In vitro and in vivo anti-inflammatory and antinociceptive activities of a synthetic hydrangenol derivative: 5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one

In the present study, we developed and synthesized novel hydrangenol derivatives and featured their anti-inflammatory activities. Especially, a synthetic derivative 11 (compound 11), which possesses the 4H-1-benzopyran-4-one moiety, 5-hydroxyl group in A-ring, and 4′-hydroxyl group in B-ring, most dominantly downregulated nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. In addition, compound 11 suppressed the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) expression by inhibiting nuclear factor kappa-B (NF-κB), activator protein 1 (AP-1), and signal transducer and activator of transcription protein (STAT) pathways in LPS-provoked RAW264.7 macrophages. Additionally, we confirmed that compound 11 had better plasma stability than hydrangenol with a plasma-labile δ-valerolactone moiety. In carrageenan-induced rats, compound 11 potently reduced paw inflammation (as measured by paw volume, width, and thickness) by inhibiting the iNOS and COX-2 expression in paw tissue, thereby reducing inflammatory pain. All things considered, as compound 11 shows anti-inflammatory and antinociceptive properties, converting metabolically unstable hydrangenol into a stable compound 11 could be a promising strategy for developing new drugs.