“Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase

Sulfur-Fluoride Exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled approach exploiting the “sleeping beauty” phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the “sleeping beauty” phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines.