New 8-Nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi Pedron J. auteur aut IRD Boudot C. auteur aut IRD Brossas J. Y. auteur aut IRD Pinault E. auteur aut IRD Bourgeade-Delmas Sandra auteur aut IRD Sournia-Saquet A. auteur aut IRD Boutet-Robinet E. auteur aut IRD Destere A. auteur aut IRD Tronnet A. auteur aut IRD Berge J. auteur aut IRD Bonduelle C. auteur aut IRD Deraeve C. auteur aut IRD Pratviel G. auteur aut IRD Stigliani J. L. auteur aut IRD Paris L. auteur aut IRD Mazier D. auteur aut IRD Corvaisier S. auteur aut IRD Since M. auteur aut IRD Malzert-Freon A. auteur aut IRD Wyllie S. auteur aut IRD Milne R. auteur aut IRD Fairlamb A. H. auteur aut IRD Valentin A. auteur aut IRD Courtioux B. auteur aut IRD Verhaeghe P. auteur aut IRD text journalArticle eng text/pdf reformatted digital access 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 mu M). 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 degrees = -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. specialized Trypanosoma brucei brucei Trypanosoma cruzi 8-nitroquinolin-2(1H)-ones redox potentials NTR1 050 020 052 ACS Medicinal Chemistry Letters 11 4 464-472 2020 1948-5875 https://www.documentation.ird.fr/hor/fdi:010078998 10.1021/acsmedchemlett.9b00566 1948-5875 [F B010078998] https://www.documentation.ird.fr/hor/fdi:010078998 https://horizon.documentation.ird.fr/exl-doc/pleins_textes/divers20-05/010078998.pdf IRD - Base Horizon / Pleins textes 2020-06-09 2025-02-24 fdi:010078998 fre