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; Meĺanie Piednoel; Alix Sournia-Saquet; Valère Belle Mbou; Bertrand Courtioux; Eĺisa Boutet-Robinet; Marc Since; Rachel Milne; Susan Wyllie; Alan Fairlamb; Alexis Valentin; Pascal Rathelot; Pierre Verhaeghe; Patrice Vanelle; Nadine Azas

doi:10.1021/acsmedchemlett.8b00347

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

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 Meĺanie Piednoel ¹ Alix Sournia-Saquet ⁴ Valère Belle Mbou ⁷ Bertrand Courtioux ^{8, 3} Eĺisa Boutet-Robinet ⁹ Marc Since ¹⁰ Rachel Milne ¹¹ Susan Wyllie ¹¹ Alan Fairlamb ¹¹ Alexis Valentin ⁶ Pascal Rathelot ¹ Pierre Verhaeghe ⁴ Patrice Vanelle ¹ Nadine Azas ²

1 ICR - Institut de Chimie Radicalaire

2 VITROME - Vecteurs - Infections tropicales et méditerranéennes

3 NET - Neuroépidémiologie Tropicale

4 LCC - Laboratoire de chimie de coordination

5 AMU - Aix Marseille Université

6 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement

7 CHU Limoges

8 UNILIM - Université de Limoges

9 ToxAlim - ToxAlim

10 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie

11 University of Dundee

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 (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.

Keywords : comet assay Leishmania ssp imidazopyridine nitroaromatic nitroreductases Ames test

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Journal articles

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Life Sciences [q-bio]

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