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.
© 2013 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3-L1 Cells
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Animals
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Barbiturates / chemistry*
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Barbiturates / pharmacology
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Binding Sites
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Blood Glucose / analysis
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Catalytic Domain
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Diabetes Mellitus, Experimental / drug therapy
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Drug Evaluation, Preclinical
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Glucose Transporter Type 4 / genetics
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Glucose Transporter Type 4 / metabolism
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Humans
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Hydrogen Bonding
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacology
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Hypoglycemic Agents / therapeutic use
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Male
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Mice
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Molecular Docking Simulation
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Nitriles / chemistry*
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Nitriles / pharmacology
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Nitriles / therapeutic use
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PPAR alpha / agonists
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PPAR alpha / genetics
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PPAR alpha / metabolism*
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PPAR gamma / agonists
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Thiazolidinediones / chemistry*
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Thiazolidinediones / pharmacology
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Thiazolidinediones / therapeutic use
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Thiazolidines / chemistry*
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Thiazolidines / pharmacology
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Thiazolidines / therapeutic use
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Transcription, Genetic / drug effects
Substances
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4'-((4-((Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl)phenoxy)methyl)-1,1'-biphenyl-2-carbonitrile
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Barbiturates
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Blood Glucose
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Glucose Transporter Type 4
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Hypoglycemic Agents
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Nitriles
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PPAR alpha
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PPAR gamma
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RNA, Messenger
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Thiazolidinediones
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Thiazolidines
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thiazolidine-2,4-dione
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barbituric acid