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.
Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell
From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I - V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active as- and less cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC = 0.4 μM, selectivity index = 100), but also highlighted an active (IC = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.
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