Novel Tri-substituted Thiazoles Bearing Piperazine Ring: Synthesis and Evaluation of their Anticancer Activity

Author(s): Asaf Evrim Evren*, Leyla Yurttaş, Busra Eksellı, Gulsen Akalın-Cıftcı.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 5 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Cancer cells are described as an unregulated growth and spread of abnormal cells. Recently, cancer has become the most important major reason for deaths in the world.

Methods: For anticancer activity, we have used the MTT method and determine the early/late apoptosis by flow cytometry.

Results: The title compounds were procured by reacting 2-chloro-N-[4-(pyridin-4-yl)thiazol-2- yl]acetamide with some substituted piperazine derivatives. The in vitro anticancer activity of synthesized compounds was tested against C6 rat glioma cells and A549 human lung carcinoma cells. As a result, the compounds 3d, 3e, 3f and 3g have shown anticancer activity against both cell line.

Conclusion: Specifically, compound 3f was determined as the most active compound against C6 rat glioma cells. Also, as understood, the core structure which is substituted with piperazine bridge, the heterocyclic aromatic derivatives are more active than phenyl or benzyl derivatives.

Keywords: Thiazole, azole, piperazine, acetamide, anticancer activity, phenyl, benzyl.

[1]
Asati, V.; Mahapatra, D.K.; Bharti, S.K. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur. J. Med. Chem., 2016, 109, 314-341.
[2]
Fitzmaurice, C. 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, 524-548.
[3]
Morigi, R.; Locatelli, A.; Leoni, A.; Rambaldi, M. Recent Patents on Thiazole Derivatives Endowed with Antitumor Activity. Recent Pat Anticancer Drug Discov., 2015, 10, 280-297.
[4]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer, 2013, 13, 714-726.
[5]
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.
[6]
Carbone, A.; Pennati, M.; Parrino, B.; Lopergolo, A.; Barraja, P.; Montalbano, A.; Spano, V.; Sbarra, S.; Doldi, V.; De Cesare, M. Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: synthesis and antitumor activity in peritoneal mesothelioma experimental models. J. Med. Chem., 2013, 56, 7060-7072.
[7]
Soares, M.I.; Brito, A.F.; Laranjo, M.; Paixao, J.A.; Botelho, M.F.; Pinho e Melo, T.M. Chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles with anti-breast cancer properties. Eur. J. Med. Chem., 2013, 60, 254-262.
[8]
Siddiqui-Jain, A.; Bliesath, J.; Macalino, D.; Omori, M.; Huser, N.; Streiner, N.; Ho, C.B.; Anderes, K.; Proffitt, C.; O’Brien, S.E. CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol. Cancer Ther., 2012, 11, 994-1005.
[9]
Rabalski, A.J.; Gyenis, L.; Litchfield, D.W. Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells. Clin. Cancer Res., 2016, 22, 2840-2847.
[10]
Rouf, A.; Tanyeli, C. Bioactive thiazole and benzothiazole derivatives. Eur. J. Med. Chem., 2015, 97, 911-927.
[11]
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., 2008, 341, 424-434.
[12]
Sashidhara, K.V.; Rao, K.B.; Kushwaha, V.; Modukuri, R.K.; Verma, R.; Murthy, P.K. Synthesis and antifilarial activity of chalcone-thiazole derivatives against a human lymphatic filarial parasite, Brugia malayi. Eur. J. Med. Chem., 2014, 81, 473-480.
