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

A unified synthesis of skeletally-diverse sulfonyl fluorides was developed using photoredox-catalysed dehydrogenative couplings between hetaryl sulfonyl fluorides and hydrogen donor building blocks. A set of 32 diverse electrophilic probes was prepared and screened against Trypanosoma brucei; four probes showed sub-micromolar activity. An alkynylated analogue and broad-spectrum fluorophosphonate tools enabled chemical proteomic studies that suggest anti-trypanosomal activity arises from covalent modification of multiple protein targets. This unified diversity-oriented approach may facilitate discovery of electrophilic probes valuable for elucidating biological mechanisms.