Design and synthesis of pterostilbene derivatives bearing triazole moiety that might treat DSS-induced colitis in mice through modulation of NF-κB/MAPK signaling pathways

Abstract

In this study, a series of novel anti-inflammatory compounds with high activity and low toxicity were designed and synthesized based on the natural product pterostilbene skeleton. According to the strategy of pharmacophore combination, we introduced thiazole moiety into pterostilbene skeleton to design and synthesize a novel series of pterostilbene derivatives (a total of 41 compounds), and lipopolysaccharide (LPS)-treated RAW 264.7 cells were screened for anti-inflammatory activity and cytotoxicity. Among them, compound 8 was found to be the most active (against NO: IC₅₀ = 0.6 μM) compared with pterostilbene and indomethacin. Anti-inflammatory mechanism studies revealed that compound 8 inhibited pro-inflammatory cytokines by blocking the NF-κB/MAPK signaling pathway in LPS-treated RAW 264.7 cells. In vivo experiments showed that compound 8 had a good relieving effect on DSS-induced acute colitis in mice, and also demonstrated a good safety in acute toxicity experiments. In conclusion, compound 8 may be a promising anti-inflammatory lead compound in the treatment of acute colitis.

Keywords: IBD; Inflammation; Inhibitor; Pterostilbene derivatives.