[13]
Gan, L.L.; Fang, B.; Zhou, C.H. Synthesis of azole-containing piperazine derivatives and evaluation of their antibacterial, antifungal and cytotoxic activities. Bull. Korean Chem. Soc., 2010, 31, 3684-3692.
[14]
Stana, A.; Vodnar, D.C.; Tamaian, R.; Pirnau, A.; Vlase, L.; Ionut, I.; Oniga, O.; Tiperciuc, B. Design, synthesis and antifungal activity evaluation of new thiazolin-4-ones as potential lanosterol 14alpha-demethylase inhibitors. Int. J. Mol. Sci., 2017, 18, 177.
[15]
Rizk, O.H.; Shaaban, O.G.; Abdel Wahab, A.E. Synthesis of Oxadiazolyl, Pyrazolyl and Thiazolyl Derivatives of Thiophene-2-Carboxamide as Antimicrobial and Anti-HCV Agents. Open Med. Chem. J., 2017, 11, 38-53.
[16]
Abhale, Y.K.; Sasane, A.V.; Chavan, A.P.; Shekh, S.H.; Deshmukh, K.K.; Bhansali, S.; Nawale, L.; Sarkar, D.; Mhaske, P.C. Synthesis and antimycobacterial screening of new thiazolyl-oxazole derivatives. Eur. J. Med. Chem., 2017, 132, 333-340.
[17]
Yu, L.; Gan, X.; Zhou, D.; He, F.; Zeng, S.; Hu, D. Synthesis and antiviral activity of novel 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety. Molecules, 2017, 22, E658.
[18]
Hosseinzadeh, L.; Aliabadi, A.; Rahnama, M.; Sadeghi, H.M.M.; Khajouei, M.R. Synthesis and cytotoxic evaluation of some new 3-(2-(2-phenylthiazol-4-yl) ethyl)-quinazolin-4(3H) one derivatives with potential anticancer effects. Res. Pharm. Sci., 2017, 12, 290-298.
[19]
Radwan, R.R.; Zaher, N.H.; El-Gazzar, M.G. Novel 1,2,4-triazole derivatives as antitumor agents against hepatocellular carcinoma. Chem. Biol. Interact., 2017, 274, 68-79.
[20]
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.
[21]
Kasparkova, J.; Marini, V.; Najajreh, Y.; Gibson, D.; Brabec, V. DNA binding mode of the cis and trans geometries of new antitumor nonclassical platinum complexes containing piperidine, piperazine, or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines. Biochemistry, 2003, 42, 6321-6332.
[22]
Saeed, A.; Mahesar, P.A.; Channar, P.A.; Abbas, Q.; Larik, F.A.; Hassan, M.; Raza, H.; Seo, S.Y. Synthesis, molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase. Bioorg. Chem., 2017, 74, 187-196.
[23]
Xu, R.; Tian, Y.; Huang, S.; Yu, J.; Deng, Y.; Zhan, M.; Zhang, T.; Wang, F.; Zhao, L.; Chen, Y. Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor. Chem. Biol. Drug Des., 2017, 91, 172-180.
[24]
Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem., 2015, 97, 699-718.
[25]
Mangel, N.; Fudge, J.B.; Fitzpatrick, T.B.; Gruissem, W.; Vanderschuren, H. Vitamin B1 diversity and characterization of biosynthesis genes in cassava. J. Exp. Bot., 2017, 68, 3351-3363.
[26]
Phillips, O.A.; Udo, E.E.; Samuel, S.M. Synthesis and structure-antibacterial activity of triazolyl oxazolidinones containing long chain acyl moiety. Eur. J. Med. Chem., 2008, 43, 1095-1104.
[27]
Reddy, G.M.; Garcia, J.R.; Reddy, V.H.; de Andrade, A.M.; Camilo, A., Jr; Pontes Ribeiro, R.A.; de Lazaro, S.R. Synthesis, antimicrobial activity and advances in Structure-activity Relationships (SARs) of novel tri-substituted thiazole derivatives. Eur. J. Med. Chem., 2016, 123, 508-513.
[28]
