Li Yuxing, Qiang Xiaoming, Li Yan, Yang Xia, Luo Li, Xiao Ganyuan, Cao Zhongcheng, Tan Zhenghuai, Deng Yong
Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan academy of Chinese Medicine Sciences, Chengdu 610041, China.
Bioorg Med Chem Lett. 2016 Apr 15;26(8):2035-9. doi: 10.1016/j.bmcl.2016.02.079. Epub 2016 Feb 27.
A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
设计、合成并评估了一系列对羟基二苯乙烯 - O - 乙酰氨基烷基苄胺作为乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的双重抑制剂。为进一步探究这些新衍生物的多功能特性，还测试了它们的抗氧化活性以及对自身诱导的Aβ1 - 42聚集和人源AChE诱导的Aβ1 - 40聚集的抑制作用。结果表明，这些化合物大多能有效抑制AChE和BuChE。特别是化合物21d表现出最佳的AChE抑制活性（IC50 = 0.06 μM）和良好的BuChE抑制作用（IC50 = 28.04 μM）。抑制动力学分析和分子模拟研究均表明，这些化合物呈现混合型抑制，同时结合到AChE的催化活性中心（CAS）和外周阴离子位点（PAS）。除胆碱酯酶抑制活性外，这些化合物还表现出不同程度的抗氧化活性。然而，这些新衍生物对自身诱导和人源AChE诱导的Aβ聚集的抑制活性并不理想。考虑到生物学评价结果，将设计进一步的修饰以提高对不同靶点的活性。本信函中展示的结果可为阿尔茨海默病多功能药物的进一步开发提供新的起点。
