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

Twenty nine original 3-nitroimidazo[1,2-]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. evaluation highlighted compound as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC > 100 μM) alongside good antileishmanial activities (IC = 1-2.1 μM) against , , and ; and good antitrypanosomal activities (IC = 1.3-2.2 μM) against and , in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC = 0.6 to 13.3 μM). Molecule , presenting a low reduction potential (° = -0.63 V), was shown to be selectively bioactivated by the type 1 nitroreductase (NTR1). Importantly, molecule was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making a good candidate for further studies.