Design and Efficient Synthesis of Novel 4,5-Dimethylthiazole-Hydrazone Derivatives and their Anticancer Activity

Asaf    Evrim    Evren; Leyla       Yurttaş; Büşra       Ekselli; Onur       Aksoy; Gülşen       Akalin-Çiftçi

Abstract

Background: Recently, researchers have been warning about the increased mortality of the various cancer types. Also, the lung adenocarcinoma and the glioma types are burning issues for world's health due to late or wrong diagnosis and/or insufficient treatment methods. For this purpose, our research group designed and synthesized novel 4,5-dimethyl thiazole-hydrazone derivatives which were tested against cancer and normal cell lines to understand the structureactivity relationship (SAR).

Methods: The lead compounds were obtained by reacting 2-(substituted aryl-2-ylmethylene) hydrazin-1-carbothioamide with 3-chloro-2-butanone derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR, and LC/MS-IT-TOF spectral and elemental analyses. The synthesized compounds were tested in vitro for the anticancer activity against A549 human lung adenocarcinoma and C6 rat glioma cells and investigated for which pathway to induce cell death. Also, the docking study of the active compounds was achieved to understand the SAR.

Results: The targeted compounds (2a-2l) were synthesized successfully above 70% yields, and the analysis findings proved their purity. In general, the results of activity studies displayed significant effects against at least one cell line, except compounds 2e (indol-3-yl) and 2h (4-dimethylaminophenyl). Furthermore, compounds 2b and 2f displayed potential anticancer activity. With the help of molecular docking study, a potential selectivity of compound 2f was observed for type II protein kinase. On the other hand, compound 2b interacted with the active site nearly the same as Dasatinib. Therefore, these two compounds could be used as a base on developing selective anticancer drugs.

Conclusion: Pyridin-2-yl (2b) derivative was found to be a favorable molecule with high anticancer potency against C6 and A549 cell lines. Additionally, 1-naphthyl (2f) derivative was a worthy compound for potential selectivity. In future studies, it will be our priority to focus on developing derivatives of these two compounds (2b and 2f) and elucidate their mechanisms.

Keywords: Thiazole, hydrazone, A549, C6, apoptosis, anticancer activity.

