Synthesis of novel quorum sensing inhibitors of DSF

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Horgan, Conor
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University College Cork
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Antimicrobial resistance (AMR) has become a growing concern among the medical community with many previously effective antibiotics losing their efficacy. Much of this AMR is thought to stem from biofilm formation controlled by cell-to-cell signalling. Chapter 1 introduces quorum sensing with a particular focus on the Diffusible Signal Factor (DSF) family of autoinducers. Given that these molecules contain a carboxylic acid, this chapter also contains a review of the literature relating to carboxylic acid bioisosteres which have emerged since 2013. Quorum sensing interference is an increasingly attractive target for combatting bacterial infections. Accordingly, the work in this thesis focusses on the synthesis of sulfonamide-based bioisosteric derivatives of Burkholderia DSF (BDSF). In Chapter 2, 15 novel N-acyl sulfonamide analogues of BDSF are prepared and tested for biological activity. Some of these compounds display significant activity against many strains of bacteria both in vitro and in vivo. The cis-α,β-unsaturated double bond, a key factor in the biological activity of BDSF, is susceptible to isomerisation. The preparation and subsequent biological evaluation of 16 potentially more stable aromatic N-acyl sulfonamide analogues of BDSF is detailed in Chapter 3. Many of these compounds significantly inhibited biofilm formation and enhanced the efficacy of last-resort antibiotics against S. maltophilia and B. cenocepacia. In Chapter 4, X. fastidiosa, a bacterium responsible for diseases such as olive quick decline syndrome, is introduced. Some of the aromatic N-acyl sulfonamide analogues inhibited the formation of biofilm biomass and cell growth in the bacterium. The synthesis and subsequent testing of the parent signalling molecules and aromatic analogues containing a longer alkyl chain is also described. A practical synthetic route to a new class of aryl sulfonamide analogues of BDSF is presented in Chapter 5. Using SwissADME and MarvinSketch, important ADME properties of a virtual library containing 16 potential aryl sulfonamides, and the pre-existing olefinic and aromatic N-acyl sulfonamides are analysed to determine their suitability as drug candidates.
Quorum sensing , Diffusible signal factor , Isosteres , Bioisosterism , Sulfonamides , Antimicrobial resistance , Biofilms
Horgan, C. 2022. Synthesis of novel quorum sensing inhibitors of DSF. PhD Thesis, University College Cork.