesterase (AChE) to butyrylcholinesterase (BuChE) as the disease progresses. This review synthesizes preclinical evidence from in-silico computational studies to in-vivo animal models, demonstrating that various phytochemical classes such as alkaloids, flavonoids, terpenoids, and coumarins effectively inhibit AChE and BuChE. Beyond enzyme inhibition, these natural compounds exhibit multi-target neuroprotective effects, including antioxidant, anti-inflammatory, and anti-amyloid activities. Furthermore, this review evaluates the drug-correspondence of these candidates through Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling and molecular docking analyses and discusses innovative drug delivery strategies, such as nanotechnology and nose-to-brain administration, designed to overcome the blood-brain barrier (BBB) and enhance therapeutic efficacy. These findings highlight plant-derived compounds as promising multi-target leads for AD, though their application into clinical practice requires further mechanistic validation and precise clinical trials.