RESUMO
Tribulus terrestris fruits are well known for their usage in pharmaceutical preparations and food supplements. The methanol extract of T. terrestris fruits showed potent inhibition against the papain-like protease (PLpro), an essential proteolylic enzyme for protection to pathogenic virus and bacteria. Subsequent bioactivity-guided fractionation of this extract led to six cinnamic amides (1-6) and ferulic acid (7). Compound 6 emerged as new compound possessing the very rare carbinolamide motif. These compounds (1-7) were evaluated for severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro inhibitory activity to identify their potencies and kinetic behavior. Compounds (1-6) displayed significant inhibitory activity with IC50 values in the range 15.8-70.1 µM. The new cinnamic amide 6 was found to be most potent inhibitor with an IC50 of 15.8 µM. In kinetic studies, all inhibitors exhibited mixed type inhibition. Furthermore, the most active PLpro inhibitors (1-6) were proven to be present in the native fruits in high quantities by HPLC chromatogram and liquid chromatography with diode array detection and electrospray ionization mass spectrometry (LC-DAD-ESI/MS).
Assuntos
Cinamatos/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Extratos Vegetais/química , Tribulus/química , Proteínas Virais/antagonistas & inibidores , Amidas , Cinamatos/isolamento & purificação , Cinamatos/uso terapêutico , Proteases 3C de Coronavírus , Cisteína Endopeptidases/genética , Inibidores de Cisteína Proteinase/isolamento & purificação , Inibidores de Cisteína Proteinase/uso terapêutico , Relação Dose-Resposta a Droga , Escherichia coli/genética , Frutas/química , Humanos , Concentração Inibidora 50 , Cinética , Estrutura Molecular , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Relação Estrutura-Atividade , Proteínas Virais/genéticaRESUMO
Oxidation of low density lipoprotein (LDL) is strongly implicated as a key process in the onset of atherosclerosis. In this study, nine alkylated (C10-C5) flavonoids from Sophora flavescens were examined for their inhibitory effects on copper-induced LDL oxidation. Of the flavonoids tested, sophoraflavanone G (1), kurarinone (2), kurarinol (3), norkurarinol (4), and kuraridin (9) inhibited the generation of thiobarbituric acid reactive substances (TBARS) with IC50s of 7.9, 14.5, 22.0, 26.9, and 17.5 microM, respectively. The most potent inhibitor, compound 1, also demonstrated significant activities in complementary in vitro investigations, such as lag time (130 min at 5 microM), relative electrophoretic mobility (REM) of ox-LDL (80% inhibition at 20 microM), and fragmentation of apoB-100 (inhibition of 71% at 20 microM). Analysis of the structures of these compounds reveals that a resorcinol moiety in the B-ring is strongly correlated with protection of LDL-oxidation.