Exploration and optimization of indole derivatives as novel anti-HBV agent with potential TLR7-agonistic effect.

Hepatitis B virus (HBV) remains a major worldwide health challenge, with disease progression being closely associated with host immune dysregulation, and limited by the resistance of the current anti-HBV drugs. In this study, twenty-six indole derivatives were designed and synthesized as potential immunomodulatory anti-HBV agents. Biological evaluation revealed that compound 11r potently inhibited HBV DNA replication in HepG2.2.15 (wild type strain) and HepG2 A64 (resistant type strain) cells, exhibiting an IC50 values of 0.25 μM and 0.45 μM, respectively. Mechanism studies indicated that 11r promoted the production of TLR7 downstream cytokines such as IL-12 and IFN-α in human PBMCs. Docking analysis indicated that 11r could stably bind within the ligand-binding pocket of TLR7, which was further confirmed by surface plasmon resonance (SPR) experiment demonstrating the direct interaction. In silico prediction of physicochemical properties supported the favorable drug-likeness of 11r. Taken together, these findings indicated 11r as a promising lead compound for further development of immunomodulatory therapies against HBV.