五元杂环并嘧啶类MTH1抑制剂的设计、合成及生物活性评价

Design, synthesis and biological evaluation of five-membered heterocyclopyrimidines as MTH1 inhibitors

摘要: 在MTH1抑制剂TH287的基础上，采用闭环、骨架跃迁和生物电子等排等药物设计策略，结合计算机辅助药物设计方法，设计并合成了17个五元杂环并嘧啶类目标化合物( I_1~10 ， II_1~7 )。采用孔雀石绿显色法评价了目标化合物对MTH1酶活性的影响，结果表明该类化合物具有良好的MTH1抑制活性，其中7个化合物的( I₃ ， I₄ ， I_7~9 )IC₅₀低于1 μmol/L，可以作为新型MTH1抑制剂开展进一步的研究。

Abstract: Based on the reported inhibitors TH287, 17 five-membered heterocyclopyrimidine derivatives were designed and synthesized by cyclization, scaffold hopping, bioisosterism and molecular docking technology. The bioassays determined by malachite green method demonstrated that the target compounds displayed good inhibitory activity against MTH1. Among them, the IC₅₀ value of 7 compounds was less than 1 μmol/L, suggesting that these compounds may be candidates for further investigation.