School of Chemistry and Chemical Engineering, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China.
Bioorg Med Chem Lett. 2010 Jun 1;20(11):3254-8. doi: 10.1016/j.bmcl.2010.04.059. Epub 2010 Apr 18.
A series of novel cholinesterase inhibitors, being composed of 4-[(diethylamino)methyl]-phenoxy and secondary amine which were linked with a different length alkyl chain, were designed and synthesized from the starting material p-hydroxybenzaldehyde. These compounds were evaluated as acetylcholinesterase and butyrylcholinesterase (AChE/BChE) inhibitors. Compounds 25-31 having a secondary amine moiety connected to the phenyl ring via eight CH(2) units spacer were found to be the most potent inhibitors with IC(50) value lower than 220nM and 48nM against AChE and BChE, respectively. Interestingly, these inhibitors showed a surprising selectively toward BChE, and compounds 26, 27, and 30 displayed 12.5, 18.6, and 18.8-fold higher affinity to BChE. The inhibition kinetics analyzed by Linewear-Burk plots revealed that such compounds were mix-type inhibitors.
从起始原料对羟基苯甲醛出发，设计并合成了一系列新型的胆碱酯酶抑制剂，它由 4-[(二乙氨基)甲基]-苯氧基和连接不同长度烷基链的仲胺组成。这些化合物被评估为乙酰胆碱酯酶和丁酰胆碱酯酶（AChE/BChE）抑制剂。具有仲胺部分通过八个 CH(2)单元间隔基连接到苯环的化合物 25-31 是最有效的抑制剂，对 AChE 和 BChE 的 IC(50)值分别低于 220nM 和 48nM。有趣的是，这些抑制剂对 BChE 表现出惊人的选择性，化合物 26、27 和 30 对 BChE 的亲和力分别高出 12.5、18.6 和 18.8 倍。通过 Linewear-Burk 图进行的抑制动力学分析表明，这些化合物是混合类型抑制剂。
