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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

Synthesis of Novel 1,2-Dihydro-1,2,4-Triazin-6(5H)-one Derivatives as Anticancer Agents

Author(s): Tarawanti Verma, Manish Sinha and Nitin Bansal*

Volume 16, Issue 7, 2020

Page: [1116 - 1131] Pages: 16

DOI: 10.2174/1573407215666191022123310

Price: $65

Abstract

Introduction: Cancer is still an untreatable disease and the second leading cause of death globally. The heterocyclic compounds have always played a major role in the anticancer drug discovery program. 1,2,4-Triazine-6-ones is a heterocyclic privileged structure with diversified activities. In the presented study, 21 novel 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6 (5H)-one derivatives (13(a-k), 18(a-j) and 21(a1-a4, b)) have been synthesized and tested for their anticancer activity.

Methods: The 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one derivatives (13(a-k), 18(a-j) and 21(a1-a4, b) were synthesized by refluxing substituted-2-phenyloxazol-5(4H)-one and hydrazine derivatives. Substituted aldehydes were synthesized via Vilsmeier-Haack reaction, while substituted- 2-phenyloxazol-5(4H)-one derivatives were synthesized by Erlenmeyer Plochl azlactone synthesis. Twenty-one compounds were selected and screened at the National Cancer Institute (NCI), USA, for anticancer activity at a single high dose (10-5M) in full NCI 60 cell panel assay.

Results and Conclusion: The selected compounds (13a, 13b, 13c, 13f, 13h, 13i, 13j, 18h, 18i, 21a4) were found to be active against different cancer cell lines. The compound, 5-((5-chloro-3-methyl-1- phenyl-1H-pyrazol-4-yl)methylene)-2-(4-nitrobenzoyl)-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one (13a) was found to be a potent anti-cancer agent as electron-rich moiety on phenyl at position 2 of triazine nucleus, having a great impact on anticancer activity.

Keywords: Cancer, anticancer screening, hydrazide, triazine, erlenmeyer plochl azalactone.

