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

CASASCO A; ASÍS SE; URBANO K; FRANK FM; MUSCIA GC; PETRAY PB

CABA

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Patricia B Petray (1), Fernanda M Frank

Chagas disease and Leishmaniasis are a major public health issue in our country, mainly in the north where the endemic areas overlap. The efficacy of treatments is variable depending on the infecting species and the stage of infection, in addition to presenting adverse effects and increasing resistance of the parasites. Natural products, such as tetrahydro-β-carbolines (βC), indole-type alkaloids with a common tricyclic nucleus, have shown a variety of pharmacological activities including anti-trypanosomatids effects.We studied 12 alkaloid derivatives in vitro in order to find molecules for the design of new alternatives to treatment. Four of them were presented significant activity against T. cruzi (IC50 = 4-23μM) and 3 of them behaved similarly in Leishmania spp. βC showed to be active also in the in vivo murine model of acute T. cruzi infection.We evaluated possible mechanisms of action of the βC determining the DNA intercalating power by spectrometry: calf thymus DNA was incubated with the βC and intercalating drugs were used as positive control (C). The binding percentage (B%) was determined from the area under the curve of absorbance vs wavelength. To view morphological and physiological changes, T. cruzi epimastigotes and L. amazonensis promastigotes (2x106) were treated for 48h with IC50 of the βC, stained with acridine orange (AO) and observed under a fluorescence microscope. Positive C was performed with 4mM H2O2 and untreated parasites were used as negative C. βC showed similar % of DNA binding than the C drugs except for one, which has a p-chlorophenyl rest, that presented a greater B%. OA staining showed that the treatment with IC50 of the βC causes epimastigotes and promastigotes to round up, increasing the amount of acidic vesicles in the cytoplasm and changes in chromatin. Further studies are required in order to evaluate underlying mechanisms.