title: In silico design, chemical synthesis and toxicological evaluation of 1,3-thiazolidine-2,4-dione derivatives as PPARγ agonists.
abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the metabolism of lipids and carbohydrates. The exogenous ligands of these receptors are thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus (DM2). However, drugs from this group produce adverse effects such as hepatic steatosis. Hence, the aim of this work was to design a set of small molecules that can activate the γ isoform of PPARs while minimizing the adverse effects. The derivatives were designed containing the polar head of TZD and an aromatic body, serving simultaneously as the body and tail. Two ligands were selected out of 130 tested. These compounds were synthesized in a solvent-free reaction and their physicochemical properties and toxicity were examined. Acute oral toxicity was determined by administering these compounds to female Wistar rats in increasing doses (as per the OECD protocol 425). The median lethal dose (LD50) of the compound substituted with a hydroxyl heteroatom was above 2000 mg/kg, and that of the compound substituted with halogens was 700-1400 mg/kg. The results suggest that the compounds can interact with PPARγ and elicit biological responses similar to other TZDs, but without showing adverse effects. The compounds will be subsequently evaluated in a DM2 animal model.
authors.affiliation: Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, 11340, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Alemán-González-Duhart
authors.affiliation: Laboratorio de Investigación en Bioquímica, Departamento de Formación Básica Disciplinaria y Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, 11340, Mexico. Electronic address: dr.felicianotamay@gmail.com.
authors.forename: Feliciano
authors.initials: F
authors.lastname: Tamay-Cach
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Ciudad de México, 11340, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Laboratorio de Investigación Química, Departamento de Ciencias Básicas, Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Av. Acueducto s/n, Barrio La Laguna Ticomán, Ciudad de México, 07340, Mexico.
authors.forename: Itzia Irene
authors.initials: II
authors.lastname: Padilla-Martínez
authors.affiliation: Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, 11340, Mexico.
authors.forename: Samuel
authors.initials: S
authors.lastname: Álvarez-Almazán
authors.affiliation: Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, 11340, Mexico. Electronic address: jesmenwej@yahoo.com.
authors.forename: Jessica Elena
authors.initials: JE
authors.lastname: Mendieta-Wejebe
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000633:toxicity*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000633:toxicity*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione
keywords: Acute toxicity; Chemical synthesis; In silico studies; PPARγ agonists; Thiazolidinedione