2025-11-192025-11-192025CARDOSO, Éder Jéferson Souza et al. Antileishmanial, cytotoxic activities, and membrane rigidity effects of three synthetic compounds. Biochimica et Biophysica Acta (BBA): biomembranes, Amsterdam, v. 1867, n. 8, e184450, 2025. DOI: 10.1016/j.bbamem.2025.184450. Disponível em: https://www.sciencedirect.com/science/article/pii/S0005273625000446?via%3Dihub. Acesso em: 18 nov. 2025.1879-2642e- 0005-2736https://www.sciencedirect.com/science/article/pii/S0005273625000446?via%3DihubThree antileishmanial compounds incorporating a butylated hydroxytoluene (BHT) moiety and an acrylate-based Michael acceptor scaffold were rationally designed from the lead structures LQFM064 and LQFM332, which feature a chalcone-derived core. Their activities against Leishmania (L.) amazonensis were evaluated. Acrylate derivatives (5), (6), and (7) displayed IC50 values comparable to miltefosine, while showing markedly lower cytotoxicity toward J774.A1 and differentiated THP-1 macrophages, along with reduced hemolytic potential. Spin-label electron paramagnetic resonance (EPR) spectroscopy revealed that treatment with these compounds induces membrane rigidity after 24 h in a concentration-dependent manner. This effect is unlikely due to direct membrane interaction, as it does not occur after short incubations or at low concentrations, suggesting a correlation with oxidative stress, such as lipid peroxidation and/or protein oxidation, likely triggered by elevated reactive oxygen species (ROS) production. In contrast, no oxidative stress-induced membrane rigidity was detected in uninfected macrophages, suggesting that nitric oxide production may mitigate oxidative damage in these cells. However, significant membrane rigidity was observed in Leishmania-infected macrophages at concentrations slightly above the IC50 for amastigotes, indicating that the compounds may selectively target infected macrophages. Additionally, compound (5) exhibited moderate cytotoxicity in the rapidly proliferating J774.A1 macrophage line but displayed very low cytotoxicity in differentiated, non-proliferative THP-1 macrophages. Overall, this study suggests that the primary mechanisms underlying the antileishmanial activity of these compounds are associated with their effects on the parasite plasma membrane, potentially leading to ionic leakage, subsequent disruption of mitochondrial membrane potential, and enhanced ROS generation.engAcesso RestritoLeishmaniaMembrane fluidityElectron paramagnetic resonanceArtigo10.1016/j.bbamem.2025.184450