Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection.

ABSTRACT

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50 = 2.46 ± 0.33 µM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50 = 0.51 ± 0.20 µM, EC50 = 2.24 ± 0.43 µM, CC50 = 84.29 µM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.