Journal of Diabetes & Metabolism

ISSN - 2155-6156


In silico design, synthesis and toxicological evaluation of 1,3-thiazolidine-2,4-dione derivatives as PPARγ agonists

14th International Conference and Exhibition on Targeting Diabetes and Novel Therapeutics

October 17-18, 2016 Kuala Lumpur, Malaysia

Diana Aleman G D, Feliciano Tamay C, Samuel Alvarez A and Jessica E Mendieta W

Instituto Politecnico Nacional, Mexico

: J Diabetes Metab

Abstract :

Thiazolidinediones (TZD) are ligands for PPARγ used for the treatment of type 2 diabetes mellitus (DM2), though, drugs from this group have been shown to produce hepatic toxicity. The aim of this work was 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. 130 derivatives were designed. 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 and 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, in a solvent free reaction. The products were identified using spectroscopic techniques. Acute oral toxicity was performed as per OECD 425 guideline (up & down method) using healthy female albino Wistar rats. It was found that the compounds were in accordance with Lipinski??s rule of five and none of them were toxic according to the predictions. In the 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 proposed methodology was optimal for obtaining the desired products. 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.

Biography :

Diana Aleman G D is a Mexican researcher focused on the development of new drugs targeting the nuclear receptor PPARγ for the treatment of diabetes and metabolic syndrome. She completed her Bachelor’s Degree in Optometry at the Interdisciplinary Health Sciences Center from the National Polytechnic Institute, then, she got a Master’s Degree in Pharmacology and a PhD in Biochemical Research, both at the School of Medicine from the National Polytechnic Institute in Mexico City. Since 2009, she has been a professor in anatomy, pharmacology and physiology for public and private universities in Mexico City.

Email: [email protected]