Redesigning Berberines and Sanguinarines to Target Soluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy

Amino-berberine has remained underexplored due to limited biological evaluation and total synthesis approaches. In inflammation therapy, soluble Epoxide Hydrolase (sEH) is a promising target, yet natural scaffolds remain underutilized. Our study advances the field by redesigning natural compounds─berberine and sanguinarine─with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced <i>in vivo</i> efficacy. Through total synthesis and structure-activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine <b>(<i>R</i>)-14i</b> (coded <b>LXZ-42</b>) emerged as the most potent lead, with an IC₅₀ value of 1.20 nM. <b>(<i>R</i>)-14i</b> showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute <i>in vivo</i> toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of <b>(<i>R</i>)-14i</b> bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting <b>(<i>R</i>)-14i</b> as a novel lead for sEH-targeted therapies in inflammation.