Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, and there are currently no effective treatment options available. Selective inhibition of butyrylcholinesterase (BuChE) has emerged as a promising strategy for AD therapeutics. In this study, we identified compound 6a as a lead candidate derived from the structural modification of rivastigmine. Our findings indicated that 6a acts as a potent selective BuChE inhibitor, demonstrating an IC50 value of 0.33 μM (SI > 151.5). Furthermore, compound 6a displayed favorable neuroprotective properties, along with excellent blood-brain barrier (BBB) permeability and drug-like characteristics. In vivo investigations utilizing an AlCl3-induced zebrafish model of AD revealed that compound 6a significantly improved cognitive function, which was further supported by its ability to mitigate memory impairment induced by scopolamine. Overall, these results highlight compound 6a as a promising selective BuChE inhibitor with potential therapeutic implications for the treatment of Alzheimer's disease.