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

Julien Pedron (1) , Clotilde Boudot (2) , Sandra Bourgeade-Delmas (3) , Alix Sournia-Saquet (1) , Lucie Paloque (1) , Maryam Rastegari (1) , Mansour Abdoulaye (1) , Hussein El-Kashef (4) , Colin Bonduelle (1) , Geneviève Pratviel (1) , Susan Wyllie (5) , Alan Fairlamb (5) , Bertrand Courtioux (2) , Pierre Verhaeghe (1) , Alexis Valentin (3)

1 LCC - Laboratoire de chimie de coordination
2 NET - Neuroépidémiologie Tropicale
3 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
4 Department of Chemistry
5 Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee

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.

Mots clés: trypanosomatids; parasitic nitroreductases; palladium-catalysed cross-coupling; antikinetoplastid pharmacomodulation; 8-nitroquinolin-2(1H)-ones

Domaines: Santé publique et épidémiologie

Julien Pedron, Clotilde Boudot, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Lucie Paloque, et al.. Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1 H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions. ChemMedChem, 2018, 13 (20), pp.2217-2228. ⟨10.1002/cmdc.201800456⟩. ⟨hal-01888530⟩