Generic placeholder image

Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Synthesis, Anticancer, and Antibacterial Studies of Benzylidene Bearing 5-substituted and 3,5-disubstituted-2,4-Thiazolidinedione Derivatives

Author(s): Navjot S. Sethi, Deo N. Prasad and Rajesh K. Singh*

Volume 17, Issue 4, 2021

Published on: 12 May, 2020

Page: [369 - 379] Pages: 11

DOI: 10.2174/1573406416666200512073640

Price: $65


Aim: To develop novel compounds having potent anticancer and antibacterial activities.

Background: Several studies have proved that benzylidene analogues of clinical 2,4-TZDs, such as troglitazone and ciglitazone, have more potent antiproliferative activity than their parent compounds. Literature studies also revealed that the attachment of more heterocyclic rings, containing nitrogen on 5th position of 2,4-TZD, can enhance the antimicrobial activity. Hence, attachment of various moieties on the benzylidene ring may produce safe and effective compounds in the future.

Objective: The objective of the present study was to synthesize a set of novel benzylidene ring containing 5- and 3-substituted-2,4-thiazolidinedione derivatives and evaluate them for their anticancer and antibacterial activity.

Methods: The synthesized compounds were characterized by IR, NMR, mass, and elemental studies. The in vitro cytotoxicity studies were performed for human breast cancer (MCF-7) and human lung cancer (A549) cells and HepG2 cell-line and compared to standard drug doxorubicin by MTT assay. Antimicrobial activity of the synthesized 2,4-thiazolidinediones derivatives was carried out using the cup plate method with slight modification.

Results: The results obtained showed that TZ-5 and TZ-13 exhibited good antiproliferative activity against A549 cancer cell-line, whereas TZ-10 exhibited moderate antiproliferative activity against HepG2 cell-line when compared to standard drug doxorubicin. TZ-5 also exhibited reasonable activity against the MCF-7 cell-line with doxorubicin as standard. TZ-4, TZ-5, TZ-6, TZ-7, and TZ- 16 exhibited remarkable antibacterial activity against Gram positive and moderate activity against Gram negative bacteria with the standard drug ciprofloxacin.

Conclusion: Attachment of heterocyclic rings containing nitrogen as the hetero atom improves the anticancer and antimicrobial potential. Attachment of electronegative elements like halogens can also enhance the antimicrobial activity. Further structure modifications may lead to the development of more potent 2,4-TZD leads that can be evaluated for further advanced studies.

Keywords: 2, 4-Thiazolidinedione, anticancer, antibacterial, structure-activity relationship, MTT assay, 2, 4-Thiazolidinedione, anticancer, antibacterial, ciprofloxacin, structure-activity relationship, MTT assay.

