Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses

  • Bioorg Chem. 2023 Apr:133:106408. doi: 10.1016/j.bioorg.2023.106408.
María Del Rosario García-Lozano  1 ,  Filippo Dragoni  2 ,  Paloma Gallego  3 ,  Sarah Mazzotta  4 ,  Alejandro López-Gómez  5 ,  Adele Boccuto  6 ,  Carlos Martínez-Cortés  7 ,  Alejandro Rodríguez-Martínez  8 ,  Horacio Pérez-Sánchez  7 ,  José Manuel Vega-Pérez  5 ,  José Antonio Del Campo  9 ,  Ilaria Vicenti  10 ,  Margarita Vega-Holm  11 ,  Fernando Iglesias-Guerra  5
Affiliations
  • 1. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain; SeLiver Group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital CSIC University of Seville, Seville, Spain.
  • 2. Department of Medical Biotechnologies, Siena University Hospital, Policlinico Le Scotte, Viale Bracci 16, 53100 Siena, Italy.
  • 3. Unit for Clinical Management of Digestive Diseases and CIBERehd, Valme University Hospital, 41014 Seville, Spain.
  • 4. Department of Chemistry, University of Milan, 20133 Milan, Italy.
  • 5. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain.
  • 6. Department of Medical Biotechnologies, Siena University Hospital, Policlinico Le Scotte, Viale Bracci 16, 53100 Siena, Italy; VisMederi Research srl, Siena, Italy.
  • 7. Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, UCAM Universidad Católica de Murcia, 30107 Murcia, Spain.
  • 8. Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva sn, 18071 Granada, Spain.
  • 9. ALGAENERGY S.A., Avda. Europa 19, 28108 Alcobendas, Madrid, Spain. Electronic address: [email protected].
  • 10. Department of Medical Biotechnologies, Siena University Hospital, Policlinico Le Scotte, Viale Bracci 16, 53100 Siena, Italy. Electronic address: [email protected].
  • 11. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain. Electronic address: [email protected].
PMID: 36801791 DOI: 10.1016/j.bioorg.2023.106408
Abstract

Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) Viral Proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with Other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 Protease Inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC50) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC50 6.6 µM and 1.9 µM respectively) and DENV (IC50 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases' active sites.

Keywords
Acyl and urea piperazine derivatives; Flavivirus; Live virus phenotypic assay; Molecular docking; Molecular modeling; NS3 protease; Privileged structures; Small molecules inhibitors.
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