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目的初步探讨乙酰胆碱酯酶(AChE)抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及构效关系。方法利用分子对接技术设计一些新的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,采用化学方法合成这些目标化合物,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。首先由芳基乙烯在温和条件下的氧化反应得到2-芳基-2-氧代乙酸,2-芳基-2-氧代乙酸与硫代氨基脲在碱性水溶液中缩合得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮衍生物,3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮衍生物与取代的α-氯代苯乙酮在乙酸中反应得到4个目标化合物;6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应得到7个6-芳基-3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。结果合成了11个未见文献报道的新化合物,其结构均经质谱、红外光谱和核磁共振氢谱确证。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5个化合物在10μmo.lL-1时的抑制活性超过了40%。结论综合分子对接和体外AChE抑制活性的测试结果发现,3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物可与AChE的CAS区、PAS区和阴离子亚位点发生相互作用,C-6位苯环对位的卤原子可增强化合物对AChE的抑制活性。
Objective To investigate the synthesis and structure-activity relationship of acetylcholinesterase (AChE) inhibitor 7H-thiazolo [3,2-b] -1,2,4-triazin-7-one. Methods Some new 7H-thiazolo [3,2-b] -1,2,4-triazin-7-one compounds were designed by molecular docking. The target compounds were synthesized by chemical methods. The target compounds In vitro acetylcholinesterase activity screening. 2-Aryl-2-oxoacetic acid is obtained from the oxidation of arylethylene under mild conditions. The condensation of 2-aryl-2-oxoacetic acid with thiosemicarbazone in basic aqueous solution gives the 3,4- Dihydro-6-aryl-3-thioxo-1,2,4-triazin-5 (2H) -one derivatives, 3,4- 4-triazine-5 (2H) -one derivative and substituted α-chloroacetophenone in acetic acid to give 4 target compounds; 6-aryl-3- Thiazolo [3,2-b] -1,2,4-triazin-7-one compounds were further subjected to Williamson reaction to give 7 6-aryl-3- (alkoxyaryl) [3,2-b] -1,2,4-triazine-7-one compounds. Results Eleven new compounds were synthesized and their structures were confirmed by MS, IR and 1H NMR. In vitro screening of AChE activity showed that all of the target compounds had AChE inhibitory activity, of which 5 showed more than 40% inhibitory activity at 10 μmo.LL -1. Conclusion The results of the comprehensive molecular docking and in vitro AChE inhibitory activity test showed that 3,6-diaryl-7H-thiazolo [3,2-b] -1,2,4-triazin-7-one compounds can be used with AChE the CAS region, PAS region and anionic sub-site interaction occurs, C-6 position of the benzene ring para-halogen atoms can enhance the inhibitory activity of compounds on AChE.