Design, synthesis, and investigation of lipid-lowering and hepatoprotective effects of clofibrate-vanillin derivative based on structural optimization

The study aimed to optimize the structure of clofibrate to create a lipid-lowering medication with reduced liver damage properties. A new compound, clofibrate-vanillin (CF-Vanillin), was synthesized and tested in hyperlipidemic mice. The results showed that CF-Vanillin significantly reduce triglycerides (TG) and total Cholesterol (TC), which was stronger than that of CF. The molecular docking results suggested that CF-Vanillin exhibits a favorable affinity towards PPAR-α. The results of the liver damage evaluation showed that CF-Vanillin significantly reduced liver damage compared to CF. The liver weight and liver coefficient of the CF-Vanillin group mice were significantly reduced (P < 0.01). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly reduced (P < 0.05). Pathological analysis of liver tissue revealed a notable decrease in nuclear deformation, dissolution, inflammatory cell infiltration, and necrosis among mice treated with CF-Vanillin. Investigation into the liver damage reduction mechanism revealed a significant upregulation of Nrf2 and HO-1 expression (P < 0.01) in the liver tissue of CF-Vanillin group mice. Furthermore, CF-Vanillin exhibited notable antioxidant and anti-inflammatory properties. The results imply that CF-Vanillin shows improved lipid-lowering effects and decreased liver damage possibly due to its antioxidant and anti-inflammatory actions by activating the Nrf2/HO-1 signaling pathway.