点击化学制备AChE/MAO-B双抑制剂及活性评价  

Preparation and the Activity Evaluation of AChE/MAO-B Dual Inhibitors Using Click

作　　者：贾朝 梁旭华 周伟 潘婷婷 李世玺 JIA Zhao;LIANG Xu-hua;ZHOU Wei;PAN Ting-ting;LI Shi-xi(College of Biology Pharmacy and Food Engineering,Shangluo University,Shangluo 726000,China;Shaanxi Xiangju Pharmaceutical Group Real Estate Co.,Ltd.,Shangluo 726000,China)

机构地区：[1]商洛学院生物医药与食品工程学院,陕西商洛726000 [2]陕西香菊药业集团有限公司,陕西商洛726000

出　　处：《化学试剂》2024年第5期112-120,共9页Chemical Reagents

基　　金：陕西省教育厅项目(20JK0610);张生勇院士项目(18YSZX003)。

摘　　要：通过点击化学(Click)设计、合成了22个香豆素衍生物。多数化合物在微摩尔范围内表现出良好的AChE和MAO-B双抑制活性,具有良好的生物相容性。尤其是一种名为A2B5的化合物,对AChE和MAO-B的IC_(50)分别为(0.23±0.02)、(0.31±0.03)μmol/L,是最佳的AChE/MAO-B双抑制剂。实验结果表明香豆素基团是一类有效的AChE和MAO-B双抑制活性基团,羟基取代苯环的存在能够增强抑制活性。分子对接研究发现A2B5是双位点抑制剂,苯基部分结合到AChE的CAS位点,香豆素结合到PAS位点,三氮唑环占据两个活性位点的中间峡谷。A2B5的香豆素部分结合到MAO-B的入口空腔,苯基部分结合到底物空腔,并嵌入到Tyr435、Tyr398和FAD形成的“芳香笼”。总之,香豆素C7位置取代衍生物可以被开发为AChE/MAO-B双抑制剂,为进一步开发抗阿尔茨海默病的双靶点药物提供一个新的起点。The Click was utilized to design and manufacture 22 coumarin derivatives.In the micromolar range,the majority of these compounds exhibite potent dual inhibitory activity against AChE and MAO-B,suggesting favorable biocompatibility.Among these derivatives,A2B5 emerged as the most effective AChE/MAO-B dual inhibitor,with IC_(50)values of(0.23±0.02)μmol/L for AChE and(0.31±0.03)μmol/L for MAO-B,respectively.Experimental results highlight,coumarin groups as robust dual inhibitory functional groups for MAO-B and AChE,with enhanced inhibitory activity observed in the presence of hydroxyl substituted benzene rings.Molecular docking studies revealed that A2B5 functions as a dual-site inhibitor,with the triazole moiety binding to the center canyon of the active sites and the phenyl and the coumarin units attaching to the CAS site of AChE and the the PAS site of MAO-B,respectivley.Specially,the phenyl component of A2B5 links to the substrate cavity,forming interactions within the“aromatic cage”created by Tyr435,Tyr398,and FAD,while the coumarin portion binds to the entrance cavity of MAO-B.In conclusion,the development of coumarin C7 substituted compounds as AChE/MAO-B dual inhibitors presents a promising approach for advancing research and development efforts focused on dual-target medications for Alzheimer′s disease.

关 键 词：阿尔茨海默病(AD) 点击化学 香豆素 AChE/MAO-B双抑制剂 分子对接 生物相容性 

分 类 号：TQ46[化学工程—制药化工]