Graphical Abstract
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89103021
[] [PMID: 31176854]
Kumari, A.; Singh, R.K. Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR). Bioorg. Chem., 2020, 96103578
[] [PMID: 31978684]
Sethi, N.; Prasad, D.N.; Singh, R.K. An insight into the synthesis and structure-activity relationship (SAR) of 2, 4-thiazolidinedione (2, 4-TZD): A review. Mini-Reviews. Med. Chem., 2020, 20(4), 308-330.
[] [PMID: 31660809]
Kaur Manjal, S.; Kaur, R.; Bhatia, R.; Kumar, K.; Singh, V.; Shan-kar, R.; Kaur, R.; Rawal, R.K. Synthetic and medicinal perspective of thiazolidinones: A review. Bioorg. Chem., 2017, 75, 406-423.
[] [PMID: 29102723]
Ortiz, A.; Sansinenea, E. Synthetic thiazolidinediones: Potential antidiabetic compounds. E. Curr. Org. Chem., 2011, 15, 108-127.
Sucheta, T.; Tahlan, S.; Verma, P.K. Biological potential of thia-zolidinedione derivatives of synthetic origin. Chem. Cent. J., 2017, 11(1), 130.
[] [PMID: 29222671]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[] [PMID: 29313949]
Tseng, C.H. Rosiglitazone reduces breast cancer risk in Taiwanese female patients with type 2 diabetes mellitus. Oncotarget, 2017, 8(2), 3042-3048.
[] [PMID: 27936468]
Bolden, A.; Bernard, L.; Jones, D.; Akinyeke, T.; Stewart, L.V. The PPAR gamma agonist troglitazone regulates erk 1/2 phosphorylation via a PPARγ-independent, MEK-dependent pathway in human prostate cancer cells. PPAR Res., 2012, 2012929052
Costa, V.; Foti, D.; Paonessa, F.; Chiefari, E.; Palaia, L.; Brunetti, G.; Gulletta, E.; Fusco, A.; Brunetti, A. The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-gamma (PPARγ) and thiazolidinedione-PPARγ agonists. Endocr. Relat. Cancer, 2008, 15(1), 325-335.
[] [PMID: 18310298]
Lu, M.; Kwan, T.; Yu, C.; Chen, F.; Freedman, B.; Schafer, J.M.; Lee, E.J.; Jameson, J.L.; Jordan, V.C.; Cryns, V.L. Peroxisome proliferator-activated receptor gamma agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest. J. Biol. Chem., 2005, 280(8), 6742-6751.
[] [PMID: 15569667]
Han, S.; Roman, J. Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol. Cancer Ther., 2006, 5(2), 430-437.
[] [PMID: 16505118]
Yang, B.; Lin, P.; Carrick, K.M.; McNulty, J.A.; Clifton, L.G.; Winegar, D.A.; Strum, J.C.; Stimpson, S.A.; Pahel, G.L. PPARgamma agonists diminish serum VEGF elevation in diet-induced insulin resistant SD rats and ZDF rats. Biochem. Biophys. Res. Commun., 2005, 334(1), 176-182.
[] [PMID: 15993383]
Kaminskyy, D.; Zimenkovsky, B.; Lesyk, R. Synthesis and in vitro anticancer activity of 2,4-azolidinedione-acetic acids derivatives. Eur. J. Med. Chem., 2009, 44(9), 3627-3636.
[] [PMID: 19299038]
Bhanushali, U.; Rajendran, S.; Sarma, K.; Kulkarni, P.; Chatti, K.; Chatterjee, S.; Ramaa, C.S. 5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2. Bioorg. Chem., 2016, 67, 139-147.
[] [PMID: 27388635]
Sharma, P.; Reddy, T.S.; Kumar, N.P.; Senwar, K.R.; Bhargava, S.K.; Shankaraiah, N. Conventional and microwave-assisted synthesis of new 1H-benzimidazole-thiazolidinedione derivatives: A potential anticancer scaffold. Eur. J. Med. Chem., 2017, 138, 234-245.
[] [PMID: 28668476]
Elkamhawy, A.; Kim, N.Y.; Hassan, A.H.E.; Park, J.E.; Yang, J.E.; Oh, K-S.; Lee, B.H.; Lee, M.Y.; Shin, K.J.; Lee, K-T.; Hur, W.; Roh, E.J. Design, synthesis and biological evaluation of novel thiazolidinedione derivatives as irreversible allosteric IKK-β modulators. Eur. J. Med. Chem., 2018, 157, 691-704.
