The synthesis and evaluation of N-methyl-2-phenylmaleimide analogues as inhibitors of MAO-B
Manley-King, Clarina Ilara
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We have recently demonstrated that 1-methyl-3-phenylpyrrole analogues are moderately potent competitive inhibitors of the enzyme monoamine oxidase B (MAO-B). The most potent analogue was 1-methyl-(4-trifluoromethylphenyl) pyrrole with an enzyme-inhibitor dissociation constant (K¡ value) of 1.30 µM. The least potent inhibitor was 1-methyl-3-phenylpyrrole with a K¡ value of 118 µM. Since 1-methyl-3-phenylpyrroles probably bind to the active site of MAO-B via hydrophobic interactions, we speculated that modification of the structure to include hydrogen bond acceptors may enhance binding affinity. An example of such a modified structure is N-methyl-2-phenylmaleimide, which may interact with MAO-B via both hydrogen bonding and hydrophobic burial, and hence may act as a more potent inhibitor. In this study we have prepared N-methyl-2-phenylmaleimide and selected phenyl ring substituted analogues. In order to test the merit of N-methyl-2-phenylmaleimides as potential MAO-B inhibitors, the chosen structures were modeled within the active site of human recombinant MAO-B. Results indicated that the carbonyl oxygens of the maleimide ring is stabilized by hydrogen bonding with amino acid residues and water molecules in the substrate cavity of the enzyme while the phenyl ring extends into the entrance cavity. Since similar interactions are not possible with 1-methyl-3-phenylpyrroles, we conclude that N-methyl-2-phenylmaleimides may inhibit MAO-B with enhanced potency compared to the pyrroles. For the purpose of this study, seven N-methyl-2-phenylmaleimides analogues were synthesized and their enzyme-inhibitor dissociation constants (K, values) for reversible interaction with MAO-B were determined. The most potent inhibitor among the oxidation products considered was the unsubstituted N-methyl-2-phenylmaleimide with a K¡ value of 3.49 µM. The least potent inhibitor was found to be N-methyl-2-(3-trifluromethylphenyl) maleimide with a K¡ value of 10.99 µM. The unsubstituted maleimide showed an approximately 30 fold increase in inhibition potency compared to the corresponding 1-methyl-3-phenylpyrrole. This may be in part due to the ability of the carbonyl oxygens of the maleimide ring to interact via hydrogen bonding with active site residues, an interaction which is impossible for the pyrroles.
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