Design and Synthesized 3,4‐Dimethoxybenzene‐Based Fibrate Derivatives as Potential Hypolipidemic and Liver Protection Agents

A series of 3,4-dimethoxybenzene-based fibrate derivatives were designed and synthesized, which were screened for preliminary lipid-lowering activity in a Triton WR-1339-induced hyperlipidemic mouse model. T5 had the strongest triglyceride (TG) and total cholesterol (TC) lowering effect among these target compounds. In a dose-dependent study, the lowering effects of T5 on TG and TC were progressively enhanced with increasing doses administered. Further studies revealed that T5 had a hypolipidemic significant effect on high-fat diet (HFD)-induced hyperlipidemia mouse model, with substantial reductions in TG, TC, and low-density lipoprotein cholesterol (LDL-C) levels, and a significant reduction in aspartate transaminase (AST) and alanine aminotransferase (ALT) levels in the liver, which had a protective effect on the liver. The of liver pathology showed that T5 could effectively inhibit lipid accumulation as well as inflammatory infiltration in the liver, thus reducing the degree of liver tissue damage. The expression of peroxisome proliferator-activated receptor-α (PPAR-α), which regulates lipid metabolism, was significantly upregulated in liver tissues. Molecular docking assays also confirmed the high binding affinity between T5 and PPAR-α active sites. In addition, T5 exhibited significant anti-inflammatory and antioxidant effects. These findings suggest that T5 has multiple activities and may be a potential novel hypolipidemic drug with hypolipidemic and hepatoprotective effects.