Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents

Bioorg Med Chem. 2019 Mar 1;27(5):748-759. doi: 10.1016/j.bmc.2019.01.007. Epub 2019 Jan 16.

Abstract

To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC50 values (0.20-0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.

Keywords: Anti-HCV; Double prodrug; Nucleoside; Phosphoramidate; Pyrazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Blood / metabolism
  • Cell Line, Tumor
  • Drug Discovery
  • Drug Stability
  • Hepacivirus / drug effects*
  • Humans
  • Microsomes, Liver / metabolism
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacology*
  • Sofosbuvir / analogs & derivatives*
  • Sofosbuvir / chemical synthesis
  • Sofosbuvir / pharmacology*

Substances

  • Antiviral Agents
  • Prodrugs
  • Pyrazines
  • Sofosbuvir