Syntheses and Evaluation of 2- or 3-(N-Cyclicamino)chromone Derivatives as Monoamine Oxidase Inhibitors

A series of 2-(N-cyclicamino)chromone derivatives (1a–4c) and 3-(N-cyclicamino)chromone derivatives (5a–8c) were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were studied as part of a structure–activity relationship investigation. Compounds 1a–4c showed no remarkable inhibition for MAO-A or MAO-B, whereas compounds 5a–8c (with a few exceptions) showed significant and selective inhibition of MAO-B. Of these compounds, 7c, 7-methoxy-3-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one inhibited MAO-B the most potently and selectively, having IC50 of 15 nM and an MAO-B selectivity index of more than 6700; c.f, 50 nM and 2000, respectively, for safinamide. The mode of inhibition of 7c to MAO-B was competitive and reversible. Considering the IC50 values and selectivity indices of the other synthetic compounds, the presence of the methoxy group on the chromone ring (R2) of 7c seemed to increase MAO-B inhibition. Molecular docking analysis also supports this hypothesis. Our results suggest that 3-(N-cyclicamino)chromones are useful lead compounds for the development of MAO-B inhibitors