Synthesis of a Novel Class of 1,3-oxathiolane Nucleoside Derivatives of T- 705 and Evaluation of Their Anti-influenza A Virus and Anti-HIV Activity

Med Chem. 2018;14(6):595-603. doi: 10.2174/1573406414666180112102225.

Abstract

Background: T-705 (Favipiravir) is a broad spectrum antiviral agent approved for stockpiling in Japan and currently in Phase 3 testing in the United States. Against influenza, it acts as a prodrug, converted intracellularly to selectively inhibit viral RNA-dependent RNA polymerase or similar enzymes. This is regarded as a novel antiviral mechanism of action, reducing crossresistance to other existing anti-influenza drugs.

Objective: To develop new analogs, a class of 1,3-oxathiolane nucleoside derivatives of T-705 was designed and synthesized in this work.

Results: Anti-influenza activity and Anti-HIV activity of these compounds were evaluated. Compound 1a displayed activity against A H1N1 with an IC50 of 40.4 µmol/L. Compound 1b showed weak activity against HIV with a viral suppression rate of 70-80% at 30 µmol/L.

Conclusion: A class of 1,3-oxathiolane nucleoside derivatives of T-705 was designed and synthesized, and one of them was identified as a novel scaffold against viral infection.

Keywords: 1,3-oxathiolane nucleoside; Nucleotide analog; anti-HIV; anti-influenza; favipiravi; viral enzymes..

MeSH terms

  • Amides / pharmacology
  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Dogs
  • HEK293 Cells
  • HIV / drug effects
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Isomerism
  • Madin Darby Canine Kidney Cells / virology
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Nucleosides / toxicity
  • Pyrazines / pharmacology
  • Ribavirin / pharmacology
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Thiophenes / toxicity

Substances

  • Amides
  • Anti-HIV Agents
  • Nucleosides
  • Pyrazines
  • Thiophenes
  • Ribavirin
  • favipiravir