3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性  

Design,synthesis and acetylcholinesterase inhibitory activity of 3-(aminoalkoxyaryl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives

作　　者：金辄[1] 刘斯婕[1] 毕春雨[1] 温志昌[2] 林煌权[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]香港中文大学生物医学学院,香港新界999077

出　　处：《沈阳药科大学学报》2012年第6期416-422,共7页Journal of Shenyang Pharmaceutical University

基　　金：国家自然科学基金资助项目(21072130)

摘　　要：目的初步探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-3位苯环侧链中引入二乙胺基团的3-(氨基烷氧基芳基)-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。方法以取代的苯甲醛和乙酰甘氨酸为初始原料,经Erlenmeyer-Plchl反应、缩合反应、水解反应、缩合反应,生成6-芳甲基-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-芳甲基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;以芳基乙烯为原料,经温和的氧化反应、缩合反应得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮在乙酸中反应得到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。两条合成路线得到的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反应制备得到10个3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。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。结果根据前期已筛选化合物的活性数据和总结出的初步构效关系,设计并合成了10个C-3位苯环侧链中含有二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。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7个化合物在10μmol.L-1浓度水平抑制活性超过了50%。结论根据体外重组人源AChE(rhAChE)抑制活性的测试结果,发现C-3位苯环侧链中含有二乙胺基团的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物均具有较好的rh-AChE抑制活性。在这一位置的侧链中引入二乙胺基团,可以增强化合物对rhAChE的抑制活性。Objective To study the synthetic methods of 3-（aminoalkoxylaryl）-7H-thiazolo [ 3,2-b ]-1,2,4- triazin-7-one derivatives and the influence of the N,N-diethylamino group in the side chains at C-3 position of the 7H-thiazolo E 3,2-b ]-1,2,4-triazin-7-one scaffold on the AChE inhibitory activity and the active sites. Methods The two synthetic routes of the target compounds were as follows： The first one, the key intermedi- ate fl-arylpyruvic acid was synthesized from the initial materials which were aromatic aldehydes and N- acetylglycine by using Erlenmeyer-P16chl reaction, condensation, hydrolysis, and condensation reaction. Then, the β-arylpyruvic acid reacted with thiosemicarbazide to obtain 6-arylmethyl-3-sulpho-1,2,4-triazin-5 （2H）-one derivatives. The compounds reacted with substituted ot-choloroacetophenone to obtain 6-arylmeth- yl-3- （hydroxyaryl） -7H-thiazolo[ 3,2-b ] -1,2,4-triazin-7-one derivatives. The second one, 3,4-dihydro-6-ar- yl-3-thioxo-1,2,4-triazin-5 （2H）-one derivatives were prepared by using oxidation reaction and the conden- sation with arylethylenes, followed by the reaction with substituted α-choloroacetophenone in acetic acid to form 6-aryl-3 - （ hydroxyaryl ） -7H-thiazolo [ 3,2-b ] -1,2,4-triazin-7-ones. Finally, ten 3 - （ aminoalkoxyaryl ） - 7H-thiazolo [ 3, 2-b 1-1,2, 4-triazin-7-ones were prepared through Williamson reaction from 6-aryl-3- （hydroxyaryl）-7H-thiazolo E 3,2-b ]-1,2,4-triazin-7-ones. The structures of all of the target compounds were characterized by mass spectra, infrared spectra, and proton NMR. According to the search results of SciFind- er, all of the target compounds were unreported in literature. The study of AChE inhibitory activity was car- ded out using the Ellman colorimetric assay with huperzine-A as the positive control. Results Based on our previous studies on the acetylcholinesterase （ACHE）inhibiting activity data and the structure-activity relation- ships of 7H-thiazolo [3,2-b ] -1,2,4-triazin-7-ones derivatives, ten 3- �

关 键 词：乙酰胆碱酯酶抑制剂 3-(氨基烷氧基芳基)-7H-噻唑并[3 2-b]-1 2 4-三嗪-7-酮 合成 构效关系 

分 类 号：R914[医药卫生—药物化学]