Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives

Chromone has been reported to be a useful scaffold for the design of monoamine oxidase (MAO) inhibitors. In an attempt to discover highly potent MAO inhibitors and to contribute to the known structure–activity relationships (SAR) of MAO inhibition by chromones, in the present study, we have synthesized a series of chromone derivatives substituted at C6 with a variety of alkyloxy substituents, and evaluated the resulting compounds as inhibitors of recombinant human MAO-A and -B. The results document that the C6-substituted chromones are potent reversible MAO-B inhibitors with IC50 values in the low nM range (2–76 nM). The chromones were also found to bind reversibly to MAO-A, but with lower affinities compared to MAO-B. It may therefore be concluded that C6-substituted chromones are highly potent MAO-B selective inhibitors and promising lead compounds for the development of therapy for neurodegenerative disorders such as Parkinson’s disease. The results of this study are discussed with reference to possible binding orientations of a selected C6-substituted chromone in the active site cavities of MAO-A and -B.

C6-substituted chromone derivatives (3a–o) act as highly potent and reversible inhibitors of human MAO-B.Figure optionsDownload as PowerPoint slideHighlights
► C6-Substituted chromones are highly potent MAO-B inhibitors.
► IC50 values for the inhibition of MAO-B are in the low nM range (2–76 nM).
► A wide variety of C6 substituents lead to potent MAO-B inhibition.
► Chromones are ideal scaffolds for the design of reversible MAO-B inhibitors.