3-芳基-6-(4-氟苄基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物的合成及乙酰胆碱酯酶抑制活性研究  

3-Aryl-6-(4-fluorobenzyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as acetylcholinesterase inhibitors:synthesis,characterization and biological activity

作　　者：童丰 侯世澄 徐赫男[2] 刘忠旭 高建飞 李涛[2] 周晓光 胡春[2] TONG Feng;HOU Shi-cheng;XU He-nan;LIU Zhong-xu;GAO Jian-fei;LI Tao;ZHOU Xiao-guang;HU Chun(Beijing Chengji Pharmaceutical Co.,Ltd.,Beijing 101301,China;Key Laboratory of Structure-Based Drug Design&Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]北京诚济制药股份有限公司,北京101301 [2]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,沈阳110016

出　　处：《中国药物化学杂志》2022年第9期661-668,共8页Chinese Journal of Medicinal Chemistry

基　　金：National Science Foundation of China(NSFC)(21072130);Program for Innovative Research Team of the Ministry of Education of China(IRT_14R36)。

摘　　要：目的进一步探究含有氟原子的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物作为乙酰胆碱酯酶抑制剂的构效关系。方法利用分子对接和分子模拟技术,设计合成了一系列新的3-芳基-6-(4-氟苄基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物,并用质谱、红外光谱、质子核磁共振和元素分析对其进行结构表征。以石杉碱甲为阳性对照,采用Ellman比色法测试了目标化合物的乙酰胆碱酯酶抑制活性。结果实验结果表明所有目标化合物在10μmol·L^(-1)时均表现出40%以上的抑制作用,一些目标化合物对乙酰胆碱酯酶表现出显著的抑制作用。结论目标化合物母体骨架中C6位苯环上的氟原子对目标化合物的乙酰胆碱酯酶抑制活性发挥着重要作用。Fluorine substitution was used as a strategy to improve biological activity in medicinal chemistry.In order to study the structure-activity relationships of the novel acetylcholinesterase inhibitors with7H-thiazolo[3,2-b]-1,2,4-triazin-7-one scaffold,based on our previous work and molecular docking,a series of novel3-aryl-6-(4-fluorobenzyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were synthesized and characterized by mass spectra,infrared spectra,proton NMR and elemental analyses.The study of acetylcholinesterase inhibitory activity was carried out by using the Ellman colorimetric assay with huperzine-A as the positive control.All target compounds showed more than40%inhibition at10μmol·L.Some target compounds exhibited good inhibition against acetylcholinesterase.The preliminary structure-activity relationship analysis demonstrated that the fluorine atom on the benzyl ring at the C6position of the parent scaffold played significant roles in the acetylcholinesterase inhibitory activity of the target compounds.

关 键 词：乙酰胆碱酯酶抑制剂 杂环化合物 合成 7H-噻唑并[3 2-b]-1 2 4-三嗪-7-酮衍生物 分子对接 

分 类 号：R914[医药卫生—药物化学]