Abstact

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 horizontal line berberine and sanguinarine horizontal line with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced in vivo efficacy. Through total synthesis and structure-activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine (R)-14i (coded LXZ-42) emerged as the most potent lead, with an IC(50) value of 1.20 nM. (R)-14i showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute in vivo toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of (R)-14i bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting (R)-14i as a novel lead for sEH-targeted therapies in inflammation.