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

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

Edité par CCSD ; American Chemical Society -

International audience. 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.

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