Neutrophil dysregulation is implicated in a spectrum of inflammatory pathologies, suggesting the potential for targeting neutrophilic hyperactivation as a pharmacological strategy to manage inflammatory disorders. Building upon prior research where 2-thiolphenoxychromone derivatives were found to inhibit neutrophilic generation of superoxide anions, this study focused on exploring the structure-activity relationship (SAR) of different C2 bridging moieties and anti-inflammatory effects using bioisosteric replacements and scaffold-hopping approaches. Among various chemotypes, the N-(4-oxo-4H-chromen-2-yl)benzenesulfonamide derivatives emerged as robust inhibitors of both superoxide anion generation and elastase release from fMLF-activated human neutrophils, with IC