Inhibition of monoamine oxidase by E_-styrylisatin analogues

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dc.contributor.author Van Der Walt, Elizna Magdalena en_US
dc.contributor.author Bergh, Jacobus en_US
dc.contributor.author Petzer, Jacobus en_US
dc.contributor.author Malan, Sarel en_US
dc.contributor.author Castagnoli, N Jr
dc.contributor.author Milczek, E M
dc.contributor.author Edmondsonb, Dale E
dc.date.accessioned 2010-08-04T15:36:05Z
dc.date.available 2010-08-04T15:36:05Z
dc.date.issued 2009 en_US
dc.identifier.citation VAN DER WALT, E.M., BERGH, J., PETZER, J., MALAN, S., CASTAGNOLI, N. Jr., MILCZEK, E. M., & Edmondsonb, D.L. 2009. Inhibition of monoamine oxidase by E_-styrylisatin analogues. Bioorganic and Medicinal Chemistry Letters, 19(9):2509-2513, May [http://journals.elsevier.com/09680896/bioorganic-and-medicinal-chemistry/] en_US
dc.identifier.issn 0968-0896
dc.identifier.uri http://hdl.handle.net/10394/3358
dc.description.abstract Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors.
dc.description.uri http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VV2NH2-7-H&_cdi=5221&_user=4050432&_pii=S0960894X09003503&_origin=search&_coverDate=05%2F01%2F2009&_sk=999809990&view=c&wchp=dGLzVzb-zSkWA&md5=30a9d3bfb8096ead66342cbdb89a79a1&ie=/sdarticle.pdf
dc.description.uri http://dx.doi.org/10.1016/j.bmcl.2009.03.030
dc.publisher Elsevier Ltd
dc.title Inhibition of monoamine oxidase by E_-styrylisatin analogues en_US

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