2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮的设计合成及生物活性

Design, synthesis and biological activity of 2H-thiazole[3,2-b][1,2,4] triazine-3,7-dione

摘要:

为寻找高活性的乙酰胆碱酯酶（AChE）抑制剂，以取代的苯甲醛和N-乙酰甘氨酸为原料经过五步反应合成了13个2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮类化合物，目标化合物结构经1H NMR，13C NMR和HRMS确认。采用Ellman法测试了化合物在10 μmol/L浓度下对AChE的抑制活性，结果显示所有目标化合物均具有抑制活性，其中化合物6-(4-甲氧基苄基)-2-(4-甲氧基苯亚甲基)-2H-噻唑并[3,2-b]-1,2,4-三嗪-3,7-二酮（Ⅴk）活性最好，抑制率达到80.1%。通过分子对接研究了化合物Ⅴk和AChE的结合模式，Ⅴk可以跟AChE的多个催化位点结合。2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮类化合物可以为开发具有自主知识产权的新型AChE抑制剂提供参考。

Abstract:

In order to search for high activity acetylcholinesterase (AChE) inhibitors, thirteen 2H-thiazole[3,2-b][1,2,4]triazine-3,7-diones were synthesized from substituted benzaldehyde and N-Acetylglycine through five steps. The structures of the target compounds were confirmed by 1H NMR, 13C NMR and HRMS. Ellman method was used to test AChE inhibitory activity of the compounds at 10 μmol/L. The results showed that all the target compounds had inhibitory activity against AChE, and the compound 6-(4-methoxybenzyl)-2-(4-methoxybenzylidene)-2H-thiazolo[3,2-b]-1,2,4-triazine-3,7-dione (Ⅴk) had the best activity (80.1%). The binding mode of the compound Ⅴk and AChE was studied by molecular docking. The compound Ⅴk could bind to multiple catalysis sites of AChE. 2H-thiazole[3,2-b][1,2,4]triazine-3,7-diones could provide reference for the development of new AChE inhibitors with independent intellectual property rights.