Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues.

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Manley-King CI, Bergh JJ, Petzer JP

Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues.

Bioorg Med Chem. 2011 Jan 1;19(1):261-74. doi: 10.1016/j.bmc.2010.11.028. Epub 2010 Nov 13.

PubMed ID

21134756 [ View in PubMed

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Abstract

Previous studies have shown that (E)-5-styrylisatin and (E)-6-styrylisatin are reversible inhibitors of human monoamine oxidase (MAO) A and B. Both homologues are reported to exhibit selective binding to the MAO-B isoform with (E)-5-styrylisatin being the most potent inhibitor. To further investigate these structure-activity relationships (SAR), in the present study, additional C5- and C6-substituted isatin analogues were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. With the exception of 5-phenylisatin, all of the analogues examined were selective MAO-B inhibitors. The C5-substituted isatins exhibited higher binding affinities to MAO-B than the corresponding C6-substituted homologues. The most potent MAO-B inhibitor, 5-(4-phenylbutyl)isatin, exhibited an IC(50) value of 0.66nM, approximately 13-fold more potent than (E)-5-styrylisatin and 18,500-fold more potent than isatin. The most potent MAO-A inhibitor was found to be 5-phenylisatin with an IC(50) value of 562nM. The results document that substitution at C5 with a variety of substituents is a general strategy for enhancing the MAO-B inhibition potency of isatin. Possible binding orientations of selected isatin analogues within the active site cavities of MAO-A and MAO-B are proposed.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Isatin	Amine oxidase [flavin-containing] B	IC 50 (nM)	12400	N/A	N/A	Details
Isatin	Amine oxidase [flavin-containing] B	Ki (nM)	5340	N/A	N/A	Details