Design, Synthesis, and Biological Evaluation of Highly Potent Boronic Acid (Boronate Ester)-Bearing Heteroaryldihydropyrimidine Derivatives as HBV Capsid Assembly Modulators

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) are a new class of specific antiviral agents that interfere with the capsid assembly process to exert antiviral effects. In this study, we rationally designed and chemically synthesized a series of novel boronic acid (boronate ester)-bearing heteroaryldihydropyrimidine (HAP) derivatives based on a multisite-binding strategy in the solvent-exposed region. Among them, <b>CAB7-3</b> exhibited significant anti-HBV activity in HBV-integrated HepDES19 (EC₅₀ = 0.07 μM), HepAD38 (EC₅₀ = 0.001 μM) and HBV-infected HLCZ01 cells (EC₅₀ = 0.002 μM), respectively. Additionally, <b>CAB7-3</b> effectively reduced the level of HBV core protein (Cp) and repressed HBV replication in HBV carrier mice. Preliminary drug-likeness evaluation indicated that <b>CAB7-3</b> displayed improved water solubility, superior microsomal metabolic stability in liver (<i>T</i>_1/2 = 169.0 min) and lower hERG cardiotoxicity (IC₅₀ = 6.5375 μM) compared to GLS4. All data demonstrated that <b>CAB7-3</b> may be used as a potential candidate for further drug development.