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ChemMedChem. 2018 Oct 22;13(20):2217-2228. doi: 10.1002/cmdc.201800456. Epub 2018 Sep 17.

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions.

Author information

1
LCC-CNRS, Université de Toulouse, CNRS, UPS, 205 route de Narbonne, 31077, Toulouse, France.
2
Université de Limoges, UMR INSERM 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025, Limoges, France.
3
UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, 35 Chemin des Maraîchers, 31400, Toulouse, France.
4
Assiut University, Faculty of Science, Department of Chemistry, 71516, Assiut, Egypt.
5
University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee, DD1 5EH, UK.

Abstract

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

KEYWORDS:

8-nitroquinolin-2(1H)-ones; antikinetoplastid pharmacomodulation; palladium-catalysed cross-coupling; parasitic nitroreductases; trypanosomatids

PMID:
30221468
DOI:
10.1002/cmdc.201800456

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