[] [PMID: 30130718]
High levels of antibiotic resistance found worldwide, new data shows. Available at: [January 20, 2018]
Liu, X.F.; Zheng, C.J.; Sun, L.P.; Liu, X.K.; Piao, H.R. Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents. Eur. J. Med. Chem., 2011, 46(8), 3469-3473.
[] [PMID: 21624712]
da Silva, I.M.; da Silva Filho, J.; Santiago da Silva Santiago, P.B.G.; do Egito, M.S.; de Souza, C.A.; Gouveia, F.L.; Ximenes, R.M.; de Sena, K.X.; de Faria, A.R.; Brondani, D.J.; de Albuquerque, J.F. Synthesis and antimicrobial activities of 5-arylidene-thiazolidine-2,4-dione derivatives. BioMed Res. Int., 2014, 2014316082
Zvarec, O.; Polyak, S.W.; Tieu, W.; Kuan, K.; Dai, H.; Pedersen, D.S.; Morona, R.; Zhang, L.; Booker, G.W.; Abell, A.D. 5-benzy-lidenerhodanine and 5-benzylidene-2-4-thiazolidinedione based antibacterials. Bioorg. Med. Chem. Lett., 2012, 22(8), 2720-2722.
[] [PMID: 22444680]
Marc, G.; Araniciu, C.; Oniga, S.D.; Vlase, L.; Pîrnău, A.; Duma, M.; Măruțescu, L.; Chifiriuc, M.C.; Oniga, O. New N-(oxazolyl-methyl)-thiazolidinedione Active against Candida albicans Biofilm: Potential Als Proteins Inhibitors. Molecules, 2018, 23(10), 2522.
[] [PMID: 30279343]
Wu, S.; Zhang, Y.; He, X.; Che, X.; Wang, S.; Liu, Y.; Jiang, Y.; Liu, N.; Dong, G.; Yao, J.; Miao, Z.; Wang, Y.; Zhang, W.; Sheng, C. From antidiabetic to antifungal: discovery of highly potent triazole-thiazolidinedione hybrids as novel antifungal agents. ChemMedChem, 2014, 9(12), 2639-2646.
[] [PMID: 25196996]
Nastasă, C.M.; Duma, M.; Pîrnău, A.; Vlase, L.; Tiperciuc, B.; Oniga, O. Development of new 5-(chromene-3-yl)methylene-2,4-thiazolidinediones as antimicrobial agents. Clujul Med., 2016, 89(1), 122-127.
[PMID: 27004035]
Bahare, R.S.; Ganguly, S.; Choowongkomon, K.; Seetaha, S. Synthesis, HIV-1 RT inhibitory, antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones. Daru, 2015, 23, 6.
[] [PMID: 25617150]
Purohit, S.S.; Alman, A.; Shewale, J. Synthesis & antimicrobial activity of a new series of 3, 5-disubstituted thiazolidine-2, 4-diones. Int. J. Pharm. Pharm. Sci., 2012, 4, 273-276.
Moorthy, P.; Ekambaram, S.P.; Perumal, S.S. Synthesis, characterization and antimicrobial evaluation of imidazolyl thiazolidinedione derivatives. Arab. J. Chem., 2019, 12(3), 413-419.
Alagawadi, K.R.; Alegaon, S.G. Synthesis, characterization and antimicrobial activity evaluation of new 2,4-thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety. Arab. J. Chem., 2011, 4(4), 465-472.
Mandal, S.P. Mithuna.; Garg, A.; Sahetya, S.S.; Nagendra, S.R.; Sripad H.S.; Manjunath, M.M.; Sitaram.; Soni, M.; Baig, R.N.; Kumar, S.V.; Kumar, B.R.P. Novel rhodanines with anticancer activity: design, synthesis and CoMSIA study. RCS Adv., 2016, 6, 58641-58653.
Yang, C.C.; Ku, C.Y.; Wei, S.; Shiau, C. Thiazolidinediones Modulate the Expression of β-Catenin and Other Cell-Cycle Regulatory Proteins by Targeting the F-Box Proteins of SCF E3 Ubiquitin Ligase Independently of PPARγ. Mol. Pharmacol., 2006, 69, 1564-1570.
[] [PMID: 16452400]
Huang, J.W.; Shiau, C.W.; Yang, Y.T.; Kulp, S.K.; Chen, K.F.; Brueggemeier, R.W.; Shapiro, C.L.; Chen, C.S. Peroxisome Proliferator-Activated Receptor γ-Independent Repression of Prostate Specific Antigen Expression by Thiazolidinediones in Prostate Cancer Cells. Mol. Pharmacol., 2005, 67, 1342-1348.
