Structural and functional approaches to the design of multitarget cholinesterase inhibitors

Abstract

. Disruption of cholinergic neurotransmission is one of the earliest and most significant pathological events in neurodegenerative disorders, particularly in Alzheimer’s disease (AD). Progressive loss of cholinergic neurons in the basal forebrain and decreased levels of acetylcholine in cortical and hippocampal regions correlate strongly with cognitive decline and memory deficits. Acetylcholinesterase (AChE), the key enzyme responsible for terminating synaptic transmission through hydrolysis of acetylcholine, is therefore a central molecular target in the treatment of AD. Currently, AChE inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine represent the principal therapeutic agents for symptomatic management of mild to moderate AD. By increasing acetylcholine concentrations in synaptic clefts, these drugs temporarily restore cholinergic neurotransmission and improve cognitive performance. However, their effectiveness is limited to symptomatic relief and declines as neurodegeneration progresses, underscoring the urgent need for novel agents with broader and more sustained activity. Recent studies have revealed that AChE is involved not only in neurotransmitter hydrolysis but also in several pathogenic processes, including β-amyloid aggregation, oxidative stress, and apoptosis. This multifaceted role positions AChE as a multifunctional therapeutic target, suitable for the development of multitarget inhibitors capable of modulating several disease mechanisms simultaneously.