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Avaliação in vitro da atividade anti-Leishmania de compostos sintéticos
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A leishmaniose é uma doença tropical negligenciada causada por protozoários do género Leishmania e transmitida aos hospedeiros vertebrados por vetores flebotomíneos. Está associada a taxas de morbidade e mortalidade global significativas, cujas estratégias atuais de controlo são principalmente baseadas na quimioterapia, que presentemente apresenta opções terapêuticas limitadas com elevada toxicidade, eficácia decrescente e resistência crescente, tornando cada vez mais relevante a procura de compostos com atividade anti-Leishmania que sejam de fácil administração, seletivos e com elevado índice terapêutico. No presente trabalho foram realizados ensaios in vitro com peróxidos sintéticos - 6 trioxolanos, 6 tetraoxanos e 4 derivados de artemisinina - em diferentes concentrações, para avaliar a atividade leishmanicida. Destes, foram selecionados os que apresentaram menor CI50 contra as formas promastigotas de Leishmania infantum (MHOM/PT/88/IMT151), Leishmania donovani (MHOM/BD/2006/BD14) e Leishmania tropica (MHOM/PS/2002/63jnF21) e foram submetidos a testes contra as formas amastigotas intracelulares. A anfotericina B, miltefosina e a pentamidina foram usadas como controle positivo. Também foi avaliada a citotoxicidade dos compostos em linhagens de células monocíticas/ macrofágicas J774.A1 e THP-1, utilizando o método colorimétrico com metil-tiazol-tetrazólio (MTT). Os resultados demonstraram que a maioria dos compostos pesquisados apresentaram baixa citotoxicidade contra as linhas celulares em estudo e níveis variados de ação leishmanicida contra as formas promastigotas e amastigotas das diferentes espécies, sendo que, no entanto, a forma amastigota se apresentou mais sensível aos compostos testados. Observou-se que em concentrações micromolares o tetraoxano LC138 demonstrou uma melhor atividade contra as formas amastigotas intracelulares de L. infantum (CI50 = 23,19 μM), apresentando um índice de seletividade de 22,8 o que indica ser este um composto promissor para estudos adicionais. Foi também avaliado o efeito dos compostos LC132, LC137 e LC138 na morfologia das formas promastigotas de L. infantum, observando-se alterações no tamanho do flagelo, tamanho médio e desorganização citoplasmática.
Leishmaniasis is a neglected tropical disease caused by a protozoan belonging to the genus Leishmania and is transmitted by the bite of sand flies (genus Phlebotomus). It is associated with significant global morbidity and mortality rates whose current control strategies are primarily based on chemotherapy, which currently presents limited therapeutic options, involving high level of toxicity and decreasing efficacy due to increasing resistance. Thus, the search for compounds with antileishmanial activity, which can be easily administrated, are selective and show high therapeutic index, is imperative. In this work, in vitro tests were performed by screening synthetic peroxides - 6 trioxolanes, 6 tetraoxanes and 4 artemisinin derivatives - at different concentrations, to evaluate their leishmanicidal potential. The compounds that evidenced lower CI50 values against promastigote forms of Leishmania infantum (MHOM/PT/88/IMT151), Leishmania donovani (MHOM/BD/2006/BD14) and Leishmania tropica (MHOM/PS/2002/63jnF21) were selected for further tests against intracellular amastigote forms. Amphotericin B, miltefosine and pentamidine were used as positive controls. The cytotoxicity of the compounds was also evaluated in monocyte/ macrophage cell lines J774.A1 and THP-1, by using the colorimetric assay methyl-tiazole-tetrazolium (MTT). The results showed that most of the compounds studied presented low cytotoxicity against the cell lines under study and varied levels of antileishmanial activity against promastigotes and amastigotes of different species, with the amastigote forms showing comparatively higher sensitivity to the tested compounds. It was observed that, in the micromolar range of concentrations, the tetraoxane LC138 showed the best activity against intracellular amastigotes of L. infantum (with CI50 = 23,19 μM), presenting a selectivity index of 22,8 and was selected as a promising compound for further studies. The effects of compounds LC132, LC137, LC138 on the morphology of the L. infantum promastigotes were evaluated and changes in flagellum size, medium size and cytoplasmic disorganization were observed.
Leishmaniasis is a neglected tropical disease caused by a protozoan belonging to the genus Leishmania and is transmitted by the bite of sand flies (genus Phlebotomus). It is associated with significant global morbidity and mortality rates whose current control strategies are primarily based on chemotherapy, which currently presents limited therapeutic options, involving high level of toxicity and decreasing efficacy due to increasing resistance. Thus, the search for compounds with antileishmanial activity, which can be easily administrated, are selective and show high therapeutic index, is imperative. In this work, in vitro tests were performed by screening synthetic peroxides - 6 trioxolanes, 6 tetraoxanes and 4 artemisinin derivatives - at different concentrations, to evaluate their leishmanicidal potential. The compounds that evidenced lower CI50 values against promastigote forms of Leishmania infantum (MHOM/PT/88/IMT151), Leishmania donovani (MHOM/BD/2006/BD14) and Leishmania tropica (MHOM/PS/2002/63jnF21) were selected for further tests against intracellular amastigote forms. Amphotericin B, miltefosine and pentamidine were used as positive controls. The cytotoxicity of the compounds was also evaluated in monocyte/ macrophage cell lines J774.A1 and THP-1, by using the colorimetric assay methyl-tiazole-tetrazolium (MTT). The results showed that most of the compounds studied presented low cytotoxicity against the cell lines under study and varied levels of antileishmanial activity against promastigotes and amastigotes of different species, with the amastigote forms showing comparatively higher sensitivity to the tested compounds. It was observed that, in the micromolar range of concentrations, the tetraoxane LC138 showed the best activity against intracellular amastigotes of L. infantum (with CI50 = 23,19 μM), presenting a selectivity index of 22,8 and was selected as a promising compound for further studies. The effects of compounds LC132, LC137, LC138 on the morphology of the L. infantum promastigotes were evaluated and changes in flagellum size, medium size and cytoplasmic disorganization were observed.
Descrição
Palavras-chave
Biologia molecular Ciencias biomédicas Leishmania spp Atividade anti-Leishmania in vitro Compostos peroxídicos sintéticos MTT Análise morfométrica
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical