Selected C7-substituted chromone derivatives as monoamine oxidase inhibitors

A series of C7-substituted chromone (1-benzopyran-4-one) derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The chromones are structurally related to a series of C7-functionalized coumarin (1-benzopyran-2-one) derivatives which has been reported to act as potent MAO inhibitors. The results of the current study document that the chromones are highly potent reversible inhibitors of MAO-B with IC50 values ranging from 0.008 to 0.370 μM. While the chromone derivatives also exhibit affinities for MAO-A, with IC50 values ranging from 0.495 to 8.03 μM, they are selective for the MAO-B isoform. Structure–activity relationships (SAR) show that 7-benzyloxy substitution of chromone is suitable for MAO-B inhibition with tolerance for a variety of substituents and substitution patterns on the benzyloxy ring. It may be concluded that 7-benzyloxychromones are appropriate lead compounds for the design of reversible and selective MAO-B inhibitors. With the aid of modeling studies, potential binding orientations and interactions of selected chromone derivatives in the MAO-A and -B active sites are examined.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► C7-substituted chromones are potent and selective MAO-B inhibitors. ► IC50 values range from 0.008 to 0.370 μM for the inhibition of human MAO-B. ► Docking studies suggest differential binding modes in MAO-A and -B. ► Tolerance exists for a variety of substituents and substitution patterns.