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 1–4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR (1H, 13C) spectroscopy. Their in vitro relative expression of peroxisome proliferator‐activated receptor and peroxisome proliferator‐activated receptor 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 50 mg/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 and peroxisome proliferator‐activated receptor . 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 residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator‐activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314. Compound 1 was prepared using a short synthetic route. It showed an increase in the mRNA expression of PPARα and PPARγ, as well as the GLUT‐4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single oral dose using a NIDDM rat model, showing a significant decrease in plasma glucose levels. Molecular docking of 1 into the ligand binding pocket of both PPAR´s isoforms showed important short contacts with the active PPARα and PPARγ residues.