RESUMO
Diante da falta de uma terapia eficaz e segura para o tratamento da doença de Chagas (DC) e da leishmaniose visceral, a busca por novos fármacos continua imprescindível. O ambiente marinho é uma rica fonte de produtos naturais bioativos, com aplicações contra parasitas, bactérias e outros patógenos que possam afetar humanos e animais. Entre as diversas classes de produtos naturais, os alcaloides têm um importante papel em aplicações terapêuticas. Neste trabalho, colônias de coral Tubastraea tagusensis foram coletadas, e a extração de seus metabolitos secundários foi realizada utilizando o solvente orgânico. Após fracionamento cromatográfico por diferentes técnicas, um alcaloide indolico foi isolado e elucidado estruturalmente por meio de técnicas espectrométricas e espectroscópicas. O alcaloide 6-bromo-2'-de-N-metillaplisinopsina (MR01), demonstrou atividade contra tripomastigotas e amastigota intracelulares de Trypanosoma cruzi, com valores de Concentração Efetiva 50% de 62 µM e 5 µM, respectivamente...(AU)
Considering the lack of effective and safe therapy for the treatment of Chagas disease (CD) and visceral leishmaniasis, the search for new chemotherapies remains indispensable. The marine environment is a well-known source of bioactive products, with applications against parasites, bacteria and other human / animal pathogenic microorganisms. Among different classes of natural products, alkaloids have a rich history of therapeutic applications. In this work, colonies of the coral Tubastraea tagusensis were collected and their secondary metabolites were extracted with ethyl acetate. Using different chromatographic techniques, an indole alkaloid was isolated and elucidated through spectroscopic and spectrometric techniques, resulting in the 6-bromo-2'-de-Nmethylaplisinopsin (MR01). The compound MR01 demonstrated activity against Trypanosoma cruzi, against both trypomastigote and amastigote forms, resulting in 50% Effective Concentration (EC50) values of 62 µM and 5 µM, respectively. The studies with Leishmania infantum amastigotes showed lack of activity. No cytotoxicity was observed for NCTC cells, to the maximal concentration of 200 µM. The mechanism of action was also explored. After incubation with the trypomastigotes, no alteration was observed in the permeability of the plasma membrane. The compound reduced the ATP and induced mitochondrial depolarization with no alterations in the reactive oxygen species levels. The intracellular calcium levels were reduced after treatment with MR01, including the pH alterations of the acidocalcisomes. Using MALDI-TOF/MS, the protein profile of the parasite was altered to a different manner to that observed for the standard drug benznidazole, suggesting a distinct mechanism of action. In silico studies of the pharmacokinetic / pharmacodynamic properties (PKPD) and physicochemical properties using the SwissADME software, suggested a good drug-like. In conclusion, this study showed for the first time the anti-T. cruzi activity of the alkaloid MR01. In addition, considering the potency and selectiveness, our study can suggest this compound to be explored as a new prototype for CD. (AU)