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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Development of Novel Glitazones as Antidiabetic Agents: Molecular Design, Synthesis, Evaluation of Glucose Uptake Activity and SAR Studies

Author(s): Mahendra Gowdru Srinivas, Prabitha Prabhakaran, Subhankar Probhat Mandal, Yuvaraj Sivamani, Pranesh Guddur and Bommenahally Ravanappa Prashantha Kumar*

Volume 17 , Issue 7 , 2020

Page: [840 - 849] Pages: 10

DOI: 10.2174/1570180816666191105124535

Price: $65

Abstract

Background: Thiazolidinediones and its bioisostere, namely, rhodanines have become ubiquitous class of heterocyclic compounds in drug design and discovery. In the present study, as part of molecular design, a series of novel glitazones that are feasible to synthesize in our laboratory were subjected to docking studies against PPAR-γ receptor for their selection.

Methods and Results: As part of the synthesis of selected twelve glitazones, the core moiety, pyridine incorporated rhodanine was synthesized via dithiocarbamate. Later, a series of glitazones were prepared via Knovenageal condensation. In silico docking studies were performed against PPARγ protein (2PRG). The titled compounds were investigated for their cytotoxic activity against 3T3-L1 cells to identify the cytotoxicity window of the glitazones. Further, within the cytotoxicity window, glitazones were screened for glucose uptake activity against L6 cells to assess their possible antidiabetic activity.

Conclusion: Based on the glucose uptake results, structure activity relationships are drawn for the title compounds.

Keywords: Rhodanines, glitazones, Type 2 diabetes mellitus, glucose uptake, L6 cells, SAR.

