Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents

Abstract A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity were weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE2 level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity. Abbreviatios: IC50, half-maximum inhibitory concentration; COX-2, Cyclooxygenase-2; COX-1, Cyclooxygenase-1; NSAID, nonsteroidal anti-inflammatory drug; DCM, dichloromethane; AA, arachidonic acid; DMSO, dimethyl sulphoxide; FBS, fetal bovine serum; LD50, dose that is lethal in 50% of test subjects; LPS, lipopolysaccharide; m, multiplet (spectral); m-CPBA, meta-chloroperoxybenzoic acid; NO, nitric oxide; PBS, phosphate buffered saline; PDB, Protein Data Bank; TLC, thin-layer chromatography; TNF-alpha, tumor necrosis factor-alpha.