Proximal fleximer analogues of 2'-deoxy-2'-fluoro-2'-methyl purine nucleos(t)ides: Synthesis and preliminary pharmacokinetic and antiviral evaluation

Bioorg Med Chem. 2024 Oct 1:112:117898. doi: 10.1016/j.bmc.2024.117898. Epub 2024 Aug 24.

Abstract

In this study, proximal fleximer nucleos(t)ide analogues of Bemnifosbuvir were synthesized and evaluated for their potential to serve as antiviral therapeutics. The final parent flex-nucleoside and ProTide modified flex-nucleoside analogues were tested against several viral families including flaviviruses, filoviruses, and coronaviruses. Modest activity against Zaire Ebola virus was observed at 30 μM for compound ProTide modified analogue. Neither compound exhibited activity for any of the other viruses tested. The parent flex-nucleoside analogue was screened for toxicity in CD-1 mice and showed no adverse effects up to 300 mg/kg, the maximum concentration tested.

Keywords: Ebola Virus; Filovirus; Fleximers; Nucleosides; Prodrugs.

MeSH terms

  • Animals
  • Antiviral Agents* / chemical synthesis
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacokinetics
  • Antiviral Agents* / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Purine Nucleosides / chemical synthesis
  • Purine Nucleosides / chemistry
  • Purine Nucleosides / pharmacokinetics
  • Purine Nucleosides / pharmacology
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Purine Nucleosides