Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/8472
Title: Modes of action of arjunolic acid and derivatives on Trypanosoma cruzi
Authors: Souza Neta, Lourdes Cardoso de
Menezes, Diego Silva
Lima, Milena da Silva
Cerqueira, Martins Dias de
Cruz, Frederico Guaré
Martins, Dirceu
Santos, Marcos André Vannier dos
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Biologia Parasitária. Salvador, BA, Brasil / Universidade Federal da Bahia. Instituto de Química. Grupo de Estudo de Produtos Naturais. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Biologia Parasitária. Salvador, BA, Brasil
Universidade Federal da Bahia. Instituto de Química. Grupo de Estudo de Produtos Naturais. Salvador, BA, Brasil
Universidade Federal da Bahia. Instituto de Química. Grupo de Estudo de Produtos Naturais. Salvador, BA, Brasil
Universidade Federal da Bahia. Instituto de Química. Grupo de Estudo de Produtos Naturais. Salvador, BA, Brasil
Universidade Federal da Bahia. Instituto de Química. Grupo de Estudo de Produtos Naturais. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Biologia Parasitária. Salvador, BA, Brasil / Conselho Nacional de Desenvolvimento Científico e Tecnológico/ Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica. Amazonia, MA, Brasil
Abstract: Chagas disease causes considerable morbimortality in the Americas, with circa 7 to 8 million infected people, causing at least 12,000 annual deaths and 100 million people at risk. Its chemotherapy is poorly selective and effective, associated to severe side effects and unresponsive cases. Thus, R&D on therapeutic alternatives is undoubtedly required. The Brazilian poorly studied biodiversity offers uncountable bioagents, which may be exploited for chemotherapy. The triterpene arjunolic acid (AA), reduced the Trypanosoma cruzi epimastigote in vitro proliferation with an apparent IC50 of 171 μM. Electron microscopy analysis revealed remarkable effects on the parasite surface and architecture. AA-treated parasites displayed minutely corrugated plasma membranes devoid of subpellicular microtubules as well as biogenesis of multiple basal bodies. As the AA effects appeared mainly restricted or originated at the parasite peripheral cytoplasm, including the cytoskeleton membrane linkage, we inferred that the compound targeted primarily the lipid bilayer; therefore, we performed synthetic modification to increase the molecule lipophilicity and thus membrane permeability. The methyl ester (MeAA) and tri-acetylated derivatives (3AcAA) had potentiated trypanocidal activity, producing IC50 values of 21.9 and 15.8 μM, respectively. Both derivatives were able to produce remarkable ultrastructural alterations in the parasites, including inner compartments such as Golgi apparatus and the endocytic/autophagic pathway. Parasites cultured with both derivatives displayed numerous and large autophagic vacuoles, altered flagellar length and cell body connection. These data indicate that synthetically-modified natural products comprise valuable tools in antiparasitic chemotherapy and that electron microscopy may be useful not only in determining the mechanisms of action but also in directing such modifications for rational drug design.
Keywords: Chemotherapy
Electron microscopy
Natural products
Triterpene
Trypanosoma cruzi
Issue Date: 2014
Publisher: Bentham Science Publishers
Citation: SOUZA-NETA, L. C. et al. Modes of action of arjunolic acid and derivatives on Trypanosoma cruzi. Current Topics in Medicinal Chemistry, v. 14, p. 1022-1032, 2014.
ISSN: 1568-0266
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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