Background: Chagas disease, also known as American trypanosomiasis, is classified as
one of the 17 most important neglected diseases by the World Health Organization. The only drugs
with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show
adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search
for new effective chemical entities is a challenge to research groups and the pharmaceutical industry.
Objective: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones
and semicarbazones containing 1,2,3-1H triazole isatin scaffold.
Method: 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar
cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions
of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride,
respectively, in methanol, using conventional reflux or microwave heating. The compounds were
assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of
Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic
intermediates were also evaluated for comparison.
Results: A series of compounds were prepared in good yields. Among the 37 compounds evaluated,
18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated
alkyl chain (IC50 = 24.1, 38.6, and 83.2 μM; SI = 11.6, 11.8, and 14.0, respectively). To further
elucidate the mechanism of action of these new compounds, the redox behaviour of some active
and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also
performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase
Conclusion: A class of thio/semicarbazones structurally simple and easily accessible was synthesized.
Compounds containing thiosemicarbazone moieties showed the best results in the series, being
more active than the corresponding semicarbazones. Our results indicated that the activity of
these compounds does not originate from an oxidation-reduction pathway but probably from the
interactions with trypanosomal enzymes.