Anti-norovirus activity of C7-modified 4-amino-pyrrolo[2,1-f][1,2,4]triazine C-nucleosides

  • Eur J Med Chem. 2020 Jun 1;195:112198. doi: 10.1016/j.ejmech.2020.112198.
Qingfeng Li  1 ,  Elisabetta Groaz  2 ,  Joana Rocha-Pereira  3 ,  Johan Neyts  3 ,  Piet Herdewijn  4
Affiliations
  • 1. KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, Leuven, 3000, Belgium.
  • 2. KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, Leuven, 3000, Belgium. Electronic address: [email protected].
  • 3. KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Herestraat 49 - Box 1041, Leuven, 3000, Leuven, Belgium.
  • 4. KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, Leuven, 3000, Belgium. Electronic address: [email protected].
PMID: 32294613 DOI: 10.1016/j.ejmech.2020.112198
Abstract

Synthetic nucleoside analogues characterized by a C-C anomeric linkage form a family of promising therapeutics against infectious and malignant diseases. Herein, C-nucleosides comprising structural variations at the sugar and nucleobase moieties were examined for their ability to inhibit both murine and human norovirus RNA-dependent RNA polymerase (RdRp). We have found that the combination of 4-amino-pyrrolo[2,1-f][1,2,4]triazine and its 7-halogenated congeners with either a d-ribose or 2'-C-methyl-d-ribose unit resulted in analogues with good Antiviral activity against murine norovirus (MNV), albeit coupled with a significant cytotoxicity. Among this series, 4-aza-7,9-dideazaadenosine notably retained a strong Antiviral effect in a human norovirus (HuNoV) replicon assay with an EC50 = 0.015 μM. This study demonstrates that C-nucleosides can be used as viable starting scaffolds for further optimization towards the development of nucleoside-based inhibitors of norovirus replication.

Keywords
Antiviral activity; C-Nucleosides; Norovirus; Structure-activity relationship.
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