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Eur J Med Chem. 2018 Jul 15;155:135-152. doi: 10.1016/j.ejmech.2018.06.001. Epub 2018 Jun 5.

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study.

Author information

1
LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France.
2
Université de Limoges, UMR INSERM 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025, Limoges, France.
3
IHU Méditerranée Infection, équipe VITROME « Vecteurs, Infections Tropicales et Méditerranéennes, 19-21 boulevard Jean Moulin, 13385, Marseille Cedex 05, France.
4
UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, Toulouse, France.
5
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
6
UMR MD1, U1261, AMU, INSERM, SSA, IRBA, MCT, Marseille, France.
7
University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee, DD1 5EH, Scotland, United Kingdom.
8
LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address: pierre.verhaeghe@lcc-toulouse.fr.

Abstract

To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

KEYWORDS:

8-Nitroquinolin-2(1H)-one; Anti-kinetoplastids; Electrochemistry; Leishmania; Nitroreductases; Trypanosoma

PMID:
29885575
DOI:
10.1016/j.ejmech.2018.06.001
[Indexed for MEDLINE]

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