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

BACKGROUND: Leishmaniasis 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Enhydrin, 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.

Natural Sesquiterpene Lactones as Potential Trypanocidal Therapeutic Agents: A Review.

Chagas' disease and Human African Trypanosomiasis are parasitic diseases that remain major health problems, mainly among the poorest and the most marginalized communities from Latin America and Africa. The scarcity of effective chemotherapy, due to the low investment in the research and development (R&D) of new drugs, together with a high incidence of side effects, and the emergence of drug resistance phenomena emphasize the urgent need for new prophylactic and therapeutic agents. Over the ages, humans have employed natural products to treat a wide spectrum of diseases. Recently, the pharmaceutical industry has focused on plant research and a large body of evidence has been collected to demonstrate the immense potential of medicinal plants as a source of bioactive compounds and lead molecules. In the field of parasitic diseases, drug development from plants has been successful for the sesquiterpene lactone (STL) artemisinin, which is employed as an antimalarial agent. STLs are a large group of naturally occurring terpenoids derived from plants that mostly belong to the Asteraceae family which exhibit a variety of skeletal arrangements and are the largest and most diverse category of natural products with an a- m6thylene-lactone motif. STLs display a broad spectrum of biological activities such as antitumor, cytotoxic, antibacterial, anthelmintic, uterus contracting, antimalarial, neurotoxic, antiprotozoal and allergic (contact dermatitis) activities. In this context, the purpose of the present review is to provide an overview of the trypanocidal activity reported for STLs against Trypanosoma cruzi and T. brucei rhodesiense over the period 1993-2015.

The sesquiterpene lactone polymatin B from Smallanthus sonchifolius induces different cell death mechanisms in three cancer cell lines.

A 8ß-angeloyloxy-9α-hydroxy-14-oxo-acanthospermolide and five known melampolide sesquiterpene lactones (uvedalin, enhydrin, polymatin B, sonchifolin, and fluctuanin) were isolated from the leaves of Smallanthus sonchifolius. The compounds were identified by 1D-, 2D-NMR, HRMS, IR and UV analyses. In vitro cytotoxicity assays (MTT) showed that these sesquiterpene lactones display poor cytotoxic effects on peripheral blood mononuclear cells (PBMC) of healthy human subjects, whereas a strong cytotoxicity was observed in leukemia and pancreas cancer cells. For the mechanism of action of polymatin B, oxidative stress seems to be involved. Interestingly, reactive oxygen species (ROS) formation mainly induced different effects: apoptosis in CCRF-CEM cells, necroptosis in CEM-ADR5000 cells through induction of RIP1K, neither apoptosis nor necroptosis in MIA-PaCa-2 cells. Additionally, cells also died partly by necrosis.