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
- 21 March 2013
- journal article
- Published by Wiley in Chemical Biology & Drug Design
- Vol. 81 (4), 474-483
- https://doi.org/10.1111/cbdd.12102
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 ((1)H, (13)C) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ 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 α and peroxisome proliferator-activated receptor γ. 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 γ 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.Keywords
This publication has 23 references indexed in Scilit:
- Medicinal Chemistry and Actions of Dual and Pan PPAR ModulatorsThe Open Medicinal Chemistry Journal, 2011
- A comparative study of flavonoid analogues on streptozotocin–nicotinamide induced diabetic rats: Quercetin as a potential antidiabetic agent acting via 11β-Hydroxysteroid dehydrogenase type 1 inhibitionEuropean Journal of Medicinal Chemistry, 2010
- Prediction of Human Drug-Drug Interactions from Time-Dependent Inactivation of CYP3A4 in Primary Hepatocytes Using a Population-Based SimulatorDrug Metabolism and Disposition, 2009
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- New PPARγ ligands based on barbituric acid: Virtual screening, synthesis and receptor binding studiesBioorganic & Medicinal Chemistry Letters, 2008
- Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3-L1 cellsEuropean Journal of Pharmacology, 2008
- Antidiabetic activity of N-(6-substituted-1,3-benzothiazol-2-yl)benzenesulfonamidesBioorganic & Medicinal Chemistry Letters, 2008
- PPAR dual agonists: Are they opening Pandora's Box?Pharmacological Research, 2007
- Tesaglitazar: A promising approach in type 2 diabetesDrugs of Today, 2006
- The PPARs: From Orphan Receptors to Drug DiscoveryJournal of Medicinal Chemistry, 2000