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.