New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

Julien Pedron; Clotilde Boudot; Jean-yves Brossas; Emilie Pinault; Sandra Bourgeade-Delmas; Alix Sournia-Saquet; Elisa Boutet-Robinet; Alexandre Destere; Antoine Tronnet; Justine Bergé; Colin Bonduelle; Céline Deraeve; Genevieve Pratviel; Jean-Luc Stigliani; Luc Paris; Dominique Mazier; Sophie Corvaisier; Marc Since; Aurélie Malzert-Freon; Susan Wyllie; Rachel Milne; Alan H. Fairlamb; Alexis Valentin; Bertrand Courtioux; Pierre Verhaeghe

doi:10.1021/acsmedchemlett.9b00566

New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

Julien Pedron, Clotilde Boudot, Jean-yves Brossas, Emilie Pinault, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Elisa Boutet-Robinet, Alexandre Destere, Antoine Tronnet, Justine Bergé, Colin Bonduelle, Céline Deraeve, Genevieve Pratviel, Jean-Luc Stigliani, Luc Paris, Dominique Mazier, Sophie Corvaisier, Marc Since, Aurélie Malzert-Freon, Susan WyllieRachel Milne, Alan H. Fairlamb, Alexis Valentin, Bertrand Courtioux, Pierre Verhaeghe (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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11 Citations (Scopus)

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Abstract

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC ₅₀ values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC ₅₀ ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

Original language	English
Pages (from-to)	464-472
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	4
Early online date	6 Feb 2020
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00566
Publication status	Published - 9 Apr 2020

Keywords

8-nitroquinolin-2(1 H)-ones
NTR1
Trypanosoma brucei brucei
Trypanosoma cruzi
redox potentials

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00566Licence: CC BY

Final Published VersionFinal published version, 1.82 MBLicence: CC BY

Cite this

Pedron, J., Boudot, C., Brossas, J., Pinault, E., Bourgeade-Delmas, S., Sournia-Saquet, A., Boutet-Robinet, E., Destere, A., Tronnet, A., Bergé, J., Bonduelle, C., Deraeve, C., Pratviel, G., Stigliani, J.-L., Paris, L., Mazier, D., Corvaisier, S., Since, M., Malzert-Freon, A., ... Verhaeghe, P. (2020). New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi. ACS Medicinal Chemistry Letters, 11(4), 464-472. https://doi.org/10.1021/acsmedchemlett.9b00566

@article{312c8c4f8990431797d0f36a52ca6306,

title = "New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi",

abstract = "An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds. ",

keywords = "8-nitroquinolin-2(1 H)-ones, NTR1, Trypanosoma brucei brucei, Trypanosoma cruzi, redox potentials",

author = "Julien Pedron and Clotilde Boudot and Jean-yves Brossas and Emilie Pinault and Sandra Bourgeade-Delmas and Alix Sournia-Saquet and Elisa Boutet-Robinet and Alexandre Destere and Antoine Tronnet and Justine Berg{\'e} and Colin Bonduelle and C{\'e}line Deraeve and Genevieve Pratviel and Jean-Luc Stigliani and Luc Paris and Dominique Mazier and Sophie Corvaisier and Marc Since and Aur{\'e}lie Malzert-Freon and Susan Wyllie and Rachel Milne and Fairlamb, {Alan H.} and Alexis Valentin and Bertrand Courtioux and Pierre Verhaeghe",

note = "Funding: Wellcome Trust (WT105021).",

year = "2020",

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day = "9",

doi = "10.1021/acsmedchemlett.9b00566",

language = "English",

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Pedron, J, Boudot, C, Brossas, J, Pinault, E, Bourgeade-Delmas, S, Sournia-Saquet, A, Boutet-Robinet, E, Destere, A, Tronnet, A, Bergé, J, Bonduelle, C, Deraeve, C, Pratviel, G, Stigliani, J-L, Paris, L, Mazier, D, Corvaisier, S, Since, M, Malzert-Freon, A, Wyllie, S , Milne, R , Fairlamb, AH, Valentin, A, Courtioux, B & Verhaeghe, P 2020, 'New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi', ACS Medicinal Chemistry Letters, vol. 11, no. 4, pp. 464-472. https://doi.org/10.1021/acsmedchemlett.9b00566

TY - JOUR

T1 - New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

AU - Pedron, Julien

AU - Boudot, Clotilde

AU - Brossas, Jean-yves

AU - Pinault, Emilie

AU - Bourgeade-Delmas, Sandra

AU - Sournia-Saquet, Alix

AU - Boutet-Robinet, Elisa

AU - Destere, Alexandre

AU - Tronnet, Antoine

AU - Bergé, Justine

AU - Bonduelle, Colin

AU - Deraeve, Céline

AU - Pratviel, Genevieve

AU - Stigliani, Jean-Luc

AU - Paris, Luc

AU - Mazier, Dominique

AU - Corvaisier, Sophie

AU - Since, Marc

AU - Malzert-Freon, Aurélie

AU - Wyllie, Susan

AU - Milne, Rachel

AU - Fairlamb, Alan H.

AU - Valentin, Alexis

AU - Courtioux, Bertrand

AU - Verhaeghe, Pierre

N1 - Funding: Wellcome Trust (WT105021).

PY - 2020/4/9

Y1 - 2020/4/9

N2 - An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

AB - An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

KW - 8-nitroquinolin-2(1 H)-ones

KW - NTR1

KW - Trypanosoma brucei brucei

KW - Trypanosoma cruzi

KW - redox potentials

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U2 - 10.1021/acsmedchemlett.9b00566

DO - 10.1021/acsmedchemlett.9b00566

M3 - Article

C2 - 32292551

SN - 1948-5875

VL - 11

SP - 464

EP - 472

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -

New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

Abstract

Keywords

ASJC Scopus subject areas

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

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New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

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

Cite this