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 D 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 H Fairlamb (10) , Alexis Valentin (6) , Pascal Rathelot (1) , Pierre Verhaeghe (4) , Patrice Vanelle (1) , Nadine D 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
9 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
10 University of Dundee

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: nitroaromatic; Ames test; nitroreductases; comet assay; Leishmania ssp; imidazopyridine

Domains: Life Sciences [q-bio]

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, 2019, 10 (1), pp.34-39. ⟨10.1021/acsmedchemlett.8b00347⟩. ⟨hal-02478935⟩