Huo Jingwen, Xiao Jizhen, Zhang Yushi, Qiu Xinhui, Huang Xuechen, Wang Ge, Wang Jianhao, Liu Kuancheng, Xu Jimin
School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China
School of Public Health (Shenzhen), Sun Yat-sen University Guangzhou 510275 China.
RSC Med Chem. 2025 May 8. doi: 10.1039/d5md00222b.
Current HBV treatment with nucleos(t)ide analogs requires lifelong administration and is associated with the risk of drug resistance, underscoring the urgent need for novel antivirals with alternative targets. Herein, we reported the design, synthesis, and biological evaluation of a series of salicylamide derivatives as potent anti-HBV agents. The nine selected compounds exhibited dose-dependent inhibitory effects on HBV replication, as evidenced by significant reductions in both virion DNA and the secretion levels of HBsAg and HBeAg. Among them, compounds 50 and 56 exhibited the highest anti-HBV activity (IC = 0.52 and 0.47 μM, respectively) and selectivity (SI = 20.1 and 17.6, respectively). Mechanistic studies revealed that compounds 27, 31, and 47 impaired HBV core protein (HBc) expression, while compound 50 disrupted capsid formation without significantly affecting HBc expression. These findings highlight the therapeutic potential of salicylamide derivatives as promising anti-HBV agents and provide a foundation for further structural optimization and mechanistic exploration.
目前使用核苷（酸）类似物治疗乙肝病毒需要终身用药，且存在耐药风险，这凸显了迫切需要开发具有替代靶点的新型抗病毒药物。在此，我们报道了一系列水杨酰胺衍生物作为强效抗乙肝病毒药物的设计、合成及生物学评价。所选的9种化合物对乙肝病毒复制表现出剂量依赖性抑制作用，病毒粒子DNA以及乙肝表面抗原和乙肝e抗原的分泌水平均显著降低，证明了这一点。其中，化合物50和56表现出最高的抗乙肝病毒活性（IC50分别为0.52和0.47 μM）和选择性（SI分别为20.1和17.6）。机制研究表明，化合物27、31和47会损害乙肝病毒核心蛋白（HBc）的表达，而化合物50则会破坏衣壳形成，且对HBc表达无显著影响。这些发现突出了水杨酰胺衍生物作为有前景的抗乙肝病毒药物的治疗潜力，并为进一步的结构优化和机制探索奠定了基础。