Graphical Abstract

[1]
Balunas, M.J.; Kinghorn, A.D. Drug discovery from medicinal plants. Life Sci., 2005, 78(5), 431-441.
[http://dx.doi.org/10.1016/j.lfs.2005.09.012 ] [PMID: 16198377]
[2]
Al-Abdullah, E.S. Synthesis and anticancer activity of some novel tetralin-6-yl-pyrazoline, 2-thioxopyrimidine, 2-oxopyridine, 2-thioxo-pyridine and 2-iminopyridine derivatives. Molecules, 2011, 16(4), 3410-3419.
[http://dx.doi.org/10.3390/molecules16043410 ] [PMID: 21512449]
[3]
Abdel-Rahman, R.M.; Morsy, J.M.; Hanafy, F.; Amene, H.A. Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs: Part I. Pharmazie, 1999, 54(5), 347-351.
[PMID: 10368828]
[4]
Kumar, D.; Khan, S.I.; Ponnana, P.; Rawat, D.S. Triazine-pyrimidine based molecular hybrids: Synthesis, docking studies and evaluation of antimalarial activity. New J. Chem., 2014, 38(10), 5087-5095.
[http://dx.doi.org/10.1039/C4NJ00978A]
[5]
Sahu, S.; Ghosh, S.K.; Kalita, J.; Dutta, M.; Bhat, H.R. Design, synthesis and antimalarial screening of some hybrid 4-aminoquinoline-triazine derivatives against pf-DHFR-TS. Exp. Parasitol., 2016, 163, 38-45.
[http://dx.doi.org/10.1016/j.exppara.2016.01.010 ] [PMID: 26821296]
[6]
Shandilya, A.; Hoda, N.; Khan, S.; Jameel, E.; Kumar, J.; Jayaram, B. De novo lead optimization of triazine derivatives identifies potent antimalarials. J. Mol. Graph. Model., 2017, 71, 96-103.
[http://dx.doi.org/10.1016/j.jmgm.2016.10.022 ] [PMID: 27880887]
[7]
Kalita, J.M.; Ghosh, S.K.; Sahu, S.; Dutta, M. Rational design and microwave assisted synthesis of some novel phenyl thiazolyl clubbed s-triazine derivatives as antimalarial antifolate. Future J. Pharm. Sci., 2017, 3(1), 11-17.
[http://dx.doi.org/10.1016/j.fjps.2016.09.004]
[8]
Sharma, M.; Chauhan, K.; Chauhan, S.S.; Kumar, A.; Singh, S.V.; Saxena, J.K.; Agarwal, P.; Srivastava, K.; Kumar, S.R.; Puri, S.K.; Shah, P.; Siddiqi, M.I.; Chauhan, P.M.S. Synthesis of hybrid 4-anilinoquinoline triazines as potent antimalarial agents, their in silico modeling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors. New J. Chem., 2012, 3(1), 71-79.
[9]
Kidwai, M.; Goel, Y.; Kumar, R. Microwave assisted synthesis and antifungal activity of 1, 2, 4-triazine, 1, 2, 4-triazole, tetrazole and pyrazole derivatives. Indian J. Chem., 1998, 37B(2), 174-179.
[http://dx.doi.org/10.1002/chin.199840047]
[10]
Baldaniya, B.B.; Patel, P.K. Synthesis, antibacterial and antifungal activities of s-triazine derivatives. E-J. Chem., 2009, 6(3), 673-680.
[http://dx.doi.org/10.1155/2009/196309]
[11]
Saravanan, J.; Mohan, S.; Roy, J.J. Synthesis of some 3-substituted amino-4,5-tetramethylene thieno[2,3-d][ 1,2,3]-triazin-4(3H)-ones as potential antimicrobial agents. Eur. J. Med. Chem., 2010, 45(9), 4365-4369.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.061 ] [PMID: 20579782]
[12]
Al-Adiwish, W.M.; Abubakr, M.A.S.; Alarafi, N.M. Synthesis of new pyrazolo [5, 1-c] [1, 2, 4] triazines from 5-aminopyrazole and study biological activity and cytotoxicity. Int. J. Photochem. Photobiol., 2017, 2, 41-48.
[http://dx.doi.org/10.11648/j.cb.20170505.11]
[13]
Desai, N.C.; Makwana, A.H.; Senta, R.D. Synthesis, characterization and antimicrobial activity of some new 4-(4-(2-isonicotinoylhydrazinyl)-6-((aryl)amino)-1,3,5-triazin-2-ylamino)-N-(pyrimidin-2-yl) benzenesulfonamides. J. Saudi Chem. Soc., 2017, 21(1), S25-S34.
[http://dx.doi.org/10.1016/j.jscs.2013.09.006]
[14]
Desai, N.C.; Makwana, A.H.; Rajpara, K.M. Synthesis and study of 1,3,5-triazine based thiazole derivatives as antimicrobial agents. J. Saudi Chem. Soc., 2016, 20(S1), S334-S341.
[http://dx.doi.org/10.1016/j.jscs.2012.12.004]
