Novel Hybrids of Pyrazolidinedione and Benzothiazole as TZD Analogues. Rationale Design, Synthesis and In Vivo Anti-Diabetic Evaluation

Author(s): Michelyne Haroun* .

Journal Name: Medicinal Chemistry

Volume 15 , Issue 6 , 2019

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Abstract:

Background: The development of new classes of blood glucose–lowering medications has increased the number of treatment opportunities available for type 2 diabetes. Nevertheless, long term complicated treatments and side effects of available antidiabetic therapies have urged huge demands for effective affordable anti-diabetic agents that can lessen negative health consequences. In this sense, the exploration of alternative medicinal remedies associated with new significant antidiabetic efficiencies with minimized adverse effects is an active domain of research.

Objective: The aim of this study was to synthesize a series of benzothiazole-pyrazolidinedione hybrids and evaluate their antidiabetic activity along with molecular docking and in silico analysis.

Methods: The hybrids were synthesized by a multi-step synthesis and were further subjected for in vivo anti-hyperglycemic assessment on rat models of type II diabetes. Molecular modelling study was undertaken against peroxisome proliferator-activated receptor γ (PPARγ) to highlight possible key interactions.

Results: Docking studies revealed that appropriate substituents on benzothiazole ring interacted favorably with the hydrophobic Ω-pocket of PPARγ binding site resulting in improving their antihyperglycemic activity. All the synthesized hybrids manifested promising anti-hyperglycemic potency. Excitingly, 5a, 5b and 5c were even more potent than the standard drug.

Conclusion: The newly synthesized hybrids can be considered as a new class of antidiabetic agents and this study provided useful information on further optimization.

Keywords: Benzothiazole, Pyrazolidinedione, PPARgamma, Ligand binding domain: Ω-loop, Molecular modeling, Antihyperglycemic activity.

