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

Julien Pedron; Clotilde Boudot; Jean-Yves Brossas; Emilie Pinault; Sandra Bourgeade-Delmas; Alix Sournia-Saquet; Elisa Boutet-Robinet; Alexandre Destere; Antoine Tronnet; Justine Bergé; Colin Bonduelle; Céline Deraeve; Céline Deraeve; Geneviève Pratviel; Jean-Luc Stigliani; Luc Paris; Dominique Mazier; Sophie Corvaisier; Marc Since; Aurélie Malzert-Fréon; Aureĺie Malzert-Freón; Susan Wyllie; Rachel Milne; Alan Fairlamb; Alexis Valentin; Bertrand Courtioux; Pierre Verhaeghe

doi:10.1021/acsmedchemlett.9b00566

Article dans une revue

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

Julien Pedron ¹ Clotilde Boudot ^{2, 3} Jean-Yves Brossas ⁴ Emilie Pinault ³ 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 Céline Deraeve ¹ Geneviève Pratviel ¹ Jean-Luc Stigliani ¹ Luc Paris ⁴ Dominique Mazier ⁸ Sophie Corvaisier ⁹ Marc Since ⁹ Aurélie Malzert-Fréon ⁹ Aureĺie Malzert-Freón ⁹ Susan Wyllie ¹⁰ Rachel Milne ¹⁰ Alan Fairlamb ¹⁰ Alexis Valentin ¹ Bertrand Courtioux ^{3, 2} Pierre Verhaeghe ^{1, *}

* Auteur correspondant

1 LCC - Laboratoire de chimie de coordination

2 NET - Neuroépidémiologie Tropicale

3 UNILIM - Université de Limoges

4 Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière]

5 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement

6 ToxAlim - ToxAlim

7 Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges]

8 CIMI - Centre d'Immunologie et de Maladies Infectieuses

9 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie

10 University of Dundee

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.

Keywords : Trypanosoma cruzi redox potentials Trypanosoma brucei brucei NTR1 8-nitroquinolin-2(1H)-ones

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Santé publique et épidémiologie

Chimie / Chimie de coordination

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https://hal-unilim.archives-ouvertes.fr/hal-02476867
Contributeur : Elisabeth Grelier <>
Soumis le : vendredi 15 mai 2020 - 09:04:37
Dernière modification le : mercredi 21 avril 2021 - 09:12:01

Pedron et al ACSmedchemlett 20...

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