Discovery of a novel C2-functionalized chromen-4-one scaffold for the development of p38α MAPK signaling inhibitors to mitigate neutrophilic inflammatory responses.

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 values in the single-digit micromolar range. Leveraging a forward pharmacology approach through computational prediction, compound 15b, a representative within this active molecular class, was discovered to exert these anti-inflammatory functions by blocking the p38α mitogen-activated protein kinase (MAPK) signaling cascade. This responded to a significant reduction in p38α MAPK and its downstream MK2 phosphorylation in activated neutrophils treated with 15b, with no apparent impact on extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) phosphorylation levels. Additionally, this molecule exhibited inhibitory potential on intracellular reactive oxygen species (ROS) production, granule exocytosis, and chemotactic responses. Collectively, this study provides a novel skeleton for the development of inhibitors targeting the p38α MAPK pathway to mitigate neutrophilic inflammation.