• Login
    View Item 
    •   NWU-IR Home
    • Research Output
    • Faculty of Health Sciences
    • View Item
    •   NWU-IR Home
    • Research Output
    • Faculty of Health Sciences
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Monoamine oxidase inhibition by C4-substituted phthalonitriles

    Thumbnail
    Date
    2012
    Author
    Manley-King, Clarina I.
    Bergh, Jacobus J.
    Petzer, Jacobus P.
    Metadata
    Show full item record
    Abstract
    It was recently reported that a series of C5-substituted phthalimides are remarkably potent reversible inhibitors of recombinant human monoamine oxidase (MAO) B. Modeling studies suggested that the phthalimide ring forms numerous polar interactions with the polar region of the MAO-B substrate cavity while the C5 side chain extends to, and interacts via Van der Waals interactions with the hydrophobic regions of the enzyme entrance cavity. Interactions with both cavities appear to be requirements for high affinity binding. In the present study we have examined an analogs series of C4-substituted phthalonitriles as potential human MAO inhibitors. The phthalonitriles were found to be highly potent reversible MAO-B inhibitors with most analogs exhibiting IC50 values in the low nM range. The phthalonitriles also interacted with human MAO-A, although with lower binding affinities compared to MAO-B. Modeling studies suggest that the high binding affinities of the phthalonitriles to MAO-B may depend, at least in part, on the formation of polar interactions between the nitrile functional groups and the enzyme substrate cavity. Examination of a homologs series of benzonitriles established that the phthalonitrile moiety is more optimal for MAO-B inhibition than the corresponding benzonitrile moiety, and that C3-substituted benzonitriles are better MAO-B inhibitors than C4-substituted benzonitriles. Since elimination of the nitrile functional group yielded compounds with only moderate MAO-B inhibition potencies, it may be concluded that this functional group is privileged for MAO-B inhibition.
    URI
    http://hdl.handle.net/10394/9894
    https://www.sciencedirect.com/science/article/pii/S0045206811000745
    https://doi.org/10.1016/j.bioorg.2011.10.003
    Collections
    • Faculty of Health Sciences [2369]

    Copyright © North-West University
    Contact Us | Send Feedback
    Theme by 
    Atmire NV
     

     

    Browse

    All of NWU-IR Communities & CollectionsBy Issue DateAuthorsTitlesSubjectsAdvisorThis CollectionBy Issue DateAuthorsTitlesSubjectsAdvisor

    My Account

    LoginRegister

    Copyright © North-West University
    Contact Us | Send Feedback
    Theme by 
    Atmire NV