Design and Synthesis of Bis-3,4-Dimethoxybenzene-Fibrate Derivatives as Potential Lipid-Lowering and Hepatoprotective Agents Based on the Principles of Structural Simplification and Bioisosterism.

A series of bis-3, 4-dimethoxy-fibrate derivatives was designed using structural simplification and bioisosteric principles. The hypolipidemic effects of these compounds were initially evaluated in a Triton WR 1339-induced hyperlipidemic mouse model. The results indicated that compound T4 significantly reduced in levels of triglycerides (TG) and total cholesterol (TC). The dosage-dependent results show that reductions in TG and TC are greater as the T4 dosage increases. In the high-fat diet-induced hyperlipidemia model, T4 was found to significantly lower TG, TC, and LDL-C levels. Moreover, T4 exhibited hepatoprotective effects by substantially reducing levels of aspartate transaminase (AST) and alanine transaminase (ALT) in the liver. Histopathological examination indicated that T4 could inhibit hepatic lipid deposition and alleviate liver injury. Mechanistic investigations indicate that T4 upregulates hepatic peroxisome proliferator-activated receptor-alpha (PPAR-α) protein expression, contributing to its lipid-lowering effects. Molecular docking research has indicated a strong affinity between T4 and the active site of PPAR-α. Furthermore, T4 has demonstrated antioxidant and anti-inflammatory properties. These results suggest T4 could function as both an effective lipid-lowering compound and a potential hepatoprotective agent.