Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Cyril Fersing; Louise Basmaciyan; Clotilde Boudot; Julien Pedron; Sébastien Hutter; Anita Cohen; Caroline Castera-Ducros; Nicolas Primas; Michèle Laget; Magali Casanova; Sandra Bourgeade-Delmas; Mélanie Piednoel; Alix Sournia-Saquet; Valère Belle Mbou; Bertrand Courtioux; Élisa Boutet-Robinet; Marc Since; Rachel Milne; Susan Wyllie; Alan H. Fairlamb; Alexis Valentin; Pascal Rathelot; Pierre Verhaeghe; Patrice Vanelle; Nadine Azas

doi:10.1021/acsmedchemlett.8b00347

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Cyril Fersing, Louise Basmaciyan, Clotilde Boudot, Julien Pedron, Sébastien Hutter, Anita Cohen, Caroline Castera-Ducros, Nicolas Primas, Michèle Laget, Magali Casanova, Sandra Bourgeade-Delmas, Mélanie Piednoel, Alix Sournia-Saquet, Valère Belle Mbou, Bertrand Courtioux, Élisa Boutet-Robinet, Marc Since, Rachel Milne, Susan Wyllie, Alan H. FairlambAlexis Valentin, Pascal Rathelot, Pierre Verhaeghe, Patrice Vanelle, Nadine Azas

Biological Chemistry and Drug Discovery

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Abstract

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moi-ety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1 – 2.1 µM) against L. donovani, L. infantum and L. major; and good antitrypanosomal activities (IC50 = 1.3 – 2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E°= - 0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and non-mutagenic, making 5 a good candidate for further in vivo studies.

Original language	English
Pages (from-to)	34-39
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	1
Early online date	19 Dec 2018
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00347
Publication status	Published - 10 Jan 2019

Keywords

Ames test
comet assay
imidazopyridine
Leishmania ssp
nitroaromatic
nitroreductases

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.8b00347Licence: CC BY

Final Published VersionFinal published version, 980 KBLicence: CC BY

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Fersing, C., Basmaciyan, L., Boudot, C., Pedron, J., Hutter, S., Cohen, A., Castera-Ducros, C., Primas, N., Laget, M., Casanova, M., Bourgeade-Delmas, S., Piednoel, M., Sournia-Saquet, A., Belle Mbou, V., Courtioux, B., Boutet-Robinet, É., Since, M., Milne, R., Wyllie, S., ... Azas, N. (2019). Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity. ACS Medicinal Chemistry Letters, 10(1), 34-39. https://doi.org/10.1021/acsmedchemlett.8b00347

@article{c5ea886055a748ef9f884f62dfd47d50,

title = "Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity",

abstract = "Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moi-ety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1 – 2.1 µM) against L. donovani, L. infantum and L. major; and good antitrypanosomal activities (IC50 = 1.3 – 2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E°= - 0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and non-mutagenic, making 5 a good candidate for further in vivo studies.",

keywords = "Ames test, comet assay, imidazopyridine, Leishmania ssp, nitroaromatic, nitroreductases",

author = "Cyril Fersing and Louise Basmaciyan and Clotilde Boudot and Julien Pedron and S{\'e}bastien Hutter and Anita Cohen and Caroline Castera-Ducros and Nicolas Primas and Mich{\`e}le Laget and Magali Casanova and Sandra Bourgeade-Delmas and M{\'e}lanie Piednoel and Alix Sournia-Saquet and {Belle Mbou}, Val{\`e}re and Bertrand Courtioux and {\'E}lisa Boutet-Robinet and Marc Since and Rachel Milne and Susan Wyllie and Fairlamb, {Alan H.} and Alexis Valentin and Pascal Rathelot and Pierre Verhaeghe and Patrice Vanelle and Nadine Azas",

