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Thiophene-thiosemicarbazone derivative (L10) exerts antifungal activity mediated by oxidative stress and apoptosis in C. albicans

2020; Elsevier BV; Volume: 320; Linguagem: Inglês

10.1016/j.cbi.2020.109028

1872-7786

Luiz Nascimento de Araújo Neto, Maria do Carmo Alves de Lima, Jamerson Ferreira de Oliveira, Edson Rubhens de Souza, Suellen Emilliany Feitosa Machado, Gláucia Manoella de Souza Lima, Maria Daniela Silva Buonafina, Fábio André Brayner, Luiz Carlos Alves, Jana Messias Sandes, Márcia Vanusa da Silva, Maria Carolina Accioly Brelaz de Castro, Rejane Pereira Neves, Francisco Jaime Bezerra Mendonça,

Sulfur Compounds in Biology

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 μg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 μg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.