Identification of Imidazole-Benzenesulfonamide Derivatives with Anti-Inflammatory Activity Through Modulation of NF-κB Signaling

Inflammatory disorders remain an important therapeutic challenge, highlighting the need to identify novel small molecules capable of modulating inflammatory signaling. In this study, an in-house library of aromatic and heterocyclic drug-like compounds was screened for inhibition of lipopolysaccharide (LPS)-induced nuclear factor kappa B (NF-κB) activation using THP-1 dual-reporter cells. Eight compounds markedly suppressed NF-κB activity, and five structurally related 4-phenylimidazole-based benzenesulfonamide derivatives (1232, 1239, 1241, 1242, and 1245) were prioritized based on their cytotoxicity profiles. Functional activity was subsequently evaluated in LPS-stimulated RAW 264.7 macrophages. The selected compounds reduced nitrite production, attenuated LPS-induced nuclear localization of NF-κB, and differentially affected IL-6, KC/CXCL1, and TNF-α production. The naphthyl-substituted derivative 1239 showed prominent inhibition of nitrite, IL-6, and KC/CXCL1 production, whereas the ethylthio derivative 1232 preferentially reduced TNF-α. Molecular docking against a panel of inflammation-associated proteins revealed favorable predicted interactions of compound 1239 with IκB kinase(IKK) and p38 mitogen-activated protein kinase (p38 MAPK), with docking scores of -10.3 kcal/mol for both proteins and binding poses overlapping the corresponding crystallographic ligand-binding regions. Collectively, these findings identify 4-phenylimidazole-based benzenesulfonamides as a promising chemical series with anti-inflammatory activity and suggest IKK and p38 MAPK as potential components of the affected signaling network. Further structure-activity and mechanistic studies are required to define the molecular targets and optimize the activity of this compound class.