RESUMO
Bacterial resistance to antibiotics has become a serious problem of public health that concerns almost all currently used antibacterial agents and that manifests in all fields of their application. To find more antibacterial agents from natural resources is all the time considered as an important strategy. Sophora flavescens is a popularly used antibacterial herb in Chinese Medicine, from which prenylated flavones were reported as the antibacterial ingredients but with a major concern of toxicity. In our screening on the antibacterial activities of various chemicals of this herb, 18 fractions were obtained from 8 g of 50% ethanol extract on a preparative high-speed counter-current chromatography (HSCCC, 1000 ml). The system of n-hexane/ethyl acetate/methanol/water (1:1:1:1) was used as the two-phase separation solvent. A chalcone named kuraridin was isolated from the best anti-MRSA fraction, together with sophoraflavanone G, a known active ingredient of S. flavescens. Their structures were elucidated by analysis of the NMR spectra. Both compounds exhibited significant anti-MRSA effects, compared to baicalein that is a well known anti-MRSA natural product. More important, kuraridin showed no toxicity on human peripheral blood mononuclear cells (PBMC) at the concentration up to 64 µg/ml while sophoraflavanone G inhibited over 50% of cellular activity at 4 µg/ml or higher concentration. These data suggested that opening of ring A of the prenylated flavones might decrease the toxicity and remain the anti-MRSA effect, from a viewpoint of structure-activity relationship.
Assuntos
Antibacterianos/isolamento & purificação , Chalconas/isolamento & purificação , Distribuição Contracorrente/métodos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Monoterpenos/isolamento & purificação , Sophora/química , Antibacterianos/química , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Cromatografia Líquida de Alta Pressão , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Humanos , Leucócitos Mononucleares , Testes de Sensibilidade Microbiana , Monoterpenos/química , Monoterpenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/químicaRESUMO
New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.