Esmkhani Maryam, Javanshir Shahrzad, Iraji Aida, Mahdavi Mohammad
Pharmaceutical and Heterocyclic Compounds Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran.
Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran.
Sci Rep. 2025 Jun 2;15(1):19346. doi: 10.1038/s41598-025-04266-z.
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 (IC = 19.74 ± 0.96 µM), while compound 5q, possessing a 4-ethoxy-3-methoxy moiety, demonstrated superior BChE inhibition (IC = 13.49 ± 0.44 µM). Kinetic studies revealed mixed-type inhibition for compound 5b (K = 10.03 µM, K = 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.
在寻找阿尔茨海默病（AD）治疗药物的过程中，本研究采用分子杂交策略设计并合成了取代肉桂酰哌啶基乙酸酯。共评估了17种新型衍生物对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制作用，这两种关键酶与AD发病机制有关。值得注意的是，具有2-氯取代基的化合物5b是最有效的AChE抑制剂（IC = 19.74 ± 0.96 µM），而具有4-乙氧基-3-甲氧基部分的化合物5q则表现出优异的BChE抑制作用（IC = 13.49 ± 0.44 µM）。动力学研究表明化合物5b为混合型抑制（K = 10.03 µM，K = 36.16 µM），分子对接证实其与AChE的催化位点和外周阴离子位点有稳定的相互作用。这些发现强调了肉桂酰哌啶基乙酸酯衍生物作为有前景的骨架用于进一步优化和开发成有效的AD治疗药物的潜力。
