Leishmaniases are neglected diseases that can be treated with a limited drug arsenal;
the development of new molecules is therefore a priority. Recent evidence indicates that
endoperoxides, including artemisinin and its derivatives, possess antileishmanial
activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans
lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric
requirement for the antileishmanial bioactivity. Newly synthesized compounds were
examined
in vitro
, and their mechanism of action was preliminarily
investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively
inhibited the growth of
Leishmania donovani
promastigotes and
amastigotes, and iron did not play a significant role in their activation. Further,
reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated
promastigotes. In conclusion, the peroxide group proved not to be crucial for the
antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings
reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for
novel therapies against
Leishmania
.