Cholinergic-targeted molecular hybrids: a renewed strategy for Alzheimer's disease?

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by a complex and multifactorial etiology that complicates its diagnosis, prevention, and treatment. Among the most historically and extensively investigated therapeutic targets are cholinesterases (ChEs), which have guided the development of most currently available symptomatic drugs. Consequently, anti-ChE activity is frequently incorporated into the design of potential multi-target anti-AD compounds.

This critical perspective highlights recent advances in multi-target derivatives with a central anti-ChE property. Various structural scaffolds have been explored, bearing additive properties to the final hybrids, designed by combining structural features of anti-AD drugs (namely rivastigmine and donepezil). Many of these compounds have demonstrated promising outcomes, with some exhibiting greater potency than their reference drugs.

Multi-target small-molecule hybrids may represent a promising perspective for Alzheimer's disease, shifting the focus from cholinesterase-centered design to compounds primarily aimed at interfering with protein misfolding and aggregation, as well as other targets. In this framework, anticholinesterase activity would remain an accessory but still important component for symptomatic control.