TY - JOUR
T1 - In silico design, chemical synthesis and toxicological evaluation of 1,3-thiazolidine-2,4-dione derivatives as PPARγ agonists
AU - Alemán-González-Duhart, Diana
AU - Tamay-Cach, Feliciano
AU - Correa-Basurto, José
AU - Padilla-Martínez, Itzia Irene
AU - Álvarez-Almazán, Samuel
AU - Mendieta-Wejebe, Jessica Elena
N1 - Publisher Copyright:
© 2017
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - Acute toxicity
KW - Chemical synthesis
KW - In silico studies
KW - PPARγ agonists
KW - Thiazolidinedione
UR - http://www.scopus.com/inward/record.url?scp=85013826962&partnerID=8YFLogxK
U2 - 10.1016/j.yrtph.2017.02.008
DO - 10.1016/j.yrtph.2017.02.008
M3 - Artículo
C2 - 28202347
SN - 0273-2300
VL - 86
SP - 25
EP - 32
JO - Regulatory Toxicology and Pharmacology
JF - Regulatory Toxicology and Pharmacology
ER -