From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease.

TNFα and related inflammatory factor antibody drugs have been orchestrated for the treatment of inflammatory bowel disease (IBD). However, antibody drugs elicited inevitable disadvantages and small molecule drugs are in an urgent need. Herein, we described the discovery, design, synthesis, and SAR studies from furanone glycoside compound Phoenicein (hit) isolated from Chimonanthus salicifolius to D228 (lead). Remarkably, D228 exhibited good inhibitory activity on B and T lymphocyte and excellent anti-IBD efficacy in vivo . Mechanistically, D228 alleviated the inflammation response by downregulating the MyD88/TRAF6/p38 signaling. Importantly, the relationship of D228 , Phoenicein , and their aglycone 7a was deduced: D228 could be considered as a prodrug and metabolized to intermediate Phoenicein . In turn, Phoenicein released their shared active aglycone 7a . Additionally, D228 demonstrated good and balanced profiles of safety and efficacy both in vitro and in vivo . These results suggested that D228 could be used as an ideal lead and potentially utilized for IBD chemotherapy.