Bacterial neuraminidase inhibitory effects of prenylated isoflavones from roots of Flemingia philippinensis

• Published in: Bioorganic & medicinal chemistry 2013-11, Vol.21 (21), p.6398-6404
• Main Authors: Wang, Yan, Curtis-Long, Marcus J., Yuk, Heung Joo, Kim, Dae Wook, Tan, Xue Fei, Park, Ki Hun
• Format: Article
• Language: English
• Subjects: Bacteria; Bacteria - enzymology; catechol; chemistry; Clostridium perfringens - enzymology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - metabolism; Fabaceae - chemistry; Fabaceae - metabolism; Flemingia; Flemingia philippinensis; Flemingsin; high performance liquid chromatography; inflammation; inhibitory concentration 50; isoflavones; Isoflavones - chemistry; Isoflavones - isolation & purification; Isoflavones - metabolism; Kinetics; methanol; Neuraminidase; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; pathogenesis; Plant Roots - chemistry; Plant Roots - metabolism; Prenylated isoflavone; Prenylation; Protein Binding; roots; sialidase; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.08.049

Flemingia philippinensis yieled a series of isoflavones having a potent neuraminidase inhibition up to 300μM of IC50. Bacterial neuraminidase (NA) is one of the key enzymes involved in pathogenesis of inflammation during infection. The organic extract of the roots of Flemingia philippinensis showed high bacterial NA inhibitory activity with an IC50 of around 5μg/mL. Activity-guided separation of the methanol extract yielded nine prenylated isoflavones together with the novel species isoflavone (2) which was given the name flemingsin. Isolated prenylated isoflavones (1–9) were evaluated for NA inhibition and their IC50 values were determined to range between 0.30 and 56.8μM. The most potent inhibitor 4 (IC50=300nM, Ki=130nM) features a catechol motif in the B-ring and a furan in the A-ring. Structure–activity analysis also showed a 4-hydroxyl group within the B-ring was essential for NA inhibitory activity, because isoflavone (9) having protected 4-hydroxyl group was much less potent than its hydroxylated counterpart. All neuraminidase compounds screened were found to be reversible noncompetitive inhibitors. Furthermore, the most active NA inhibitors (1–9) were proven to be present in the native roots in high quantities by HPLC and LC-DAD-ESI/MS.