Discovery, Synthesis of Myrtucommulone B Analogs as Soluble Epoxide Hydrolase Inhibitors and Their Biological Activities.

No specific drugs exist for acute pancreatitis (AP). Soluble epoxide hydrolase (sEH) inhibitors hold therapeutic potential. Myrtus communis L. is a traditional herb with anti-inflammatory and antiseptic effects; however, the underlying mechanism of its anti-inflammatory activity remains unclear. Here, novel myrtucommulone B derivatives were synthesized and evaluated for their activity as sEH inhibitors. Bioassays showed derivative (+)-34 potently inhibited sEH, with low toxicity and robust in vitro/vivo anti-inflammatory and analgesic effects. Notably, (+)-34 showed significant protection in a murine AP model. Its in vivo mechanism involves elevating anti-inflammatory epoxyeicosatrienoic acids (EETs) and reducing proinflammatory dihydroxyeicosatrienoic acids (DHETs) by blocking sEH, thereby suppressing proinflammatory cytokines (TNF-α, IL-6). This study lays a foundation for developing myrtucommulone-based sEH inhibitors as novel anti-inflammatory/analgesic agents, particularly potential therapeutics for AP.