Synthesis and in vitro inhibitory activity of N-arylsulfonamide adenosine analogues designed to target SARS-CoV-2 nsp14 N7-methyltransferase

  • Bioorg Chem. 2025 Nov:166:109104. doi: 10.1016/j.bioorg.2025.109104.
Marcel Hausdorff  1 ,  Adrien Delpal  2 ,  Hugo Machin  1 ,  Amina Tahir  1 ,  Jim Zoladek  3 ,  Floriane Gucciardi  4 ,  Jitendriya Swain  4 ,  Nathalie Gros  4 ,  Delphine Muriaux  4 ,  Sébastien Nisole  3 ,  Bruno Canard  2 ,  Jean-Jacques Vasseur  1 ,  Etienne Decroly  5 ,  Françoise Debart  6
Affiliations
  • 1. IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France.
  • 2. AFMB, University of Aix-Marseille, CNRS, Marseille, France.
  • 3. IRIM, University of Montpellier, CNRS, Montpellier, France.
  • 4. CEMIPAI, University of Montpellier, CNRS, Montpellier, France.
  • 5. AFMB, University of Aix-Marseille, CNRS, Marseille, France. Electronic address: [email protected].
  • 6. IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France. Electronic address: [email protected].
PMID: 41124802 DOI: 10.1016/j.bioorg.2025.109104
Abstract

This study presents the design, synthesis, and biological evaluation of novel N-arylsulfonamide nucleosides as inhibitors of the SARS-CoV-2 nsp14 N7-methyltransferase. Several compounds demonstrate potent nanomolar inhibition in vitro, with structure-activity relationship analysis revealing the importance of aryl substituents on activity and physicochemical properties. Approaches aimed to improve cellular delivery using carbonate and isobutyryl prodrugs show partial conversion to the active form upon incubation in cell extracts, while orthoester prodrugs remain stable and inactive. Additionally, a fluorescent analogue was synthesized to track intracellular uptake and distribution, confirming cytoplasmic localization. These results highlight the N-arylsulfonamide nucleoside scaffold as a promising Antiviral chemotype against SARS-CoV-2, and emphasize the critical role of chemical modifications for optimizing biological activity and pharmacokinetic profiles toward effective COVID-19 therapies.

Keywords
Adenosine; Arylsulfonamide; Bisubstrate; C-nucleoside; Nsp14 inhibitors; Prodrug; RNA cap methyltransferase; SARS-CoV-2.
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