Thiazolidine-2,4-diones derivatives as PPAR-γ agonists: synthesis, molecular docking, in vitro and in vivo antidiabetic activity with hepatotoxicity risk evaluation and effect on PPAR-γ gene expression

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3034-42. doi: 10.1016/j.bmcl.2014.05.034. Epub 2014 May 22.

Abstract

A library of conjugates of chromones and 2,4-thiazolidinedione has been synthesized by Knoevenagel condensation followed by reduction using hydrogen gas and Pd/C as a catalyst. Compounds 5c and 5e were most effective in lowering the blood glucose level comparable to standard drug pioglitazone. Compound 5e exhibited potent PPAR-γ transactivation of 48.72% in comparison to pioglitazone (62.48%). All the molecules showed good glide score against the PPAR-γ target in molecular docking study. PPAR-γ gene expression was significantly increased by compound 5e (2.56-fold) in comparison to standard drug pioglitazone. Compounds 5e and 5c did not cause any damage to the liver and may be considered as promising candidates for the development of new antidiabetic agents.

Keywords: 2,4-Thiazolidinedione; Antidiabetic activity; Chromone; Hepatotoxicity; PPAR-γ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacology*
  • Liver / drug effects*
  • Liver / pathology
  • Molecular Docking Simulation*
  • Molecular Structure
  • PPAR gamma / agonists*
  • PPAR gamma / genetics*
  • Rats
  • Rats, Wistar
  • Risk Assessment
  • Streptozocin
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / pharmacology*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • thiazolidine-2,4-dione
  • Streptozocin