Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 mu M. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 +/- 0.655 mu M), IL-6 (IC50 = 7.767 +/- 0.871 mu M), and TNF-alpha (IC50 = 7.089 +/- 0.775 mu M) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-kappa B/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo, b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-kappa B/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Automated summary

This study designed a new anti-inflammatory compound, b2, which showed potential therapeutic effects on lung injury. In vitro and in vivo experiments demonstrated that b2 could attenuate pathological changes in ALI by inhibiting inflammatory factors and related signaling pathways.