Lead Optimization of Xanthone Derivatives as Hepatitis B Virus cccDNA Reducers: Design, Synthesis, and Bioevaluation

Chronic hepatitis B virus (HBV) infection remains a significant global health challenge, yet current available treatment options are still limited. Roche first reported the efficacy of a class of xanthone derivatives in diminishing covalently closed circular DNA (cccDNA) levels; however, their coplanarity constrained their drug-likeness. We introduced more flexible and hydrophilic side chains to xanthones, yielding a series of compounds with enhanced antiviral activity and better pharmacokinetic (PK) profiles. The representative compound 35 outperformed Rf.59 with respect to both antiviral activity (0.1 μM vs 0.68 μM) and PK properties, including a longer half-life (2.54 h vs 1.48 h), a 2-fold higher AUC0–∞ (1571 vs 783 ng·h/mL), and improved oral bioavailability (43.7% vs 36.4%).