donepezil
donepezil
Overview
Donepezil is a centrally acting acetylcholinesterase inhibitor used in the symptomatic treatment of cognitive impairment, especially in Alzheimer’s disease. By inhibiting acetylcholinesterase, it increases synaptic acetylcholine availability in the brain, supporting cholinergic neurotransmission that is typically reduced in neurodegenerative disease. In biomedical research, donepezil is frequently used as a reference drug, positive control, or comparator in studies evaluating novel anti-Alzheimer’s agents.
Beyond its established therapeutic role, donepezil is commonly used in preclinical models of memory loss and neurodegeneration to benchmark compounds that target acetylcholinesterase, butyrylcholinesterase, oxidative stress, neuroinflammation, and related pathways involving Beta amyloid, microtubule associated protein tau, NMDA receptor antagonist memantine, and inflammatory mediators such as Interleukin 1 beta and Tumour necrosis factor alpha. Its repeated use in experimental systems reflects its importance as a standard against which new neuroprotective or cognition-enhancing interventions are measured.
Focus of Latest Publications
Recent publications involving donepezil have focused mainly on Alzheimer’s disease research, either as a reference drug in comparative screening of new cholinesterase inhibitors or as a compound studied in analytical and formulation contexts. Several medicinal chemistry studies evaluated newly synthesized candidates against acetylcholinesterase and butyrylcholinesterase relative to donepezil, using docking, molecular dynamics, and in vitro enzyme assays to benchmark activity. In these comparisons, donepezil served as the standard against which novel quinazolinone-chalcone, thieno[3,2-d]pyrimidine, coumarin, and benzimidazole derivatives were assessed, with multiple candidates reported to outperform donepezil in one or both cholinesterase assays.
Among the anti-Alzheimer studies, the quinazolinone-chalcone series identified compound 3e as a particularly strong dual inhibitor of acetylcholinesterase and butyrylcholinesterase, with activity exceeding donepezil in both assays. Similarly, thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids showed low-nanomolar inhibition of both enzymes, and compounds 5 and 9 were reported to surpass donepezil and tacrine, with computational analyses supporting stronger binding than donepezil. Coumarin-based derivatives also showed potent acetylcholinesterase inhibition, with several compounds outperforming donepezil and one derivative, 10f, additionally showing stronger butyrylcholinesterase inhibition than donepezil and activity against glycogen synthase kinase-3β. In the benzimidazole study, IMS48 inhibited both acetylcholinesterase and butyrylcholinesterase more potently than donepezil and improved behavioral, histopathological, and oxidative stress outcomes in an animal model of Alzheimer’s-like pathology.
Donepezil was also used in a study of a natural product extract from Malpighia glabra fruits, where synergistic interactions were observed in vitro between the extract and donepezil, alongside interactions with acarbose. The extract itself showed antioxidant activity and inhibited alpha-glucosidase and Beta-secretase 1, suggesting potential functional food applications. In a separate analytical publication, donepezil hydrochloride was quantified in tablets and human plasma using a green spectrofluorimetric quenching method based on complexation with erythrosine B, with the assay showing linearity, high recovery, and validation according to ICH Q2R2 recommendations.