note = "This work was supported by Aix-Marseille Universit{\'e}, the Universit{\'e} de Toulouse and the CNRS. A. H. Fair-lamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). C. Fersing thanks the Assistance Publique-H{\^o}pitaux de Marseille for hospital appointment. J. Pedron thanks the Universit{\'e} Paul Sabatier and the Conseil R{\'e}gional Occitanie for PhD funding. C. Piveteau and A. Biela (Institut Pasteur de Lille) are acknowledged for their contribution in deter-mining PK parameters.",

year = "2019",

month = jan,

day = "10",

doi = "10.1021/acsmedchemlett.8b00347",

language = "English",

volume = "10",

pages = "34--39",

journal = "ACS Medicinal Chemistry Letters",

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publisher = "American Chemical Society",

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Fersing, C, Basmaciyan, L, Boudot, C, Pedron, J, Hutter, S, Cohen, A, Castera-Ducros, C, Primas, N, Laget, M, Casanova, M, Bourgeade-Delmas, S, Piednoel, M, Sournia-Saquet, A, Belle Mbou, V, Courtioux, B, Boutet-Robinet, É, Since, M, Milne, R , Wyllie, S , Fairlamb, AH, Valentin, A, Rathelot, P, Verhaeghe, P, Vanelle, P & Azas, N 2019, 'Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity', ACS Medicinal Chemistry Letters, vol. 10, no. 1, pp. 34-39. https://doi.org/10.1021/acsmedchemlett.8b00347

TY - JOUR

T1 - Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

AU - Fersing, Cyril

AU - Basmaciyan, Louise

AU - Boudot, Clotilde

AU - Pedron, Julien

AU - Hutter, Sébastien

AU - Cohen, Anita

AU - Castera-Ducros, Caroline

AU - Primas, Nicolas

AU - Laget, Michèle

AU - Casanova, Magali

AU - Bourgeade-Delmas, Sandra

AU - Piednoel, Mélanie

AU - Sournia-Saquet, Alix

AU - Belle Mbou, Valère

AU - Courtioux, Bertrand

AU - Boutet-Robinet, Élisa

AU - Since, Marc

AU - Milne, Rachel

AU - Wyllie, Susan

AU - Fairlamb, Alan H.

AU - Valentin, Alexis

AU - Rathelot, Pascal

AU - Verhaeghe, Pierre

AU - Vanelle, Patrice

AU - Azas, Nadine

N1 - This work was supported by Aix-Marseille Université, the Université de Toulouse and the CNRS. A. H. Fair-lamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). C. Fersing thanks the Assistance Publique-Hôpitaux de Marseille for hospital appointment. J. Pedron thanks the Université Paul Sabatier and the Conseil Régional Occitanie for PhD funding. C. Piveteau and A. Biela (Institut Pasteur de Lille) are acknowledged for their contribution in deter-mining PK parameters.

PY - 2019/1/10

Y1 - 2019/1/10

N2 - Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moi-ety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1 – 2.1 µM) against L. donovani, L. infantum and L. major; and good antitrypanosomal activities (IC50 = 1.3 – 2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E°= - 0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and non-mutagenic, making 5 a good candidate for further in vivo studies.

AB - Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moi-ety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 µM) alongside good antileishmanial activities (IC50 = 1 – 2.1 µM) against L. donovani, L. infantum and L. major; and good antitrypanosomal activities (IC50 = 1.3 – 2.2 µM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine and benznidazole (IC50 = 0.6 to 13.3 µM). Molecule 5, presenting a low reduction potential (E°= - 0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and non-mutagenic, making 5 a good candidate for further in vivo studies.

KW - Ames test

KW - comet assay

KW - imidazopyridine

KW - Leishmania ssp

KW - nitroaromatic

KW - nitroreductases

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U2 - 10.1021/acsmedchemlett.8b00347

DO - 10.1021/acsmedchemlett.8b00347

M3 - Article

C2 - 30655943

SN - 1948-5875

VL - 10

SP - 34

EP - 39

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 1

ER -

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Abstract

Keywords

ASJC Scopus subject areas

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Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

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Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

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Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

Cite this