Watkins, W.J.; Chong, L.; Cho, A.; Hilgenkamp, R.; Ludwikow, M.; Garizi, N.; Iqbal, N.; Barnard, J.; Singh, R.; Madsen, D. Quinazolinone fungal efflux pump inhibitors. Part 3: (N-methyl)piperazine variants and pharmacokinetic optimization. Bioorg. Med. Chem. Lett., 2007, 17, 2802-2806.
[29]
Becker, O.M.; Dhanoa, D.S.; Marantz, Y.; Chen, D.; Shacham, S.; Cheruku, S.; Heifetz, A.; Mohanty, P.; Fichman, M.; Sharadendu, A. An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. J. Med. Chem., 2006, 49, 3116-3135.
[30]
Bala, S.; Sharma, N.; Kajal, A.; Kamboj, S.; Saini, V. Mannich bases: An important pharmacophore in present scenario. Int. J. Med. Chem., 2014, 2014, 191072.
[31]
Lombardo, L.J.; Lee, F.Y.; Chen, P.; Norris, D.; Barrish, J.C.; Behnia, K.; Castaneda, S.; Cornelius, L.A.; Das, J.; Doweyko, A.M. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem., 2004, 47, 6658-6661.
[32]
Chen, J.; Lu, M.; Jing, Y.; Dong, J. The synthesis of L-carvone and limonene derivatives with increased antiproliferative effect and activation of ERK pathway in prostate cancer cells. Bioorg. Med. Chem., 2006, 14, 6539-6547.
[33]
Murty, M.S.R.; Ram, K.R.; Rao, B.R.; Rao, R.V.; Katiki, M.R.; Rao, J.V.; Pamanji, R.; Velatooru, L.R. Synthesis, characterization, and anticancer studies of S and N alkyl piperazine-substituted positional isomers of 1,2,4-triazole derivatives. Med. Chem. Res., 2013, 23, 1661-1671.
[34]
She, E.X.; Hao, Z. A novel piperazine derivative potently induces caspase-dependent apoptosis of cancer cells via inhibition of multiple cancer signaling pathways. Am. J. Transl. Res., 2013, 5, 622-633.
[35]
Patel, R.V.; Park, S.W. An evolving role of piperazine moieties in drug design and discovery. Mini Rev. Med. Chem., 2013, 13, 1579-1601.
[36]
Foroumadi, A.; Emami, S.; Rajabalian, S.; Badinloo, M.; Mohammadhosseini, N.; Shafiee, A. N-Substituted piperazinyl quinolones as potential cytotoxic agents: Structure-activity relationships study. Biomed. Pharmacother., 2009, 63, 216-220.
[37]
Liu, L.; Hussain, M.; Luo, J.; Duan, A.; Chen, C.; Tu, Z.; Zhang, J. Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors. Chem. Biol. Drug Des., 2017, 89, 420-427.
[38]
El-Miligy, M.M.; Abd El Razik, H.A.; Abu-Serie, M.M. Synthesis of piperazine-based thiazolidinones as VEGFR2 tyrosine kinase inhibitors inducing apoptosis. Fut Med. Chem., 2017, 9, 1709-1729.
[39]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth, 1983, 65, 55-63.
[40]
Keiser, K.; Johnson, C.C.; Tipton, D.A. Cytotoxicity of mineral trioxide aggregate using human periodontal ligament fibroblasts. J. Endod., 2000, 26, 288-291.
[41]
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2, 192-204.
[42]
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., 1997, 23, 3-25.
[43]
Molinspiration Calculation of Molecular Properties and Bioactivity Score.. http://www.molinspiration.com/cgi-bin/properties [Accessed on: 27.09.2017]
[44]
Cbligand BBB predictor web-based program. http://www.cbligand.
org/BBB/predictor.php [Accessed on: 27.09.2017]
[45]
Molsoft Drug-Likeness and molecular property prediction. http://molsoft.com/mprop/ [Accessed on: 27.09.2017]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 16
ISSUE: 5
Year: 2019
Page: [547 - 555]
Pages: 9
DOI: 10.2174/1570180815666180731122118
Price: $58

Article Metrics

PDF: 22
HTML: 2
EPUB: 1
PRC: 1