Discovery of potent and reversible MAO-B inhibitors as furanochalcones

F1Ki of MAO-B = 0.0041 μM LazabemideKi of MAO-B = 0.0079 μM [Display omitted] •A series of twelve furanochalcones (F1-F12) was synthesized.•Investigated for their human monoamine oxidase inhibitory activities.•F1 showed Ki value of 0.0041 μM and SI of 172.4.•Single-crystal X-ray diffraction of F1.•Molecular docking study. A series of twelve furanochalcones (F1-F12) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2E, 4E)-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one (F1), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant (Ki) value of 0.0041 μM and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The Ki value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 μM) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong π-π stacking between the phenyl system and FAD nucleus.