From Hit to\nLead: Discovery of First-In-Class Furanone\nGlycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease

TNFα\nand related inflammatory factor antibody drugs\nhave\nbeen orchestrated for the treatment of inflammatory bowel disease\n(IBD). However, antibody drugs elicited inevitable disadvantages and\nsmall molecule drugs are in an urgent need. Herein, we described the\ndiscovery, design, synthesis, and SAR studies from furanone glycoside\ncompound <b>Phoenicein</b> (hit) isolated from Chimonanthus salicifolius to <b>D228</b> (lead).\nRemarkably, <b>D228</b> exhibited good inhibitory activity on\nB and T lymphocyte and excellent anti-IBD efficacy <i>in vivo</i>. Mechanistically, <b>D228</b> alleviated the inflammation\nresponse by downregulating the MyD88/TRAF6/p38 signaling. Importantly,\nthe relationship of <b>D228</b>, <b>Phoenicein</b>, and\ntheir aglycone <b>7a</b> was deduced: <b>D228</b> could\nbe 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\nbalanced 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\nfor IBD chemotherapy.