Graphical Abstract

[1] 
Carmeliet, P.; Jain, R.K. Angiogenesis in cancer and other diseases. Nature,  2000, 407(6801), 249-257.
[http://dx.doi.org/10.1038/35025220] [PMID:  11001068] 
[2] 
Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature,  2001, 414(6859), 105-111.
[http://dx.doi.org/10.1038/35102167] [PMID:  11689955] 
[3] 
Fitzmaurice, C.; Allen, C.; Barber, R.M.; Barregard, L.; Bhutta, Z.A.; Brenner, H.; Dicker, D.J.; Chimed-Orchir, O.; Dandona, R.; Dandona, L. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol.,  2017, 3(4), 524-548.
[http://dx.doi.org/10.1001/jamaoncol.2016.5688] [PMID:  27918777] 
[4] 
de Sá, V.K.; Coelho, J.C.; Capelozzi, V.L.; de Azevedo, S.J. Lung cancer in Brazil: Epidemiology and treatment challenges. Lung Cancer (Auckl.),  2016, 7, 141-148.
[http://dx.doi.org/10.2147/LCTT.S93604] [PMID:  28210170] 
[5] 
Dela Cruz, C.S.; Tanoue, L.T.; Matthay, R.A. Lung cancer: epidemiology, etiology, and prevention. Clin. Chest Med.,  2011, 32(4), 605-644.
[http://dx.doi.org/10.1016/j.ccm.2011.09.001] [PMID:  22054876] 
[6] 
Walker, M.D.; Alexander, E., Jr; Hunt, W.E.; MacCarty, C.S.; Mahaley, M.S., Jr; Mealey, J., Jr; Norrell, H.A.; Owens, G.; Ransohoff, J.; Wilson, C.B.; Gehan, E.A.; Strike, T.A. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J. Neurosurg.,  1978, 49(3), 333-343.
[http://dx.doi.org/10.3171/jns.1978.49.3.0333] [PMID:  355604] 
[7] 
Sulu, E.; Tasolar, O.; Berk Takir, H.; Yagci Tuncer, L.; Karakurt, Z.; Yilmaz, A. Delays in the diagnosis and treatment of non-small-cell lung cancer. Tumori,  2011, 97(6), 693-697.
[http://dx.doi.org/10.1177/030089161109700603] [PMID:  22322833] 
[8] 
Wen, P.Y.; Chang, S.M.; Lamborn, K.R.; Kuhn, J.G.; Norden, A.D.; Cloughesy, T.F.; Robins, H.I.; Lieberman, F.S.; Gilbert, M.R.; Mehta, M.P.; Drappatz, J.; Groves, M.D.; Santagata, S.; Ligon, A.H.; Yung, W.K.; Wright, J.J.; Dancey, J.; Aldape, K.D.; Prados, M.D.; Ligon, K.L. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro-oncol.,  2014, 16(4), 567-578.
[http://dx.doi.org/10.1093/neuonc/not247] [PMID:  24470557] 
[9] 
Lassman, A.B.; Pugh, S.L.; Gilbert, M.R.; Aldape, K.D.; Geinoz, S.; Beumer, J.H.; Christner, S.M.; Komaki, R.; DeAngelis, L.M.; Gaur, R.; Youssef, E.; Wagner, H.; Won, M.; Mehta, M.P. Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Neuro-oncol.,  2015, 17(7), 992-998.
[http://dx.doi.org/10.1093/neuonc/nov011] [PMID:  25758746] 
[10] 
Banerjee, A.; Jakacki, R.I.; Onar-Thomas, A.; Wu, S.; Nicolaides, T.; Young Poussaint, T.; Fangusaro, J.; Phillips, J.; Perry, A.; Turner, D.; Prados, M.; Packer, R.J.; Qaddoumi, I.; Gururangan, S.; Pollack, I.F.; Goldman, S.; Doyle, L.A.; Stewart, C.F.; Boyett, J.M.; Kun, L.E.; Fouladi, M. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a pediatric brain Tumor Consortium (PBTC) study. Neuro-oncol.,  2017, 19(8), 1135-1144.
[http://dx.doi.org/10.1093/neuonc/now282] [PMID:  28339824] 
[11] 
Helal, M.H.; El-Awdan, S.A.; Salem, M.A.; Abd-elaziz, T.A.; Moahamed, Y.A.; El-Sherif, A.A.; Mohamed, G.A. Synthesis, biological evaluation and molecular modeling of novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic agents. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2015, 135, 764-773.
[http://dx.doi.org/10.1016/j.saa.2014.06.145] [PMID:  25150427] 
[12] 
