Design and synthesis of guaiacol-based fibrate derivatives with potential hypolipidemic and liver protective actions

Hypolipidemic and hepatoprotective effectives of the newly synthesized guaiacol-based fibrate derivatives were evaluated in Triton WR-1339-induced hyperlipidemic mice. All the target compounds were preliminary screened, in which compound T5 showed significant hypolipidemic effects, decreasing triglycerides (TG) and total cholesterol (TC), which was better than the positive drug clofibrate. Furthermore, compound T5 has a dosedependent effect on the blood lipid lowering activity of hyperlipidemia mice, and hepatic transaminases (AST and ALT) induced by hyperlipidemia have a significant improvement effect. Histological examination of the liver of hyperlipidemic mice supplemented with T5 revealed a significant amelioration in hepatic lipid accumulation when compared with the effect of the positive drug clofibrate. The mechanism of lipid-lowering showed that T5 could significantly increase the expression of PPAR-alpha protein in the liver of hyperlipidemic mice. In addition, T5 can also improve the lipid peroxidation process induced by hyperlipidemia, reducing the level of malondialdehyde (MDA). These findings reinforced the effects of T5 as a hypolipidemic candidate compound with liver protective activity.