Streptochlorin‐derived sulfonamides: discovery of novel antifungal scaffold through structural modification and SAR analysis

BACKGROUND Streptochlorin, a marine indole alkaloid with broad‐spectrum bioactivity, has been structurally modified by introducing sulfonamide at the 3‐position of the indole scaffold to enhance its antifungal potential. RESULTS A series of sulfonamide‐containing derivatives were designed, synthesized, and evaluated against seven phytopathogenic fungi. Notably, derivatives D35 – D37 exhibited potent antifungal activity, demonstrating >60% inhibition against most tested fungi and > 85% efficacy against Valsa mali . Structure–activity relationship (SAR) analysis revealed that 3‐phenylsulfonamide substitution conferred optimal activity. Molecular docking studies suggested that these derivatives likely targeted the cytochrome bc 1 complex, implicating fungal respiration disruption as a potential mode of action. CONCLUSION The 3‐phenylsulfonamide‐modified streptochlorin derivatives exhibited potent antifungal activity, with D35 ‐ D37 showing particular efficacy. Their successful synthesis offers a novel antifungal scaffold, while preliminary studies suggest potential cytochrome bc 1 complex inhibition as a mode of action.