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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-Plchl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 investigate the effect of diethylamine on the C-3 benzene ring side chain of 7H-thiazolo [3,2-b] -1,2,4-triazin-7- (Aminoalkoxyaryl) -7H-thiazolo [3,2-b] -1,2,4-triazin-7-one and its acetylcholinesterase inhibitory activity. Methods The substituted benzaldehyde and acetylglycine were used as starting materials to synthesize 6-arylmethyl-3-thioxo-1,2,4-triazine through Erlenmeyer-Plchl reaction, condensation reaction, hydrolysis reaction and condensation reaction -5 (2H) -one and reacted with the substituted α-chloroacetophenone to give 6-arylmethyl-3- (hydroxyaryl) -7H-thiazolo [3,2-b] 1,2,4-triazin-7-ones; aryl ethers as raw materials, mild oxidation reaction, condensation reaction to give 3,4-dihydro-6-aryl-3-thio- 2,4-triazin-5 (2H) -one and the substituted α-chloroacetophenone in acetic acid to give 6-aryl-3- (hydroxyaryl) -7H-thiazolo [ 3,2-b] -1,2,4-triazine-7-one compounds. The 3- (hydroxyaryl) -7H-thiazolo [3,2-b] -1,2,4-triazin-7-one compounds obtained by the two synthetic routes were further subjected to Williamson reaction to give 10 3- (Alkoxyaryl) -7H-thiazolo [3,2-b] -1,2,4-triazin-7-one. All target compounds were confirmed by MS, IR and 1H NMR. Ellman’s method was used to screen the target compounds for acetylcholinesterase inhibition in vitro. Results According to the activity data of the pre-screened compounds and the preliminary structure-activity relationship summarized, the 3- (aminoalkoxyaryl) group containing diethylamine groups in the C-3 benzene ring was designed and synthesized. -7H-thiazolo [3,2-b] -1,2,4-triazin-7-one. In vitro screening of AChE inhibitory activities showed that all of the target compounds had AChE inhibitory activity, of which seven compounds exceeded 50% at a concentration of 10 μmol.L-1. Conclusion According to the test results of in vitro recombinant human AChE (rhAChE) inhibitory activity, it was found that the 7H-thiazolo [3,2-b] -1,2,4 - triazin-7-one compounds have better rh-AChE inhibitory activity. The incorporation of diethylamine groups in the side chain at this site enhances the inhibitory activity of the compounds on rhAChE.