Synthesis and Evaluation of Substituted Coumarin Derivatives as Inhibitors of Monoamine Oxidase B

Monoamine oxidase B (MAO B) is of clinical importance due to its perceived role in neurodegenerative diseases such as Parkinson's, making inhibitors of MAO B popular candidates for drug design. A series of coumarin derivatives containing 7‐nitrobenzyloxy substitution, as well as 4‐methyl and 3,4‐dimethyl substitution, have been prepared and assayed, revealing that the synthesized inhibitors act through a competitive mode of inhibition. With Ki values in the nanomolar range, these coumarin derivatives are effective inhibitors of MAO B. Within this series, p ‐nitrobenzyloxy substitution has been experimentally shown to provide the best inhibition of MAO B. Furthermore, 3,4‐dimethyl substitution lowers the Ki value when compared to the 4‐methyl substituted coumarins. Computational docking with UCSF Chimera predicts that m ‐nitrobenzyloxy and 4‐methyl substitution should provide the best inhibition of MAO B, which is in opposition to the experimental results reported herein.