[15]
Mewada, N.S.; Shah, D.R.; Lakum, H.P.; Chikhalia, K.H. Synthesis and biological evaluation of novel s-triazine based aryl/heteroaryl entities: Design, rationale and comparative study. J. Asso. Arab Uni. Basic Appl. Sci., 2016, 20, 8-18.
[http://dx.doi.org/10.1016/j.jaubas.2014.08.003]
[16]
Saleh, M.; Abbott, S.; Perron, V.; Lauzon, C.; Penney, C.; Zacharie, B. Synthesis and antimicrobial activity of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines. Bioorg. Med. Chem. Lett., 2010, 20(3), 945-949.
[http://dx.doi.org/10.1016/j.bmcl.2009.12.063 ] [PMID: 20053565]
[17]
Indorkar, D.; Parteti, A.; Chourasia, O.P. Limaye, SN. PC-Model computational studies of 4′, 6 -bis-(2, 4-dinitro-aniline)-(2′-arylamine)-s-triazine and biological activity studies. Int. J. Curr. Microbiol. Appl. Sci., 2013, 2(10), 283-292.
[18]
Aly, M.R.E.; Gobouri, A.A.; Abdel Hafez, S.H.; Saad, H.A. Synthesis, reactions, and biological activity of some triazine derivatives containing sulfa drug moieties. Bioorg. Khim., 2015, 41(4), 491-504.
[http://dx.doi.org/10.7868/S013234231504003X ] [PMID: 26615645]
[19]
Sztanke, K.; Pasternak, K.; Sztanke, M.; Kandefer-Szerszeń, M.; Kozioł, A.E.; Dybała, I. Crystal structure, antitumour and antimetastatic activities of disubstituted fused 1,2,4-triazinones. Bioorg. Med. Chem. Lett., 2009, 19(17), 5095-5100.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.036 ] [PMID: 19631534]
[20]
Zein, M.A.E.; El-Shenawy, A.I. An efficient synthesis of 1,2,4-triazine-6-one derivatives and their in vitro anticancer activity. Int. J. Pharmacol., 2016, 12(3), 188-194.
[http://dx.doi.org/10.3923/ijp.2016.188.194]
[21]
Mohareb, R.M.; Samir, E.M. The reaction of cyanoacetylhydrazine with chloroacetone: Synthesis of 1,2,4-triazine, 1,3,4-oxadiazine and their fused derivatives with antitumor activities. Open J. Med. Chem., 2012, 2(1), 1-9.
[http://dx.doi.org/10.4236/ojmc.2012.21001]
[22]
Abd El-All, A.S.; Hassan, A.S.; Osman, S.A.; Yosef, H.A.A.; Abdel-Hady, W.H.; El-Hashash, M.A.; Atta-Allah, S.R.; Ali, M.M.; El Rashedy, A.A. Synthesis, characterization and biological evaluation of new fused triazine derivatives based on 6-methyl-3-thioxo-1,2,4-triazin-5-one. Acta Pol. Pharm., 2016, 73(1), 79-92.
[PMID: 27008803]
[23]
Manohar, S.; Pepe, A.; Gerena, C.E.V.; Zayas, B.; Malhotra, S.V.; Rawat, D.S. Anticancer activity of 4-aminoquinoline-triazine based molecular hybrids. RSC Advances, 2014, 4(14), 7062-7067.
[http://dx.doi.org/10.1039/c3ra45333b]
[24]
Patel, A.B.; Chikhalia, K.H.; Kumari, P. An efficient synthesis of new thiazolidin-4-one fused s-triazines as potential antimicrobial and anticancer agents. J. Saudi Chem. Soc., 2014, 18(5), 646-656.
[http://dx.doi.org/10.1016/j.jscs.2014.02.002]
[25]
Cascioferro, S.; Parrino, B.; Spanò, V.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G. Synthesis and antitumor activities of 1,2,3-triazines and their benzo- and heterofused derivatives. Eur. J. Med. Chem., 2017, 142(142), 74-86.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.003 ] [PMID: 28615111]
[26]
Fu, D.J.; Song, J.; Hou, Y.H.; Zhao, R.H.; Li, J.H.; Mao, R.W.; Yang, J.J.; Li, P.; Zi, X.L.; Li, Z.H.; Zhang, Q.Q.; Wang, F.Y.; Zhang, S.Y.; Zhang, Y.B.; Liu, H.M. Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers. Eur. J. Med. Chem., 2017, 138, 1076-1088.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.011 ] [PMID: 28763643]
[27]
Lauria, A.; Alfio, A.; Bonsignore, R.; Gentile, C.; Martorana, A.; Gennaro, G.; Barone, G.; Terenzi, A.; Almerico, A.M. New benzothieno[3,2-d]-1,2,3-triazines with antiproliferative activity: Synthesis, spectroscopic studies, and biological activity. Bioorg. Med. Chem. Lett., 2014, 24(15), 3291-3297.
