Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ

Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPAR γ ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPAR γ . The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g , which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPAR γ with IC 50 being 1790 nM, and dose-dependently increased the transcriptional activity of PPAR γ . Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPAR γ . Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and β -fold is increased, showing the characteristics of some PPAR γ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPAR γ agonist that deserves further investigation.