New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi - Archive ouverte HAL Access content directly
Journal Articles ACS Medicinal Chemistry Letters Year : 2020

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

Jean-Yves Brossas
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Alix Sournia-Saquet
Colin Bonduelle
Céline Deraeve
Alan H. Fairlamb
Alexis Valentin
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  • PersonId : 1098843

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.
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hal-02476867 , version 1 (15-05-2020)

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Julien Pedron, Clotilde Boudot, Jean-Yves Brossas, Emilie Pinault, Sandra Bourgeade-Delmas, et al.. New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi. ACS Medicinal Chemistry Letters, 2020, 11 (4), pp.464-472. ⟨10.1021/acsmedchemlett.9b00566⟩. ⟨hal-02476867⟩
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