From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from <i>Chimonanthus salicifolius</i> 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 <b>Phoenicein</b> (hit) isolated from <i>Chimonanthus salicifolius</i> to <b>D228</b> (lead). Remarkably, <b>D228</b> exhibited good inhibitory activity on B and T lymphocyte and excellent anti-IBD efficacy <i>in vivo</i>. Mechanistically, <b>D228</b> alleviated the inflammation response by downregulating the MyD88/TRAF6/p38 signaling. Importantly, the relationship of <b>D228</b>, <b>Phoenicein</b>, and their aglycone <b>7a</b> was deduced: <b>D228</b> could be considered as a prodrug and metabolized to intermediate <b>Phoenicein</b>. In turn, <b>Phoenicein</b> released their shared active aglycone <b>7a</b>. Additionally, <b>D228</b> demonstrated good and balanced profiles of safety and efficacy both <i>in vitro</i> and <i>in vivo</i>. These results suggested that <b>D228</b> could be used as an ideal lead and potentially utilized for IBD chemotherapy.