Abstract
Based on a recent report that 1-methyl-3-phenylpyrrolyl analogues are moderately potent reversible inhibitors of the enzyme monoamine oxidase B (MAO-B), a series of structurally related N-methyl-2-phenylmaleimidyl analogues has been prepared and evaluated as inhibitors of MAO-B. In general, the maleimides were more potent competitive inhibitors than the corresponding pyrrolyl analogues. N-Methyl-2-phenylmaleimide was found to be the most potent inhibitor with an enzyme–inhibitor dissociation constant ( K i value) of 3.49 μM, approximately 30-fold more potent than 1-methyl-3-phenylpyrrole ( K i = 118 μM). This difference in activities may be dependent upon the ability of the maleimidyl heterocyclic system to act as a hydrogen bond acceptor. This is in correspondence with literature reports which suggest that hydrogen bond formation is involved in stabilizing inhibitor–MAO-B complexes. Also reported here is a brief kinetic study of the hydrolysis of the N-methyl-2-phenylmaleimidyl analogues in aqueous solution. The findings of the inhibition studies are discussed with reference to the rate and extent of hydrolysis.
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