In Silico Design, Synthesis, and Toxicological Evaluation of 1,3‐Thiazolidine‐2,4‐dione Derivatives as PPARγ Agonists
Authors: Alemán Diana , Tamay Feliciano , Correa José , Fragoso Jonathan , Wejebe Jessica Mendieta 
Published: November 2023

Peroxisome proliferator‐activated receptors (PPAR) are nuclear receptors which regulate gene expression, mainly in the metabolism of lipids and carbohydrates. The γ isotype has as exogenous ligands the thiazolidinediones (TZD), which are used for the treatment of type 2 diabetes mellitus (DM2), though, drugs from this group have been shown to produce severe adverse effects such as hepatic steatosis and massive weight gain. Since this, the aim of this work is to design a new set of molecules based on the substitution of TZD with electro donating and electro withdrawing heteroatoms, which might activate the PPARγ while minimizing the adverse effects.

One hundred and thirty derivatives where design and drawn using Chemdraw 3.0. The derivatives contained the polar head of TZD and an aromatic body which served simultaneously as the body and the tail.

The physicochemical properties of the derivatives were evaluated using the Molinspiration software. Later, a toxicity prediction was made using the software Osiris Property Explorer. Additionally, docking studies were carried out using Autodock 4.0.

Two ligands were selected in order to synthesize them through a Knoevenagel condensation, using the polar head of TZD and the corresponding aromatic aldehydes in a solvent free reaction. The products were identified using spectroscopic techniques such as infrared (IR), nuclear magnetic resonance (RMN, 1H and C 13) and mass spectroscopy (MS).

Acute oral toxicity was performed as per OECD (Organization of Economic Cooperation and Development) 425 guideline (Up & Down method) using healthy female albino Wistar rats. The animals were administered orally with increasing doses in a 0.5 progression factor, starting at 175 mg/kg.

It was found that the compounds are in accordance with Lipinki's rule of 5, so as with the considerations made by Veber et al., it was also found that none of the compounds are toxic according to the parameters of mutagenicity, teratogenicity, carcinogenesis, and reproductive effects. According to docking results, the interaction of the ligands was more likely when the derivatives were substituted with electro withdrawing heteroatoms since these enhanced the formation of hydrogen bonding between the head of compound and the ligand binding domain (LBD), leading to the selection of the best two compounds to be synthetized, which will be further mentioned as C40 and C81. C40 consists of the polar head and salycilaldehyde, while C81 consists of the polar head and chlorofluorobenzaldehyde. The results mentioned above suggest that, besides of interacting with the LBD, they will probably not show any adverse effects.

Regarding to the chemical synthesis, the proposed methodology was optimal for obtaining the desired products, being more likely to obtain C40 since it is substituted with and electro donating heteroatom, enhancing a nucleophilic attack, which leads to an easy, short‐timed and high yield reaction, rather than C81 which is substituted with two electro withdrawing heteroatoms, which favored the dehydration of the molecule and increase the reaction time giving a low yield. The compounds were obtained with a yield of 98% and 67%, respectively.

According to the toxicity study, it was found that C40 had a LD50 above 2000 mg/kg, while C81 had a LD50 between 700 and 1400 mg/kg.

It is suggested that the proposed compounds will have a good interaction with PPARγ, so as they will not have any adverse effects. The synthetized products will be further evaluated in an animal DM2 model.

Support or Funding Information

Funding source:

CONAYT IO10/0532/2014, BEIFI‐SIP‐COFAA 20150946 & 20150322.