2. Academic Validation
  3. Synthesis of LAVR-289, a new [(Z)-3-(acetoxymethyl)-4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug with pronounced antiviral activity against DNA viruses

Synthesis of LAVR-289, a new [(Z)-3-(acetoxymethyl)-4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug with pronounced antiviral activity against DNA viruses

  • Eur J Med Chem. 2024 May 5:271:116412. doi: 10.1016/j.ejmech.2024.116412.
Maximes Bessières 1,  Vincent Roy 2,  Tuniyazi Abuduani 1,  Patrick Favetta 1,  Robert Snoeck 3,  Graciela Andrei 3,  Jennifer Moffat 4,  Franck Gallardo 5,  Luigi A Agrofoglio 6
Affiliations

Affiliations

  • 1 Institute of Organic and Analytical Chemistry (ICOA UMR 7311), University of Orleans, CNRS, F-45067 Orléans, France.
  • 2 Institute of Organic and Analytical Chemistry (ICOA UMR 7311), University of Orleans, CNRS, F-45067 Orléans, France. Electronic address: vincent.roy@univ-orleans.fr.
  • 3 Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 4 Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA.
  • 5 NeoVirTech, SAS, Toulouse, France.
  • 6 Institute of Organic and Analytical Chemistry (ICOA UMR 7311), University of Orleans, CNRS, F-45067 Orléans, France. Electronic address: luigi.agrofoglio@univ-orleans.fr.
PMID: 38643669 DOI: 10.1016/j.ejmech.2024.116412
Abstract

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro Antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC50 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC50 0.018 μM, SI 145), with a low morphological toxicity in Cell Culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited Antiviral activity against HCMV (EC50 0.021 μM) and VV (EC50 0.050 μM), as well as against HSV-1 (TK-) (EC50 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.

Keywords

Acyclic nucleoside phosphonate; Broad spectrum antiviral; DNA viruses; O-(2,4-diaminopyrimidin-6-yl); Olefin cross-metathesis; Varicella-zoster virus.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163525
    抗病毒剂
    HSV
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