Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials
| Autor: | Andre G. Tempone, Thais A. Costa-Silva, Guilherme Medeiros Antar, Fernanda Thevenard, João Batista Baitello, Vinicius S. Londero, João Henrique G. Lago, Gislene Mitsue Namiyama |
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| Rok vydání: | 2020 |
| Předmět: |
Trypanosoma cruzi
Molecular Conformation Vacuole Mitochondrion 01 natural sciences Biochemistry Cell Line Lauraceae Mice Structure-Activity Relationship Drug Discovery Organelle Animals Humans Sesquiterpenes Eudesmane Chagas Disease Inner mitochondrial membrane Amastigote Molecular Biology Membrane Potential Mitochondrial chemistry.chemical_classification Mice Inbred BALB C Reactive oxygen species Dose-Response Relationship Drug Plant Stems biology 010405 organic chemistry Cell Membrane Organic Chemistry biology.organism_classification Trypanocidal Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Reactive Oxygen Species Intracellular |
| Zdroj: | Bioorganic Chemistry. 95:103510 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2019.103510 |
| Popis: | As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC50 of 37.8 and 7.9 μM to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC50 > 200 μM), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskis rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease. |
| Databáze: | OpenAIRE |
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