SYNTHETIC DERIVATIVES OF THE INDOLE ALKALOID TETRAHYDRO-β-CARBOLINE FOR THE TREATMENT OF CHAGAS DISEASE AND LEISHMANIASIS AND ITS POSSIBLE MODE OF ACTION

A. CASASCO; G. C. MUSCIA; K. URBANO; S. E. ASÍS; P. PETRAY; F. M. FRANK

CABA

Otro; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Protozoología

Chagas disease and Leishmaniasis are a major public health issuein our country, mainly in the north where the endemic areasoverlap. The efficacy of treatments is variable depending on the infectingspecies and the stage of infection, in addition to presentingadverse effects and increasing resistance of the parasites. Naturalproducts, such as tetrahydro-β-carbolines (βC), indole-type alkaloidswith a common tricyclic nucleus, have shown a variety ofpharmacological activities including anti-trypanosomatids effects.We studied 12 alkaloid derivatives in vitro in order to find moleculesfor the design of new alternatives to treatment. Four of them werepresented significant activity against T. cruzi (IC50 = 4-23μM) and3 of them behaved similarly in Leishmania spp. βC showed to beactive also in the in vivo murine model of acute T. cruzi infection.We evaluated possible mechanisms of action of the βC determiningthe DNA intercalating power by spectrometry: calf thymus DNAwas incubated with the βC and intercalating drugs were used aspositive control (C). The binding percentage (B%) was determinedfrom the area under the curve of absorbance vs wavelength. To viewmorphological and physiological changes, T. cruzi epimastigotesand L. amazonensis promastigotes (2x106) were treated for 48h withIC50 of the βC, stained with acridine orange (AO) and observed undera fluorescence microscope. Positive C was performed with 4mMH2O2 and untreated parasites were used as negative C. βC showedsimilar % of DNA binding than the C drugs except for one, whichhas a p-chlorophenyl rest, that presented a greater B%. OA stainingshowed that the treatment with IC50 of the βC causes epimastigotesand promastigotes to round up, increasing the amount of acidic vesiclesin the cytoplasm and changes in chromatin. Further studies arerequired in order to evaluate underlying mechanisms.