[1]
Forouhi, N.G.; Misra, A.; Mohan, V.; Taylor, R.; Yancy, W. Dietary and nutritional approaches for prevention and management of type 2 diabetes. BMJ, 2018, 361, k2234.
[http://dx.doi.org/10.1136/bmj.k2234] [PMID: 29898883]
[2]
Baynes, H.W. Classification, pathophysiology, diagnosis and management of diabetes mellitus. J. Diabetes Metab., 2015, 6(5), 1-9.
[3]
Chen, C.; Cohrs, C.M.; Stertmann, J.; Bozsak, R.; Speier, S. Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol. Metab., 2017, 6(9), 943-957.
[http://dx.doi.org/10.1016/j.molmet.2017.06.019] [PMID: 28951820]
[4]
Oh, Y.S.; Bae, G.D.; Baek, D.J.; Park, E.Y.; Jun, H.S. Fatty acid-induced lipotoxicity in pancreatic Beta-cells during development of type 2 diabetes. Front. Endocrinol., 2018, 9, 384.
[http://dx.doi.org/10.3389/fendo.2018.00384] [PMID: 30061862]
[5]
Chawla, A.; Chawla, R.; Jaggi, S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J. Endocrinol. Metab., 2016, 20(4), 546-551.
[http://dx.doi.org/10.4103/2230-8210.183480] [PMID: 27366724]
[6]
Chew, B-H.; Fernandez, A.; Shariff-Ghazali, S. Psychological interventions for behavioral adjustments in diabetes care - a value-based approach to disease control. Psychol. Res. Behav. Manag., 2018, 11, 145-155.
[http://dx.doi.org/10.2147/PRBM.S117224] [PMID: 29765258]
[7]
Tratrat, C.; Haroun, M.; Paparisva, A.; Geronikaki, A.; Kamoutsis, C.; Ćirić, A.; Glamočlija, J.; Soković, M.; Fotakis, C.; Zoumpoulakis, P.; Bhunia, S.S.; Saxena, A.K. Design, synthesis and biological evaluation of new substituted 5-benzylideno-2-adamantylthiazol[3,2-b] [1,2,4] triazol-6(5H) ones. Pharmacophore models for antifungal activity. Arab. J. Chem., 2018, 11(4), 573-590.
[http://dx.doi.org/10.1016/j.arabjc.2016.06.007]
[8]
Choudhury, H.; Pandey, M.; Hua, C.K.; Mun, C.S.; Jing, J.K.; Kong, L.; Ern, L.Y.; Ashraf, N.A.; Kit, S.W.; Yee, T.S.; Pichika, M.R.; Gorain, B.; Kesharwani, P. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J. Tradit. Complement. Med., 2017, 8(3), 361-376.
[http://dx.doi.org/10.1016/j.jtcme.2017.08.012] [PMID: 29992107]
[9]
Garcia-Vallvé, S.; Guasch, L.; Tomas-Hernández, S.; del Bas, J.M.; Ollendorff, V.; Arola, L.; Pujadas, G.; Mulero, M. Peroxisome proliferator-activated receptor γ (PPARγ) and ligand choreography: Newcomers take the stage. J. Med. Chem., 2015, 58(14), 5381-5394.
[http://dx.doi.org/10.1021/jm501155f] [PMID: 25734377]
[10]
Soccio, R.E.; Chen, E.R.; Lazar, M.A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab., 2014, 20(4), 573-591.
[http://dx.doi.org/10.1016/j.cmet.2014.08.005] [PMID: 25242225]
[11]
He, J.; Xu, C.; Kuang, J.; Liu, Q.; Jiang, H.; Mo, L.; Geng, B.; Xu, G. Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance. Metabolism, 2015, 64(7), 826-836.
[http://dx.doi.org/10.1016/j.metabol.2015.02.005] [PMID: 25825274]
[12]
Medicine, U.P.S.O. Using genetics of human fat cells to predict response to anti-diabetes drugs: Study shows that individual genetic variation affects which meds to take. In: ; ScienceDaily, 2019.
[13]
Fukunaga, T.; Zou, W.; Rohatgi, N.; Colca, J.R.; Teitelbaum, S.L. An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss. J. Bone Miner. Res., 2015, 30(3), 481-488.
[http://dx.doi.org/10.1002/jbmr.2364]
[14]
