Design and evaluation of substituted cinnamoyl piperidinyl acetate derivatives as potent cholinesterase inhibitors

In the pursuit of therapeutic agents for Alzheimer's disease (AD), this study employed a molecular hybridization strategy to design and synthesize substituted cinnamoyl piperidinyl acetates. A total of 17 novel derivatives were evaluated for their inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), key enzymes implicated in AD pathogenesis. Notably, compound 5b, featuring a 2-chloro substitution, emerged as the most potent AChE inhibitor (IC₅₀ = 19.74 ± 0.96 µM), while compound 5q, possessing a 4-ethoxy-3-methoxy moiety, demonstrated superior BChE inhibition (IC₅₀ = 13.49 ± 0.44 µM). Kinetic studies revealed mixed-type inhibition for compound 5b (K_i = 10.03 µM, K_is = 36.16 µM), and molecular docking confirmed its stable interactions with AChE's catalytic and peripheral anionic sites. These findings underscore the potential of cinnamoyl piperidinyl acetate derivatives as promising scaffolds for further optimization and development into effective AD therapeutics.