Discovery of novel Bis-amide analogue ST12 for the treatment of inflammatory bowel diseases (IBD) by inhibiting NLRP3 inflammasome activation

  • Bioorg Chem. 2025 Jun 1:159:108402. doi: 10.1016/j.bioorg.2025.108402.
Zhiqiang Sun  1 ,  Qinru Zang  1 ,  Chenglong Xu  1 ,  Xuewen Zhang  1 ,  Zhenghui Kang  2 ,  Yushe Yang  3 ,  Ling Li  4 ,  Jianjun Chen  5
Affiliations
  • 1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: [email protected].
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 4. The Eighth Affiliated Hospital Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen 518000, China. Electronic address: [email protected].
  • 5. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 40154236 DOI: 10.1016/j.bioorg.2025.108402
Abstract

Herein, we designed and synthesized a series of novel bis-amide small molecule anti-inflammatory agents, among them, compound ST12 showed most potent anti-inflammatory activity. ST12 effectively inhibited the production of nitric oxide (NO) (inhibition rate of 52.67 ± 0.03 % at 10 μM) and downregulated the mRNA levels of proinflammatory cytokines iNOS, IL-6, IL-1β and TNF-α in lipopolysaccharide (LPS) induced RAW264.7 cells. Furthermore, mechanism studies suggest that compound ST12 exerted anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. Importantly, ST12 effectively ameliorated DSS-induced colitis in vivo. Taken together, ST12 is worthy of further investigation as a small molecule anti-inflammatory agent for treatment of inflammatory bowel diseases (IBD).

Keywords
Anti-inflammatory agents; Inflammatory bowel diseases (IBD); NLRP3 inflammasome; Nitric oxide (NO).
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