Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue ACS Medicinal Chemistry Letters Année : 2019

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

Cyril Fersing
Alix Sournia-Saquet
Valère Belle Mbou
  • Fonction : Auteur
Bertrand Courtioux
  • Fonction : Auteur
  • PersonId : 855399
Pierre Verhaeghe
Patrice Vanelle
  • Fonction : Auteur
  • PersonId : 973296

Résumé

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.
Fichier principal
Vignette du fichier
Nongenotoxic 3-Nitroimidaz[1,2-a]pyridines AreNTR1 Substrates.pdf (979.65 Ko) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-02478935 , version 1 (14-02-2020)

Licence

Paternité

Identifiants

Citer

Cyril Fersing, Louise Basmaciyan, Clotilde Boudot, Julien Pedron, Sébastien Hutter, et al.. Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity. ACS Medicinal Chemistry Letters, 2019, 10 (1), pp.34-39. ⟨10.1021/acsmedchemlett.8b00347⟩. ⟨hal-02478935⟩
379 Consultations
68 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More