Carbone, A.; Pennati, M.; Parrino, B.; Lopergolo, A.; Barraja, P.; Montalbano, A.; Spanò, V.; Sbarra, S.; Doldi, V.; De Cesare, M.; Cirrincione, G.; Diana, P.; Zaffaroni, N. Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: Synthesis and antitumor activity in peritoneal mesothelioma experimental models. J. Med. Chem.,  2013, 56(17), 7060-7072.
[http://dx.doi.org/10.1021/jm400842x] [PMID:  23919303] 
[13] 
Jones, V.S.; Huang, R.Y.; Chen, L.P.; Chen, Z.S.; Fu, L.; Huang, R.P. Cytokines in cancer drug resistance: Cues to new therapeutic strategies. Biochim. Biophys. Acta,  2016, 1865(2), 255-265.
[PMID:  26993403] 
[14] 
Salgia, R.; Kulkarni, P. The genetic/non-genetic duality of drug ‘resistance’ in cancer. Trends Cancer,  2018, 4(2), 110-118.
[http://dx.doi.org/10.1016/j.trecan.2018.01.001] [PMID:  29458961] 
[15] 
Siegfried, Z.; Karni, R. The role of alternative splicing in cancer drug resistance. Curr. Opin. Genet. Dev.,  2018, 48, 16-21.
[http://dx.doi.org/10.1016/j.gde.2017.10.001] [PMID:  29080552] 
[16] 
Franceschini, G.; Martin Sanchez, A.; Di Leone, A.; Magno, S.; Moschella, F.; Accetta, C.; Masetti, R. New trends in breast cancer surgery: A therapeutic approach increasingly efficacy and respectful of the patient. G. Chir.,  2015, 36(4), 145-152.
[PMID:  26712068] 
[17] 
Eberli, D.; Mortezavi, A.; Sulser, T. Focal therapy-a new era in the treatment of prostate cancer.,  Praxis (Bern 1994), 2014, 103, pp.	(7)391-397.. 
[18] 
Salama, J.K.; Vokes, E.E. New radiotherapy and chemoradiotherapy approaches for non-small-cell lung cancer. J. Clin. Oncol.,  2013, 31(8), 1029-1038.
[http://dx.doi.org/10.1200/JCO.2012.44.5064] [PMID:  23401449] 
[19] 
Yurttas, L.; Ozkay, Y.; Akalin, G. Ulusoylar, Yildirim Synthesis and anticancer activity evaluation of N-[4-(2-methylthiazol-4-yl)phenyl]acetamide derivatives containing (benz)azole moiety. J. Enzyme Inhib. Med. Chem.,  2014, 29(2), 175-184.
[http://dx.doi.org/10.3109/14756366.2013.763253] [PMID:  23391122] 
[20] 
Vashist, S.K.; Luppa, P.B.; Yeo, L.Y.; Ozcan, A.; Luong, J.H.T. Emerging technologies for next-generation point-of-care testing.	trends Biotechnol., 2015, 33(11), 692-705.. 
[http://dx.doi.org/10.1016/j.tibtech.2015.09.001 ] [PMID: 26463722] 
[21] 
Porcari, P.; Hegi, M.E.; Lei, H.; Hamou, M.F.; Vassallo, I.; Capuani, S.; Gruetter, R.; Mlynarik, V. Early detection of human glioma sphere xenografts in mouse brain using diffusion MRI at 14.1 T. NMR Biomed.,  2016, 29(11), 1577-1589.
[http://dx.doi.org/10.1002/nbm.3610] [PMID:  27717037] 
[22] 
van Dijken, B.R.J.; van Laar, P.J.; Holtman, G.A.; van der Hoorn, A. Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis. Eur. Radiol.,  2017, 27(10), 4129-4144.
[http://dx.doi.org/10.1007/s00330-017-4789-9] [PMID:  28332014] 
[23] 
Cai, S.X.; Nguyen, B.; Jia, S.; Herich, J.; Guastella, J.; Reddy, S.; Tseng, B.; Drewe, J.; Kasibhatla, S. Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay. J. Med. Chem.,  2003, 46(12), 2474-2481.
[http://dx.doi.org/10.1021/jm0205200] [PMID:  12773051] 
[24] 
Yurttas, L.; Demir, B.; Ciftci, G.A. Some Thiazole Derivatives	Combined With Different Heterocycles : Cytotoxicity Evaluation	And Apoptosis Inducing StudiesAnti-Cancer Agent Me,. 2018.
[25] 
