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

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.