title: Novel sulfonyl(thio)urea derivatives act efficiently both as insulin secretagogues and as insulinomimetic compounds.
abstract: Glibenclamide is widely used in the management of non-insulin dependent diabetes mellitus, but numerous risks limit its use in therapy. In the search for novel structures that are safer and more efficient than glibenclamide, we obtained new chemical analogs based on bioisosterism, through the treatment of benzenesulfonamide derivatives with isothiocyanates and isocyanates, affording (thio)ureas with good yield. We also verified the hypoglycemic activity, through an in vivo approach. Most of these synthesized compounds improved glucose tolerance, and the mechanism of action of the best compound (7) suggests that its effect is mediated by insulin secretion, while its hypoglycemic action is triggered by glucose uptake involving GLUT4 expression and translocation through PI-3K and PKA activity and active de novo protein synthesis in skeletal muscle. Taking all these factors together, sulfonylthiourea 7 acts as an insulin secretagogue and insulinomimetic agent on glucose homeostasis, and does not exhibit toxicity in acute treatment.
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Química, Centro de Ciências Físicas e Matemáticas, Campus Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Trindade, Cx. Postal 5069, 88040-970 Florianópolis, SC, Brazil.
authors.forename: Marisa Jádna Silva
authors.initials: MJ
authors.lastname: Frederico
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Trindade, Cx. Postal 5069, 88040-970 Florianópolis, SC, Brazil.
authors.forename: Alisson Jhonathan Gomes
authors.initials: AJ
authors.lastname: Castro
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Trindade, Cx. Postal 5069, 88040-970 Florianópolis, SC, Brazil.
authors.forename: Camila P
authors.initials: CP
authors.lastname: Mendes
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Campus Trindade, 88040-970 Florianópolis, SC, Brazil.
authors.forename: Márcio Ferreira
authors.initials: MF
authors.lastname: Dutra
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Ciências Morfológicas, Centro de Ciências Biológicas, Campus Trindade, Cx. Postal 5069, 88040-970 Florianópolis, SC, Brazil.
authors.forename: Viviane Mara
authors.initials: VM
authors.lastname: Woehl
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Química, Centro de Ciências Físicas e Matemáticas, Campus Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Trindade, Cx. Postal 5069, 88040-970 Florianópolis, SC, Brazil. Electronic address: mena.barreto@ufsc.br.
authors.forename: Fátima Regina
authors.initials: FR
authors.lastname: Mena Barreto Silva
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Química, Centro de Ciências Físicas e Matemáticas, Campus Trindade, 88040-900 Florianópolis, SC, Brazil. Electronic address: nunes@qmc.ufsc.br.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism* / Q000502:physiology; D000078790:Insulin Secretion; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds
keywords: Diabetes; Glibenclamide; Insulinomimetic; Sulfonylthioureas