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.
Highlights
Nitroaromatic molecules, such as fexinidazole[9] and delamanid,[10] showed a renewed interest against infectious diseases such as human African trypanosomiasis (HAT), visceral leishmaniasis (VL), Chagas disease (CD), and even tuberculosis.[11]. These compounds act as prodrugs, requiring the bioactivation of their nitro group into reduced reactive intermediates, in order to display their antiparasitic properties. This bioactivation step is catalyzed by nitroreductases (NTR), enzymes found in some bacteria and parasites, but not in mammalian cells
We reported the antileishmanial activity of 3nitroimidazo[1,2-a]pyridine derivatives
After identifying a hit molecule bearing bromine atoms at positions 6 and 8 of the imidazopyridine ring,[19] a pharmacomodulation study led to a series of 8-aryl-6-chloro-3-nitroimidazo[1,2-a]pyridines that displayed an improved activity against Leishmania spp and Trypanosoma b. brucei,[20] suggesting the key role of the substituent at position 8 of the scaffold (Figure 1)
Summary
Both molecules demonstrated promising activity against the promastigote stage of L. donovani and of L. infantum axenic amastigotes Likewise, both molecules demonstrated antitrypanosomal activity, compound 5 appears to resemble fexinidazole in that it is metabolized into bioactive sulfoxide and sulfone derivatives.[13] These results suggest that the poor microsomal stability of 5 should not be a barrier to further in vivo evaluation. Introducing a para-chlorophenylthioether moiety at position 8 of the antileishmanial 3-nitroimidazo[1,2-a]pyridine pharmacophore led to hit molecule 5 that displayed improved in vitro antikinetoplastid activity against both Leishmania (donovani and infantum) and Trypanosoma (brucei brucei and cruzi) parasites, in comparison with the previously identified hit molecules in the series.
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