Membrane dynamics in Leishmania amazonensis and antileishmanial activities of β-carboline derivatives
| Autor: | César Armando Contreras Lancheros, Celso Vataru Nakamura, Danielle Lazarin-Bidóia, Hélito Volpato, Antonio Alonso, Nilma de Souza Fernandes, Lais Alonso, Jéssica Carreira de Paula, Tânia Ueda-Nakamura, Maria Helena Sarragiotto, Paula Baréa |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
030106 microbiology Antiprotozoal Agents Protozoan Proteins Biophysics Biochemistry Mice 03 medical and health sciences Membrane fluidity Animals Humans Spin label Amastigote Leishmania Membrane potential biology Chemistry Cell Membrane Depolarization Cell Biology biology.organism_classification In vitro 030104 developmental biology Membrane Carbolines |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Biomembranes. 1863:183473 |
| ISSN: | 0005-2736 |
| DOI: | 10.1016/j.bbamem.2020.183473 |
| Popis: | Two β-carboline compounds, 8i and 6d, demonstrated in vitro antileishmanial activity against Leishmania (L.) amazonensis promastigotes similar to that of miltefosine (MIL). Estimates of the membrane-water partition coefficient (KM/W) and the compound concentrations in the membrane (cm50) and aqueous phase (cw50) for half maximal inhibitory concentration were made. Whereas these biophysical parameters for 6d were not significantly different from those reported for MIL, 8i showed lower affinity for the parasite membrane (lower KM/W) and a lower concentration of the compound in the membrane required to inhibit the growth of the parasite (lower cm50). A 2-hour treatment of Leishmania promastigotes with the compounds 8i and 6d caused membrane rigidity in a concentration-dependent manner, as demonstrated by the electron paramagnetic resonance (EPR) technique and spin label method. This increased rigidity of the membrane was interpreted to be associated with the occurrence of cross-linking of oxidized cytoplasmic proteins to the parasite membrane skeleton. Importantly, the two β-carboline-oxazoline derivatives showed low hemolytic action, both in experiments with isolated red blood cells or with whole blood, denoting their great Leishmania/erythrocyte selectivity index. Using electron microscopy, changes in the membrane of both the amastigote and promastigote form of the parasite were confirmed, and it was demonstrated that compounds 8i and 6d decreased the number of amastigotes in infected murine macrophages. Furthermore, 8i and 6d were more toxic to the protozoa than to J774A.1 macrophages, with treated promastigotes exhibiting a decrease in cell volume, mitochondrial membrane potential depolarization, accumulation of lipid bodies, increased ROS production and changes in the cell cycle. |
| Databáze: | OpenAIRE |
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