Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer's Diseases
Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer's Diseases
复制标题
DOI：
10.3390/molecules25030489
复制
发表时间：
2020-02-01
期刊：
影响因子：
4.6
通讯作者：
Liu, Zongliang
中科院分区：
文献类型：
--
作者：
Guo, Yan;Yang, Hongyu;Liu, Zongliang
合成了一系列新的化合物6a-h、8i-1、10s-v和16a-d，并与已知的类似物11a-f一起对乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）进行了抑制活性评价。采用Ellman法测定乙酰胆碱酯酶（AChE）和乙酰胆碱酯酶（BChE）体外抑制活性。结果表明，部分化合物对AChE和BChE具有良好的抑制活性。其中，化合物8i对AChE （eeAChE IC50 = 0.39 μ M）和BChE （eqBChE IC50 = 0.28 μ M）的抑制作用最强。酶抑制动力学和分子模拟研究表明，化合物8i同时结合AChE和BChE的外周阴离子位点（PAS）和催化位点（CAS）。此外，化合物8i的细胞毒性低于他克林，提示其作为抗阿尔茨海默病（anti-AD）药物的潜在安全性。综上所述，这些数据表明化合物8i是一种很有前景的治疗AD的多能药物。
A series of novel compounds 6a-h, 8i-1, 10s-v, and 16a-d were synthesized and evaluated, together with the known analogs 11a-f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 mu M) and BChE (eqBChE IC50 = 0.28 mu M). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.