Synthesis and evaluation of 6-methylcoumarin derivatives as potent and selective monoamine oxidase B inhibitors

A new series of 6-methyl-3-phenylcoumarins (3a-c and 5a-o) and 6-methyl-3-heteroarylcoumarins (5p-s) have been designed, synthesized and evaluated as monoamine oxidase inhibitors. The results demonstrated that a large proportion of the synthesized compounds selectively inhibited monoamine oxidase B with IC50 values in the sub-micromolar range. Among them, compound 5n (IC50 = 0.0601 mu M) exhibited the most potent inhibitory activity and the highest selectivity for monoamine oxidase B (SI > 1664-fold). In addition, the possible binding model of the active compound 5n was measured by docking it into the active site of the hMAO-B complex structure. The results showed that compound 5n interacted with the well-known binding pocket of MAO-B, and a pi-pi interaction was found between the phenyl ring at position 3 of the coumarin and the phenyl ring of Tyr 326. Consequently, we supplied useful information about the interaction between the enzyme and inhibitor, and developed the 6-methyl-3-phenylcoumarin scaffold as an agent for multifaceted brain disorders.