RESUMO
Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 µM against L. infantum amastigote forms and CC50 value superior to 500 µM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 µM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.
Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Leishmania infantum/efeitos dos fármacos , Óxidos/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Biomarcadores/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ligantes , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Óxido Nítrico/análise , Nitritos/análise , Oxidiazóis/síntese química , Oxidiazóis/química , Óxidos/síntese química , Óxidos/química , Carga Parasitária , Pichia/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Proteínas de Protozoários/metabolismoRESUMO
Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1).