Part 1: Palladium catalysed deuteration of indoles: Part 2: Development of vovel inhibitors for influenza hemagglutinin

Fitzgerald, Liam
For the first two years of my Ph.D programme, I conducted research under the supervision of Dr. Miriam O’Duill. This research is outlined in Part 1 of this thesis. Following Dr. O.Duill’s appointment at the University of Nottingham in 2020, I joined the research group of Prof. Paul Murphy. The research I carried out in Prof. Murphy’s group is detailed in Part 2 of this thesis. Part 1: Chapters 1-3 In recent times deuteration has become a critical tool in drug discovery and development. It has proven to improve the metabolic stability, pharmacokinetics and toxicity profile of drugs as well as allowing deuterated drugs to be classified as new chemical entities. Nitrogen heterocycles such as indoles often find themselves at the core of many small molecule drugs. Therefore, strategies to deuterate these compounds have become a significant interest. Previous Work has focused on using transition metal catalysts such as Ir and Ru, however no investigation into the use of Pd(II) catalysts has been reported in this field. This is surprising as Pd(II) is a widely used metal in the C-H activation field. In Chapter 1 a more detailed background is given on deuteration and the current state of the field. Chapter 2 details Pd(II) methodology for the selective deuteration of indoles is investigated and developed giving access to selective C-2, C-3 and simultaneous C-2/C-3 deuterated indoles. Finally, Chapter 3 details the experimental procedures used to obtain these deuterated indoles. Part 2: Chapters 4-7 Influenza is a disease responsible for over half a million deaths each year. It was responsible for both the 1912 Spanish Flu pandemic where an estimated 50 million died and the 2009 pandemic resulting in close to half a million deaths. The virus consists of two main envelope proteins Hemagglutinin (HA) and neuraminidase (NA). Current approved treatments rely on vaccines which must be updated seasonally and small molecules targeting NA. HA is a trimeric protein responsible for binding to host cells via complex glycoproteins terminating with a sialic acid residue, however the binding interactions between sialic acid and HA are quite weak. One technique to overcome these weak carbohydrate interactions is the display of multiple carbohydrate residues on a single scaffold (multivalency). As targeting HA would prevent cell infection it can be seen as a valid target in treating the disease. No clinical treatment exists for targeting HA. The purpose of this work was to develop novel potent inhibitors to target HA, through techniques such as multivalency and computational studies. Chapter 4 gives a more detailed background on Influenza, current treatments and multivalency. Chapter 5 details the synthesis of multivalent sialic acid based on a tetraphenylethylene ring, attempts to synthesis novel C-3 sialic acid derivatives was also investigated however the attempts were unfruitful. The binding affinity of the synthesised multivalent compounds were then analysed using a microscale thermophoresis assay. Chapter 6 details attempt to identify novel scaffolds to inhibit HA through use of computational techniques, some of the identified scaffolds were then also evaluated using a MST assay. Chapter 7 details the synthetic procedures used to obtain the multivalent compounds described in chapter 5
NUI Galway
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland