Sesquiterpene lactones from Argentine native flora as potential antiprotozoal agents

SÜLSEN V

Bogotá

Congreso; 3rd Research Network Natural Products against Neglected Diseases ? ResNet NPND Scientific Meeting; 2016

Protozoan parasitic diseases, such as Chagas' disease and Leishmaniasis, affect mostly poor people in developing countries. The chemotherapy for these diseases is not satisfactory due to the partial effectiveness and the toxicity associated with long-term treatments. Sesquiterpene lactones (STLs) are an important group of metabolites mainly found in the Astaeraceae. They are C15-terpenoid compounds and possess a cyclic arrangement generally with an α,β unsaturated lactone ring. Many biological activities presented by STLs such as antimicrobial, antiinflammatory, antiproliferative and antiprotozoal activities have been attributed to the presence of the α-metilene-γ-lactone moiety. Taking in account these considerations, the aim of our investigation was to identify STLs from Asteraceae native flora with antiprotozoal activity, which could be considered potential candidates for novel therapeutics for the treatment of Chagas? disease and leishmaniasis. Species of the genera Ambrosia, Mikania and Stevia, among others were selected for the investigation. Psilostachyin, peruvin, psilostachyin C, cordilin and cumanin were some of the STLs isolated from Ambrosia tenuifolia, A. scabra and A. elatior. Psilostachyin, psilostachyin C and cumanin displayed in vitro trypanocidal activity against the infective and intracellular forms of Trypanosoma cruzi with low cytotoxicity to mammalian cells. Psilostachyin was the most active compound against trypomastigotes with an IC50 value of 0.8 µg/ml [1], while psilostachyin C and cumanin demonstrated to be active against amastigotes (IC50: 0.9 and 2.1 µg/ml) [2,3]. Psilostachyin, psilostachyin C and cumanin showed in vivo trypanocidal activity [1-3]. Psilostachyin increased about 5 times the generation of reactive oxygen species in T. cruzi. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol. Both STLs induced ultrastructural alterations on T. cruzi and parasite death by apoptosis [2, 4, 5]. Peruvin and cumanin were the most active compounds against promastigotes of Leishmania sp. with IC50 values of 0.4 and 0.8 µg/ml [1, 3]. From the aerial parts of Mikania micrantha four STLs, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated. Deoxymikanolide was the most active and selective compound against T. cruzi. This STL showed in vitro trypanocidal activity with IC50 values of 0.08 (epimastigotes), 1.5 (trypomastigotes) and 6.3 (amastigotes) µg/ml.   The results obtained suggest that this group of compounds could be considered as potential candidates for novel therapeutics for the treatment of Chagas? disease and leishmaniasis. Further investigations are being carried on with some of these compounds in order to best understand its mode of action. Besides, other Asteraceae species are being studied in the search of novel antiprotozoal compounds.  Keywords: sesquiterpenelactones, Trypanosoma cruzi, Leishmania sp., Asteraceae Acknowledgements: This workwas supported by grants from PICT 1753 (2012-2015) (The National Agency for Science and TechnologyPromotion), PIP 0324 (National Scientific and TechnicalResearch Council), andUBACYT 20020130200270 (University of Buenos Aires).