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

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.