Novel Cinnamic Acid Derivatives as Potential PPARδ Agonists for Metabolic Syndrome: Design, Synthesis, Evaluation and Docking Studies

Author(s): Ajay Chauhan, Ajmer S. Grewal*, Deepti Pandita, Viney Lather

Journal Name: Current Drug Discovery Technologies

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background: Peroxisome proliferator-activated receptor (PPAR) δ is expressed universally in the entire tissues, particularly in those concerned with the lipid metabolism. PPAR δ stimulation alters body’s energy fuel preference to fat from glucose and shows up as an emerging pharmacological target for the treatment of metabolic disorders.

Methods: A new series of cinnamic acid derivatives was synthesized and evaluated for the antidiabetic and antiinflammatory activities in the animal models followed by in silico docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPARδ protein.

Results: Amongst the synthesized molecules, compound 3 showed higher antidiabetic activity in oral glucose tolerance test and compound 1 showed higher antiinflammatory activity in the carrageenan induced rat paw oedema method. The in vivo study results were supported by the similar in silico molecular docking results. Most of the synthesized derivatives showed drug likeness as depicted via Lipinski’s rule of 5.

Conclusion: These molecules can serve as the early hit molecules for the discovery of safe, effective and bioavailable PPARδ agonists for the potential treatment of various metabolic disorders.

Keywords: Cinnamic acid derivatives, diabetes mellitus, inflammation, metabolic syndrome, PPARδ agonists, docking.

Bragt MC, Popeijus HE. Peroxisome proliferator-activated receptors and the metabolic syndrome. Physiol Behav 2008; 94(2): 187-97.
[] [PMID: 18191967]
Boitier E, Gautier JC, Roberts R. Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease. Comp Hepatol 2003; 2(1): 3.
[] [PMID: 12622871]
Duval C, Chinetti G, Trottein F, Fruchart JC, Staels B. The role of PPARs in atherosclerosis. Trends Mol Med 2002; 8(9): 422-30.
[] [PMID: 12223313]
Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000; 43(4): 527-50.
[] [PMID: 10691680]
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409-35.
[] [PMID: 11818483]
Ferré P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53(Suppl. 1): S43-50.
[] [PMID: 14749265]
Schoonjans K, Martin G, Staels B, Auwerx J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997; 8(3): 159-66.
[] [PMID: 9211064]
Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2011; 2(4): 236-40.
[] [PMID: 22247890]
Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med 2004; 10(4): 355-61.
[] [PMID: 15057233]
Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm 2013; 2013549627
[] [PMID: 23781121]
Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J 2014; 13: 17.
[] [PMID: 24524207]
Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006; 116(3): 590-7.
[] [PMID: 16511591]
Rosenson RS, Wright RS, Farkouh M, Plutzky J. Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects. Am Heart J 2012; 164(5): 672-80.
[] [PMID: 23137497]
Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003; 144(6): 2201-7.
[] [PMID: 12746275]
Gilde AJ, Van Bilsen M. Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 2003; 178(4): 425-34.
[] [PMID: 12864748]
Reilly SM, Lee CH. PPAR δ as a therapeutic target in metabolic disease. FEBS Lett 2008; 582(1): 26-31.
[] [PMID: 18036566]
Choi KM. Peroxisome Proliferator Activated Receptor-δ (PPAR-δ). J Korean Diabetes Assoc 2007; 31: 297-301.
Mackenzie LS, Lione L. Harnessing the benefits of PPARβ/δ agonists. Life Sci 2013; 93(25-26): 963-7.
[] [PMID: 24184294]
Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res 2005; 51(2): 85-94.
[] [PMID: 15629253]
Takahashi S, Tanaka T, Sakai J. New therapeutic target for metabolic syndrome: PPARdelta. Endocr J 2007; 54(3): 347-57.
[] [PMID: 17409576]
Sznaidman ML, Haffner CD, Maloney PR, et al. Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARdelta)--synthesis and biological activity. Bioorg Med Chem Lett 2003; 13(9): 1517-21.
[] [PMID: 12699745]
Ham J, Kang H. A highly efficient synthesis of antiobestic ligand GW501516 for the peroxisome proliferator-activated receptor δ through in situ protection of the phenol group by reaction with a Grignard reagent. Tetrahedron Lett 2005; 46: 6683-6.
Grewal AS, Beniwal M, Pandita D, Sekhon BS, Lather V. Recent updates on peroxisome proliferator-activated receptor δ agonists for the treatment of metabolic syndrome. Med Chem 2016; 12 03- 21.
Grewal AS, Lather V, Pandita D, Bhayana G. Synthesis, docking and biological evaluation of phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPARδ agonists. Lett Drug Des Discov 2017; 14: 1239-51.
Ahmed MF, Kazim SM, Ghori SS, et al. Antidiabetic activity of Vincarosea extracts in alloxan-induced diabetic rats. Int J Endocrinol 2010; 2010841090
[] [PMID: 20652054]
Tiwari D, Haque S, Mishra S, Chandra R. Synthesis and pharmacological screening of N-substituted anthranilic acid derivatives. Int J Drug Develop Res 2011; 3: 265-71.
Mane BY, Vidyadhara S. Synthesis and screening of antiinflammatory activity of benzofuran derivatives bearing oxadiazole. Orient J Chem 2011; 27: 1227-31.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[] [PMID: 19399780]
Miteva MA, Guyon F, Tufféry P. Frog2: Efficient 3D conformation ensemble generator for small compounds Nucleic Acids Res 2010. 38(Web Server issue)W622-7
[] [PMID: 20444874]
Grewal AS, Lather V, Pandita D, Dalal R. Synthesis, docking and antiinflammatory activity of triazole amine derivatives as potential phosphodiesterase-4 inhibitors. Antiinflamm Antiallergy Agents Med Chem 2017; 16(1): 58-67.
[PMID: 28618988]
Charaya N, Pandita D, Grewal AS, Lather V. Design, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators. Comput Biol Chem 2018; 73: 221-9.
[] [PMID: 29518630]
Rathee D, Lather V, Grewal AS, Dureja H. Targeting matrix metalloproteinases with novel diazepine substituted cinnamic acid derivatives: design, synthesis, in vitro and in silico studies. Chem Cent J 2018; 12(1): 41.
[] [PMID: 29679218]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 15 July, 2020
Page: [338 - 347]
Pages: 10
DOI: 10.2174/1570163816666190314124543
Price: $65

Article Metrics

PDF: 26