Design, synthesis and evaluation of Bis-3,4-dimethoxybenzene-based fibrate derivatives guided by structural simplification and Bioisosterism principle as potential hypolipidemic and hepatoprotective agents.

Using Phillygenin as the lead compound, a series of fibrate derivatives featuring a bis-3,4-dimethoxyphenyl skeleton were designed and synthesized based on bioelectronic isosterism and structural simplification principles. Preliminary screening using a Triton WR-1339-induced acute hyperlipidemia mouse model revealed that compound T2 significantly reduced triglyceride (TG) and total cholesterol (TC) levels. Further investigation in a high-fat diet-induced chronic hyperlipidemia animal model revealed that T2 not only significantly reduced TG, TC, and low-density lipoprotein cholesterol (LDL-C) levels but also elevated high-density lipoprotein cholesterol (HDLC) levels. Moreover, T2 effectively improved liver injury by significantly reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Histopathological analysis indicated that T2 mitigated hepatic lipid deposition and alleviated liver tissue damage. T2 significantly upregulated the protein expression level of PPAR-α, a key nuclear receptor regulating lipid metabolism in the liver. Simultaneously, T2 exhibits pronounced antioxidant and anti-inflammatory activities. Molecular docking simulations reveal strong binding affinity between T2 and the PPAR-α protein binding site. Collectively, T2 emerges as a potential candidate compound with dual lipid-lowering and hepatoprotective effects, warranting further investigation.