A semi-synthetic molecule derived from dehydroleucodine affects the trypanosoma cruzi cell cycle

Abstract

Trypanosoma cruzi is a parasite causing Chagas disease, which is endemic in Latin America, but in the last 20 years, it has expanded worldwide. The current treatment is restricted to Nifurtimox and Benznidazole, but both are relatively toxic and have limited efficacy on the patients. The development of new effective therapeutic agents is urgently needed. The sesquiterpene lactones (STLs) are natural compounds purified from native plants of Argentina with multiple pharmacological applications. The STL dehydroleucodine (DhL), has an alpha-methylene group that could react with multiple sulfhydryl group-containing proteins, affecting cellular functions such as proliferation, the activity mitochondrial, leading to the cell death/apoptosis. This study is focused on elucidating the action mechanisms of DhL and its derivative DC-X11, obtained by chemical substitution, on T. cruzi epimastigotes (strain Dm28c). We observed that DhL and DC-X11 have antiproliferative and cytostatic effects on the parasites. By morphological and ultrastructural studies, we observed an increase of parasites with multiple cell nuclei, kinetoplasts, or flagella after the treatment with DC-X11, suggesting an effect on late steps of the cell cycle (i.e., cellular division). These results were confirmed with parasites synchronized with hydroxyurea (HU 20 mM) for 24 h, and then they were treated with the compound. We concluded that the derivative DC-X11 inhibits T. cruzi proliferation by delaying the progression of the cell division. Further studies are necessary to identify the molecular targets affected by DC-X11.