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Novel anti-inflammatory compounds were synthesised by derivatization of militarin, a compound isolated from Cordyceps militaris that is an ethnopharmacologically well-known herbal medicine with multiple benefits such as anti-cancer, anti-inflammatory, anti-obesity, and anti-diabetic properties. In this study, we explored the in vitro and in vivo anti-inflammatory potencies of these compounds during inflammatory responses, their inhibitory mechanisms, and acute toxicity profiles. To do this, we studied inflammatory conditions using in vitro lipopolysaccharide-treated macrophages and several in vivo inflammatory models such as dextran sodium sulphate (DSS)-induced colitis, EtOH/HCl-induced gastritis, and arachidonic acid-induced ear oedema. Methods used included real-time PCR, immunoblotting analysis, immunoprecipitation, reporter gene assays, and direct kinase assays. Of the tested compounds, compound III showed the highest nitric oxide (NO) inhibitory activity. This compound also inhibited the production of prostaglandin (PG)E2 at the transcriptional level by suppression of Syk/NF-κB, IKKε/IRF-3, and p38/AP-1 pathways in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages. Consistent with these findings, compound III strongly ameliorated inflammatory symptoms in colitis, gastritis, and ear oedema models. In acute toxicity tests, there were no significant differences in body and organ weights, serum parameters, and stomach lesions between the untreated and compound III-treated mice. Therefore, this compound has the potential to be served as a lead chemical for developing a promising anti-inflammatory drug candidate with multiple kinase targets.