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, Geneviève Pratviel, Jean-Luc Stigliani, Luc Paris, Dominique Mazier, Sophie Corvaisier, Marc Since, Aurélie Malzert-Fréon, Susan Wyllie, Rachel Milne, Alan H. Fairlamb, Alexis Valentinm Bertrand Courtiouxm, Pierre Verhaeghe
ACS Medicinal Chemistry Letters Article ASAP
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.