2. Academic Validation
  3. New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi

New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi

  • ACS Med Chem Lett. 2020 Feb 6;11(4):464-472. doi: 10.1021/acsmedchemlett.9b00566.
Julien Pedron 1,  Clotilde Boudot 2,  Jean-Yves Brossas 3,  Emilie Pinault 4,  Sandra Bourgeade-Delmas 5,  Alix Sournia-Saquet 1,  Elisa Boutet-Robinet 6,  Alexandre Destere 7,  Antoine Tronnet 1,  Justine Bergé 1,  Colin Bonduelle 1,  Céline Deraeve 1,  Geneviève Pratviel 1,  Jean-Luc Stigliani 1,  Luc Paris 3,  Dominique Mazier 8,  Sophie Corvaisier 9,  Marc Since 9,  Aurélie Malzert-Fréon 9,  Susan Wyllie 10,  Rachel Milne 10,  Alan H Fairlamb 10,  Alexis Valentin 5,  Bertrand Courtioux 2,  Pierre Verhaeghe 1
Affiliations

Affiliations

  • 1 LCC-CNRS, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
  • 2 Université de Limoges, UMR INSERM 1094, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025 Limoges, France.
  • 3 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Parasitologie Mycologie, 75013 Paris, France.
  • 4 Université de Limoges, BISCEm Mass Spectrometry Platform, CBRS, 2 rue du Pr. Descottes, F-87025 Limoges, France.
  • 5 UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, 31077 Toulouse, France.
  • 6 Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, 31077 Toulouse, France.
  • 7 Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, France, INSERM, UMR 1248, University of Limoges, F-87025 Limoges, France.
  • 8 CIMI-Paris, Sorbonne Université, 91 Boulevard de l'Hôpital, 75013 Paris, France.
  • 9 Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Normandie Université, 14032 Caen, France.
  • 10 University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee DD1 5EH, United Kingdom.
PMID: 32292551 DOI: 10.1021/acsmedchemlett.9b00566
Abstract

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

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