Salicylamide derivatives as potent HBV inhibitors: insights into structure-activity relationships

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 (IC₅₀ = 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.