Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities

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• 作者：Wen Luo^a ; ^&dagger ; ; ^{luowen83@henu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Ying Chen^a ; ^&dagger ; ; Ting Wang^a ; Chen Hong^a ; Li-Ping Chang^a ; Cong-Cong Chang^a ; Ya-Cheng Yang^a ; Song-Qiang Xie^b ; Chao-Jie Wang^a ; ^{wcjsxq@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Flavonoid derivatives ; Cholinesterase ; Anti-Alzheimer agent ; Molecular modeling ; Cytotoxicity
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：672-680
• 全文大小：2092 K

文摘

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC₅₀, 0.64 μM for AChE and 0.42 μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a–5r) did not affect PC12 and HepG2 cell viability at the concentration of 10 μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer’s disease.