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

Julien Pedron, Clotilde Boudot, Sébastien Hutter, Sandra Bourgeade-Delmas, Jean-Luc Stigliani, Alix Sournia-Saquet, Alain Moreau, Elisa Boutet-Robinet, Lucie Paloque, Emmanuelle Mothes, Michèle Laget, Laure Vendier, Geneviève Pratviel, Susan Wyllie, Alan Fairlamb, Nadine Azas, Bertrand Courtioux, Alexis Valentin, Pierre Verhaeghe (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)135-152
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume155
Early online date5 Jun 2018
DOIs
Publication statusPublished - 15 Jul 2018

Fingerprint

Nitroquinolines
Oxidation-Reduction
Leishmania infantum
Antiparasitic Agents
Trypanosoma brucei brucei
Molecules
Derivatives
Nitroreductases
Computational chemistry
Lactams
Comet Assay
Pharmacokinetics
Hep G2 Cells
Structure-Activity Relationship
Cytotoxicity
X-Ray Diffraction
Cyclic voltammetry
Half-Life
Hydrogen
Albumins

Keywords

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

Cite this

Pedron, J., Boudot, C., Hutter, S., Bourgeade-Delmas, S., Stigliani, J-L., Sournia-Saquet, A., ... Verhaeghe, P. (2018). Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study. European Journal of Medicinal Chemistry, 155, 135-152. https://doi.org/10.1016/j.ejmech.2018.06.001
Pedron, Julien ; Boudot, Clotilde ; Hutter, Sébastien ; Bourgeade-Delmas, Sandra ; Stigliani, Jean-Luc ; Sournia-Saquet, Alix ; Moreau, Alain ; Boutet-Robinet, Elisa ; Paloque, Lucie ; Mothes, Emmanuelle ; Laget, Michèle ; Vendier, Laure ; Pratviel, Geneviève ; Wyllie, Susan ; Fairlamb, Alan ; Azas, Nadine ; Courtioux, Bertrand ; Valentin, Alexis ; Verhaeghe, Pierre. / Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules : Synthesis, electrochemical and SAR study. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 155. pp. 135-152.
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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.",
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author = "Julien Pedron and Clotilde Boudot and S{\'e}bastien Hutter and Sandra Bourgeade-Delmas and Jean-Luc Stigliani and Alix Sournia-Saquet and Alain Moreau and Elisa Boutet-Robinet and Lucie Paloque and Emmanuelle Mothes and Mich{\`e}le Laget and Laure Vendier and Genevi{\`e}ve Pratviel and Susan Wyllie and Alan Fairlamb and Nadine Azas and Bertrand Courtioux and Alexis Valentin and Pierre Verhaeghe",
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Pedron, J, Boudot, C, Hutter, S, Bourgeade-Delmas, S, Stigliani, J-L, Sournia-Saquet, A, Moreau, A, Boutet-Robinet, E, Paloque, L, Mothes, E, Laget, M, Vendier, L, Pratviel, G, Wyllie, S, Fairlamb, A, Azas, N, Courtioux, B, Valentin, A & Verhaeghe, P 2018, 'Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study', European Journal of Medicinal Chemistry, vol. 155, pp. 135-152. https://doi.org/10.1016/j.ejmech.2018.06.001

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules : Synthesis, electrochemical and SAR study. / Pedron, Julien; Boudot, Clotilde; Hutter, Sébastien; Bourgeade-Delmas, Sandra; Stigliani, Jean-Luc; Sournia-Saquet, Alix; Moreau, Alain; Boutet-Robinet, Elisa; Paloque, Lucie; Mothes, Emmanuelle; Laget, Michèle; Vendier, Laure; Pratviel, Geneviève; Wyllie, Susan; Fairlamb, Alan; Azas, Nadine; Courtioux, Bertrand; Valentin, Alexis; Verhaeghe, Pierre (Lead / Corresponding author).

In: European Journal of Medicinal Chemistry, Vol. 155, 15.07.2018, p. 135-152.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules

T2 - Synthesis, electrochemical and SAR study

AU - Pedron, Julien

AU - Boudot, Clotilde

AU - Hutter, Sébastien

AU - Bourgeade-Delmas, Sandra

AU - Stigliani, Jean-Luc

AU - Sournia-Saquet, Alix

AU - Moreau, Alain

AU - Boutet-Robinet, Elisa

AU - Paloque, Lucie

AU - Mothes, Emmanuelle

AU - Laget, Michèle

AU - Vendier, Laure

AU - Pratviel, Geneviève

AU - Wyllie, Susan

AU - Fairlamb, Alan

AU - Azas, Nadine

AU - Courtioux, Bertrand

AU - Valentin, Alexis

AU - Verhaeghe, Pierre

N1 - A. Fairlamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). J. Pedron thanks the Université Paul Sabatier de Toulouse and the Région Occitanie/Pyrénées-Méditerranée for PhD funding. C. Piveteau from Institut Pasteur de Lille, C. Bijani from Laboratoire de Chimie de Coordination de Toulouse and the mass spectrometry team of the Institut de Chimie de Toulouse are also acknowledged for their support, respectively for pharmacokinetics, NMR and HRMS experiments.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - 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.

AB - 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.

KW - Anti-kinetoplastids

KW - Leishmania

KW - Trypanosoma

KW - 8-Nitroquinolin-2(1H)-one

KW - Nitroreductases

KW - Electrochemistry

U2 - 10.1016/j.ejmech.2018.06.001

DO - 10.1016/j.ejmech.2018.06.001

M3 - Article

C2 - 29885575

VL - 155

SP - 135

EP - 152

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -