Synthesis and antiviral evaluation of bis(POM) prodrugs of (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides

Eur J Med Chem. 2012 Nov:57:126-33. doi: 10.1016/j.ejmech.2012.08.042. Epub 2012 Sep 7.

Abstract

Seventeen hitherto unknown bis(POM) prodrugs of novel (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides were prepared in a straight approach and at good yields. Those compounds were synthesized by the reaction of purine nucleobases directly with the phosphonate synthon 3 bearing POM biolabile groups under Mitsunobu conditions. All obtained compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex viruses 1 and 2, varicella zoster virus, Feline herpes virus, human cytomegalovirus, HIV-1 and HIV-2. Among these molecules, some of them exhibit anti-VZV and anti-HIV activity at submicromolar concentrations. This class of compound will be of further interest for lead optimization as anti-infectious agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Chlorocebus aethiops
  • DNA Viruses / drug effects*
  • DNA Viruses / growth & development
  • Dogs
  • Drug Design
  • Drug Discovery
  • HeLa Cells
  • Humans
  • Madin Darby Canine Kidney Cells
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Purine Nucleosides / chemical synthesis*
  • Purine Nucleosides / pharmacology
  • RNA Viruses / drug effects*
  • RNA Viruses / growth & development
  • Vero Cells
  • Viral Plaque Assay

Substances

  • Antiviral Agents
  • Organophosphonates
  • Prodrugs
  • Purine Nucleosides