新型乙酰胆碱酯酶抑制剂6-芳甲基-3-(4-烷氧苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性研究  

Design,synthesis and biological activity of the novel acetylcholinesterase inhibitors 6-arylmethyl-3-(4-alkoxyphenyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives

作　　者：徐赫男[1,2] 娄晶莹[2] 张灿[2] 刘宏民[1] 刘斯婕[2] 温志昌[3] 王言[3] 林煌权[3] 胡春[2] 

机构地区：[1]郑州大学化学与分子工程学院,郑州450052 [2]沈阳药科大学制药工程学院,沈阳110016 [3]香港中文大学生物医学学院,香港999077

出　　处：《中国新药杂志》2013年第22期2692-2697,2706,共7页Chinese Journal of New Drugs

基　　金：国家自然科学基金(21072130)

摘　　要：目的:探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C6位芳甲基中引入不同类型的取代基及C3位苯环中引入含氮侧链的6-芳甲基-3-(4-烷氧苯基)-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(AChE)抑制活性和构效关系。方法:以苯甲醛或取代的苯甲醛和乙酰甘氨酸为原料,经Erlenmeyer-Plchl反应、水解反应、缩合反应生成6-芳甲基-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;将6-芳甲基-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson醚化反应,制备得到9个6-芳甲基-3-(4-烷氧苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。采用Ellman法对目标化合物进行体外AChE抑制活性筛选。结果:所有目标化合物的结构均经红外光谱、质谱和核磁共振氢谱确证。目标化合物经体外AChE抑制活性筛选的结果显示:所有目标化合物均具有AChE抑制活性,其中8个化合物在10μmol·L-1浓度水平抑制活性超过40%。结论:C3位苯环中引入含氮侧链的6-芳甲基-3-(4-烷氧苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物普遍具有较高的AChE抑制活性,并且在母核的C6位芳甲基上引入供电子基团的化合物的AChE抑制活性明显高于引入吸电子基团的化合物。Objective： To design and synthesize nine 6-arylmethyl-3-（4-alkoxyphenyl）-7H-thiazolo[3,2- b]-1 ,2,4-triazin-7-one derivatives based on our previous work and molecular modeling, and to determine the ace-tylcholinesterase （ACHE） inhibitory activity, the structure-activity relationship and the influences of group types on C6 arylmethyl and the side chain containing nitrogen at C3 phenyl on the 7H-thiazolo[ 3,2-b ]-1,2,4-triazin-7-one scaffold. Methods： Benzaldehyde or substituted benzaldehyde was reacted with N-acetoglycine by using Erlenmey- er-Pl^chl reaction, hydrolyzation reaction and condensation reaction to obtain 6-arylmethyl-3-（4-hydroxyphenyl）- 7H-thiazolo[3,2-b l-l, 2,4-triazin-7-one derivatives. Then the c[erivatives were transferred to nine target com- pounds 6-arylmethyl-3 - （ 4-alkoxyphenyl ） -7H-thiazolo [ 3,2 -b ] -1,2,4-triazin-7-one derivatives by using Williamson reaction. AChE inhibitory activity was determined by the Ellman colorimetric assay with huperzine-A as the positive control. Results ： The structures of all of the target compounds were characterized by mass spectra, infrared spectra and proton NMR. All of the target compounds exhibited inhibitory activities against human AChE in vitro, eight of them exhibited more than 40% inhibition at 10 umol L- 1 Conclusion ： 6-Arylmethyl-3- （4-alkoxyphenyl） -7H-thi- azolo[3,2-b]-1,2,4-triazin-7-one derivatives would be a kind of highly active AChE inhibitors. The inhibitory ac- tivities of target compounds with electron-donating group are more powerful than those of target compounds with e- lectron-withdrawing group at C6 arylmethyl on the 7H-thiazolo[ 3,2-b]-1,2,4-triazin-7-one scaffold.

关 键 词：阿尔茨海默病 乙酰胆碱酯酶抑制剂 6-芳甲基-3-(4-烷氧苯基)-7H 噻唑并[3 2-b]-1 2 4 三嗪-7-酮类化合物 合成 构效关系 

分 类 号：R914.5[医药卫生—药物化学]