Abstract
Synthetic and binding affinity prediction studies of two sets of indolyl linked meta-substituted benzylidene containing 2,4-thiazolidinediones, diethylmalonates, and methyl acetoacetates-based compounds as novel PPAR ligands are reported. All the targets, except 8, were synthesized by condensation of 2,4-thiazolidinedone, diethyl malonate and methyl acetoacetate with the required 3-substituted benzaldehyde. The methyl acetoacetate-based benzylidene 8 was obtained by coupling of indolyl-sbstituted methanol with the corresponding 3-substituted phenol. The results of comparison of the binding modes of the synthesized compounds in the active sites of PPARα and PPARγ proteins to that of tesaglitazar are also discussed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Berger J, Moller DE (2002) The mechanisms of action of PPARS. Annu Rev Med 53:409–435
Cronet P, Petersen JF, Folmer R, Blomberg N, Sjoblom K, Karlsson U, Lindstedt EL, Bamberg K (2001) Structure of the PPAR alpha and gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure 9:699–706
Dropinski JF, Akiyama T, Einstein M, Habulihaz B, Doebber T, Berger JP, Meinke PT, Shi GQ (2005) Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARγ partial agonists. Bioorg Med Chem Lett 15:5035–5038
Fiévet C, Fruchart JC, Staels B (2006) PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Curr Opin Pharmacol 6:606
Galida–Dual PPAR agonist for type 2 diabetes and metabolic syndrome. http://www.drugdevelopment-technology.com
Hopkins CR, O’Neil SV, Laufersweiler MC, Wang Y, Pokross M, Mekel M, Evdokimov A, Walter R, Kontoyianni M, Petrey ME, Sabatakos G, Roesgen JT, Richardson E, Demuth TP (2006) Design and synthesis of novel N-sulfonyl-2-indole carboxamides as potent PPAR-gamma binding agents with potential application to the treatment of osteoporosis. Bioorg Med Chem Lett 16:5659
Karalliedde J, Buckingham RE (2007) Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. Drug Saf 30:741–753
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849
Kim NJ, Lee KO, Koo BW, Li F, Yoo JK, Park HJ, Min KH, Lim JI, Kim MK, Kimc JK, Suha YG (2007) Design, synthesis, and structure–activity relationship of carbamate-tethered aryl propanoic acids as novel PPARa/γ dual agonists. Bioorg Med Chem Lett 17:3595–3598
Li YY, Wu HS, Tang L, Feng CR, Yu JH, Li Y, Yang YS, Yang B, He QJ (2007) The potential insulin sensitizing and glucose lowering effects of a novel indole derivative in vitro and in vivo. Pharmacol Res 56:335–343
Liu K, Xu L, Berger JP, MacNaul KL, Zhou G, Doebber TW, Forrest MJ, Moller DE, Jones AB (2005) Discovery of a novel series of peroxisome proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes and dyslipidemia. J Med Chem 48:2262–2265
Mohler ML, He Y, Wu Z, Hwang DJ, Miller DD (2009) Recent and emerging antidiabetes targets. Med Res Rev 29:125–195
Moller DE (2001) New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414:821–827
Nissen SE, Wolski K, Topol EJ (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. J Am Med Assoc 294:2581
Sharma R (2008) Novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonists. J Clin Diagon Res 2:659–667
Suh YG, Kim NJ, Koo BW, Lee KO, Moon SH, Shin DH, Jung JW, Paek SM, Chang DJ, Li F, Kang HJ, Le TVT, Chae YN, Shin CY, Kim MK, Lim JI, Ryu JS, Park HJ (2008) Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor α and γ dual agonists. J Med Chem 51:6318–6333
Sybyl 7.3 (2006) Tripos Inc. 1699 Hanley Road, St. Louis 63144, USA
Verma RK, Ghosh P, Kumar V, Wadhwa LK (2012a) The application of comparative molecular field analysis for the design of α-anilino substituted-3-phenyl propanoic acids as novel PPARα/γ dual ligands. Med Chem Res 21:2873–2884
Verma RK, Kumar V, Ghosh P, Wadhwa LK (2012b) Heterocyclyl linked anilines and benzaldehydes as precursors for biologically significant new chemical entities. J Chem Sci 124:1063–1069
Verma RK, Kumar V, Ghosh P, Wadhwa LK (2013a) 3D-QSAR study of tyrosine and propanoic acid derivatives as PPARα/γ dual agonists using CoMSIA. Med Chem Res 22:287–302
Verma RK, Mall R, Ghosh P, Kumar V (2013b) Design and synthesis of benzimidazole linked meta-substituted benzylidienes/benzyls as biologically significant new chemical entities. Synth Commun 43:1882
Verma RK, Ghosh P, Kumar V, Wadhwa LK (2013c) Design, synthesis and computational validation of novel benzimidazole/indole-based PPARα and PPARγ partial agonists. J Chem Sci 125:1555–1571
Acknowledgments
We are thankful to the Punjabi University, Patiala authorities for providing the necessary research facilities. We are also grateful to the Director and Mr. Avtar Singh of Regional sophisticated Instrumentation Centre (RSIC), Panjab University, Chandigarh and Director National Institute of Pharmaceutical Sciences and Research (NIPER), SAS Nagar, Mohali, Punjab, respectively, for extending the facilities for spectral analysis of the compounds reported in this paper. The experimental and technical support provided by Dr. Prithwish Ghosh and Dr. Vijay Kumar is also acknowledged. One of the authors, Mr. Rajiv Mall, is thankful to the Ministry of Social Justice and Empowerment, Govt. of India for providing research fellowship.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Verma, R.K., Mall, R. & Singh, A. Indolyl linked meta-substituted benzylidene-based novel PPAR ligands: synthetic and docking studies. Med Chem Res 24, 1396–1407 (2015). https://doi.org/10.1007/s00044-014-1215-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-014-1215-6