In vitro trypanocidal activity of helenalin and hymenin derivatives

BEER MF; BIVONA A; CERNY N; CAZORLA SI; MALCHIODI E; MARTINO V; TONN C; DONADEL O; SÜLSEN V

Bogota

Congreso; ResNet NPND Scientific Meeting; 2016

Parasitic diseases such as Chagas´ disease, affect millions of peoplemainly in developing countries. This parasitosis is part of a group of diseasesconsidered neglected, abandoned and poverty-related. According to the World HealthOrganization 6-7 million people are infected with Trypanosoma cruzi, the etiological agent of Chagas´ disease. Drugs available to treatthis protozoan disease, nifurtimox and benznidazol, have limitations due toadverse effects and lack of effectively.Natural products play animportant role in the discovery and development of new drugs. Many naturalcompounds and its derivatives are used in current chemotherapy. It is noteworthy that some semi-synthetic compoundsderived from a natural framework sometimes improve the biological activityrespect the original natural product or enhance its biodisponibility. Sesquiterpenelactones (STLs) are a group of natural terpenoids with a wide range ofbiological activities, being antiparasitic and antitumor among the mostrelevant. The STL artemisinin and its semi-synthetic derivatives are used nowadays in combination therapies for the treatment ofmalaria. In this sense, the aim ofthe present work was to obtain derivatives from the STLs helenalin and hymenin andfurther evaluate their activity on Trypanosomacruzi.From the STL helenalin,isolated from Gaillardia megapotamica (Asteraceae), the corresponding acetate and a silyl derivative, obtained with dimethylisopropylchlorosilane (DMIPSCl), were synthesized. TheSTL 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 againstepimastigotes with IC50 values of 6.3, 0.9 (acetate) and 1.1 µg/ml (DMIPSCl derivative),respectively. Hymenin and its TMSCl derivative showed trypanocidal activitywith IC50 of 2.1 and 2.5 µg/ml, respectively.Bothacetate and DMIPSCl helenalin derivativesshowed higher activitythan the natural compound. Besides, both hymenin and its analogue presentedsimilar IC50 values. Chemical modification of natural compounds is a strategyto enhance the activity and reduce toxic effects. The cytotoxicity of the compoundson mammalian cells will be evaluated in order to determine their selectivity ofaction. The assessment of their activity against trypomastigote and amastigote formsof the parasite will also be performed