乙酰胆碱酯酶抑制剂3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性  

Design,synthesis and biological activity of 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as acetylcholinesterase inhibitors

作　　者：金辄[1] 刘晓光[1] 刘斯婕[1] 高海燕[1] 鞠蕾[1] 雷杰喻[1] 温志昌[2] 林煌权[2] 李硕[2] 胡春[1] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]香港中文大学生物化学系

出　　处：《中国药物化学杂志》2011年第1期25-31,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21072130)

摘　　要：目的初步探讨乙酰胆碱酯酶(AChE)抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及构效关系。方法利用分子对接技术设计一些新的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,采用化学方法合成这些目标化合物,采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。首先由芳基乙烯在温和条件下的氧化反应得到2-芳基-2-氧代乙酸,2-芳基-2-氧代乙酸与硫代氨基脲在碱性水溶液中缩合得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮衍生物,3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮衍生物与取代的α-氯代苯乙酮在乙酸中反应得到4个目标化合物;6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应得到7个6-芳基-3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。结果合成了11个未见文献报道的新化合物,其结构均经质谱、红外光谱和核磁共振氢谱确证。体外乙酰胆碱酯酶抑制活性筛选表明,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中5个化合物在10μmo.lL-1时的抑制活性超过了40%。结论综合分子对接和体外AChE抑制活性的测试结果发现,3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物可与AChE的CAS区、PAS区和阴离子亚位点发生相互作用,C-6位苯环对位的卤原子可增强化合物对AChE的抑制活性。Based on our previous work that 6-arylmethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones derivatives inhibiting acetylcholinesterase（AChE） activity,in order to study on the influence of the different groups and side chains on the 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one scaffold on the AChE inhibitory activity and the active sites of AChE,eleven 3,6-diaryl-7H-thiazolo-[3,2-b]-1,2,4-triazin-7-one derivatives were designed using molecular docking and synthesized.The synthetic routes of the target compounds were as follows：firstly,2-aryl-2-oxoacetic acids were prepared by mild oxidation from aryl ethylenes.2-Aryl-2-oxoacetic acids was condensed with thiosemicarbazide in alkaline aqueous solution to give 3,4-dihydro-6-aryl-3-thioxo[3,2-b]-1,2,4-triazin-5（2H）-one derivatives.3,4-Dihydro-6-aryl-3-thioxo-[3,2-b]-1,2,4-triazin-5（2H）-ones was treated with substituted α-phenacyl chlorides in acetic acid to obtain four 3,6-diaryl-7H-thiazolo-[3,2-b]-1,2,4-triazin-7-ones as target compounds.Among above target compounds,Then 6-aryl-3-（hydroxyaryl）-7H-thiazolo-[3,2-b]-1,2,4-triazin-7-ones were substituted by using Williamson reaction to give seven 6-aryl-3-（alkoxylphenyl）-7H-thiazolo-[3,2-b]-1,2,4-triazin-7-ones derivatives.The structures of all target compounds were characterized by mass spectra,infrared spectra,and proton NMR.The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control.All target compounds exhibited medium inhibitory activity against human AChE in vitro,five of them with the inhibitory rates above 40% at 10 μmol · L-1.3,6-Diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were found to be a new series of acetylcholinesterase inhibitors.Based on the docking studies and test results of AChE inhibitory activity in vitro,there are some interactions between target compounds and CAS,PAS and anionic binding site of AChE.The inhibitory activity could be enhanced with the presence of the halogen atoms which located at para

关 键 词：乙酰胆碱酯酶抑制剂 3 6-二芳基-7H-噻唑并[3 2-b]-1 2 4-三嗪-7-酮 分子对接 合成 构效关系 

分 类 号：R914[医药卫生—药物化学]