Structural simplification and bioisostere principle lead to Bis-benzodioxole-fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

Abstract

The bis-benzodioxole-fibrate hybrids were designed by structural simplification and bioisostere principle. Lipids lowering activity was preliminarily screened by Triton WR 1339 induced hyperlipidemia mice model, in which T3 showed the best hypolipidemia, decreasing plasma triglyceride (TG) and total cholesterol (TC), which were better than sesamin and fenofibrate (FF). T3 was also found to significantly reduce TG, TC and low density lipoprotein cholesterin (LDL-C) both in plasma and liver tissue of high fat diet (HFD) induced hyperlipidemic mice. In addition, T3 showed hepatoprotective activity, which the noteworthy amelioration in liver aminotransferases (AST and ALT) was evaluated and the histopathological observation exhibited that T3 inhibited lipids accumulation in the hepatic and alleviated liver damage. The expression of PPAR-α receptor involved lipids metabolism in liver tissue significantly increased after T3 supplementation. Other potent activity, such as antioxidation and anti-inflammation, was also observed. The molecular docking study revealed that T3 has good affinity activity toward to the active site of PPAR-α receptor. Based on these findings, T3 may serve as an effective hypolipidemic agent with hepatoprotection.

• Authors: Yundong Xie, Jiping Liu, Yongheng Shi, Bin Wang, Xiaoping Wang, Wei Wang, Meng Sun, Xinya Xu, Lifei Cheng, Shipeng He
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 117 Pg. 105454 (12 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34740054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Benzodioxoles
• Fibric Acids
• Hypolipidemic Agents
• PPAR alpha
• Ppara protein, mouse
• Protective Agents

Topics

• Administration, Oral
• Animals
• Benzodioxoles (administration & dosage, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Fibric Acids (administration & dosage, chemistry, pharmacology)
• Hyperlipidemias (drug therapy, metabolism)
• Hypolipidemic Agents (administration & dosage, chemistry, pharmacology)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred Strains
• Molecular Docking Simulation
• Molecular Structure
• PPAR alpha (antagonists & inhibitors, metabolism)
• Protective Agents (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship