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  • Scaffold-oriented Synthesis for Drug Discovery

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    Sarnpitak_2017_01Thesis.pdf (7.908Mb)
    Author(s)
    Sarnpitak, Pakornwit
    Primary Supervisor
    Coster, Mark
    Quinn, Ronald
    Year published
    2017
    Metadata
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    Abstract
    The design and synthesis of three different scaffolds of nitrogen heterocycles have been achieved by using either methods described in the literature or newly developed synthetic methodologies/routes. The three synthesised libraries in this thesis were based on Pd-catalysed N-arylations, Castagnoli-Cushman multicomponent reaction, and Rh(II)-catalysed intramolecular C-H insertions. The compounds were successfully synthesised in moderate to excellent yields. Firstly, one of the synthesised diaryl imidazolines was found to be a selective COX-2 inhibitor due to its comparable activity to the approved drugs, celecoxib, and the ...
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    The design and synthesis of three different scaffolds of nitrogen heterocycles have been achieved by using either methods described in the literature or newly developed synthetic methodologies/routes. The three synthesised libraries in this thesis were based on Pd-catalysed N-arylations, Castagnoli-Cushman multicomponent reaction, and Rh(II)-catalysed intramolecular C-H insertions. The compounds were successfully synthesised in moderate to excellent yields. Firstly, one of the synthesised diaryl imidazolines was found to be a selective COX-2 inhibitor due to its comparable activity to the approved drugs, celecoxib, and the binding mode was identical to the native ligand and other similar compounds. These observations are good starting points for the further development of selective COX-2 inhibitors based on imidazoline and related scaffolds. Secondly, the synthesis of novel scaffolds, pyrazino- and diazepino-fused isoquinolones, has been explored by using aryl glyoxals and diamines in the Castagnoli-Cushman multicomponent reaction, followed by post-MCR modifications. Unfortunately, all compounds in the library and their intermediates were inactive for antimicrobial activity. Moreover, the Rh(II)-catalysed intramolecular C-H insertion reactions of diazoesters to the C-H bond adjacent to the nitrogen atom yielded 2,3-disubstituted pyrrolidines. The selectivity of this reaction was influenced by the electron density of the C-H bonds undergoing insertion and steric hindrance around the reaction sites.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Natural Sciences
    DOI
    https://doi.org/10.25904/1912/1116
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Subject
    Nitrogen heterocycles
    Synthetic methodologies/route
    Pd-catalysed N-arylations
    Castagnoli-Cushman multicomponent reaction
    Rh(II)-catalysed intramolecular C-H insertions
    Drug discovery
    Publication URI
    http://hdl.handle.net/10072/366103
    Collection
    • Theses - Higher Degree by Research

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