2. Academic Validation
  3. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

  • Eur J Med Chem. 2020 Nov 15:206:112668. doi: 10.1016/j.ejmech.2020.112668.
Cyril Fersing 1,  Clotilde Boudot 2,  Romain Paoli-Lombardo 1,  Nicolas Primas 1,  Emilie Pinault 3,  Sébastien Hutter 4,  Caroline Castera-Ducros 1,  Youssef Kabri 1,  Julien Pedron 5,  Sandra Bourgeade-Delmas 6,  Alix Sournia-Saquet 5,  Jean-Luc Stigliani 5,  Alexis Valentin 6,  Amaya Azqueta 7,  Damián Muruzabal 7,  Alexandre Destere 8,  Susan Wyllie 9,  Alan H Fairlamb 9,  Sophie Corvaisier 10,  Marc Since 10,  Aurélie Malzert-Fréon 10,  Carole Di Giorgio 11,  Pascal Rathelot 1,  Nadine Azas 4,  Bertrand Courtioux 2,  Patrice Vanelle 1,  Pierre Verhaeghe 12
Affiliations

Affiliations

  • 1 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
  • 2 Université de Limoges, UMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 Rue Du Dr Marcland, 87025, Limoges, France.
  • 3 Université de Limoges, BISCEm, US 042 INSERM - UMS 2015 CNRS, Mass Spectrometry Platform, CBRS, 2 Rue Du Pr. Descottes, F-87025, Limoges, France.
  • 4 Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME - Tropical Eukaryotic Pathogens, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.
  • 5 LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 6 UMR 152 PHARMA-DEV, Université de Toulouse, IRD, UPS, Toulouse, France.
  • 7 Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C/ Irunlarrea 1, CP 31008, Pamplona, Navarra, Spain.
  • 8 Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France; INSERM, UMR 1248, University of Limoges, France.
  • 9 University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
  • 10 Normandie Univ, UNICAEN, CERMN, 14000, Caen, France.
  • 11 Institut Méditerranéen de Biodiversité et D'Ecologie Marine et Continentale (IMBE), Aix-Marseille Université, UMR CNRS IRD Avignon Université, Campus Timone - Faculté de Pharmacie, 27 Boulevard Jean-Moulin, F13385, Marseille Cedex 05, France.
  • 12 LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address: pierre.verhaeghe@lcc-toulouse.fr.
PMID: 32795774 DOI: 10.1016/j.ejmech.2020.112668
Abstract

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.

Keywords

Imidazo[1,2-a]pyridine; Kinetoplastids; Nitroaromatic; Nitroreductases; Redox potentials; SARs.

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