Inhibition of monoamine oxidase by C5-substituted phthalimide analogues.

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Manley-King CI, Bergh JJ, Petzer JP

Inhibition of monoamine oxidase by C5-substituted phthalimide analogues.

Bioorg Med Chem. 2011 Aug 15;19(16):4829-40. doi: 10.1016/j.bmc.2011.06.070. Epub 2011 Jun 29.

PubMed ID

21778064 [ View in PubMed

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Abstract

Literature reports that isatin as well as C5- and C6-substituted isatin analogues are reversible inhibitors of human monoamine oxidase (MAO) A and B. In general, C5- and C6-substitution of isatin leads to enhanced binding affinity to both MAO isozymes compared to isatin and in most instances result in selective binding to the MAO-B isoform. Crystallographic and modeling studies suggest that the isatin ring binds to the substrate cavities of MAO-A and -B and is stabilized by hydrogen bond interactions between the NH and the C2 carbonyl oxygen of the dioxoindolyl moiety and water molecules present in the substrate cavities of MAO-A and -B. Based on these observations and the close structural resemblances between isatin and its phthalimide isomer, a series of phthalimide analogues were synthesized and evaluated as MAO inhibitors. While phthalimide and N-aryl-substituted phthalimides were found to be weak MAO inhibitors, phthalimide homologues containing C5 substituents were potent reversible inhibitors of recombinant human MAO-B with IC(50) values ranging from 0.007 to 2.5 muM and moderately potent reversible inhibitors of recombinant human MAO-A with IC(50) values ranging from 0.22 to 9.0 muM. By employing molecular docking the importance of hydrogen bonding between the active sites of MAO-A and -B and the phthalimide inhibitors are highlighted.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Isatin	Amine oxidase [flavin-containing] B	Ki (nM)	3000	N/A	N/A	Details