In vitro Trypanocidal activity of helenalin and hymenin derivates.

NATACHA CERNY; VIRGINIA SUSANA MARTINO; VALERIA PATRICIA SULSEN; MARÍA FLORENCIA BEER; SILVIA INES CAZORLA; CARLOS E TOON; AUGUSTO E BIVONA; EMILIO MALCHIODI; OSVALDO J DONADEL

Bogotá

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

Parasitic diseases such as Chagas´ disease, affect millions of people mainly in developing countries. This parasitosis is part of a group of diseases considered neglected, abandoned and poverty-related. According to the World Health Organization 6-7 million people are infected with Trypanosoma cruzi, the etiological agent of Chagas´ disease [1]. Drugs available to treat this protozoan disease, nifurtimox and benznidazol, have limitations due to adverse effects and lack of effectively. Natural products play an important role in the discovery and development of new drugs. Many natural compounds and its derivatives are used in current chemotherapy. It is noteworthy that some semi-synthetic compounds derived from a natural framework sometimes improve the biological activity respect the original natural product or enhance its biodisponibility. Sesquiterpene lactones (STLs) are a group of natural terpenoids with a wide range of biological activities, being antiparasitic and antitumor among the most relevant. The STL artemisinin and its semi-synthetic derivatives are used nowadays in combination therapies for the treatment of malaria. In this sense, the aim of the present work was to obtain derivatives from the STLs helenalin and hymenin and further evaluate their activity on Trypanosoma cruzi.From the STL helenalin, isolated from Gaillardia megapotamica (Asteraceae), the corresponding acetate and a silyl derivative, obtained with dimethylisopropylchlorosilane (DMIPSCl), were synthesized. The STL hymenin was isolated from Parthenium hysterophorus (Asteraceae). The corresponding analogue of this STL with trimethylchlorosilane (TMSCl) was synthetized. Both helenalin and hymenin and its derivatives were evaluated against T. cruzi epimastigotes (RA) by a [3H]-thymidine uptake assay.Helenalin and its derivatives were active against epimastigotes with IC50 values of 6.3, 0.9 (acetate) and 1.1 µg/ml (DMIPSCl derivative), respectively. Hymenin and its TMSCl derivative showed trypanocidal activity with IC50 of 2.1 and 2.5 µg/ml, respectively.Both acetate and DMIPSCl helenalin derivatives showed higher activity than the natural compound. Besides, both hymenin and its analogue presented similar IC50 values. Chemical modification of natural compounds is a strategy to enhance the activity and reduce toxic effects. The cytotoxicity of the compounds on mammalian cells will be evaluated in order to determine their selectivity of action. The assessment of their activity against trypomastigote and amastigote forms of the parasite will also be performed.Keywords: sesquiterpene lactone, Trypanosoma cruzi, derivativesAcknowledgements: This work was supported by grants from PICT 1753 (2012-2015) (The National Agency for Science and Technology Promotion), PIP 0324 (National Scientific and Technical Research Council), and UBACYT 20020130200270 (University of Buenos Aires).References[1] World Health Organization 2016. Fact sheet Chagas disease (American trypanosomiasis). http://www.who.int/mediacentre/factsheets/fs340/en/. Accessed August 2016.