Efeito tripanocida de 2-hidroxi-3,4,6- trimetoxifenilchalconas em cepa Y de Trypanosoma cruzi

• Ano de defesa: 2022
• Autor(a) principal: Magalhães, Emanuel Paula
• Orientador(a): Martins, Alice Maria Costa
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Trypanosoma cruzi; Chalconas; Doença de Chagas; Estresse Oxidativo
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/66452

Chagas disease, caused by Trypanosoma cruzi, is a neglected disease that has become endemic in developed countries and whose existing therapies have limited efficacy and low safety, with the need for new therapeutic alternatives with less toxicity. Thus, chalcones, endowed with diverse biological properties, are potential candidates for new trypanocidal substances. Thus, the present work evaluated the trypanocidal effect of three semi-synthetic and chlorinated chalcones on T. cruzi. For this, the cytotoxicity of the molecules was evaluated in host cells (LLC-MK2) was evaluated by MTT reduction assay, being observed a reduction in the CC50 values (60.4 ± 11.5 µM; 658.5 ± 138.3 µM and 1100.0 ± 259.7 µM) as the halogenation of the molecules was increased. The investigation of the effect on epimastigote forms was carried out by determining the percentage of viable parasites, obtaining similar values of IC50 at the times of 24 (81.5 ± 19,4 µM; 97.6 ± 14.2 µM and 79.3 ± 14.8 µM), 48 (35.1 ± 7.6 µM; 41.1 ± 5.2 µM and 69.5 ± 14.6 µM) and 72 hours (26.3 ± 3.2 µM; 10.9 ± 2.4 µM and 41.5 ± 6.8 µM) for ChC, Ch-4Cl and Ch-DiCl, respectively. The effect on trypomastigote forms also showed that the three chalcones presented similar values of LC50 (Ch-C: 165.2 ± 24.9 µM, Ch4Cl: 164.8 ± 33.0 and Ch-DiCl: 147.4 ± 20.9 µM). When the IS (CC50/LC50) of the three molecules were evaluated, we obtained values equal to 0.36; 3.99 and 7.46, respectively. Because it showed better effect in epimastigotes and trypomatigotes, the antiamastigote effect was performed only with Ch-DiCl. Through flow cytometry assays, the cell death profile (7-AAD/AxPE), percentage of intact cells (7-AAD), cytoplasmic ROS production (DCFH2-DA) and mitochondrial transmembrane potential (Rho123 - ΔΨm) were evaluated) of the treated groups were evaluated, and a possible necrotic mechanism of cell death and occurrence of oxidative stress were observed, with an increase in ROS production and a reduction of ΔΨm. Furthermore, molecular docking simulations were performed with the parasite targets cruzain and trypanothione reductase, showing the possible occurrence of interactions with the catalytic site and other important regions of these proteins. In conclusion, the studied chalcones showed a trypanocidal effect, and the replacement of the B ring with chlorine was able to maintain the activity with reduced toxicity to host cells. The effect of the molecules may be related to the inhibition of vital enzymes of the parasite, and they induced cell death mediated by membrane damage and oxidative stress.