3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成及其乙酰胆碱酯酶抑制活性研究

Desingn,synthesis and acetylcholinesterase inhibitory activity of 3-aryl-6-(bromoaryl-methyl)-7H-thiazolo-1,2,4-triazin-7-one derivatives

目的设计合成3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,并探讨C-6位芳甲基上引入溴原子对其乙酰胆碱酯酶抑制活性的影响。方法以4-羟基苯甲醛为原料,经溴代反应,得到3-溴-4-羟基苯甲醛和3,5-二溴-4-羟基苯甲醛,再将溴代的4-羟基苯甲醛与乙酰甘氨酸经Erlenmeyer-Plchl反应、水解反应、缩合反应合成目标化合物3-芳基-6-(溴代芳甲基)-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乙酰胆碱酯酶抑制活性筛选。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。目标化合物经体外乙酰胆碱酯酶抑制活性筛选,结果显示:所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中8个化合物在10μmol.L-1浓度水平抑制活性超过了40%。结论在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-6位芳甲基中引入溴原子的3-芳基-6-(溴代芳甲基)-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,并且引入2个溴原子的化合物抑制活性明显高于引入1个溴原子的化合物。

Objective To study the influence of the bromine atom（s）at C6 arylmethyl on AChE inhibitory activity.Methods Based on our previous work and structure-activity relationships,ten 3-aryl-6-（bromoarylmethyl）-7H-thiazolo-1,2,4-triazin-7-one derivatives were designed and synthesized.4-Hydroxybenzaldehyde was converted to 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde by bromination.Then brominated 4-hydroxybenzaldehyde reacted with N-acetoglycine,by using Erlenmeyer-Plchl reaction,hydrolyzation reaction,condensation reaction to obtain 3-aryl-6-（bromoarylmethyl）-7H-thiazolo-1,2,4-triazin-7-one derivatives.The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control.Results The structures of all target compounds were characterized by mass spectra,infrared spectra,and proton NMR.All target compounds exhibited inhibitory activities against recombinant human AChE in vitro;eight of them exhibited more than 40% inhibition at 10 μmol · L-1.Conclusions 3-Aryl-6-（bromoarylmethyl）-7H-thiazolo-1,2,4-triazin-7-one derivatives exhibit highly activity against recombinant human AChE.The inhibitory activity can be enhanced with the presence of the hydroxyl groups and the bromine atoms.The inhibitory activities of the target compounds with two bromine atoms are more powerful than that of target compounds with one bromine atom.