Synthesis and evaluation of novel quorum sensing inhibitors

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Lyons, Thérèse
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University College Cork
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This thesis details the synthesis of a range of furanones and the subsequent evaluation of their quorum sensing inhibitory effects. Chapter One focuses on the role of quorum sensing in bacteria and fungi. It explores the potential use of quorum sensing inhibitors as an alternative to, or in combination with antibiotics during the treatment of microbial infections. This chapter is also comprised of a review which details the structure activity relationships of halogenated furanones which have previously been evaluated in the literature. Synthetic routes to a number of these analogues are also detailed. In Chapter Two a concise preparation of gem-dibromofuranones is presented. A total of 33 novel compounds were subsequently generated via a variety of different chemistries, namely Suzuki and Sonogashira couplings. The synthesis of chlorine-, iodine- and fluorine-containing furanones is described in Chapter Three. The reactivity of various dihalofuranones is compared via palladium-catalysed Suzuki couplings, which proceed with high stereoselectivity. While modified Ramirez olefination conditions provided access to bromofluorofuranone analogues, in the end they were unstable. Chapter Four describes our ultimately unsuccessful attempt at coupling a bromofuranone with L-cysteine. Nevertheless, we were able to successfully couple the N-Boc-protected-methyl ester of L-cysteine with a tribromofuranone. The biological activity of the novel compounds generated throughout this project is detailed in Chapter Five. The furanones were subjected to AI-2 bioluminescence assays in University College Cork, anti-biofilm assays at Universitat Autònoma de Barcelona in Spain and the Cellular Microbiology Research Centre in Borstal Germany and anti-microbial assays at CO-ADD, Australia. A number of novel furanones displayed very promising activity against several different strains of bacteria and fungi including P. aeruginosa, V. harveyi, S. enterica and S. aureus. Avenues for further study on this project are detailed in Chapter Six. Full experimental procedures, including spectroscopic and analytical data, for all compounds synthesised throughout this work are outlined in Chapter Seven.
Furanones , Synthesis , Quorum sensing , Biological evaluation
Lyons, T. A. 2021. Synthesis and evaluation of novel quorum sensing inhibitors. PhD Thesis, University College Cork.