Hong, F.; Xu, P.; Zhai, Y. The opportunities and challenges of peroxisome proliferator-activated receptors ligands in clinical drug discovery and development. Int. J. Mol. Sci., 2018, 19(8)E2189
[15]
Alemán-González-Duhart, D.; Tamay-Cach, F.; Álvarez-Almazán, S.; Mendieta-Wejebe, J.E. Current advances in the biochemical and physiological aspects of the treatment of type 2 diabetes mellitus with thiazolidinediones. PPAR Res., 2016, 2016, 7614270-7614270.
[http://dx.doi.org/10.1155/2016/7614270] [PMID: 27313601]
[16]
Tucker, M.E. FDA lifts final regulatory restrictions on Rosiglitazone; Medscape, 2015.
[17]
Lee, M.A.; Tan, L.; Yang, H. Im, Y.G.; Im, Y.J. Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs. Sci. Rep., 2017, 7(1), 16837.
[http://dx.doi.org/10.1038/s41598-017-17082-x] [PMID: 29203903]
[18]
Jang, J.Y.; Bae, H.; Lee, Y.J.; Choi, Y.I.; Kim, H-J.; Park, S.B.; Suh, S.W.; Kim, S.W.; Han, B.W. Structural basis for the enhanced anti-diabetic efficacy of Lobeglitazone on PPARγ. Sci. Rep., 2018, 8(1), 31.
[http://dx.doi.org/10.1038/s41598-017-18274-1] [PMID: 29311579]
[19]
Ohashi, M.; Oyama, T.; Putranto, E.W.; Waku, T.; Nobusada, H.; Kataoka, K.; Matsuno, K.; Yashiro, M.; Morikawa, K.; Huh, N.H.; Miyachi, H. Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility. Bioorg. Med. Chem., 2013, 21(8), 2319-2332.
[http://dx.doi.org/10.1016/j.bmc.2013.02.003] [PMID: 23490155]
[20]
Ohashi, M.; Gamo, K.; Oyama, T.; Miyachi, H. Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations. Bioorg. Med. Chem. Lett., 2015, 25(14), 2758-2762.
[http://dx.doi.org/10.1016/j.bmcl.2015.05.025] [PMID: 26025876]
[21]
Shinozuka, T.; Tsukada, T.; Fujii, K.; Tokumaru, E.; Shimada, K.; Onishi, Y.; Matsui, Y.; Wakimoto, S.; Kuroha, M.; Ogata, T.; Araki, K.; Ohsumi, J.; Sawamura, R.; Watanabe, N.; Yamamoto, H.; Fujimoto, K.; Tani, Y.; Mori, M.; Tanaka, J. Discovery of DS-6930, a potent selective PPARγ modulator. Part I: Lead identification. Bioorg. Med. Chem., 2018, 26(18), 5079-5098.
[http://dx.doi.org/10.1016/j.bmc.2018.09.006] [PMID: 30241907]
[22]
Connors, R.V.; Wang, Z.; Harrison, M.; Zhang, A.; Wanska, M.; Hiscock, S.; Fox, B.; Dore, M.; Labelle, M.; Sudom, A.; Johnstone, S.; Liu, J.; Walker, N.P.; Chai, A.; Siegler, K.; Li, Y.; Coward, P. Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma. Bioorg. Med. Chem. Lett., 2009, 19(13), 3550-3554.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.151] [PMID: 19464171]
[23]
Bhutani, R.; Pathak, D.P.; Kapoor, G.; Husain, A.; Iqbal, M.A. Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment. Bioorg. Chem., 2019, 83, 6-19.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.025] [PMID: 30339863]
[24]
Ahmadi, A.; Khalili, M.; Ghaderi, P.; Rastegar, G.; Nahri-Niknafs, B. Synthesis and blood glucose and lipid-lowering effects of benzothiazole-substituted benzenesulfonylurea derivatives. Monatsh. Chem., 2015, 146(12), 2059-2065.
[http://dx.doi.org/10.1007/s00706-015-1471-2]
[25]
Mariappan, G.; Prabhat, P.; Sutharson, L.; Banerjee, J.; Patangia, U.; Nath, S. 562012,
[26]
Murtuja, S.; Shaquiquzzaman, M.; Amir, M. Design, synthesis, and screening of hybrid benzothiazolyl-oxadiazoles as anticonvulsant agents. Lett. Drug Des. Discov., 2018, 15(4), 398-405.
[http://dx.doi.org/10.2174/1570180814666170526154914]
