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, CAB7-3 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, CAB7-3 effectively reduced the level of HBV core protein (Cp) and repressed
HBV replication in HBV carrier mice. Preliminary drug-likeness evaluation
indicated that CAB7-3 displayed improved water solubility,
superior microsomal metabolic stability in liver (T1/2 = 169.0 min) and lower hERG cardiotoxicity (IC50 = 6.5375 μM) compared to GLS4. All data demonstrated
that CAB7-3 may be used as a potential candidate for
further drug development.