Atividade leishmanicida de três derivados de chalcona e sua associação com a rigidez da membrana avaliada pela espectroscopia de RPE
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Data
2023-08-11
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Universidade Federal de Goiás
Resumo
Leishmaniasis is a neglected tropical disease that affects the world's poorest populations. Currently, therapeutic options have high toxicity, with prolonged therapeutic regimens. Still, the emergence of resistance highlights the need to seek new therapeutic agents. Chalcones are precursors of flavonoid biosynthesis with clinical potential for the treatment of leishmaniasis. Novel chalcone-like compounds, LQFM332 (4), LQFM333 (5), and LQFM341 (6), were synthesized and their activity against Leishmania (L.) amazonensis was evaluated using electron paramagnetic resonance (EPR) spectroscopy and assays of cell viability. Compound 4 was synthesized from the molecular hybridization of vanillin (9) and butylated hydroxytoluene (BHT), forming a chalcone scaffold. BHT was replaced by another apocynin to give compound 5, while for compound 6 the Michael acceptor double bond from compound 4 was reduced. For cell viability assays, the IC 50 values for compounds 4, 5, and 6 against the Leishmania parasite were 7, 20, and 16 µM for the promastigote form, and 19, 11, and 1 µM for the amastigote form inside infected macrophages, respectively. EPR spectroscopy of a lipid spin label incorporated into the parasite plasma membrane demonstrated that treatment with these compounds in culture medium causes membrane rigidity in a concentration-dependent manner, owing to oxidative processes. From the IC 50 values with different cell concentrations, the membrane-water partition coefficient (K M/W ) of the compounds could be estimated, as well as their concentrations in the membrane (c m50 ) and in the aqueous culture medium (c w50 ) that reduce antiproliferative activity by 50%. Values for these biophysical parameters were similar to those reported for the antileishmanial drug, miltefosine. K M/W values indicated that the compounds have high affinity for the parasite membrane, with the compound containing the BHT group having the highest affinity. Compound 5, which contained a two 4-hydroxy-3-methoxyphenyl scaffold, showed the highest values of cw50 and cm50 . Compound 6 showed that the reduction of the double bond decreased the membrane affinity and the c w50 value, but maintained the c m50 , demonstrating the same activity as compound 4 for assays with higher concentration of cells. As cytotoxic activities were modulated by effects on the cell membrane, our results suggest that the primary action of the compounds is on the parasite membrane.
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Leishmania, Chalcona, Fluidez da membrana, Ressonância paramagnética eletrônica, Leishmania, Chalcone, Membrane fluidity, Electron paramagnetic resonance
Citação
BORGES, Ellyêssa Nascimento. Atividade leishmanicida de três derivados de chalcona e sua associação com a rigidez da membrana avaliada pela espectroscopia de RPE. 2023. 50 f. Trabalho de Conclusão de Curso (Bacharelado em Farmácia) – Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, 2023.