Altintop, M.D.; Sever, B.; Akalin, G.; Turan-Zitouni, G.; Kaplancikli, Z.A.; Ozdemir, A. Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors. Eur. J. Med. Chem.,  2018, 155, 905-924.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.049] [PMID:  29966916] 
[26] 
Asati, V.; Mahapatra, D.K.; Bharti, S.K. Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents. Eur. J. Med. Chem.,  2014, 87, 814-833.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.025] [PMID:  25440883] 
[27] 
Creelan, B.C.; Antonia, S.J. Immunotherapy in lung cancer: “b7-bombers” and other new developments. Semin. Respir. Crit. Care Med.,  2013, 34(6), 810-821.
[http://dx.doi.org/10.1055/s-0033-1358551] [PMID:  24258571] 
[28] 
Rouf, A.; Tanyeli, C. Bioactive thiazole and benzothiazole derivatives. Eur. J. Med. Chem.,  2015, 97, 911-927.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.058] [PMID:  25455640] 
[29] 
Al-Saadi, M.S.; Faidallah, H.M.; Rostom, S.A. Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents. Arch. Pharm. (Weinheim),  2008, 341(7), 424-434.
[http://dx.doi.org/10.1002/ardp.200800026] [PMID:  18574850] 
[30] 
Tsuno, N.; Yukimasa, A.; Yoshida, O.; Ichihashi, Y.; Inoue, T.; Ueno, T.; Yamaguchi, H.; Matsuda, H.; Funaki, S.; Yamanada, N.; Tanimura, M.; Nagamatsu, D.; Nishimura, Y.; Ito, T.; Soga, M.; Horita, N.; Yamamoto, M.; Hinata, M.; Imai, M.; Morioka, Y.; Kanemasa, T.; Sakaguchi, G.; Iso, Y. Discovery of novel 2′,4′-dimethyl-[4,5′-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 1. Bioorg. Med. Chem. Lett.,  2016, 26(20), 4930-4935.
[http://dx.doi.org/10.1016/j.bmcl.2016.09.013] [PMID:  27637151] 
[31] 
Chandak, N.; Kumar, P.; Kaushik, P.; Varshney, P.; Sharma, C.; Kaushik, D.; Jain, S.; Aneja, K.R.; Sharma, P.K. Dual evaluation of some novel 2-amino-substituted coumarinylthiazoles as anti-inflammatory-antimicrobial agents and their docking studies with COX-1/COX-2 active sites. J. Enzyme Inhib. Med. Chem.,  2014, 29(4), 476-484.
[http://dx.doi.org/10.3109/14756366.2013.805755] [PMID:  23777557] 
[32] 
Albuquerque, J.F.; Albuquerque, A.; Azevedo, C.C.; Thomasson, F.; Galdino, L.S.; Chantegrel, J.; Catanho, M.T.; Pitta, I.R.; Luu-Duc, C. Substituted thiazolidinediones and thio-imidazolidinones: Synthesis, structural study and pharmacological activity. Pharmazie,  1995, 50(6), 387-389.
[PMID:  7651975] 
[33] 
Akalin Ciftci, G.; Altıntop, M.D.; Edip Temel, H.; Ozdemir, A.; Kaplancıklı, Z.A. Cytotoxic, apoptotic and DNA synthesis inhibitory effects of some thiazole derivatives. Lett. Drug Des. Discov.,  2017, 14(5), 554-566.
[http://dx.doi.org/10.2174/1570180813666160907170553] 
[34] 
Yahya, S.M.M.; Abdelhamid, A.O.; Abd-Elhalim, M.M.; Elsayed, G.H.; Eskander, E.F. The effect of newly synthesized progesterone derivatives on apoptotic and angiogenic pathway in MCF-7 breast cancer cells. Steroids,  2017, 126, 15-23.
[http://dx.doi.org/10.1016/j.steroids.2017.08.002] [PMID:  28797724] 
[35] 
Saha, S.; Chan, D.S.; Lee, C.Y.; Wong, W.; New, L.S.; Chui, W.K.; Yap, C.W.; Chan, E.C.; Ho, H.K. Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti-diabetic and anti-cancer properties. Eur. J. Pharmacol.,  2012, 697(1-3), 13-23.
[http://dx.doi.org/10.1016/j.ejphar.2012.09.021] [PMID:  23041271] 
[36] 
Weber, G.; Nagai, M.; Natsumeda, Y.; Eble, J.N.; Jayaram, H.N.; Paulik, E.; Zhen, W.N.; Hoffman, R.; Tricot, G. Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. Cancer Commun.,  1991, 3(3), 61-66.
