Design, synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non-nucleoside hepatitis B virus inhibitors by exploring the solvent-exposed region

Chem Biol Drug Des. 2020 Jun;95(6):567-583. doi: 10.1111/cbdd.13512. Epub 2020 Apr 22.

Abstract

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have explored the solvent-exposed protein region of heteroaryldihydropyrimidine derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In particular, compound II-1 displayed the most potent activity against HBV DNA replication (IC50 = 0.35 ± 0.04 μM). The preliminary structure-activity relationships of the new compounds were summarized, which may help in discovering more potent anti-HBV agents via rational drug design.

Keywords: HAP; HBV; capsid; protein-solvent interface; sulfonamide; triazoles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Hepatitis B virus / drug effects
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Solvents / chemistry
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Triazoles / chemistry
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Pyrimidines
  • Solvents
  • Sulfonamides
  • Triazoles
  • heteroaryldihydropyrimidine
  • DNA-Directed RNA Polymerases