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.

Cyril Fersing, Clotilde Boudot, Romain Paoli-Lombardo, Nicolas Primas, Emilie Pinault, Sébastien Hutter, Caroline Castera-Ducros, Youssef Kabri, Julien Pedron, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Jean Luc Stigliani, Alexis Valentin, Amaya Azqueta, Damián Muruzabal, Alexandre Destere, Susan Wyllie, Alan H. Fairlamb, Sophie Corvaisier, Marc SinceAurélie Malzert-Fréon, Carole Di Giorgio, Pascal Rathelot, Nadine Azas, Bertrand Courtioux, Patrice Vanelle, Pierre Verhaeghe

Research output: Contribution to journalArticlepeer-review

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
Original languageEnglish
Article number112668
Number of pages20
JournalEuropean Journal of Medicinal Chemistry
Volume206
Early online date4 Aug 2020
DOIs
Publication statusPublished - 15 Nov 2020

Keywords

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

Fingerprint Dive into the research topics of '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.'. Together they form a unique fingerprint.

Cite this