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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

2013; Wiley; Volume: 81; Issue: 4 Linguagem: Inglês

10.1111/cbdd.12102

1747-0285

Sergio Hidalgo‐Figueroa, Juan José Ramírez‐Espinosa, Samuel Estrada‐Soto, Julio César Almanza-Pérez, Rubén Román‐Ramos, Francisco Javier Alarcón-Aguilar, Jesús V. Hernández‐Rosado, Hermenegilda Moreno‐Díaz, Daniel Díaz‐Coutiño, Gabriel Navarrete‐Vázquez,

Metabolism, Diabetes, and Cancer

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 ( 1 H , 13 C ) 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 m RNA 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: T yr 473, H is 449, S er 289, H is 323; and peroxisome proliferator‐activated receptor α residues: T yr 464, H is 440, S er 280 and T yr 314.