Design, synthesis, and biological evaluation of 7-O-methyesculin esters as potent inhibitors of renal fibrosis.

Renal fibrosis is a global health challenge with limited therapies. 7-O-methyesculin (7-ME), derived from Cortex Fraxini (Qinpi), shows notable anti-inflammatory and anti-fibrotic properties. To enhance its membrane permeability and biological activity, we performed structural optimization and synthesized 18 6'-O-acyl 7-ME esters to improve lipophilicity and efficacy. Most derivatives displayed significant anti-fibrotic effects. Among them, EA-8 and EA-10 were more active than 7-ME against key fibrosis markers, including α-SMA, fibronectin and P-Smad3, while upregulating the protective protein E-cadherin. Mechanistic studies indicated that these compounds suppress the TGF-β1/Smad3 signaling pathway, providing a promising strategy for developing effective anti-fibrotic therapeutics.