Synthesis and evaluation of the anti-hepatitis B virus activity of 4'-Azido-thymidine analogs and 4'-Azido-2'-deoxy-5-methylcytidine analogs: structural insights for the development of a novel anti-HBV agent

Nucleosides Nucleotides Nucleic Acids. 2020;39(4):518-529. doi: 10.1080/15257770.2019.1664749. Epub 2019 Sep 12.

Abstract

Hepatitis B virus (HBV) infection is a major worldwide health problem that requires the development of improved antiviral therapies. Here, a series of 4'-Azido-thymidine/4'-Azido-2'-deoxy-5-methylcytidine derivatives (6, 10-15) were synthesized, and their anti-HBV activities evaluated. Compounds 10-15 were synthesized via an SNAr reaction of 18, in which the 4-position of the thymine moiety was activated as the 2,4,6-triisopropylbenzenesulfonate. Compounds 11-15 showed no antiviral activity. However, 4'-Azido thymidine (6) and 4'-Azido-2'-deoxy-5-methylcytidine (10) displayed significant anti-HBV activity (EC50 = 0.63 and 5.99 µM, respectively) with no detectable cytotoxicity against MT-2 cells up to 100 µM.

Keywords: 4′-azido nucleoside; Anti-HBV nucleoside; modified pyrimidines.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cytidine / analogs & derivatives*
  • Cytidine / chemical synthesis
  • Cytidine / chemistry
  • Cytidine / pharmacology
  • Hep G2 Cells
  • Hepatitis B virus / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Stereoisomerism
  • Zidovudine / analogs & derivatives*
  • Zidovudine / chemical synthesis
  • Zidovudine / chemistry
  • Zidovudine / pharmacology

Substances

  • Antiviral Agents
  • 4'-azidothymidine
  • Zidovudine
  • Cytidine
  • 5-methylcytidine