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
  • 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.