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Synthesis of novel isosteric analogues of DSF
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Date
2025-12-31
Authors
O'Driscoll, Michelle M.
Journal Title
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Volume Title
Publisher
University College Cork
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Abstract
Antimicrobial resistance (AMR) poses a growing global health threat, rendering many antibiotics increasingly ineffective. A key factor in the development and persistence of AMR is bacterial communication through quorum sensing (QS), a cell-density dependent signalling mechanism that regulates gene expression, including those involved in virulence and biofilm formation.
Chapter 1 describes the Diffusible Signal Factor (DSF) family of autoinducers with a particular focus on N-acyl sulfonamide isosteres of Burkholderia DSF (BDSF). This chapter also contains a review of the literature relating to the synthesis of N-acyl sulfonamides. Quorum sensing inhibition using bioisosteres represents an attractive strategy for disrupting bacterial communication and attenuating virulence. In Chapter 2, 27 novel saturated N-acyl sulfonamide analogues of BDSF are prepared and evaluated against 11 bacterial and fungal strains for their ability to inhibit biofilm formation. Many of these compounds display significant antibiofilm activity against a variety of pathogens.
A small number of cis-unsaturated N-acyl sulfonamide BDSF analogues were previously shown to exhibit good efficacy in various pathogens. Chapter 3 outlines the preparation of a complete library of cis-unsaturated N-acyl sulfonamide analogues of BDSF. Of these, 14 novel analogues were subsequently evaluated along with the six previously prepared compounds. The importance of the presence of the cis-alkene bond was noted for some bacterial strains. Many of these compounds were identified as effective biofilm inhibitors. Chapter 4 focuses on the installation of an aromatic ring in place of the alkene bond and the transposition of the sulfonyl and carbonyl groups to generate a range of N-acyl benzenesulfonamide BDSF analogues. A total of 26 novel analogues were evaluated for their biofilm inhibitory activity in S. aureus. The best performing analogue inhibited biofilm growth in both methicillin-sensitive and methicillin-resistant S. aureus strains.
The suitability of the three libraries as drug candidates is presented in a computational study in Chapter 5. The physicochemical properties of each compound are evaluated against Lipinski’s Rule of 5, Veber’s Rules and also screened for pan-assay interference (PAINS) alerts. Finally, Chapter 6 outlines our main conclusions and avenues for future research.
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Keywords
Antimicrobials , Biofilms , Bioisosterism , Burkholderia cepacia complex , Multi drug resistance , QS inhibitors , Sulfonamides
Citation
O'Driscoll, M. 2025. Synthesis of novel isosteric analogues of DSF. PhD Thesis, University College Cork.