Synthetic modulators of acetylcholinesterase: mechanistic, SAR, and therapeutic perspectives in Alzheimer’s disease

Alzheimer’s disease (AD) is a chronically evolved neurodegenerative condition marked by dysregulation of cholinergic neurotransmission, aberrant Aβ aggregation, tau hyperphosphorylation and sustained neuroinflammatory signalling. Acetylcholinesterase inhibitors (AChEis) play a crucial role in managing neurodegenerative diseases like AD by preventing acetylcholine breakdown, thereby enhancing cognitive function. This review outlines the structural motifs, mechanisms of action, and medicinal chemistry strategies- such as virtual screening, structure-based design, multi-target-directed ligands aimed at improving potency, selectivity, and pharmacokinetic profiles. It emphasizes AChE’s role in neuroinflammation, oxidative stress, apoptosis, and pathological protein aggregation, highlighting the search for novel compounds to prevent or slow disease progression. Synthetic analogues of phytochemicals such as coumarin, chalcone, xanthone, quinoline, and quinazoline have shown notable inhibitory effects comparable to FDA-approved drugs, indicating their potential neuroprotective properties. Molecular docking analysis was carried out to visualize the feasible binding interactions of lead compounds reported in the articles against the target proteins 1EVE and 4PQE. It explains various clinical studies and different preclinical studies, including their animal models and multitargeted pathological mechanisms towards AD. These findings highlight the therapeutic potential of new chemical entities in addressing cholinergic deficits in AD. They also underscore the necessity for further research on mechanisms of action and clinical outcomes to develop effective, well-tolerated treatments that enhance cognitive functions and improve patient quality of life.