Gao Xiaohui, Tang Jingjing, Liu Haoran, Liu Linbo, Kang Lu, Chen Wen
a Key Laboratory Breeding Base of Hu'nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy , Changsha Medical University , Changsha , China.
b College of Chemistry and Chemical Engineering , Hu'nan University , Changsha , China.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):519-524. doi: 10.1080/14756366.2018.1436053.
In the present investigation, 48 new tertiary amine derivatives of cinnamic acid, phenylpropionic acid, sorbic acid and hexanoic acid (4d-6g, 10d-12g, 16d-18g and 22d-24g) were designed, synthesized and evaluated for the effect on AChE and BChE in vitro. The results revealed that the alteration of aminoalkyl types and substituted positions markedly influences the effects in inhibiting AChE. Almost of all cinnamic acid derivatives had the most potent inhibitory activity than that of other acid derivatives with the same aminoalkyl side chain. Unsaturated bond and benzene ring in cinnamic acid scaffold seems important for the inhibitory activity against AChE. Among them, compound 6g revealed the most potent AChE inhibitory activity (IC value: 3.64 µmol/L) and highest selectivity over BChE (ratio: 28.6). Enzyme kinetic study showed that it present a mixed-type inhibition against AChE. The molecular docking study suggested that it can bind with the catalytic site and peripheral site of AChE.
在本研究中，设计、合成了48种肉桂酸、苯丙酸、山梨酸和己酸的新型叔胺衍生物（4d - 6g、10d - 12g、16d - 18g和22d - 24g），并对其体外抗乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的效果进行了评估。结果表明，氨基烷基类型和取代位置的改变显著影响对AChE的抑制效果。几乎所有肉桂酸衍生物比具有相同氨基烷基侧链的其他酸衍生物具有更强的抑制活性。肉桂酸骨架中的不饱和键和苯环似乎对AChE抑制活性很重要。其中，化合物6g表现出最强的AChE抑制活性（IC值：3.64 μmol/L）以及对BChE的最高选择性（比率：28.6）。酶动力学研究表明它对AChE呈现混合型抑制。分子对接研究表明它能与AChE的催化位点和外周位点结合。