[http://dx.doi.org/10.3727/095535491820873579] [PMID:  1705812] 
[37] 
Patay, Z.; Merchant, T.E.; Nguyen, R.; Pierson, C.R.; Onar-Thomas, A.; Broniscer, A. Treatment-related noncontiguous radiologic changes in children with diffuse intrinsic pontine glioma treated with expanded irradiation fields and antiangiogenic therapy. Int. J. Radiat. Oncol. Biol. Phys.,  2017, 99(5), 1295-1305.
[http://dx.doi.org/10.1016/j.ijrobp.2017.08.021] [PMID:  29165288] 
[38] 
Broniscer, A.; Baker, S.D.; Wetmore, C.; Pai Panandiker, A.S.; Huang, J.; Davidoff, A.M.; Onar-Thomas, A.; Panetta, J.C.; Chin, T.K.; Merchant, T.E.; Baker, J.N.; Kaste, S.C.; Gajjar, A.; Stewart, C.F. Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Clin. Cancer Res.,  2013, 19(11), 3050-3058.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0306] [PMID:  23536435] 
[39] 
Narang, R.; Narasimhan, B.; Sharma, S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr. Med. Chem.,  2012, 19(4), 569-612.
[http://dx.doi.org/10.2174/092986712798918789] [PMID:  22204327] 
[40] 
Carradori, S.; Rotili, D.; De Monte, C.; Lenoci, A.; D’Ascenzio, M.; Rodriguez, V.; Filetici, P.; Miceli, M.; Nebbioso, A.; Altucci, L.; Secci, D.; Mai, A. Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies. Eur. J. Med. Chem.,  2014, 80, 569-578.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.042] [PMID:  24835815] 
[41] 
Domagala, A.; Jarosz, T.; Lapkowski, M. Living on pyrrolic foundations - advances in natural and artificial bioactive pyrrole derivatives. Eur. J. Med. Chem.,  2015, 100, 176-187.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.009] [PMID:  26087028] 
[42] 
De Coen, L.M.; Heugebaert, T.S.; García, D.; Stevens, C.V. Synthetic entries to and biological activity of pyrrolopyrimidines. Chem. Rev.,  2016, 116(1), 80-139.
[http://dx.doi.org/10.1021/acs.chemrev.5b00483] [PMID:  26699634] 
[43] 
Garuti, L.; Roberti, M.; Pizzirani, D. Nitrogen-containing heterocyclic quinones: A class of potential selective antitumor agents. Mini Rev. Med. Chem.,  2007, 7(5), 481-489.
[http://dx.doi.org/10.2174/138955707780619626] [PMID:  17504183] 
[44] 
Novak, R.F.; Kaul, K.L.; Kim, S.G. Induction of the alcohol-inducible form of cytochrome P-450 by nitrogen-containing heterocycles: Effects on pyridine N-oxide production. Drug Metab. Rev.,  1989, 20(2-4), 781-792.
[http://dx.doi.org/10.3109/03602538909103578] [PMID:  2680407] 
[45] 
Clézardin, P.; Massaia, M. Nitrogen-containing bisphosphonates and cancer immunotherapy. Curr. Pharm. Des.,  2010, 16(27), 3007-2014.
[http://dx.doi.org/10.2174/138161210793563545] [PMID:  20722623] 
[46] 
Işık, S.; Vullo, D.; Durdagi, S.; Ekinci, D.; Şentürk, M.; Çetin, A.; Şentürk, E.; Supuran, C.T. Interaction of carbonic anhydrase isozymes I, II, and IX with some pyridine and phenol hydrazinecarbothioamide derivatives. Bioorg. Med. Chem. Lett.,  2015, 25(23), 5636-5641.
[http://dx.doi.org/10.1016/j.bmcl.2015.10.021] [PMID:  26520662] 
[47] 
Abd El-All, A.S.; Osman, S.A.; Roaiah, H.M.F.; Abdalla, M.M.; Abd El Aty, A.A. AbdEl-Hady, W.H., Potent anticancer and antimicrobial activities of pyrazole, oxazole and pyridine derivatives containing 1,2,4-triazine moiety. Med. Chem. Res.,  2015, 24(12), 4093-4104.
