Enzymatic evaluation of chromenone derivatives from Flemingia philippinensis as viral neuraminidase (H3N2) inhibitors

Abstract

The chromenones (1–6) from F. philippinensis displayed significant inhibition against the viral neuraminidase of H3N2. All the target chromenones including the new compound 5 have a triketone skeleton consisting of 2-acetyl-1,3-cyclohexanedione, which provides a being stable structure as exocyclic keto and enol form itself. The most potent inhibitor was identified as chromenone 1 (IC50 = 4.6 µM), but a subtle change in the functionality markedly affected the inhibitory potency (IC50 = 4.6 ∼ 28.5 µM) and mode. In particular, chromenones (1 and 4) with the exocyclic enol form exhibited the competitive mode, whereas the keto forms (2, 3, 5, and 6) were noncompetitive. The competitive inhibitor, chromenone 1, was proved to interact in a reversible simple slow-binding mode, according to the respective parameters: Kiapp = 2.38 µM, k3 = 0.0013 µM−1min−1, and k4 = 0.0031 min−1. The binding interactions of the competitive (1 and 4) and noncompetitive (2 and 3) inhibitors at the catalytic and allosteric sites, respectively, were predicted by the molecular docking method.