Heteroaromatic Sulfonyl Halides in Drug Discovery
Heteroaromatic sulfonyl chlorides and fluorides are versatile building blocks in medicinal chemistry. Their core reactivity is straightforward: sulfonyl chlorides react readily with amines to form sulfonamides, a widely used functional group in drug discovery. Introducing a heteroaromatic ring such as pyridine, thiazole or thiophene adds another layer of molecular design, influencing electronics, hydrogen-bonding and physicochemical properties compared with simple benzenesulfonyl analogues. A clinically relevant example is vonoprazan, marketed as VOQUEZNA, a potassium-competitive acid blocker approved by the FDA for erosive and non-erosive GERD, as well as in combination regimens for H. pylori infection. Reported synthetic routes use 3-pyridinesulfonyl chloride to sulfonylate a pyrrole intermediate, installing the pyridinesulfonyl group that forms a key part of vonoprazan's structure. This illustrates how heteroaromatic sulfonyl chlorides can serve as highly effective building blocks for assembling target-relevant functionality. Sulfonyl fluorides have attracted particular interest through sulfur\(VI\) fluoride exchange, or SuFEx. Their combination of useful stability and controlled reactivity makes them valuable both as synthetic handles and as covalent warheads. SuFEx chemistry has enabled covalent engagement of residues beyond the traditionally targeted cysteine, including tyrosine, lysine, histidine, serine and threonine. One striking example comes from fragment-based discovery of acetylcholinesterase inhibitors. Sulfonyl fluoride fragments with moderate activity were diversified through SuFEx into 102 sulfonamide analogues, with the optimised compound achieving around 70-fold higher potency and an IC₅₀ of 94 nM. Together, these examples highlight why heteroaromatic sulfonyl halides remain valuable tools in modern medicinal chemistry: they combine reliable synthetic reactivity with opportunities to tune molecular recognition, while sulfonyl fluorides additionally open the door to SuFEx-enabled library synthesis and covalent drug discovery. Explore our range of building blocks using the advanced search tools at https://lnkd.in/eVbfw6Ua 1.Synthesis and applications of heterocycle-containing sulfonyl fluorides for drug discovery: a critical review https://lnkd.in/gVhkdJxK 2. Sulfur-fluoride exchange \(SuFEx\)-enabled lead discovery of AChE inhibitors by fragment linking strategies https://lnkd.in/geMksVTf 3. Covalent drug discovery using sulfur\(VI\) fluoride exchange warheads https://lnkd.in/grQUMCSb
