Usefulness of the sulfonamide motif in medicinal chemistry: exploring the pharmacological landscape of FDA-approved and investigational sulfonamide drugs.

The sulfonamide motif is widely used in the design of small molecules owing to its enzymatic stability but also its potentiality to improve target engagement and to provide a beneficial ADME profile. From the commercialization of Prontosil® in 1933 until 2023, a total of 91 compounds containing a sulfonamide moiety have received approval from the FDA. In parallel, analysis of the ChEMBl database revealed that 200 sulfonamide-containing compounds have entered clinical trials between 1998 and 2023. This review aims to present an exhaustive assessment of the sulfonamide motif in approved and investigational drugs, encompassing its pharmacokinetic and pharmacological properties, physicochemical properties, biological targets and temporal trends. Our analysis reveals a shift from traditional applications in antibacterials and diuretics toward modern oncology and antiviral therapeutics, with investigational compounds increasingly targeting GPCRs and kinases. Using selected case studies of approved drugs, we demonstrate that sulfonamide incorporation can enhance biological activity and modulate drug-like properties, providing evidence-based guidance to medicinal chemists.