Discovery of Thiazolidine-2,4-Dione/Biphenylcarbonitrile Hybrid as Dual PPAR α/γ Modulator with Antidiabetic Effect: In vitro, In Silico and In Vivo Approaches

A small series of thiazolidine-2,4-dione and barbituric acid derivatives 14 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR (H-1, C-13) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator-activated receptor isoforms, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50mg/kg single dose using a non-insulin-dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator-activated receptor gamma residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator-activated receptor alpha residues: Tyr 464, His 440, Ser 280 and Tyr 314.