Design, synthesis, and evaluation of eugenol-based fibrate derivatives as novel lipid-lowering agents

This study addresses the issue of hepatotoxicity associated with long-term fibrate drugs treatment for hypertriglyceridemia. Based on molecular hybridization and bioisosterism, a series of novel eugenol-fibrate derivatives were designed and synthesized. Their lipid-lowering potential was evaluated in both acute and chronic hyperlipidemia models (AHM/CHM). The underlying activity was investigated via molecular docking and Western blot analysis. Among eugenol-fibrate derivatives, the compound ethyl 6-(4-allyl-2-methoxyphenoxy) hexanoate (T7) demonstrated the most optimal and dose-dependent lipid-lowering activity. It functioned as a PPAR-α agonist, as confirmed by its strong binding affinity and upregulation of target protein expression. Furthermore, T7 significantly reduced serum AST and ALT levels, alleviated hepatic inflammatory infiltration and lipid accumulation, and exhibited anti-inflammatory and antioxidant effects, indicating improved liver safety. The study introduces an innovative strategy by hybridizing the eugenol scaffold with the fibrate pharmacophore. Leveraging the inherent antioxidant and anti-inflammatory properties of eugenol, this molecular integration is expected to significantly mitigate the hepatotoxicity commonly associated with conventional fibrates, thereby providing a novel approach for developing new lipid-lowering agents with enhanced efficacy and improved hepatic safety.