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.