Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides

Bioorg Med Chem Lett. 2022 Apr 1:61:128605. doi: 10.1016/j.bmcl.2022.128605. Epub 2022 Feb 2.

Abstract

Nucleoside analogues represent an historically accomplished class of antiviral drug. Notwithstanding this, new molecular scaffolds are required to overcome their limitations and evolve pharmacophore space within this established field. Herein, we develop concise synthetic access to a new 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleoside chemotype, including the ProTide form of the uridine analogue. Biological evaluation of these materials in the Hepatitis C replicon assay shows little activity for the canonical pyrimidine forms, but the phosphoramidate of 2'-deoxy-2'-fluoro-2'-C-methyl-β-d-4'-thiouridine has an EC50 of 2.99 μM. Direct comparison to the established Hepatitis C drug Sofosbuvir shows a 100-fold drop in activity upon substituting the furanose chalcogen; the reasons for this are as yet unclear.

Keywords: Antiviral; Chemical synthesis; Nucleoside analogue; Sofosbuvir; Thionucleoside.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hepacivirus / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Thionucleosides / chemical synthesis
  • Thionucleosides / chemistry
  • Thionucleosides / pharmacology*
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Thionucleosides