2. Academic Validation
  3. Discovery of Trypanosoma brucei inhibitors enabled by a unified synthesis of diverse sulfonyl fluorides

Discovery of Trypanosoma brucei inhibitors enabled by a unified synthesis of diverse sulfonyl fluorides

  • Commun Chem. 2024 Oct 19;7(1):237. doi: 10.1038/s42004-024-01327-8.
Brian S Mantilla # 1,  Jack S White # 1,  William R T Mosedale # 2,  Andrew Gomm 1,  Adam Nelson 3,  Terry K Smith 4,  Megan H Wright 5
Affiliations

Affiliations

  • 1 School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
  • 2 Schools of Biology and Chemistry, Biomedical Sciences Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK.
  • 3 School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK. a.s.nelson@leeds.ac.uk.
  • 4 Schools of Biology and Chemistry, Biomedical Sciences Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK. tks1@st-andrews.ac.uk.
  • 5 School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK. m.h.wright@leeds.ac.uk.
  • # Contributed equally.
PMID: 39427042 DOI: 10.1038/s42004-024-01327-8
Abstract

Sets of electrophilic probes are generally prepared using a narrow toolkit of robust reactions, which tends to limit both their structural and functional diversity. A unified synthesis of skeletally-diverse sulfonyl fluorides was developed that relied upon photoredox-catalysed dehydrogenative couplings between hetaryl sulfonyl fluorides and hydrogen donor building blocks. A set of 32 diverse probes was prepared, and then screened against Trypanosoma brucei. Four of the probes were found to have sub-micromolar anti-trypanosomal activity. A chemical proteomic approach, harnessing an alkynylated analogue and broad-spectrum fluorophosphonate tools, provided insights into the observed anti-trypanosomal activity, which likely stems from covalent modification of multiple protein targets. It is envisaged that the unified diversity-oriented approach may enable the discovery of electrophilic probes that have value in the elucidation of biological and biomedical mechanisms.

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