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

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

  • ACS Med Chem Lett. 2018 Dec 19;10(1):34-39. doi: 10.1021/acsmedchemlett.8b00347.
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,  Mélanie Piednoel 1,  Alix Sournia-Saquet 4,  Valère Belle Mbou 7,  Bertrand Courtioux 3,  Élisa 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 Azas 2
Affiliations

Affiliations

  • 1 Aix Marseille Univ, CNRS, ICR UMR 7273, Équipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille, France.
  • 2 Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France.
  • 3 Université de Limoges, UMR INSERM 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025 Limoges, France.
  • 4 LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 5 Aix Marseille Univ, INSERM, UMR MD1, U1261, SSA, MCT, Marseille, France.
  • 6 UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, Toulouse, France.
  • 7 CHU de Limoges, Service d'anatomopathologie, 2 avenue Martin Luther King, 87042 Limoges, France.
  • 8 Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
  • 9 Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ., UNICAEN, CERMN, 14000 Caen, France.
  • 10 University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
PMID: 30655943 DOI: 10.1021/acsmedchemlett.8b00347
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 (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.

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