Coumarin derivatives as inhibitors against monoamine oxidase: structure-activity relationships and inhibitory mechanisms

Abstract

Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Understanding the structure-activity relationship (SAR) and mechanisms underlying MAO inhibitors is crucial but challenging. The coumarin scaffold has been shown to be ideal for MAO inhibitors, yet the SAR for MAO inhibition and selectivity based on coumarin remains unclear. In this study a fluorescence-based high throughput screening method was developed using a MAO fluorescent substrate (MR2). Subsequently, three series of coumarin derivatives, including esculetin, daphnetin and 3-substituted coumarin, were synthesized and the inhibitory effects on MAO were assayed. The SAR study revealed that phenyl substitution had a unique effect on MAO inhibitory activity and selectivity. Specifically, 3-phenyl substitution in coumarin derivatives significantly enhanced MAO-B inhibition and increased selectivity for MAO-A, while 4-phenyl substitution is more effective for MAO-A inhibition. Discovery studios were also utilized to investigate the structural requirements for the effective inhibition of MAO by coumarins. Furthermore, the mechanisms underlying inhibition for five phenyl coumarin derivatives were elucidated through enzymatic kinetics analysis and molecular docking simulations. These findings provide new insights into the interactions between coumarins and MAOs and significantly contribute to the development of coumarin-based MAO inhibitors.

Keywords

Monoamine oxidase (MAO) / Inhibitor / Coumarin / Structure-activity relationship / Inhibition mechanism

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