We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC₅₀ against HBV and low cytotoxicities (>50 μM). Structure–activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.

我们在此报告从 4-氧代四氢嘧啶衍生的苯基脲的合成和评价，作为乙型肝炎病毒 (HBV) 的新型衣壳组装调节剂。在这些衍生物中，化合物27 ( 58031 ) 和几种类似物显示出亚微摩尔 EC ₅₀抗 HBV 活性和低细胞毒性 (>50 μM)。构效关系研究揭示了对 4-氧代四氢嘧啶 5 位上的另一个基团的耐受性。机理研究表明化合物27 ( 58031) 是一种 II 型核心蛋白变构调节剂 (CpAM)，可诱导核心蛋白二聚体在天然琼脂糖凝胶中以快速电泳迁移率组装空衣壳。因此，这些化合物可以作为未来开发针对 HBV 的新型抗病毒药物的线索。