[http://dx.doi.org/10.1007/s00044-015-1460-3] 
[48] 
Secci, D.; Bizzarri, B.; Bolasco, A.; Carradori, S.; D’Ascenzio, M.; Rivanera, D.; Mari, E.; Polletta, L.; Zicari, A. Synthesis, anti-Candida activity, and cytotoxicity of new (4-(4-iodophenyl)thiazol-2-yl)hydrazine derivatives. Eur. J. Med. Chem.,  2012, 53, 246-253.
[http://dx.doi.org/10.1016/j.ejmech.2012.04.006] [PMID:  22560629] 
[49] 
Evren, A.E.; Yurttaş, L.; Eksellı, B.; Akalın-Cıftcı, G. Novel Tri-substituted Thiazoles Bearing Piperazine Ring: Synthesis and evaluation of their anticancer activity. Lett. Drug Des. Discov.,  2019, 16(5), 547-555.
[http://dx.doi.org/10.2174/1570180815666180731122118] 
[50] 
Grunberg, E.; Leiwant, B. Antitubercular activity in vivo of nicotinaldehyde thiosemicarbazone and its isomers. Exp. Biol. Med.,  1951, 77(1), 47-50.
[http://dx.doi.org/10.3181/00379727-77-18673] [PMID:  14844390] 
[51] 
Anderson, F.E.; Duca, C.J.; Scudi, J.V. Some heterocyclic thiosemicarbazones. J. Am. Chem. Soc.,  1951, 73(10), 4967-4968.
[http://dx.doi.org/10.1021/ja01154a501] 
[52] 
Yurttaş, L.; Özkay, Y.; Kaplancıklı, Z.A.; Tunalı, Y.; Karaca, H. Synthesis and antimicrobial activity of some new hydrazone-bridged thiazole-pyrrole derivatives. J. Enzyme Inhib. Med. Chem.,  2013, 28(4), 830-835.
[http://dx.doi.org/10.3109/14756366.2012.688043] [PMID:  22651798] 
[53] 
Weller, L.E.; Sell, H.M.; Gottshall, R.Y. 3-Indolecarboxaldehyde thiosemicarbazone, a new antitubercular compound1. J. Am. Chem. Soc.,  1954, 76(7), 1959-1959.
[http://dx.doi.org/10.1021/ja01636a075] 
[54] 
Bernstein, J.; Yale, H.L.; Losee, K.; Holsing, M.; Martins, J.; Lott, W.A. The Chemotherapy of experimental tuberculosis. iii. the synthesis of thiosemicarbazones and related compounds1,2. J. Am. Chem. Soc.,  1951, 73(3), 906-912.
[http://dx.doi.org/10.1021/ja01147a007] 
[55] 
Jensen, K.A.; Jensen, C.L.; Frank, A.; Harvey, W.E.; Östling, S. Thiohydrazides and thiohydrazones: A new class of antibacterial substances. Acta Chem. Scand.,  1952, 6, 957-958.
[http://dx.doi.org/10.3891/acta.chem.scand.06-0957] 
[56] 
Puetzer, B.; Hamlin, W.E.; Katz, L. A Preparative method for thiosemicarbazones of aromatic aldehydes1. J. Am. Chem. Soc.,  1951, 73(6), 2958-2958.
[http://dx.doi.org/10.1021/ja01150a527] 
[57] 
Pignatello, R.; Mazzone, S.; Castelli, F.; Mazzone, P.; Raciti, G.; Mazzone, G. MAOI activity of thiosemicarbazides and related 2-thiazolylhydrazines. Pharmazie,  1994, 49(4), 272-276.
[PMID:  8197227] 
[58] 
Goldfarb, D.S. . Method for altering the lifespan of eukaryotic	organisms. US 8,642,660 B2,. 2014.
[59] 
Turan-Zitouni, G.; Altintop, M.D.; Ozdemir, A.; Kaplancikli, Z.A.; Kaplancikli, G.A.; Temel, H.E. Synthesis and evaluation of bis-thiazole derivatives as new anticancer agents. Eur. J. Med. Chem.,  2016, 107, 288-294.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.002] [PMID:  26599534] 
[60] 
Bahuguna, A.; Khan, I.; Bajpai, V.K.; Kang, S.C.S.C. MTT assay to evaluate the cytotoxic potential of a drug. Bangl J. Pharmacol,,  2017, 12(2)
[http://dx.doi.org/10.3329/bjp.v12i2.30892.]] 
[61] 
Eldeniz, A.U.; Mustafa, K.; Orstavik, D.; Dahl, J.E. Cytotoxicity of new resin-, calcium hydroxide- and silicone-based root canal sealers on fibroblasts derived from human gingiva and L929 cell lines. Int. Endod. J.,  2007, 40(5), 329-337.
