Highly potent bacterial neuraminidase inhibitors, chromenone derivatives from Flemingia philippinensis
Yan Wang1, Jeong Yoon Kim2, Yeong Hun Song2
1College of Food and Biological Engineering, Qiqihar University, Qiqihar 161006, China.
Abstract:
The chromenone derivatives (1-4) from the root part of Flemingia philippinensis showed a significant inhibition against bacterial neuraminidase (NA) which plays a pivotal role in a cellular interaction including pathogenesis of bacterial infection and subsequent inflammation. The compounds 1 and 2 were the new compounds, philippin D (1) and philippin E (2). In particular, compounds (1-3) exhibited sub micromolar levels of IC50 values with 0.75, 0.54, and 0.07 μM. This is the first report that chromenone skeleton emerged as a lead structure of bacterial NA inhibition. In kinetic study, 8,8-diprenyl compounds displayed competitive inhibitory mode, whereas 4a,8-diprenyl ones showed noncompetitive behavior. It was manifested that all competitive inhibitors (1 and 2) were simple reversible slow-binding against bacterial NA. The binding affinities (KSV) of inhibitors to enzyme were agreement with their respective inhibitory potencies. Molecular docking data confirmed that the position of 3-methyl-2-butenyl substituent affects inhibitory mechanism against CpNanI. The tri-arginyl cluster of R266, R555, and R615 and D291 in NanI tightly interact with the competitive inhibitors.
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