Design, synthesis, in silico molecular docking and biological evaluation of novel oxadiazole based thiazolidine-2,4-diones bis-heterocycles as PPAR-γ agonists

Syed Nazreen; Mohammad Sarwar Alam; Hinna Hamid; Mohammad Shahar Yar; Syed Shafi; Abhijeet Dhulap; Perwez Alam; M A Q Pasha; Sameena Bano; Mohammad Mahboob Alam; Saqlain Haider; Yakub Ali; Chetna Kharbanda; K K Pillai

doi:10.1016/j.ejmech.2014.09.010

Design, synthesis, in silico molecular docking and biological evaluation of novel oxadiazole based thiazolidine-2,4-diones bis-heterocycles as PPAR-γ agonists

Eur J Med Chem. 2014 Nov 24:87:175-85. doi: 10.1016/j.ejmech.2014.09.010. Epub 2014 Sep 16.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
² Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India. Electronic address: msalam@jamiahamdard.ac.in.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
⁴ CSIR Unit for Research and Development of Information Products, Pune 411038, India.
⁵ Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India.
⁶ Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University) New Delhi 110 062, India.

PMID: 25255433
DOI: 10.1016/j.ejmech.2014.09.010

Abstract

A library of novel 1,3,4-oxadiazole and 2-4-thiazolidinedione based bis-heterocycles 7 (a-r) has been synthesized which exhibited significant PPAR-γ transactivation and blood glucose lowering effect comparable with the standard drugs Pioglitazone and Rosiglitazone. Compounds 7m and 7r did not cause body weight gain and were found to be free from hepatotoxic and cardiotoxic side effects. Compounds 7m and 7r increased PPAR-γ gene expression by 2.10 and 2.00 folds, respectively in comparison to the standard drugs Pioglitazone (1.5 fold) and Rosiglitazone (1.0 fold). Therefore the compounds 7m and 7r may be considered as potential candidates for development of new antidiabetic agents.

Keywords: 1,3,4-Oxadiazole; 2,4-Thiazolidinedione; Antidiabetic; Cardiotoxicity; Hepatotoxicity; PPAR-γ.

Publication types

Comparative Study
Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / analysis
Computer Simulation
Diabetes Mellitus, Experimental / drug therapy*
Drug Design*
Female
Gene Expression Regulation
Glucose Tolerance Test
HEK293 Cells
Humans
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / pharmacology*
Liver / drug effects
Liver / metabolism
Liver / pathology
Male
Molecular Docking Simulation
Molecular Structure
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
PPAR gamma / agonists*
Pioglitazone
RNA, Messenger / genetics
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Rosiglitazone
Structure-Activity Relationship
Thiazolidinediones / chemistry*
Thiazolidinediones / pharmacology

Substances

Blood Glucose
Hypoglycemic Agents
Oxadiazoles
PPAR gamma
RNA, Messenger
Thiazolidinediones
thiazolidine-2,4-dione
Rosiglitazone
1,3,4-oxadiazole
Pioglitazone