RESUMO
Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and in vitro anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated in vivo. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the para position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, in vivo, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Iminas/química , Resveratrol/análogos & derivados , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/farmacocinética , Antioxidantes/farmacologia , Disponibilidade Biológica , Compostos de Bifenilo/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Regulação para Baixo/efeitos dos fármacos , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Complexo Principal de Histocompatibilidade/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/biossíntese , Picratos/metabolismo , Células RAW 264.7RESUMO
In this study, we have investigated the antileishmanial activity of ten 7-chloro-4-quinolinylhydrazone derivatives. Among the compounds tested, compounds 2a and 2j presented activity against promastigotes (IC50 values of 52.5 and 21.1 µM, respectively) and compounds 2a and 2c were active against intracellular amastigotes (IC50 of 8.1 and 15.6 µM, respectively) of Leishmania amazonensis. The majority of compounds did not show toxicity against murine macrophages. Compound 2a exhibited low cytotoxicity to human erythrocytes and induced an oxidative imbalance in promastigote forms, reflected by an increase in the formation of reactive oxygen species (ROS) and a reduction of mitochondrial membrane potential. No alteration in the plasma membrane integrity of parasites was observed. Taken together, these results suggest that compound 2a is a selective antileishmanial agent, and preliminary observations suggest that its effects appear to be mediated by mitochondrial dysfunction.