Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

详细信息    查看全文

• 作者：Chaolei Wang^a ; ^b ; Zheng Wu^a ; ^b ; Hao Cai^a ; ^b ; Shengtao Xu^a ; ^b ; Jie Liu^a ; ^c ; ^{cpu-jill@163.com" class="auth_mail" title="E-mail the corresponding author} ; Jieyun Jiang^d ; Hequan Yao^a ; ^b ; Xiaoming Wu^a ; ^b ; Jinyi Xu^a ; ^b ; ^{jinyixu@china.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alzheimer&rsquo ; s disease ; Acetylcholinesterase ; 4-Isochromanone ; Hybrids ; Dual binding site
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5212-5216
• 全文大小：831 K

文摘

A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC₅₀ value of 8.9 nM and high AChE/BuChE selectivity (SI >230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure–activity relationships were discussed.