Pedron J., Boudot C., Brossas J. Y., Pinault E., Bourgeade-Delmas Sandra, Sournia-Saquet A., Boutet-Robinet E., Destere A., Tronnet A., Berge J., Bonduelle C., Deraeve C., Pratviel G., Stigliani J. L., Paris L., Mazier D., Corvaisier S., Since M., Malzert-Freon A., Wyllie S., Milne R., Fairlamb A. H., Valentin A., Courtioux B., Verhaeghe P. (2020). New 8-Nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi. ACS Medicinal Chemistry Letters, 11 (4), p. 464-472. ISSN 1948-5875.
Titre du document
New 8-Nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi
Année de publication
2020
Auteurs
Pedron J., Boudot C., Brossas J. Y., Pinault E., Bourgeade-Delmas Sandra, Sournia-Saquet A., Boutet-Robinet E., Destere A., Tronnet A., Berge J., Bonduelle C., Deraeve C., Pratviel G., Stigliani J. L., Paris L., Mazier D., Corvaisier S., Since M., Malzert-Freon A., Wyllie S., Milne R., Fairlamb A. H., Valentin A., Courtioux B., Verhaeghe P.
Source
ACS Medicinal Chemistry Letters, 2020,
11 (4), p. 464-472 ISSN 1948-5875
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.
Plan de classement
Sciences fondamentales / Techniques d'analyse et de recherche [020]
;
Santé : généralités [050]
;
Entomologie médicale / Parasitologie / Virologie [052]
Localisation
Fonds IRD [F B010078998]
Identifiant IRD
fdi:010078998