[27]
Subramanyam, M.; Sreenivasulu, R.; Gundla, R.; Rao, M.V.; Rao, K.P. Synthesis, biological evaluation and docking studies of 1, 3, 4-oxadiazole fused benzothiazole derivatives for anticancer drugs. Lett. Drug Des. Discov., 2018, 15(12), 1299-1307.
[http://dx.doi.org/10.2174/1570180815666180219165119]
[28]
Akhtar, T.; Hameed, S.; Al-Masoudi, N.A.; Loddo, R.; La Colla, P. In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives. Acta Pharm., 2008, 58(2), 135-149.
[http://dx.doi.org/10.2478/v10007-008-0007-2] [PMID: 18515224]
[29]
Ismail, M.A.; El Ella, D.A.A.; Abouzid, K.A.; Jaballah, M. Design, synthesis and virtual screening of certain 2-pyrazolin-5-one and pyrazolidine-3, 5-dione derivatives as potential ppar [gamma] agonists. Int. J. Pharm. Sci. Res., 2012, 3(10), 3746.
[30]
Kumar, H.; Jain, S. Synthesis and antimicrobial evaluation of 4-benzylidene-pyrazolidine-3, 5-dione derivatives. Int. J. Pharm. Sci. Res., 2013, 4(1), 453.
[31]
Moydeen, M.; Kumar, R.S.; Idhayadhulla, A.; Manilal, A. Effective synthesis of some novel pyrazolidine-3,5-dione derivatives via Mg(II) catalyzed in water medium and their anticancer and antimicrobial activities. Mol. Divers., 2019, 23(1), 35-53.
[http://dx.doi.org/10.1007/s11030-018-9850-3] [PMID: 29974311]
[32]
Suma, B.; Rochani, A.K.; Venkataramana, C.; Jays, J.; Madhavan, V. Synthesis, characterization, in vitro antibacterial, anti-inflammatory evaluations of novel 4-quinolone containing pyrazolidinedione derivatives. Int. J. Chemtech Res., 2010, 2, 2156-2162.
[33]
Zhang, X. Yi-fei, g.; Chen, T.; Yang, D.-X.; Wang, X.-X.; Jiang, B.-L.; Shao, K.-P.; Zhao, W.; Wang, C.; Wang, J.-W.; Zhang, Q.-R.; Liu, H.-M. Synthesis, in vitro and in vivo anticancer activities of novel 4-substituted 1,2-bis(4-chlorophenyl)-pyrazolidine-3,5-dione derivatives. MedChemComm, 2015, 6(10), 1781-1786.
[34]
Tiwari, A.; Singh, A. Synthesis and antinociceptive activity of novel mannich base derivatives of some new fused 3,5-pyrazolidinedione. J. Adv. Pharm. Technol. Res., 2014, 5(1), 41-47.
[http://dx.doi.org/10.4103/2231-4040.126993] [PMID: 24696816]
[35]
Kornet, M.J.; Thorstenson, J.H.; Lubawy, W.C. Anticonvulsant activity of 1-alkyl-4-substituted 3,5-pyrazolidinediones. J. Pharm. Sci., 1974, 63(7), 1090-1093.
[http://dx.doi.org/10.1002/jps.2600630712] [PMID: 4850600]
[36]
Samala, G.; Kakan, S.S.; Nallangi, R.; Devi, P.B.; Sridevi, J.P.; Saxena, S.; Yogeeswari, P.; Sriram, D. Investigating structure-activity relationship and mechanism of action of antitubercular 1-(4-chlorophenyl)-4-(4-hydroxy-3-methoxy-5-nitrobenzylidene) pyrazolidine-3,5-dione.[CD59] Int. J. Mycobacteriol., 2014, 3(2), 117-126. [CD59].
[http://dx.doi.org/10.1016/j.ijmyco.2014.02.006] [PMID: 26786333]
[37]
Cauvin, C.; Le Bourdonnec, B.; Norberg, B.; Hénichart, J-P.; Durant, F. Pyrazolidine-3,5-dione angiotensin-II receptor antagonists. Acta Crystallogr. C, 2001, 57(Pt 11), 1330-1332.
[http://dx.doi.org/10.1107/S0108270101013506] [PMID: 11706265]
[38]
Bhutani, R.; Pathak, D.P.; Kapoor, G.; Husain, A.; Kant, R.; Iqbal, M.A. Synthesis, molecular modelling studies and ADME prediction of benzothiazole clubbed oxadiazole-Mannich bases, and evaluation of their anti-diabetic activity through in vivo model. Bioorg. Chem., 2018, 77, 6-15.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.037] [PMID: 29316509]
