RESUMO
In this study, we evaluated the inâ vitro and inâ vivo schistosomicidal activities of chalcones against Schistosoma mansoni worms. In vitro assays revealed that chalcones 1 and 3 were the most active compounds, without affecting significantly mammalian cells. Confocal laser scanning microscopy and scanning electron microscopy studies revealed reduction on the numbers of tubercles and morphological alterations in the tegument of S. mansoni worms after inâ vitro incubation with chalcones 1 and 3. In a mouse model of schistosomiasis, the oral treatment (400â mg/kg) with chalcone 1 or 3 significantly caused a total worm burden reduction in mice. Chalcone 1 showed significant inhibition of the S. mansoni ATP diphosphohydrolase activity, which was corroborated by molecular docking studies. The results suggested that chalcones could be explored as lead compounds with antischistosomal properties.
Assuntos
Anti-Helmínticos/química , Chalconas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Administração Oral , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/metabolismo , Sítios de Ligação , Chalconas/síntese química , Chalconas/química , Chalconas/uso terapêutico , Modelos Animais de Doenças , Proteínas de Helminto/antagonistas & inibidores , Proteínas de Helminto/metabolismo , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/patologia , Relação Estrutura-AtividadeRESUMO
Schistosomiasis is one of the world's major public health problems, and its treatment is widely dependent on praziquantel (PZQ), the only available drug. Schistosoma mansoni ATP diphosphohydrolases are ecto-enzymes localized on the external tegumental surface of S. mansoni and considered an important target for action of new drugs. In this work, the in vitro schistosomicidal activity of the crude extract of Glycyrrhiza inflata roots (GI) and its isolated compounds echinatin, licoflavone A and licoflavone B were evaluated against S. mansoni adult worms. Results showed that GI (200 µg/mL) was active against adult schistosomes, causing 100% mortality after 24 h of incubation. Chromatographic fractionation of GI led to isolation of echinatin, licoflavone A and licoflavone B. Licoflavone B (25-100 µM) caused 100% mortality, tegumental alterations, and reduction of oviposition and motor activity of all adult worms, without affecting mammalian Vero cells. Confocal laser scanning microscopy showed tegumental morphological alterations and changes on the numbers of tubercles of S. mansoni worms in a dose-dependent manner after incubation with licoflavone B. Licoflavone B also showed high S. mansoni ATPase (IC50 of 23.78 µM) and ADPase (IC50 of 31.50 µM) inhibitory activities. Docking studies predicted different interactions between licoflavone B and S. mansoni ATPDase 1, corroborating with the in vitro inhibitory activity. This report demonstrated the first evidence for the schistosomicidal activity of licoflavone B and suggests that its mechanism of action involve the inhibition of S. mansoni ATP diphosphohydrolases.