[] [PMID: 15653552]
Patil, V.; Tilekar, K.; Mehendale-Munj, S.; Mohan, R.; Ramaa, C.S. Synthesis and primary cytotoxicity evaluation of new 5-benzylidene-2,4-thiazolidinedione derivatives. Eur. J. Med. Chem., 2010, 45(10), 4539-4544.
[] [PMID: 20667627]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis, chemical and biological evaluation of brain targeted alkylating agent using reversible redox prodrug approach. Arab. J. Chem., 2017, 10, 420-429.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and in vitro cytotoxicity study of benzodiazepine-mustard conjugates as potential brain anticancer agents. J. Saudi Chem. Soc., 2017, 21(S1), S186-S193.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Hybrid pharmacophore-based drug design, synthesis and antiproliferative activity of 1, 4-dihydropyridines-linked alkylating anticancer agents. Med. Chem. Res., 2015, 24, 1534-1541.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis, physicochemical and kinetic studies of redox derivative of bis(2-chloroethylamine) as alkylating cytotoxic agent for brain delivery. Arab. J. Chem., 2015, 8, 380-387.
Li, T.; Singh, S.; Zhai, X.; Meng, X.; Singh, R.K. Microwave Assisted Synthesis, in silico ADME Prediction and Antibacterial Study of 2-(Substituted Acetamido)-5-Nitrobenzophhenone Derivatives. Asian J. Chem., 2015, 27, 2452-2456.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Reversible redox system-based drug design, synthesis and evaluation for targeting nitrogen mustard across brain. Med. Chem. Res., 2014, 23, 2405-2416.
Li, P.; Sahore, K.; Liu, J.; Singh, R.K. Synthesis and Antimicrobial Evaluation of 2-Aminobenzophenone Linked 4-Dihydropyridine Derivatives. Asian J. Chem., 2014, 26, 5291-5294.
Singh, R.K.; Prasad, D.N. Bhardwaj. T.R. Synthesis in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent. Med. Chem. Res., 2013, 22, 5324-5336.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential central nervous system antitumor agent. Med. Chem. Res., 2013, 22, 5901-5911.
Kumar, P.; Kumar, R.; Prasad, D.N. Synthesis and anticancer study of 9-aminoacridine derivatives. Arab. J. Chem., 2013, 6, 79-85.
Singh, R.K.; Kumar, S.; Prasad, D.N.; Bhardwaj, T.R. Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. Eur. J. Med. Chem., 2018, 151, 401-433.
[] [PMID: 29649739]
Sohda, T.; Mizuno, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Studies on antidiabetic agents. I. Synthesis of 5-[4-(2-methyl-2-phenylpropoxy)-benzyl]thiazolidine-2,4-dione (AL-321) and related compounds. Chem. Pharm. Bull. (Tokyo), 1982, 30(10), 3563-3573.
[] [PMID: 7160011]
Bruno, G.; Costantino, L.; Curinga, C.; Maccari, R.; Monforte, F.; Nicoló, F.; Ottanà, R.; Vigorita, M.G. Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones. Bioorg. Med. Chem., 2002, 10(4), 1077-1084.
[ PMID: 11836118]
Charles, K.B.; Frances, C.B. A New Technique For The Conversion Of Olefins Into Organoboranes and Related Alcohols. J. Am. Chem. Soc., 1956, 78, 6189-6192.
Pattan, S.R.; Suresh, C.; Pujari, V.D.; Reddy, V.V.K.; Rasal, V.P.; Koti, B.C. Synthesis and Spectral Characterization Of Some Novel N-substituted 2,4-Thiazolidinedione. Int. Biol. Chem., 2011, 5, 68-74.
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89(2), 271-277.
