Design, Synthesis and Discovery of N,N’ ‐Carbazoyl‐aryl‐urea Inhibitors of Zika NS5 Methyltransferase and Virus Replication

Sharon Spizzichino (1) , Giulio Mattedi (2) , Kate Lauder (2) , Coralie Valle (3) , Wahiba Aouadi (3) , Bruno Canard (3) , Etienne Decroly (3) , Suzanne Kaptein (4) , Johan Neyts (5) , Carl Graham (6) , Zakary Sule (2) , David Barlow (2) , Romano Silvestri (7) , Daniele Castagnolo (2)

1 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
2 King‘s College London
3 AFMB - Architecture et fonction des macromolécules biologiques
4 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
5 Department of Microbiology and Immunology, Rega Institute for Medical Research
6 Faculty of Life Sciences & Medicine - School of Cancer and Pharmaceutical Sciences [London, UK]
7 Department of Medicinal Chemistry and Technologies

The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure-based virtual screening approach using the ZIKV NS5-MTase. A novel series of molecules with a carbazoyl-aryl-urea structure has been discovered and a library of analogues has been synthesized. The new compounds inhibit ZIKV MTase with IC 50 between 23-48 μM. In addition, carbazoyl-aryl-ureas also proved to inhibit ZIKV replication activity at micromolar concentration.

Mots clés: Zika; flavivirus; methyltransferase; antiviral agents; urea

Domaines: Virologie

Sharon Spizzichino, Giulio Mattedi, Kate Lauder, Coralie Valle, Wahiba Aouadi, et al.. Design, Synthesis and Discovery of N,N’ ‐Carbazoyl‐aryl‐urea Inhibitors of Zika NS5 Methyltransferase and Virus Replication. ChemMedChem, 2020, 15 (4), pp.385-390. ⟨10.1002/cmdc.201900533⟩. ⟨hal-02890596⟩