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Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi,
Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially
affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for
alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great
variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and
mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro,
naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in
amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation
in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species.
Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal
models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use
naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry,
bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these
compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of
both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific
and safe derivative, minimizing adverse effects.