Design and Synthesis of Potential Novel Antibiotic Compounds Utilising Photoredox Catalysis

The continued emergence of widespread antibiotic resistance over the prior several decades poses an increasingly severe worldwide challenge to public health. Several frontline antibiotic treatments are being rendered obsolete due to the advent of numerous bacterial resistance mechanisms, an issue further compounded by the lack of antibiotics currently residing within the antibacterial drug discovery pipeline that operate via previously unexploited mechanisms of action. There are numerous underlying issues that have propagated this unsavoury situation, some specific to antibiotic drug development and others that negatively impact the field of drug discovery as a whole. One of the latter issues centres around the implementation of high throughput target-based screening of suboptimal compound libraries for hit identification, and the narrow range of synthetic methodologies used to explore chemical space within such compound collections. Dihydrodipicolinate synthase (DHDPS) constitutes a promising biomolecular target for novel antibiotic therapies due to its key role in the biosynthesis of essential amino acid L-lysine, a process widely specific to bacteria. Despite several prior campaigns and the development of micromolar potency inhibitors of DHDPS through target–based screening approaches, so far no compounds have been developed that display in vitro antibacterial activity in the subsequent phenotypic screens. In silico screening constitutes an invaluable range of techniques used in the identification of potential hit compounds that has been implemented to great effect in numerous drug discovery campaigns, including the discovery of novel antibacterial compounds, often aiding in the design of more focused compound libraries for assessment in vitro. Photoredox catalysis has emerged as a powerful synthetic tool for enabling access to previously unexplored regions of chemical space especially within medicinal chemistry contexts, facilitating highly chemoselective activation of reagents under benign reaction conditions. Sulfonylhydrazones are well established reagents within the field of organic synthesis capable of undergoing a myriad of transformations. Recent reports concerning the photocatalytic activation of hydrazone substrates to enable radical cyclisations served as the basis for the initial interest in developing related methodologies to generate desired compounds in the search for novel antibacterial agents. In this thesis is described the design and synthesis of potential novel antibacterial compounds, initially utilising pharmacophore searches and qualitative in silico docking investigations to identify molecular scaffolds of interest as synthetic targets. The development of a novel photoredox reaction for the generation of sulfone hit structures from sulfonyl hydrazone starting materials is described, including exploration of the substrate scope and reaction mechanism studies. The synthesis of additional in silico derived hit structures is also described, as well as attempts made to expand the synthetic utility of the developed photocatalytic methodology. Initial evaluation of antibacterial activity of the compound collection is described including preliminary discussion of structure activity relationships as a foundation for the derivation of future work. The final chapter contains technical experimental details and characterisation data pertaining to the previously discussed work.