Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication

Eur J Med Chem. 2011 Sep;46(9):4281-8. doi: 10.1016/j.ejmech.2011.06.034. Epub 2011 Jul 1.


9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Drug Stability
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacokinetics
  • Organophosphonates / pharmacology*
  • Spectrometry, Mass, Fast Atom Bombardment
  • Virus Replication / drug effects*


  • Antiviral Agents
  • Organophosphonates