Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B.

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Van der Walt MM, Terre'Blanche G, Lourens AC, Petzer A, Petzer JP

Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B.

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7367-70. doi: 10.1016/j.bmcl.2012.10.070. Epub 2012 Oct 22.

PubMed ID
23122857 [ View in PubMed
]
Abstract

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC(50)=0.025 muM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ClorgilineAmine oxidase [flavin-containing] AIC 50 (nM)2.6N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] BIC 50 (nM)79N/AN/ADetails