Redesigning\nBerberines and Sanguinarines to Target\nSoluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy

Amino-berberine has remained underexplored due to limited\nbiological\nevaluation and total synthesis approaches. In inflammation therapy,\nsoluble Epoxide Hydrolase (sEH) is a promising target, yet natural\nscaffolds remain underutilized. Our study advances the field by redesigning\nnatural compoundsberberine and sanguinarinewith strategic\nurea modifications and hydrogenated frameworks, creating novel sEH\ninhibitors with enhanced <i>in vivo</i> efficacy. Through\ntotal synthesis and structure–activity relationship studies\nof amino-berberine derivatives, chiral tetrahydroberberine <b>(<i>R</i>)-14i</b> (coded <b>LXZ-42</b>) emerged as the\nmost potent lead, with an IC<sub>50</sub> value of 1.20 nM. <b>(<i>R</i>)-14i</b> showed reduced CYP enzyme impact,\npotent therapeutic effects on acute pancreatitis, no acute <i>in vivo</i> toxicity, and superior pharmacokinetic properties,\nwith an oral bioavailability of 89.3%. Structural insights from crystallography\nof <b>(<i>R</i>)-14i</b> bound to sEH revealed key\ninteractions: three with the tetrahydroberberine framework and three\nhydrogen bonds with the urea group, highlighting <b>(<i>R</i>)-14i</b> as a novel lead for sEH-targeted therapies in inflammation.