2. Academic Validation
  3. Design, semisynthesis, and anti-inflammatory activity evaluation of a terphenyllin compound library for alleviating ulcerative colitis

Design, semisynthesis, and anti-inflammatory activity evaluation of a terphenyllin compound library for alleviating ulcerative colitis

  • Eur J Med Chem. 2026 Mar 5:305:118539. doi: 10.1016/j.ejmech.2025.118539.
Cui-Fang Wang 1,  Tian-Yi Zhou 2,  Liu-Xia Lv 2,  Xi-Zhen Cao 2,  Jun-Na Yin 2,  Wen-Hui Wang 2,  Qian-Qian Jing 2,  Yu-Cheng Gu 3,  Mei-Yan Wei 4,  Guang-Ying Chen 5,  Chang-Lun Shao 6
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, People's Republic of China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
  • 2 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
  • 3 Syngenta Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK.
  • 4 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, People's Republic of China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China. Electronic address: [email protected].
  • 5 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, People's Republic of China. Electronic address: [email protected].
  • 6 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, People's Republic of China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China; Sanya Oceanographic Institution, Ocean University of China, Sanya, 572024, People's Republic of China. Electronic address: [email protected].
PMID: 41518956 DOI: 10.1016/j.ejmech.2025.118539
Abstract

Ulcerative colitis (UC) is a chronic idiopathic enteritis, seriously affecting patients' quality of life and significantly increasing the risk of Cancer. We screened a marine natural product-derived library and identified a derivative (a4) of natural terphenyllin (1) as the bioactive scaffold for anti-inflammatory activity. To improve its activity, a total of 101 derivatives (a1-a29, b1-b40, and c1-c32) of a4 were rationally designed and semisynthesized. Among them, c13 (CHNQD-03005) emerged as the optimal lead, displaying the most potent inhibitory efficacy on the production of TNF-α, IL-6, and IL-1β with IC50 values ranging from 0.095 μM to 0.45 μM. Notably, c13 (1 mg/kg, p.o.) demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, together with a favorable safety profile (MTD >100 mg/kg, p.o.). Mechanistically, c13 alleviated colitis by suppressing the expression of inflammatory signaling iNOS/COX-2, and downregulating the levels of NO, TNF-α, IL-6, and IL-1β. In conclusion, this study provided a promising oral natural terphenyllin derivative c13, which inhibited multiple inflammatory pathways to impede colitis progression, as a therapeutic candidate in the treatment of UC for further development.

Keywords

Anti-inflammatory activity; Structural optimization; Terphenyllin derivatives; Ulcerative colitis.

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