新型乙酰胆碱酯酶抑制剂5H-噻唑并[3,2-a]嘧啶类化合物的设计、合成与生物活性研究

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的虚拟筛选方法寻找新型乙酰胆碱酯酶抑制剂，设计了10个5H-噻唑并3,2-a]嘧啶类化合物。以芳醛、硫脲等为起始原料，通过Biginelli反应生成二氢嘧啶类化合物，再与氯代苯乙酮作用经Hantzsch环合反应制得目标化合物，其结构经红外光谱、质谱、核磁共振氢谱和碳谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个5H-噻唑并3,2-a]嘧啶类化合物，体外抑制乙酰胆碱酯酶活性测试结果显示，所有目标化合物均具有乙酰胆碱酯酶抑制活性，其中3个目标化合物在10 μmol.L^-1时抑制活性均超过50%。结论5H-噻唑并3,2-a]嘧啶类化合物是潜在的乙酰胆碱酯酶抑制剂。将计算机辅助药物分子设计、有机合成和生物活性测试相结合是发现和设计新型乙酰胆碱酯酶抑制剂的有效途径。

Design, synthesis, and biological evaluation of 5H-thiazolo[3,2-a]pyrimidine derivatives as a new type of acetylcholinesterase(AChE) inhibitors

Aim To discover new chemical structures as acetylcholinesterase inhibitors. Methods Finding hits with molecular docking as virtual screening methods were adopted and 5H-thiazolo3,2-a]pyrimidine derivatives as new AChE inhibitors were designed. The target compounds were synthesized with Biginelli reaction and Hantzsch condensation of dihydropyrimidines with substituted 2-chloroacetophenone, and were characterized with IR, MS, ¹H-NMR and ¹³C-NMR. The bioactivity of the target compounds were detected with the Ellman method. Results The 10 target compounds were synthesized, and all showed medium inhibitory potency to human AChE in vitro, three of them with the inhibitory rates above 50% at 10 μmol.L^-1. Conclusion 5H-Thiazolo3,2-a]pyrimidine derivatives were found to be active acetylcholinesterase inhibitors. It would be an efficient approach to discover and design highly active and specific inhibitors of acetylcholinesterase against Alzheimer’s disease by integrating virtual screening, molecular docking and design, organic synthesis with bioassay.