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

Authors


  • This work was taken in part from the PhD thesis of S. Hidalgo-Figueroa. He is a CONACyT fellow (209159). Vladimir Hernandez-Rosado is also a CONACYT fellow. We are grateful to Korina Sánchez-Salazar for technical assistance.

Corresponding author: Gabriel Navarrete-Vázquez, gabriel_navarrete@uaem.mx

Abstract

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 &agr1; and peroxisome proliferator-activated receptor &ggr1; 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 &agr1; and peroxisome proliferator-activated receptor &ggr1;. 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 &ggr1; 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.

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