Discovery of potent and reversible MAO-B inhibitors as furanochalcones.

A series of twelve furanochalcones ( F1 - F12 ) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2 E , 4 E )-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 ( K i ) 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 K i 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. [ABSTRACT FROM AUTHOR]