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ACS Med Chem Lett. 2018 Dec 19;10(1):34-39. doi: 10.1021/acsmedchemlett.8b00347. eCollection 2019 Jan 10.

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

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Aix Marseille Univ, CNRS, ICR UMR 7273, Équipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille, France.
Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France.
Université de Limoges, UMR INSERM 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025 Limoges, France.
LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France.
Aix Marseille Univ, INSERM, UMR MD1, U1261, SSA, MCT, Marseille, France.
UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, Toulouse, France.
CHU de Limoges, Service d'anatomopathologie, 2 avenue Martin Luther King, 87042 Limoges, France.
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ., UNICAEN, CERMN, 14000 Caen, France.
University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.


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 (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 nonmutagenic, making 5 a good candidate for further in vivo studies.

[Available on 2020-01-10]

Conflict of interest statement

The authors declare no competing financial interest.

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