Year

2021

Degree Name

Doctor of Philosophy

Department

School of Chemistry and Molecular Biosciences

Abstract

Clostridium difficile is a spore-forming, anaerobic Gram-positive bacteria that results in infection in the gastrointestinal (GI) tact. C. difficile has been known as the costliest bacteria in terms of human mortality and financial burden. Furthermore, the current treatments that exist for C. difficile infection (CDI) are inefficient and expensive and often result in disease reoccurrence due to the release of spores. Therefore, it is an important medical requirement to develop novel antibacterial compounds to effectively treat CDI. As such this PhD project has investigated the modification of the binaphthyl hydrophobic region of the lead compound-1 (AVX-13616) with alkyl and benzyl substituted phenyltriazole and naphthalenetriazole peptidomimetics towards the discovery of new CDI inhibitors.

An effective and modular synthetic route was developed to prepare twenty-nine novel mono- and di-cationic peptide derivatives which incorporated a phenyltriazole or naphthalenetriazole group with the aim to achieve better water solubility over previously prepared analogues by our group which were difficult to deliver in mouse model experiments because of their poor water solubilities. Chapter 2 describes the successful synthesis of these analogues. In some cases, the attempted synthesis of the 1,5-triazole moiety using the Ru-catalysed click reaction were unsuccessful when sterically hindered azide and alkyne substrates were employed. We found, however, that the magnesium promoted click reaction conditions reported by Sharpless et al. were useful for the synthesis of these sterically hindered 1,5-triazoles.

FoR codes (2020)

3405 Organic chemistry

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.