The present study was designed to investigate the potential anti-inflammatory effects and mechanisms of water-soluble sulfonamido compounds such as Sodium-N-(2-amino-5-benzoylphenyl)-4-n-propyl-benzenesulfonamido (1), Sodium-N-(2-amino-5-benzoylphenyl)-2,4,6-trimethyl-benzenesulfonamido (2), Sodium-N-(2-amino-5-benzoylphenyl)-4-chloro-benzenesulfonamido (3) and Sodium-N-(2-amino-5-benzoylphenyl)-4-methoxy-benzenesulfonamido (4) in Raw 267.4 macrophages and BV-2 microglia cells. Compounds (1-4) identities are characterized by various methods such as H-1-NMR, C-13-NMR, FT-IR, UV-Vis, cyclic voltammetry and elemental analysis. Cytotoxicity (MTT method) and production of cytokines were determined with ELISA. Furthermore, intracellular mitogen-activated protein kinase (MAPK) signaling pathway and cyclooxygenase-2 (Cox-2) expression were analyzed by Western blot. Lowest cytotoxicity was seen in compound 4 treated cells. The compound 4 inhibited lipopolysaccharide-stimulated Cox-2 expression and p38/ERK MAPK pathway in both cell lines. In addition, the inhibitory action of compound 4 not only restricted Cox-2 and p38/ERK MAPKs, but also inhibited the secretion of pro-inflammatory cytokines TNF-alpha/IL-6 and activated anti-inflammatory cytokine IL-10. The experimental results suggest the anti-inflammatory action of water-soluble sulfonamido compounds on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases.