Next Generation Sulfonyl Fluoride Electrophiles Expand the Scope of Covalent Drug Discovery

Sulfonyl fluorides (SFs) are promising electrophiles for covalent drug discovery, enabling the targeting of diverse amino acids beyond cysteine. However, their widespread application has been hindered by limitations in stability and selectivity, often restricting their utility to early-stage tool development. We introduce heteroaryl sulfonyl fluorides as a next-generation class of tuneable electrophiles designed to overcome these challenges. These electrophiles demonstrate optimized intrinsic reactivity, enhanced solubility and lipophilicity, whilst exhibiting markedly improved stability in whole blood and plasma compared to traditional phenyl-based SFs. Employing a high-throughput chemistry direct-to-biology workflow, we rapidly explored structure-activity relationships, yielding potent covalent inhibitors of carbonic anhydrase II (CAII) with exceptional cellular selectivity. These findings establish heteroaryl SFs as versatile, tuneable electrophiles possessing superior drug-like properties and outstanding target specificity. This platform offers a powerful new avenue for developing highly selective covalent ligands that are suitable for drug discovery.