[] [PMID: 3486233]
Rose, S.B.; Miller, R.E. Studies with the agar cup-plate method I. A standardized agar cup-plate technique. J. Bacteriol., 1939, 38(5), 525-537.
[] [PMID: 16560269]
Maccari, R.; Ottanà, R.; Ciurleo, R.; Rakowitz, D.; Matuszczak, B.; Laggner, C.; Langer, T. Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives. Bioorg. Med. Chem., 2008, 16(11), 5840-5852.
[] [PMID: 18492610]
Begum, A.B.; Begum, M.; Ranganatha, V.L.; Prashanth, T.; Zameer, F.; Hegdekatte, R.; Khanum, S.A. Synthesis, antioxidant, and xanthine oxidase inhibitory activities of 5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione derivatives. Arch. Pharm. (Weinheim), 2014, 347(4), 247-255.
[] [PMID: 24343903]
El-Kashef, H.; Badr, G.; El-Mali, N.A.; Sayed, D.; Melnyk, P.; Lebegue, N.; El-Khalek, R.A. Synthesis of a novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones as promising anti-breast cancer agent. Bioorg. Chem., 2020, 96103569
[] [PMID: 31978680]
Bayoumi, W.A.; Abdel-Rhman, S.H.; Shaker, M.E. Synthesis and evaluation of new 2-iminothiazolidin-4-one and thiazolidin-2,4-dione derivatives as antimicrobial and anti-inflammatory agents. Open Chem. J., 2014, 1, 33-38.
Liu, X.F.; Zheng, C.J.; Sun, L.P.; Liu, X.K.; Piao, H.R. Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents. Eur. J. Med. Chem., 2011, 46(8), 3469-3473.
[] [PMID: 21624712]
Khillare, L.; Bhosle, M.; Bhalerao, M.; Kharat, K.; Mane, R. Synthesis of new thiazolyl coupled pyrazoles bearing 2,4-thiazolidinedionyl pharmacophore and their anti-inflammatory and antibacterial evaluation. Antiinflamm. Antiallergy Agents Med. Chem., 2017, 16(1), 46-57.
[ PMID: 28618987]
Andres, C.J.; Bronson, J.J.; D’Andrea, S.V.; Deshpande, M.S.; Falk, P.J.; Grant-Young, K.A.; Harte, W.E.; Ho, H-T.; Misco, P.F.; Robertson, J.G.; Stock, D.; Sun, Y.; Walsh, A.W. 4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB. Bioorg. Med. Chem. Lett., 2000, 10(8), 715-717.
[ PMID: 10782671]
Zidar, N.; Tomašić, T.; Šink, R.; Kovač, A.; Patin, D.; Blanot, D.; Contreras-Martel, C.; Dessen, A.; Premru, M.M.; Zega, A.; Gobec, S.; Mašič, L.P.; Kikelj, D. New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation. Eur. J. Med. Chem., 2011, 46(11), 5512-5523.
[] [PMID: 21963114]
Hranjec, M.; Starčević, K.; Pavelić, S.K.; Lučin, P.; Pavelić, K.; Karminski Zamola, G. Synthesis, spectroscopic characterization and antiproliferative evaluation in vitro of novel Schiff bases related to benzimidazoles. Eur. J. Med. Chem., 2011, 46(6), 2274-2279.
[] [PMID: 21439689]
Shaharyar, M.; Abdullah, M.M.; Bakht, M.A.; Majeed, J. Pyrazoline bearing benzimidazoles: search for anticancer agent. Eur. J. Med. Chem., 2010, 45(1), 114-119.
[] [PMID: 19883957]
Charifson, P.S.; Grillot, A.L.; Grossman, T.H.; Parsons, J.D.; Badia, M.; Bellon, S.; Deininger, D.D.; Drumm, J.E.; Gross, C.H.; LeTiran, A.; Liao, Y.; Mani, N.; Nicolau, D.P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L.L.; Tang, Q.; Tessier, P.R.; Tian, S-K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.; Stamos, D. Novel dual-targeting benzimidazole urea inhibitors of dna gyrase and topoisomerase iv possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships. J. Med. Chem., 2008, 51, 5243-5263.
[] [PMID: 18690678]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy