Synthesis and Evaluation of Aromatic Sulfonamide and Disulfonamide Derivatives as Dengue Virus NS3–NS5 Interaction Inhibitors

Emerging viral threats highlight the urgent need for antivirals targeting viral replication mechanisms. Based on previous research, we expanded a series of asymmetric benzene‐1,4‐disulfonamides. As these proved to be synthetically challenging and generally more toxic than expected, we optimized a hit structure by omitting one sulfonamide group. The resulting compound combines micromolar antiviral efficacy with low toxicity and straightforward synthesis. Molecular docking and enzyme‐linked immunosorbent assay (ELISA) assays confirmed that the compound targets the NS5 RNA polymerase domain of dengue virus‐2, blocking its interaction with NS3 and thereby inhibiting viral replication. A focused series of structural analogs further demonstrated the essential contribution of each individual part of the hit molecule.