Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

Julien Pedron, Clotilde Boudot, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Lucie Paloque, Maryam Rastegari, Mansour Abdoulaye, Hussein El-Kashef, Colin Bonduelle, Geneviève Pratviel, Susan Wyllie, Alan H. Fairlamb, Bertrand Courtioux, Pierre Verhaeghe (Lead / Corresponding author), Alexis Valentin

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Abstract

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Original languageEnglish
Pages (from-to)2217-2228
Number of pages12
JournalChemMedChem
Volume13
Issue number20
Early online date17 Sep 2018
DOIs
Publication statusPublished - 22 Oct 2018

Keywords

  • 8-nitroquinolin-2(1H)-ones
  • antikinetoplastid pharmacomodulation
  • palladium-catalysed cross-coupling
  • parasitic nitroreductases
  • trypanosomatids

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    Pedron, J., Boudot, C., Bourgeade-Delmas, S., Sournia-Saquet, A., Paloque, L., Rastegari, M., Abdoulaye, M., El-Kashef, H., Bonduelle, C., Pratviel, G., Wyllie, S., Fairlamb, A. H., Courtioux, B., Verhaeghe, P., & Valentin, A. (2018). Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions. ChemMedChem, 13(20), 2217-2228. https://doi.org/10.1002/cmdc.201800456