Graphical Abstract
[1]
Guilherme, A.; Virbasius, J.V.; Puri, V.; Czech, M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol., 2008, 9(5), 367-377.
[http://dx.doi.org/10.1038/nrm2391] [PMID: 18401346]
[2]
Kahn, S.E. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia, 2003, 46(1), 3-19.
[http://dx.doi.org/10.1007/s00125-002-1009-0] [PMID: 12637977]
[3]
Tontonoz, P.; Spiegelman, B.M. Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem., 2008, 77(77), 289-312.
[http://dx.doi.org/10.1146/annurev.biochem.77.061307.091829] [PMID: 18518822]
[4]
Spiegelman, B.M. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes, 1998, 47(4), 507-514.
[http://dx.doi.org/10.2337/diabetes.47.4.507] [PMID: 9568680]
[5]
Liao, W.; Nguyen, M.T.; Yoshizaki, T.; Favelyukis, S.; Patsouris, D.; Imamura, T.; Verma, I.M.; Olefsky, J.M. Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab., 2007, 293(1), E219-E227.
[http://dx.doi.org/10.1152/ajpendo.00695.2006] [PMID: 17389706]
[6]
Lehmann, J.M.; Moore, L.B.; Smith-Oliver, T.A.; Wilkison, W.O.; Willson, T.M.; Kliewer, S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem., 1995, 270(22), 12953-12956.
[http://dx.doi.org/10.1074/jbc.270.22.12953] [PMID: 7768881]
[7]
Alegaon, S.G.; Alagawadi, K.R.; Sonkusare, P.V.; Chaudhary, S.M.; Dadwe, D.H.; Shah, A.S. Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents. Bioorg. Med. Chem. Lett., 2012, 22(5), 1917-1921.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.052] [PMID: 22325950]
[8]
Üngören, Ş.H.; Albayrak, S.; Guenay, A.; Yurtseven, L.; Yurttaş, N. A new method for the preparation of 5-acylidene and 5-imino substituted rhodanine derivatives and their antioxidant and antimicrobial activities Tetrahedron, 2015, 24, 71(25), 4312-23.
[9]
Bhatti, R.S.; Shah, S. ; Suresh, Krishan, P..; Sandhu,. J.S Recent pharmacological developments on rhodanines and 2,4- thiazolidinediones Int. J. Med. Chem., 2013, 2013793260
[10]
Mandal, S.P.; Garg, A.; Sahetya, S.S.; Nagendra, S.R.; Sripad, H.S.; Manjunath, M.M.; Soni, M.; Baig, R.N.; Kumar, S.V.; Kumar, B.P. Novel rhodanines with anticancer activity: Design, synthesis and CoMSIA study. RSC Advances, 2016, 6(63), 58641-58653.
[http://dx.doi.org/10.1039/C6RA08785J]
[11]
Bhattarai, B.R.; Kafle, B.; Hwang, J.S.; Khadka, D.; Lee, S.M.; Kang, J.S.; Ham, S.W.; Han, I.O.; Park, H.; Cho, H. Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects. Bioorg. Med. Chem. Lett., 2009, 19(21), 6161-6165.
[http://dx.doi.org/10.1016/j.bmcl.2009.09.020] [PMID: 19783142]
[12]
Chauhan, K.; Sharma, M.; Saxena, J.; Singh, S.V.; Trivedi, P.; Srivastava, K.; Puri, S.K.; Saxena, J.K.; Chaturvedi, V.; Chauhan, P.M. Synthesis and biological evaluation of a new class of 4-aminoquinoline-rhodanine hybrid as potent anti-infective agents. Eur. J. Med. Chem., 2013, 62, 693-704.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.017] [PMID: 23454512]
[13]
Sarafidis, P.A. Thiazolidinedione derivatives in diabetes and cardiovascular disease: an update. Fundam. Clin. Pharmacol., 2008, 22(3), 247-264.
[http://dx.doi.org/10.1111/j.1472-8206.2008.00568.x] [PMID: 18422634]
[14]
Stolar, M.W.; Chilton, R.J. Type 2 diabetes, cardiovascular risk, and the link to insulin resistance. Clin. Ther., 2003, 25(25)(Suppl. B), B4-B31.
[http://dx.doi.org/10.1016/S0149-2918(03)80240-0] [PMID: 14553864]
[15]
Lebovitz, H.E. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab. Res. Rev., 2002, 18(S2)(Suppl. 2), S23-S29.
[http://dx.doi.org/10.1002/dmrr.252] [PMID: 11921435]
[16]
Kar, K.; Krithika, U. Mithuna; Basu, P.; Santhosh Kumar, S.; Reji, A.; Prashantha Kumar, B.R. Design, synthesis and glucose uptake activity of some novel glitazones. Bioorg. Chem., 2014, 56(56), 27-33.
[http://dx.doi.org/10.1016/j.bioorg.2014.05.006] [PMID: 24927033]
[17]
Zidar, N.; Tomasić, T.; Šink, R.; Rupnik, V.; Kovac, A.; Turk, S.; Patin, D.; Blanot, D.; Contreras Martel, C.; Dessen, A.; Müller Premru, M.; Zega, A.; Gobec, S.; Peterlin Masic, L.; Kikelj, D. Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase. J. Med. Chem., 2010, 53(18), 6584-6594.
[http://dx.doi.org/10.1021/jm100285g] [PMID: 20804196]
[18]
Tomasić, T.; Zidar, N.; Mueller-Premru, M.; Kikelj, D.; Mašič, L.P. Synthesis and antibacterial activity of 5-ylidenethiazolidin-4-ones and 5-benzylidene-4,6-pyrimidinediones. Eur. J. Med. Chem., 2010, 45(4), 1667-1672.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.030] [PMID: 20060624]
[19]
Tomašić, T.; Kovač, A.; Simčič, M.; Blanot, D.; Grdadolnik, S.G.; Gobec, S.; Kikelj, D.; Peterlin Mašič, L. Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting D-Glu- and diphosphate-binding sites. Eur. J. Med. Chem., 2011, 46(9), 3964-3975.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.070] [PMID: 21703731]
[20]
Kudoh, A.; Satoh, H.; Hirai, H.; Watanabe, T. Pioglitazone upregulates adiponectin receptor 2 in 3T3-L1 adipocytes. Life Sci., 2011, 88(23-24), 1055-1062.
[http://dx.doi.org/10.1016/j.lfs.2011.04.001] [PMID: 21514306]
[21]
Sargeant, R.J.; Pâquet, M.R. Effect of insulin on the rates of synthesis and degradation of GLUT1 and GLUT4 glucose transporters in 3T3-L1 adipocytes. Biochem. J., 1993, 290(Pt 3), 913-919.
[http://dx.doi.org/10.1042/bj2900913] [PMID: 8457217]
[22]
Yap, A.; Nishiumi, S.; Yoshida, K.; Ashida, H. Rat L6 myotubes as an in vitro model system to study GLUT4-dependent glucose uptake stimulated by inositol derivatives. Cytotechnology, 2007, 55(2-3), 103-108.
[http://dx.doi.org/10.1007/s10616-007-9107-y] [PMID: 19002999]
[23]
Clark, M.; Cramer, R.D., III; Van Opdenbosch, N. Validation of the general purpose Tripos 5.2 force field. J. Comput. Chem., 1989, 10(8), 982-1012.
[http://dx.doi.org/10.1002/jcc.540100804]
[24]
Tosco, P.; Stiefl, N.; Landrum, G. Bringing the MMFF force field to the RDKit: Implementation and validation. J. Cheminform., 2014, 6(1), 37.
[http://dx.doi.org/10.1186/s13321-014-0037-3]
[25]
Gasteiger, J.; Hutchings, M.G. New empirical models of substituent polarisability and their application to stabilisation effects in positively charged species. Tetrahedron Lett., 1983, 24(25), 2537-2540.
[http://dx.doi.org/10.1016/S0040-4039(00)81975-9]
[26]
Gasteiger, J.; Marsili, M. A new model for calculating atomic charges in molecules. Tetrahedron Lett., 1978, 19(34), 3181-3184.
[http://dx.doi.org/10.1016/S0040-4039(01)94977-9]
[27]
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron, 1980, 36(22), 3219-3228.
[http://dx.doi.org/10.1016/0040-4020(80)80168-2]
[28]
Zhang, C.H.; Xu, G.L.; Liu, Y.H.; Rao, Y.; Yu, R.Y.; Zhang, Z.W.; Wang, Y.S.; Tao, L. Anti-diabetic activities of Gegen Qinlian Decoction in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes. Phytomedicine, 2013, 20(3-4), 221-229.
[http://dx.doi.org/10.1016/j.phymed.2012.11.002] [PMID: 23219338]
[29]
Moyers, J.S.; Bilan, P.J.; Reynet, C.; Kahn, C.R. Overexpression of Rad inhibits glucose uptake in cultured muscle and fat cells. J. Biol. Chem., 1996, 271(38), 23111-23116.
[http://dx.doi.org/10.1074/jbc.271.38.23111] [PMID: 8798502]

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