2. Academic Validation
  3. Design and synthesis of novel thioether analogs as promising antiviral agents: In vitro activity against enteroviruses of interest

Design and synthesis of novel thioether analogs as promising antiviral agents: In vitro activity against enteroviruses of interest

  • Eur J Med Chem. 2025 Feb 14:288:117395. doi: 10.1016/j.ejmech.2025.117395.
Hugo Roux 1,  Franck Touret 2,  Antonio Coluccia 3,  Pietro Scio 4,  Hawa Sophia Bouzidi 5,  Carole di Giorgio 6,  Florence Gattacceca 7,  Omar Khoumeri 8,  Romano Silvestri 9,  Patrice Vanelle 10,  Manon Roche 11
Affiliations

Affiliations

  • 1 Aix-Marseille Université, CNRS, ICR UMR 7273, PCR, Faculté de Pharmacie, 13005, Marseille, France. Electronic address: hugo.roux@univ-amu.fr.
  • 2 Unité des Virus Émergents (UVE: Aix-Marseille Univ, Università di Corsica, IRD 190, Inserm 1207, IRBA), France. Electronic address: franck.touret@univ-amu.fr.
  • 3 Department of Drug Chemistry and Technologies, Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Italy. Electronic address: antonio.coluccia@uniroma1.it.
  • 4 Department of Drug Chemistry and Technologies, Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Italy. Electronic address: pietro.scio@uniroma1.it.
  • 5 Unité des Virus Émergents (UVE: Aix-Marseille Univ, Università di Corsica, IRD 190, Inserm 1207, IRBA), France. Electronic address: hawa-sophia.BOUZIDI@univ-amu.fr.
  • 6 Aix-Marseille Université, Avignon Université, CNRS, IRD, IMBE, Faculty of Pharmacy, Service of Environmental Mutagenesis, Marseille, France. Electronic address: carole.di-giorgio@univ-amu.fr.
  • 7 Aix-Marseille Université, COMPO INRIA-CRCM-INSERM-U1068, CNRS UMR7258, Marseille, France. Electronic address: florence.gattacceca@univ-amu.fr.
  • 8 Aix-Marseille Université, CNRS, ICR UMR 7273, PCR, Faculté de Pharmacie, 13005, Marseille, France. Electronic address: omar.khoumeri@univ-amu.fr.
  • 9 Department of Drug Chemistry and Technologies, Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Italy. Electronic address: romano.silvestri@uniroma1.it.
  • 10 Aix-Marseille Université, CNRS, ICR UMR 7273, PCR, Faculté de Pharmacie, 13005, Marseille, France. Electronic address: patrice.vanelle@univ-amu.fr.
  • 11 Aix-Marseille Université, CNRS, ICR UMR 7273, PCR, Faculté de Pharmacie, 13005, Marseille, France. Electronic address: manon.roche@univ-amu.fr.
PMID: 39986184 DOI: 10.1016/j.ejmech.2025.117395
Abstract

The Enterovirus genus contains two major subgroups: rhinovirus (RV) species A-C and Enterovirus (EV) ones A-D. While RV only infects the respiratory system, the EV can cause a wide variety of diseases, ranging from non-specific febrile illness to severe neurologic complications. To date, no curative treatments are commercially available. Our research team had recently developed EV-A71 inhibitors. To improve their activity and broaden their spectrum, we performed optimization of the structure following an iterative cycle of chemical modulations. As a result, we obtained two broad-spectrum inhibitors with micromolar activity against these 3 types of viruses (OM1260: EC50 (MRC-5, EV-A71) = 1.15 μM; EC50 (RD, EV-A71) = 4.38 μM; EC50 (MRC-5, E30) = 0.41 μM; EC50 (MRC-5, CVA24) = 1.15 μM; HR-568: EC50 (MRC-5, EV-A71) = 3.25 μM; EC50 (RD, EV-A71) = 1.53 μM; EC50 (MRC-5, E30) = 0.40 μM; EC50 (MRC-5, CVA24) = 1.22 μM). Docking studies shed light on structure-activity relationships, while time-of-drug addition assays confirmed their intervention during the early step of viral replication. Eventually, some pharmacokinetic modelling has been carried out to evaluate their druggability. All these results showed that OM1260 and HR-568 are promising candidates for further development.

Keywords

Broad-spectrum; Capsid binder; Enterovirus; Fused bicycles; Heterocyclic compounds; Structure-activity relationships.

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