Design, synthesis and evaluation of shikimic acid derivatives for the treatment of ulcerative colitis

  • Eur J Med Chem. 2026 May 5:309:118762. doi: 10.1016/j.ejmech.2026.118762.
Huiru Xie  1 ,  Zhipeng Wang  2 ,  Maojun Yao  2 ,  Shanshan Zhu  2 ,  Hong Yan  3 ,  Hualong Song  4 ,  Rubing Wang  5
Affiliations
  • 1. College of Chemistry and Life Science, Beijing University of Technology, Beijing, 100124, China.
  • 2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 3. College of Chemistry and Life Science, Beijing University of Technology, Beijing, 100124, China. Electronic address: [email protected].
  • 4. Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 41849950 DOI: 10.1016/j.ejmech.2026.118762
Abstract

Ulcerative colitis is a severe gastrointestinal disorder that can even affect multiple organs throughout the body. Therefore, developing innovative agents for the treatment of ulcerative colitis is of significant importance. In this study, sixty-four new compounds were designed and synthesized basing on the natural product shikimic acid, structurally featuring the integration of adamantane at its 1-position and various aromatic or heteroaromatic rings at 5-position. Among them, five compounds (77, 87, 110, 123, and 134) potently inhibited the inflammatory response in lipopolysaccharide-induced macrophages without detectable cytotoxicity. The structure-activity data acquired from the study validated the substitution type at 1-position was crucial and 6-membered heteroaromatic rings integration at 5-position of shikimic acid provided more potent derivatives for in-depth development of inflammatory diseases. Compound 110 significantly ameliorated colitis-related symptoms in DSS-induced ulcerative colitis mice and suppressed the levels of pro-inflammatory cytokines (TNF-α and IL-6) and downregulated the expression of key inflammatory mediators (COX-2 and iNOS) by inhibition of the PI3K/Akt signaling pathway. These findings collectively identify compound 110 as a promising lead compound for the treatment of ulcerative colitis.

Keywords
Anti-inflammatory; Natural product; Shikimic acid derivatives; Ulcerative colitis.
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