6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶抑制活性  

Synthesis and Acetylcholinesterase Inhibitory Activity of 6-Benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives

作　　者：赵阳 侯健 张庆光[1] 金辄[1] 李雪松 刘晓平[1] 温志昌[2] 胡春[1] ZHAO Yang;HOU Jian;ZHANG Qing-guang;JIN Zhe;LI Xue-song;LIU Xiao-ping;WAN David Chicheong;HU Chun(Key Laboratory of Structure-Based Drug Design ＆ Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;School of Biomedical Sciences, The Chinese University of Hongkong, Hongkong 999077, China)

机构地区：[1]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 [2]香港中文大学生物医学学院,香港999077

出　　处：《中国药学杂志》2018年第8期579-584,共6页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(21072130)

摘　　要：目的初步探讨6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶(ACh E)抑制活性。方法以苯甲醛和乙酰甘氨酸作为初始原料,经Erlenmeyer-Pl9chl反应、缩合反应、水解反应、缩合反应,生成取代的6-苄基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮反应,得到6-苄基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。该化合物经Williamson反应制备得到9个6-苄基-3-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9个6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类目标化合物。体外ACh E抑制活性筛选表明,所有目标化合物均具有ACh E抑制活性,其中有5个化合物在10μmol·L^(-1)浓度水平抑制活性超过了50%。结论综合体外ACh E抑制活性和分子对接结果,发现6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物可与ACh E的阴离子亚位点和外周活性位点区发生相互作用,具有一定的ACh E抑制活性。OBJECTIVE To explore the synthesis and acetylcholinesterase inhibitory activity of 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives.METHODS Benzaldehyde and acetylglycine were used as raw materials and underwent Erlenmeyer-Plchl reaction,condensation reaction,hydrolysis reaction,condensation reaction to obtain 6-benzyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5（2H）-ones derivatives.The derivatives reacted with substituted α-phenacyl chlorides to generate 6-benzyl-3-（hydroxylaryl）-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones derivatives.Then,Williamson reaction was used to yield 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones as target compounds.RESULTS Nine 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were prepared as target compounds.All target compounds exhibited inhibitory activities against human AChE in vitro,five of which had inhibitory rates above 50% at 10 μmol·L-1.CONCLUSION Based on the screening results of AChE inhibitory activity in vitro and docking studies,there are some interactions between 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives and the anionic binding site and PAS zones of AChE,and the target compounds have exhibited AChE inhibitory activities.

关 键 词：噻唑并三嗪 乙酰胆碱酯酶抑制剂 老年痴呆 合成 

分 类 号：R914[医药卫生—药物化学]