[http://dx.doi.org/10.1111/j.1365-2591.2007.01211.x] [PMID:  17309743] 
[62] 
Theiszová, M.; Jantova, S.; Dragunova, J.; Grznarova, P.; Palou, M. Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomedical Papers,  2005, 149(2), 393-396.
[http://dx.doi.org/10.5507/bp.2005.066] [PMID:  16601796] 
[63] 
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods,  1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID:  6606682] 
[64] 
Keiser, K.; Johnson, C.C.; Tipton, D.A. Cytotoxicity of mineral trioxide aggregate using human periodontal ligament fibroblasts. J. Endod.,  2000, 26(5), 288-291.
[http://dx.doi.org/10.1097/00004770-200005000-00010] [PMID:  11199738] 
[65] 
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep.,  2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID:  28256516] 
[66] 
Daina, A.; Michielin, O.; Zoete, V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J. Chem. Inf. Model.,  2014, 54(12), 3284-3301.
[http://dx.doi.org/10.1021/ci500467k] [PMID:  25382374] 
[67] 
Daina, A.; Zoete, V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem,  2016, 11(11), 1117-1121.
[http://dx.doi.org/10.1002/cmdc.201600182] [PMID:  27218427] 
[68] 
Maestro, S. Version 10.6,2016.
[69] 
Kwarcinski, F.E.; Brandvold, K.R.; Phadke, S.; Beleh, O.M.; Johnson, T.K.; Meagher, J.L.; Seeliger, M.A.; Stuckey, J.A.; Soellner, M.B. Conformation-selective analogues of dasatinib reveal insight into kinase inhibitor binding and selectivity. ACS Chem. Biol.,  2016, 11(5), 1296-1304.
[http://dx.doi.org/10.1021/acschembio.5b01018] [PMID:  26895387] 
[70] 
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.,  2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID:  11259830] 
[71] 
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol.,  2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID:  17562483] 
[72] 
Zhang, Z-H.; Wu, H-M.; Deng, S-N.; Chai, R-X.; Mwenda, M.C.; Peng, Y-Y.; Cai, D.; Chen, Y. Synthesis and biological evaluation of 2,4-disubstituted thiazole amide derivatives as anticancer agent. Chem. Pap.,  2018, 73(2), 355-364.
[http://dx.doi.org/10.1007/s11696-018-0587-3] 
[73] 
Demirayak, S.; Yurttas, L.; Gundogdu-Karaburun, N.; Karaburun, A.C.; Kayagil, I. Synthesis and anti-cancer activity evaluation of new aurone derivatives. J. Enzyme Inhib. Med. Chem.,  2015, 30(5), 816-825.
[http://dx.doi.org/10.3109/14756366.2014.976568] [PMID:  25716125] 
[74] 
Evren, A.E.; Yurttas, L.; Ekselli, B.; Akalin-Ciftci, G. Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents. Phosphorus Sulfur,  2019, 194(8), 820-828.
[http://dx.doi.org/10.1080/10426507.2018.1550642] 
[75] 
Turan-Zitouni, G.; Yurtta, L.; Tabbi, A.; Akalin, G.; Temel, H.E.; Kaplancikli, Z.A. New thiazoline-tetralin derivatives and biological activity evaluation. Mol.,  2018, 23(1)E135
[http://dx.doi.org/10.3390/molecules23010135] [PMID:  29320423] 
[76] 
Saglik, B.N.; Sen, A.M.; Evren, A.E.; Cevik, U.A.; Osmaniye, D.; Kaya Cavusoglu, B.; Levent, S.; Karaduman, A.B.; Ozkay, Y.; Kaplancikli, Z.A. Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors. Z. Naturforsch. C J. Biosci.,  2020, 75(9-10), 353-362.

Cite As

Letters in Drug Design & Discovery

Design and Efficient Synthesis of Novel 4,5-Dimethylthiazole-Hydrazone Derivatives and their Anticancer Activity

Abstract

Graphical Abstract