Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi

Abstract

BackgroundLeishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. They are known as “neglected diseases” due to the lack of effective drug treatments and the scarcity of research work devoted to them. Therefore, the development of novel and effective drugs is an important and urgent need. Natural products are an important source of bioactive molecules for the development of new drugs. In this study, we evaluated the activity of enhydrin, uvedalin and polymatin B, three sesquiterpene lactones (STLs) isolated from Smallanthus sonchifolius, on Leishmania mexicana (MNYC/BZ/62/M) and Trypanosoma cruzi (Dm28c). In addition, the in vivo trypanocidal activity of enhydrin and uvedalin and the effects of these STLs on parasites’ ultrastructure were evaluated.MethodsThe inhibitory effect of the three STLs on the growth of L. mexicana amastigotes and promastigotes as well as T. cruzi epimastigotes was evaluated in vitro. The changes produced by the STLs on the ultrastructure of parasites were examined by transmission electron microscopy (TEM). Enhydrin and uvedalin were also studied in a murine model of acute T. cruzi infection (RA strain). Serum activities of the hepatic enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase were used as biochemical markers of hepatotoxicity.ResultsThe three compounds exhibited leishmanicidal activity on both parasite forms with IC50 values of 0.42–0.54 μg/ml for promastigotes and 0.85–1.64 μg/ml for intracellular amastigotes. Similar results were observed on T. cruzi epimastigotes (IC50 0.35–0.60 μg/ml). The TEM evaluation showed marked ultrastructural alterations, such as an intense vacuolization and mitochondrial swelling in both L. mexicana promastigotes and T. cruzi epimastigotes exposed to the STLs. In the in vivo study, enhydrin and uvedalin displayed a significant decrease in circulating parasites (50–71%) and no signs of hepatotoxicity were detected.ConclusionsEnhydrin, uvedalin and polymatin B possess significant leishmanicidal and trypanocidal activity on different parasite stages. These results show that these compounds may provide valuable leads for the development of new drugs against these neglected parasitic diseases.

ESI‐QTof‐MS characterization of hirsutinolide and glaucolide sesquiterpene lactones: Fragmentation mechanisms and differentiation based on Na+/H+ adducts interactions in complex mixture

“…Sesquiterpene lactones (SL) are 15‐carbon terpenoids organized in different cyclic hydrocarbon skeletons containing a fused lactone ring . Considered as chemotaxonomic markers for the Asteraceae family, SL are metabolites of great interest because of their antiproliferative and antitumor, anti‐inflammatory, and antiprotozoal properties. Over 30 different skeletons have been described in the literature including hirsutinolide and glaucolide‐subtypes.…”

Asteraceae Plants as Sources of Compounds Against Leishmaniasis and Chagas Disease

“…The action of these sesquiterpene lactones was better than the positive control, amphotericin B (IC50 = 2 μM). As seen with the anti- T. cruzi activity, the highest activity toward intracellular form of L. mexicana was observed for uvedalin (IC50 = 1.89 μM), followed for enhydrin (IC50 = 3.66 μM; Ulloa et al, 2017).…”

“…The animals treated with uvedalin or enhydrin exhibited lower levels of parasitaemia, and these effects were similar to those obtained with benznidazole (positive control). Mice treated with these sesquiterpene lactones also showed higher survival ratios and reduced weight loss when compared to untreated animals (Ulloa et al, 2017).…”

Plant Terpenoids as Hit Compounds against Trypanosomiasis

“…H. Rob. and evaluated against T. cruzi epimastigotes, using benzonidazole as positive control [ 66 ]. Compounds 42 and 43 showed identical activities with IC 50 values of 0.78 and 0.79 μM, respectively.…”

“…A significant decrease in circulating parasites (50–71%) was observed, with no signs of toxicity in the dose administrated (1 mg/kg/day). Complementary studies showed marked ultrastructural alteration in trypanosome parasites when treated with these compounds [ 66 ].…”