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

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。

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

Objective To study the synthetic methods of 3-(aminoalkoxylaryl)-7H-thiazolo3,2-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-thiazolo3,2-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 intermediate β-arylpyruvic acid was synthesized from the initial materials which were aromatic aldehydes and N-acetylglycine by using Erlenmeyer-Plchl 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 α-choloroacetophenone to obtain 6-arylmethyl-3-(hydroxyaryl)-7H-thiazolo3,2-b]-1,2,4-triazin-7-one derivatives.The second one,3,4-dihydro-6-aryl-3-thioxo3,2-b]-1,2,4-triazin-5(2H)-one derivatives were prepared by using oxidation reaction and the condensation with arylethylenes,followed by the reaction with substituted α-choloroacetophenone in acetic acid to form 6-aryl-3-(hydroxyaryl)-7H-thiazolo3,2-b]-1,2,4-triazin-7-ones.Finally,ten 3-(aminoalkoxyaryl)-7H-thiazolo3,2-b]-1,2,4-triazin-7-ones were prepared through Williamson reaction from 6-aryl-3-(hydroxyaryl)-7H-thiazolo3,2-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 SciFinder,all of the target compounds were unreported in literature.The study of AChE inhibitory activity was carried 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 relationships of 7H-thiazolo3,2-b]-1,2,4-triazin-7-ones derivatives,ten 3-(aminoalkoxyaryl)-7H-thiazolo3,2-b]-1,2,4-triazin-7-ones which containing N,N-diethylamino group in the side chains at C-3 position of the parent nucleus were designed and synthesized.All of the target compounds exhibited inhibitory activities against human AChE in vitro,seven of them with the inhibitory rates above 50%at 10 μmol·L-1.Conclusions Based on the test results of AChE inhibitory activity in vitro,the 3-(aminoalkoxylaryl)-7H-thiazolo3,2-b]-1,2,4-triazin-7-one derivatives which containing diethylamino group in the side chains at C-3 position of the parent nucleus,exhibit good AChE inhibitory activity,and the activity can be enhanced with the presence of the diethylamino group which located in the side chains at C-3 position of the parent nucleus.