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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 EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 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.
|Number of pages||9|
|Journal||ACS Medicinal Chemistry Letters|
|Early online date||6 Feb 2020|
|Publication status||Published - 9 Apr 2020|
- 8-nitroquinolin-2(1 H)-ones
- Trypanosoma brucei brucei
- Trypanosoma cruzi
- redox potentials
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
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- 1 Finished
Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)
Fairlamb, A., Field, M., Gilbert, I., Gray, D., Horn, D. & Wyatt, P.
1/01/15 → 31/12/20