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1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action

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Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on <i>Leishmania</i> parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against <i>L. infantum</i> and <i>L. donovani</i> and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 <i>Leishmania</i> species, with IC<sub>50</sub> values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on <i>L. infantum</i> amastigotes (IC<sub>50</sub> 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.



Leishmania infantum Leishmania donovani Leishmaniasis 1,2,4-trioxolanes 1,2,4,5-tetraoxanes Selectivity Mode of action Reactive oxygen species


Pharmaceuticals 15 (4): 446 (2022)

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