Synthesis of FtsZ inhibitors : potential antibiotic agents

In April 2014, the World Health Organisation (WHO) acknowledged the immediate threat of antibacterial resistance and the impact it will have on modern medicine. The greatest concern noted was that the development of novel antibacterial compounds was occurring at a slower rate than the development of resistance. One method identified to tackle this issue is to develop novel drugs that inhibit novel targets. Bacterial cell division, an essential process for the viability of a bacterium, is one such novel target. The cell division protein FtsZ, which is a highly conserved, essential and druggable protein, could be utilised as a target in this fight against antibiotic resistance. This thesis aimed to develop a set of novel antibacterial compounds that inhibit the function of FtsZ. The previous discovery of the compound 11 created an opportunity to expand upon an already known active molecule, with the goal of improving activity and biologically evaluating the compound's potential as a drug. In Chapter 2 and Chapter 3, a total of thirty-three derivatives of compound 11 were synthesised. In Chapter 4, seventeen novel compounds were synthesised that contained a pyrazole substructure, a unique library independent from the previous two chapters. Each molecule developed was screened against Gram-positive and Gram-negative pathogens, with three hits discovered (20, 48 and 96), all active against Staphylococcus aureus. Compound 20 also showed activity against Mycobacterium tuberculosis. This thesis also aimed to explore the mechanism of action (MOA), toxicity profile and resistance potential of 11. It was found that 11 did not inhibit FtsZ; however, S. aureus could not develop resistance to the compound. Although the goal of developing a FtsZ inhibitor was not accomplished, the inability for S. aureus to develop resistance to 11, and its high potency, meant this molecule could be explored as an antibacterial compound with an unknown MOA. It was later found that 11 is cytotoxic to mammalian cells; however, the derivative 20 developed in Chapter 2, was found to be non-cytotoxic and had the same MIC as 11. This indicated that the negative biological results of 11 could be overcome with minor structural modifications, indicating the viability of this work to be carried further for drug development.

Author dc:creator

• Payne, Matthew

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• info:eu-repo/semantics/openAccess
• The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
• au.edu.uts.lib/ppc

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en_AU

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http://hdl.handle.net/10453/133267

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oai:opus.lib.uts.edu.au:10453/133267