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目的设计和合成了6个2-取代-9-苄基-嘌呤-6-酮衍生物并测试了其对磷酸二酯酶-2的抑制活性,进而研究PDE2酶对该类抑制剂的作用方式。方法以2-氨基-2-氰基乙酰胺为原料先合成5-氨基-4-羰酰胺咪唑类衍生物,接着用微波辅助的方法合成了目标化合物。结果与结论微波辅助的方法大大缩短反应时间,从传统的加热回流20 h缩短到目前的30 min。抑制活性结果表明,化合物2b[9-苄基-2-(3,4-二甲氧基苄基)-1,9-二氢嘌呤-6-酮]有非常明显的抑制活性(IC50=1.35μmol.L-1)。配体和蛋白质对接的结果分析表明,嘌呤-6-酮衍生物同磷酸二酯酶-2的催化区域的结合主要通过氢键和π-π堆积作用实现的。
OBJECTIVE To design and synthesize 6 2-substituted-9-benzyl-purin-6-one derivatives and test their inhibitory activity against phosphodiesterase-2 and to study the mode of action of PDE2 on these inhibitors . Methods 2-Amino-2-cyanoacetamide was used as a starting material to synthesize 5-amino-4-carboxamidimidazole derivatives, followed by microwave assisted synthesis of the target compound. RESULTS AND CONCLUSION Microwave-assisted method greatly shortened the reaction time, shortened from the traditional heating reflux 20 h to the present 30 min. The inhibitory activity results showed that Compound 2b [9-benzyl-2- (3,4-dimethoxybenzyl) -1,9-dihydropurin-6-one] had a very pronounced inhibitory activity (IC50 = 1.35 μmol.L-1). Analysis of the docking results of the ligand and protein showed that the binding of the purine-6-one derivative to the phosphodiesterase-2 catalytic domain was mainly achieved by hydrogen bonding and π-π stacking.