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

Cyril Fersing 1 Louise Basmaciyan 2 Clotilde Boudot 3 Julien Pedron 4 Sébastien Hutter 2 Anita Cohen 2 Caroline Castera-Ducros 1 Nicolas Primas 1 Michèle Laget 5 Magali Casanova 2 Sandra Bourgeade-Delmas 6 Meĺanie Piednoel 1 Alix Sournia-Saquet 4 Valère Belle Mbou 7 Bertrand Courtioux 3 Elisa Boutet-Robinet 8 Marc Since 9 Rachel Milne 10 Susan Wyllie 10 Alan Fairlamb 10 Alexis Valentin 6 Pascal Rathelot 1 Pierre Verhaeghe 4 Patrice Vanelle 1 Nadine Azas 2
1 ICR - Institut de Chimie Radicalaire
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 NET - Neuroépidémiologie Tropicale
4 LCC - Laboratoire de chimie de coordination
5 MCT - Membranes et cibles thérapeutiques
6 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
7 CHU Limoges
8 ToxAlim-COMICS - Contaminants & Stress Cellulaire
ToxAlim - ToxAlim
9 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
10 University of Dundee
Abstract : Twenty nine original 3-nitroimidazo[1,2-a]-pyridine derivatives, bearing a phenylthio (or benzylthio) moiety 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 (CC 50 > 100 μM) alongside good antileishmanial activities (IC 50 = 1−2.1 μM) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC 50 = 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 (IC 50 = 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 nonmutagenic, making 5 a good candidate for further in vivo studies.
Keywords : comet assay Leishmania ssp imidazopyridine nitroaromatic nitroreductases Ames test
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UNIV-AMU | UNIV-TLSE3 | INRA | UNILIM | IRD | INC-CNRS | COMUE-NORMANDIE | GEIST | CERMN | UNICAEN | CNRS | NET | INRAE | LCC | PHARMA-DEV | TOXALIM | TOXALIM-COMICS

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Cyril Fersing, Louise Basmaciyan, Clotilde Boudot, Julien Pedron, Sébastien Hutter, et al.. Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity. ACS Medicinal Chemistry Letters, American Chemical Society, 2019, 10 (1), pp.34-39. ⟨10.1021/acsmedchemlett.8b00347⟩. ⟨hal-02478935⟩

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