Scaffold-oriented Synthesis for Drug Discovery

Loading...
Thumbnail Image
File version
Primary Supervisor

Coster, Mark

Quinn, Ronald

Other Supervisors
Editor(s)
Date
2017
Size
File type(s)
Location
License
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 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.

Journal Title
Conference Title
Book Title
Edition
Volume
Issue
Thesis Type

Thesis (PhD Doctorate)

Degree Program

Doctor of Philosophy (PhD)

School

School of Natural Sciences

Publisher link
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement

The author owns the copyright in this thesis, unless stated otherwise.

Item Access Status
Note
Access the data
Related item(s)
Subject

Nitrogen heterocycles

Synthetic methodologies/route

Pd-catalysed N-arylations

Castagnoli-Cushman multicomponent reaction

Rh(II)-catalysed intramolecular C-H insertions

Drug discovery

Persistent link to this record
Citation