title: 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.
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.
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca Mor., 62209, México.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Ramírez-Espinosa
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
authors.forename: Julio C
authors.initials: JC
authors.lastname: Almanza-Pérez
authors.forename: Rubén
authors.initials: R
authors.lastname: Román-Ramos
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Alarcón-Aguilar
authors.forename: Jesús V
authors.initials: JV
authors.lastname: Hernández-Rosado
authors.forename: Hermenegilda
authors.initials: H
authors.lastname: Moreno-Díaz
authors.forename: Daniel
authors.initials: D
authors.lastname: Díaz-Coutiño
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001463:Barbiturates / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D020134:Catalytic Domain; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D053778:Thiazolidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C583468:4'-((4-((Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl)phenoxy)methyl)-1,1'-biphenyl-2-carbonitrile; D001463:Barbiturates; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009570:Nitriles; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D053778:Thiazolidines; C500090:thiazolidine-2,4-dione; C032232:barbituric acid