8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Cyril Fersing, Clotilde Boudot, Julien Pedron, Sébastien Hutter, Nicolas Primas, Caroline Castera-Ducros, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Alain Moreau, Anita Cohen, Jean-Luc Stigliani, Geneviève Pratviel, Maxime D. Crozet, Susan Wyllie, Alan Fairlamb, Alexis Valentin, Pascal Rathelot, Nadine Azas, Bertrand Courtioux, Pierre Verhaeghe & 1 others Patrice Vanelle

Research output: Contribution to journalArticle

Abstract

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

LanguageEnglish
Pages115-126
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume157
Early online date1 Aug 2018
DOIs
Publication statusPublished - 5 Sep 2018

Fingerprint

Nitroreductases
Inhibitory Concentration 50
Molecules
miltefosine
Scaffolds
Bearings (structural)
Eflornithine
Derivatives
Antiparasitic Agents
Suramin
Substrates
Cytotoxicity
Pharmaceutical Preparations
Hep G2 Cells
imidazo(1,2-a)pyridine
Screening
Cells
Parasites
Cell Line

Keywords

  • midazo[1,2-a]pyridine
  • Nitroheterocycles
  • Suzuki-Miyaura cross-coupling reaction
  • Nitroreductases
  • Leishmania
  • Trypanosoma
  • In vitro activity
  • HepG2 cytotoxicity
  • SARs
  • Redox potentials

Cite this

Fersing, Cyril ; Boudot, Clotilde ; Pedron, Julien ; Hutter, Sébastien ; Primas, Nicolas ; Castera-Ducros, Caroline ; Bourgeade-Delmas, Sandra ; Sournia-Saquet, Alix ; Moreau, Alain ; Cohen, Anita ; Stigliani, Jean-Luc ; Pratviel, Geneviève ; Crozet, Maxime D. ; Wyllie, Susan ; Fairlamb, Alan ; Valentin, Alexis ; Rathelot, Pascal ; Azas, Nadine ; Courtioux, Bertrand ; Verhaeghe, Pierre ; Vanelle, Patrice. / 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 157. pp. 115-126.
@article{3817cfa93cbf4b11a8710db609cd3ef2,
title = "8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases",
abstract = "Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.",
keywords = "midazo[1,2-a]pyridine, Nitroheterocycles, Suzuki-Miyaura cross-coupling reaction, Nitroreductases, Leishmania, Trypanosoma, In vitro activity, HepG2 cytotoxicity, SARs, Redox potentials",
author = "Cyril Fersing and Clotilde Boudot and Julien Pedron and S{\'e}bastien Hutter and Nicolas Primas and Caroline Castera-Ducros and Sandra Bourgeade-Delmas and Alix Sournia-Saquet and Alain Moreau and Anita Cohen and Jean-Luc Stigliani and Genevi{\`e}ve Pratviel and Crozet, {Maxime D.} and Susan Wyllie and Alan Fairlamb and Alexis Valentin and Pascal Rathelot and Nadine Azas and Bertrand Courtioux and Pierre Verhaeghe and Patrice Vanelle",
note = "This work is supported by Aix-Marseille Universit{\'e}, the Universit{\'e} de Toulouse and the CNRS. A. Fairlamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). C. Fersing thanks the Assistance Publique - H{\^o}pitaux de Marseille (AP-HM) for hospital appointment. The authors thank Dr Vincent Remusat for the NMR spectra recording, Christophe Chendo and Val{\'e}rie Monnier for the HRMS analyses and Dr Michel Giorgi for the X-ray structure determinations.",
year = "2018",
month = "9",
day = "5",
doi = "10.1016/j.ejmech.2018.07.064",
language = "English",
volume = "157",
pages = "115--126",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

Fersing, C, Boudot, C, Pedron, J, Hutter, S, Primas, N, Castera-Ducros, C, Bourgeade-Delmas, S, Sournia-Saquet, A, Moreau, A, Cohen, A, Stigliani, J-L, Pratviel, G, Crozet, MD, Wyllie, S, Fairlamb, A, Valentin, A, Rathelot, P, Azas, N, Courtioux, B, Verhaeghe, P & Vanelle, P 2018, '8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases' European Journal of Medicinal Chemistry, vol. 157, pp. 115-126. https://doi.org/10.1016/j.ejmech.2018.07.064

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases. / Fersing, Cyril; Boudot, Clotilde; Pedron, Julien; Hutter, Sébastien; Primas, Nicolas; Castera-Ducros, Caroline; Bourgeade-Delmas, Sandra; Sournia-Saquet, Alix; Moreau, Alain; Cohen, Anita; Stigliani, Jean-Luc; Pratviel, Geneviève; Crozet, Maxime D.; Wyllie, Susan; Fairlamb, Alan; Valentin, Alexis; Rathelot, Pascal; Azas, Nadine; Courtioux, Bertrand; Verhaeghe, Pierre; Vanelle, Patrice (Lead / Corresponding author).

In: European Journal of Medicinal Chemistry, Vol. 157, 05.09.2018, p. 115-126.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

AU - Fersing, Cyril

AU - Boudot, Clotilde

AU - Pedron, Julien

AU - Hutter, Sébastien

AU - Primas, Nicolas

AU - Castera-Ducros, Caroline

AU - Bourgeade-Delmas, Sandra

AU - Sournia-Saquet, Alix

AU - Moreau, Alain

AU - Cohen, Anita

AU - Stigliani, Jean-Luc

AU - Pratviel, Geneviève

AU - Crozet, Maxime D.

AU - Wyllie, Susan

AU - Fairlamb, Alan

AU - Valentin, Alexis

AU - Rathelot, Pascal

AU - Azas, Nadine

AU - Courtioux, Bertrand

AU - Verhaeghe, Pierre

AU - Vanelle, Patrice

N1 - This work is supported by Aix-Marseille Université, the Université de Toulouse and the CNRS. A. Fairlamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). C. Fersing thanks the Assistance Publique - Hôpitaux de Marseille (AP-HM) for hospital appointment. The authors thank Dr Vincent Remusat for the NMR spectra recording, Christophe Chendo and Valérie Monnier for the HRMS analyses and Dr Michel Giorgi for the X-ray structure determinations.

PY - 2018/9/5

Y1 - 2018/9/5

N2 - Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

AB - Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

KW - midazo[1,2-a]pyridine

KW - Nitroheterocycles

KW - Suzuki-Miyaura cross-coupling reaction

KW - Nitroreductases

KW - Leishmania

KW - Trypanosoma

KW - In vitro activity

KW - HepG2 cytotoxicity

KW - SARs

KW - Redox potentials

U2 - 10.1016/j.ejmech.2018.07.064

DO - 10.1016/j.ejmech.2018.07.064

M3 - Article

VL - 157

SP - 115

EP - 126

JO - European Journal of Medicinal Chemistry

T2 - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -