Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer’s disease

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• 作者：Yuxing Li^a ; ^&dagger ; ; Xiaoming Qiang^a ; ^&dagger ; ; Yan Li^a ; Xia Yang^a ; Li Luo^a ; Ganyuan Xiao^a ; Zhongcheng Cao^a ; Zhenghuai Tan^b ; ^{tanzhh616@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yong Deng^a ; ^{dengyong@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AD ; Alzheimer&rsquo ; s disease ; AChE ; acetylcholinesterase ; BuChE ; butyrylcholinesterase ; HuAChE ; human AChE ; EeAChE ; Electrophorus electricus AChE ; Aβ ; β-amyloid peptide ; CAS ; catalytic active site ; PAS ; peripheral anionic site ; EDCI ; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ; PBS ; phosphate-buffered saline ; DTNB ; 5 ; 5&prime ; -dithiobis-2-nitrobenzoic acid ; PDB ; Protein Data Bank ; TcAChE ; Torpedo californica AChE ; ORAC-FL ; Oxygen Radicals Absorbance Capacity by Fluorescence ; ThT
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：2035-2039
• 全文大小：566 K

文摘

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 Aβ_1–42 aggregation and HuAChE-induced Aβ_1–40 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.