Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease.
复制标题
新型呫吨酮-烷基苄胺杂化物作为治疗阿尔茨海默病的多功能药物的设计、合成和生物学评价。
DOI：
10.1016/j.ejmech.2021.113154
复制
发表时间：
2021
影响因子：
6.7
通讯作者：
Xie Sai-Sai
中科院分区：
文献类型：
--
作者：
Zhang Zhipeng;Guo Jie;Cheng Maojun;Zhou Weixin;Wan Yang;Wang Rikang;Fang Yuanying;Jin Yi;Liu Jing;Xie Sai-Sai
本研究将氧杂蒽酮和烷基苄胺的药效团通过烷基连接基团连接起来，设计并获得了一系列抗阿尔茨海默病的多功能杂合体。生物活性结果表明，化合物4j是最有效和平衡的双ChE抑制剂，其对eeAChE和eqBuChE的IC 50值分别为0.85 μM和0.59 μM。动力学分析和对接研究表明化合物4j是一种AChE和BuChE的混合型抑制剂。此外，它表现出良好的能力，穿透血脑屏障，自由基（4.6 trolox当量）和选择性螯合与Cu 2+和Al 3+在1：1.4配体/金属摩尔比。更重要的是，在细胞毒性和急性毒性评估后，我们发现化合物4j可以改善东莨菪碱诱导的遗忘小鼠的记忆功能。因此，化合物4j可以被认为是一个有前途的先导化合物，用于进一步研究治疗AD。
In this study, a series of multifunctional hybrids against Alzheimer’s disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound4jwas the most potent and balanced dual ChEs inhibitor with IC50values 0.85 μM and 0.59 μM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound4jwas a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu2+and Al3+at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound4jcould improve memory function of scopolamine-induced amnesia mice. Hence, the compound4jcan be considered as a promising lead compound for further investigation in the treatment of AD.