[39]
Ammazzalorso, A.; Giancristofaro, A.; D’Angelo, A.; Filippis, B.D.; Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Amoroso, R.; Benzothiazole-based, N. -(phenylsulfonyl)amides as a novel family of PPARalpha antagonists. Bioorg. Med. Chem. Lett., 2011, 21(16), 4869-4872.
[http://dx.doi.org/10.1016/j.bmcl.2011.06.028] [PMID: 21742490]
[40]
Fujieda, H.; Usui, S.; Suzuki, T.; Nakagawa, H.; Ogura, M.; Makishima, M.; Miyata, N. Phenylpropanoic acid derivatives bearing a benzothiazole ring as PPARdelta-selective agonists. Bioorg. Med. Chem. Lett., 2007, 17(15), 4351-4357.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.017] [PMID: 17524643]
[41]
Haroun, M.; Tratrat, C.; Tsolaki, E.; Geronikaki, A. Thiazole-based thiazolidinones as potent antimicrobial agents. Design, synthesis and biological evaluation. Comb. Chem. High Throughput Screen., 2016, 19(1), 51-57.
[http://dx.doi.org/10.2174/1386207319666151203002348] [PMID: 26632442]
[42]
Haroun, M.; Tratrat, C.; Kositsi, K.; Tsolaki, E.; Petrou, A.; Aldhubiab, B.; Attimarad, M.; Harsha, S.; Geronikaki, A.; Venugopala, K.N.; Elsewedy, H.S.; Sokovic, M.; Glamoclija, J.; Ciric, A. New benzothiazole-based thiazolidinones as potent antimicrobial agents. design, synthesis and biological evaluation. Curr. Top. Med. Chem., 2018, 18(1), 75-87.
[http://dx.doi.org/10.2174/1568026618666180206101814] [PMID: 29412109]
[43]
Fesatidou, M.; Zagaliotis, P.; Camoutsis, C.; Petrou, A.; Eleftheriou, P.; Tratrat, C.; Haroun, M.; Geronikaki, A.; Ciric, A.; Sokovic, M. 5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design, synthesis, molecular docking and evaluation. Bioorg. Med. Chem., 2018, 26(16), 4664-4676.
[http://dx.doi.org/10.1016/j.bmc.2018.08.004] [PMID: 30107969]
[44]
Ismail, M.A.; Tratrat, C.; Haroun, M.G. Molecular modelling design, synthesis and cytotoxic evaluation of certain substituted 2-(3,4,5-triacetoxybenzoylamino) benzo[d]thiazole and 2-(galloylamino)benzo[d]thiazole derivatives having potential topoisomerase-I inhibitory activity. J. Enzyme Inhib. Med. Chem., 2013, 28(6), 1331-1345.
[http://dx.doi.org/10.3109/14756366.2012.716835] [PMID: 22957723]
[45]
Aldhubiab, B.; Tsolaki, E.; Eleftheriou, P.; Petrou, A.; Attimarad, M.; Venugopala, K.N.; Harsha, S.; Elsewedy, H.S.; Geronikaki, A.; Tratrat, C.; Haroun, M.; Xenikakis, I.; Liaras, K.; Tsolaki, E.; Eleftheriou, P.; Petrou, A.; Aldhubiab, B.; Attimarad, M.; Venugopala, K.N.; Harsha, S.; Elsewedy, H.S.; Geronikaki, A.; Soković, M. Design, synthesis, evaluation of antimicrobial activity and docking studies of thiazole-based chalcones. Curr. Top. Med. Chem., 2019, 19(5), 356-375.
[http://dx.doi.org/10.2174/1568026619666190129121933] [PMID: 30706816]
[46]
Mariappan, G.; Saha, B.; Datta, S.; Kumar, D.; Haldar, P. Design, synthesis and antidiabetic evaluation of oxazolone derivatives. J. Chem. Sci., 2011, 123(3), 335-341.
[http://dx.doi.org/10.1007/s12039-011-0079-2]


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VOLUME: 15
ISSUE: 6
Year: 2019
Page: [624 - 633]
Pages: 10
DOI: 10.2174/1573406415666190515093657
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