NDLI: Inhibition of monoamine oxidase by (E)-styrylisatin analogues

Content Provider	PubMed Central
Author	Walt, Elizna M. Van Der Milczek, Erika M. Malan, Sarel F. Edmondson, Dale E. Castagnoli, Neal Bergh, Jacobus J. Petzer, Jacobus P.
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.
Related Links	http://dx.doi.org/10.1016/j.bmcl.2009.03.030
Ending Page	2513
Page Count	5
Starting Page	2509
File Format	PDF
ISSN	0960894X
e-ISSN	14643405
Journal	Bioorganic & medicinal chemistry letters
Issue Number	9
Volume Number	19
Language	English
Publisher Date	2009-05-01
Access Restriction	Open
Subject Keyword	Organic Chemistry Clinical Biochemistry Molecular Medicine Biochemistry Molecular Biology Drug Discovery Pharmaceutical Science Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Biochemistry Molecular Biology Clinical Biochemistry Molecular Medicine Pharmaceutical Science

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