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

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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 languageEnglish
Pages (from-to)34-39
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number1
Early online date19 Dec 2018
Publication statusPublished - 10 Jan 2019


  • Ames test
  • comet assay
  • imidazopyridine
  • Leishmania ssp
  • nitroaromatic
  • nitroreductases


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