2. Academic Validation
  3. Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates

Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates

  • Eur J Med Chem. 2018 Feb 25:146:678-686. doi: 10.1016/j.ejmech.2018.01.086.
Maxime Bessières 1,  Vincent Hervin 1,  Vincent Roy 2,  Agnès Chartier 1,  Robert Snoeck 3,  Graciela Andrei 3,  Jean-François Lohier 4,  Luigi A Agrofoglio 5
Affiliations

Affiliations

  • 1 Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France.
  • 2 Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France. Electronic address: vincent.roy@univ-orleans.fr.
  • 3 Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
  • 4 Univ. Caen, CNRS, LCMT, UMR 6507, F-14050 Caen, France.
  • 5 Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France. Electronic address: luigi.agrofoglio@univ-orleans.fr.
PMID: 29407990 DOI: 10.1016/j.ejmech.2018.01.086
Abstract

Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water-under ultrasound irradiation. Two diastereoisomers were formally identified by X-ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC50 values of 0.33 and 0.39 μM for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index ≥200 μM. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs.

Keywords

Acyclic nucleoside phosphonates; Aqueous cross-metathesis; DNA viruses; Phosphonoamidate; Ultrasound.

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