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Novel Benzylidene Thiazolidinedione Derivatives as Partial PPAR? Agonists and their Antidiabetic Effects on Type 2 Diabetes.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPAR? and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPAR?. Furthermore, docking experiments revealed that BTZDs interact with PPAR? through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36?mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPAR? for further development in the clinical treatment of type 2 diabetes mellitus.

SUBMITTER: Yasmin S

PROVIDER: S-EPMC5663708 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Agonists and their Antidiabetic Effects on Type 2 Diabetes.

Yasmin Sabina S Capone Fabio F Laghezza Antonio A Piaz Fabrizio Dal FD Loiodice Fulvio F Vijayan Viswanathan V Devadasan Velmurugan V Mondal Susanta K SK Atlı Özlem Ö Baysal Merve M Pattnaik Ashok K AK Jayaprakash Venkatesan V Lavecchia Antonio A

Scientific reports 20171031 1

Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonan ...[more]

PMID: 29089569

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Project description:Peroxisome proliferator-activated receptor-γ (PPAR-γ) partial agonists or antagonists, also termed as selective PPAR-γ modulators, are more beneficial than full agonists because they can avoid the adverse effects associated with PPAR-γ full agonists, such as weight gain and congestive heart disorders, while retaining the antidiabetic efficiency. In this study, we designed and synthesized new benzylidene-thiazolidine-2,4-diones while keeping the acidic thiazolidinedione (TZD) ring at the center, which is in contrast with the typical pharmacophore of PPAR-γ agonists. Five compounds (5a-e) were designed and synthesized in moderate to good yields and were characterized using spectral techniques. The in vivo antidiabetic efficacy of the synthesized compounds was assessed on streptozotocin-induced diabetic mice using standard protocols, and their effect on weight gain was also studied. Molecular docking and molecular dynamics (MD) simulation studies were performed to investigate the binding interactions of the title compounds with the PPAR-γ receptor and to establish their binding mechanism. Antidiabetic activity results revealed that compounds 5d and 5e possess promising antidiabetic activity comparable with the standard drug rosiglitazone. No compound showed considerable effect on the body weight of animals after 21 days of administration, and the findings showed statistical difference (p < 0.05 to p < 0.0001) among the diabetic control and standard drug rosiglitazone groups. In molecular docking study, compounds 5c and 5d exhibited higher binding energies (- 10.1 and - 10.0 kcal/mol, respectively) than the native ligand, non-thiazolidinedione PPAR-γ partial agonist (nTZDpa) (- 9.8 kcal/mol). MD simulation further authenticated the stability of compound 5c-PPAR-γ complex over the 150 ns duration. The RMSD, RMSF, rGyr, SASA, and binding interactions of compound 5c-PPAR-γ complex were comparable to those of native ligand nTZDpa-PPAR-γ complex, suggesting that the title compounds have the potential to be developed as partial PPAR-γ agonists.

Dataset Information

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPAR? Agonists and their Antidiabetic Effects on Type 2 Diabetes.

Publications

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Agonists and their Antidiabetic Effects on Type 2 Diabetes.

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