Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC50 = 0.012 mu M) and HBV-infected HLCZ01 cells (EC50 = 0.033 mu M). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.

Automated summary

In this study, benzamide derivatives were designed and synthesized, and compound 17i showed significantly increased anti-HBV activity and inhibited the assembly of HBV capsid protein. It also exhibited good metabolic stability and oral bioavailability, as well as inhibitory effects on HBV replication.