Synthesis and selective human monoamine oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarin derivatives

Several 3-carbonyl (1–26), 3-acyl (27–52), and 3-carboxyhydrazido (53–58) coumarins have been synthesized in high yields (72–99%) and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Different substituents on the coumarin nucleus were evaluated for their effect on biological activity and isoform selectivity. Substitution at position C7 of the 3-ethyl ester coumarin ring, or the introduction of a hydrazido substituent at C3, were important to obtain highly potent and selective hMAO-B inhibitors with IC50 values in the nanomolar range. Some derivatives were also submitted to a stability test and showed no chemical cleavage in vitro.

Graphical abstractSeveral 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B inhibitory activity. Furthermore, molecular modelling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We synthesized and assayed several coumarins for hMAO A and B inhibitory activity. ► We confirmed the importance of the substitution at C7 and C3 of the coumarin. ► The hydrazido derivatives were potent and selective hMAO-B inhibitors. ► Some derivatives in a stability test showed no chemical cleavage in vitro.