Discovery and synthesis of phenylthiophene sulfonamide derivatives with promising anti-inflammatory activity

Abstract

Dysregulated inflammation is central to chronic diseases such as rheumatoid arthritis and atherosclerosis. In this study, an in-house screening assay identified L464-0189 as a promising anti-inflammatory hit. Based on the phenylthiophene sulfonamide scaffold, 31 novel compounds bearing diverse electronic properties and ring systems were synthesized through multistep reactions. Preliminary structure–activity relationship (SAR) analysis revealed that compounds PTS-15 and PTS-22 significantly inhibited LPS-induced NO production in a concentration-dependent manner. Subsequent biological evaluation demonstrated that PTS-15 and PTS-22 inhibited the gene transcription of IL-1β, IL-6, and TNF-α. In addition, compound PTS-22 significantly inhibited the release of key pro-inflammatory cytokines, including IL-6 and TNF-α. Immunoblotting results further elucidated that PTS-22 exerts its anti-inflammatory efficacy by downregulating the NF-κB signaling pathway, as evidenced by the significant inhibition of p65 phosphorylation. Moreover, molecular docking analysis revealed the potential binding modes of PTS-15 and PTS-22 towards NF-κB. Collectively, these results highlighted the anti-inflammatory potential of phenylthiophene sulfonamide derivatives and supported their further optimization as scaffolds for the development of novel anti-inflammatory therapeutics.