Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Julien Pedron, Clotilde Boudot, Sébastien Hutter, Sandra Bourgeade-Delmas, Jean-Luc Stigliani, Alix Sournia-Saquet, Alain Moreau, Elisa Boutet-Robinet, Lucie Paloque, Emmanuelle Mothes, Michèle Laget, Laure Vendier, Geneviève Pratviel, Susan Wyllie, Alan Fairlamb, Nadine Azas, Bertrand Courtioux, Alexis Valentin, Pierre Verhaeghe (Lead / Corresponding author)

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Abstract

To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

Original languageEnglish
Pages (from-to)135-152
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume155
Early online date5 Jun 2018
DOIs
Publication statusPublished - 15 Jul 2018

Keywords

  • Anti-kinetoplastids
  • Leishmania
  • Trypanosoma
  • 8-Nitroquinolin-2(1H)-one
  • Nitroreductases
  • Electrochemistry

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    Pedron, J., Boudot, C., Hutter, S., Bourgeade-Delmas, S., Stigliani, J-L., Sournia-Saquet, A., Moreau, A., Boutet-Robinet, E., Paloque, L., Mothes, E., Laget, M., Vendier, L., Pratviel, G., Wyllie, S., Fairlamb, A., Azas, N., Courtioux, B., Valentin, A., & Verhaeghe, P. (2018). Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study. European Journal of Medicinal Chemistry, 155, 135-152. https://doi.org/10.1016/j.ejmech.2018.06.001