[http://dx.doi.org/10.1016/j.bmcl.2014.06.007 ] [PMID: 24986661]
[28]
Saad, H.A.; Youssef, M.M.; Mosselhi, M.A. Microwave assisted synthesis of some new fused 1,2,4-triazines bearing thiophene moieties with expected pharmacological activity. Molecules, 2011, 16(6), 4937-4957.
[http://dx.doi.org/10.3390/molecules16064937 ] [PMID: 21677606]
[29]
Irannejad, H.; Nadri, H.; Naderi, N.; Rezaeian, S.N.; Zafari, N.; Foroumadi, A.; Amini, M.; Khoobi, M. Anticonvulsant activity of 1,2,4-triazine derivatives with pyridyl side chain: Synthesis, biological, and computational study. Med. Chem. Res., 2015, 24, 2505-2513.
[http://dx.doi.org/10.1007/s00044-014-1315-3]
[30]
Sahu, M.; Siddiqui, N.; Naim, M.J.; Alam, O.; Yar, M.S.; Sharma, V.; Wakode, S. Design, synthesis and docking study of pyrimidine-triazine hybrids for GABA estimation in animal epilepsy models. Arch. Pharm. (Weinheim), 2017, 350(9)e1700146
[http://dx.doi.org/10.1002/ardp.201700146 ] [PMID: 28758238]
[31]
Amir, M.; Ali, I.; Hassan, M.Z.; Mulakayala, N. Design, synthesis, and biological evaluation of hydrazone incorporated 1,2,4-triazines as anticonvulsant agents. Arch. Pharm. (Weinheim), 2014, 347(12), 958-968.
[http://dx.doi.org/10.1002/ardp.201400045 ] [PMID: 25251582]
[32]
Irannejad, H.; Naderi, N.; Emami, S.; Ghadikolaei, R.Q.; Foroumadi, A.; Zafari, T.; Mazar-Atabaki, A.; Dadashpour, S. Microwave-assisted synthesis and anticonvulsant activity of 5,6-bisaryl-1,2,4-triazine-3-thiol derivatives. Med. Chem. Res., 2014, 23(5), 2503-2514.
[http://dx.doi.org/10.1007/s00044-013-0843-6]
[33]
Ahuja, P.; Siddiqui, N. Anticonvulsant evaluation of clubbed indole-1,2,4-triazine derivatives: A synthetic approach. Eur. J. Med. Chem., 2014, 80, 509-522.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.043 ] [PMID: 24813879]
[34]
Khan, A.A.; Siddiqui, N.; Akhtar, M.J.; Ali, Z.; Yar, M.S. Design, synthesis, and biological evaluation of 6-(2-aminosubstituted phenyl)-4-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-dione derivatives as anticonvulsant agents. Arch. Pharm. (Weinheim), 2016, 349(4), 277-292.
[http://dx.doi.org/10.1002/ardp.201500448 ] [PMID: 26996080]
[35]
Sztanke, K.; Pasternak, K.; Rzymowska, J.; Sztanke, M.; Kandefer-Szerszeń, M. Synthesis, structure elucidation and identification of antitumoural properties of novel fused 1,2,4-triazine aryl derivatives. Eur. J. Med. Chem., 2008, 43(5), 1085-1094.
[http://dx.doi.org/10.1016/j.ejmech.2007.07.009 ] [PMID: 17868955]
[36]
Wittman, M.D.; Carboni, J.M.; Yang, Z.; Lee, F.Y.; Antman, M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.; Discenza, L.; Frennesson, D.; Gottardis, M.M.; Greer, A.; Hurlburt, W.; Johnson, W.; Langley, D.R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.; Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.; Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.; Vyas, D.M. Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J. Med. Chem., 2009, 52(23), 7360-7363.
[http://dx.doi.org/10.1021/jm900786r ] [PMID: 19778024]
[37]
Zeman, E.M.; Brown, J.M.; Lemmon, M.J.; Hirst, V.K.; Lee, W.W.; Sr, S.R. -4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int. J. Radiat. Oncol. Biol. Phys., 1986, 12(7), 1239-1242.
[http://dx.doi.org/10.1016/0360-3016(86)90267-1 ] [PMID: 3744945]
[38]
Reddy, S.B.; Williamson, S.K. Tirapazamine: A novel agent targeting hypoxic tumor cells. Expert Opin. Investig. Drugs, 2009, 18(1), 77-87.
[http://dx.doi.org/10.1517/13543780802567250 ] [PMID: 19053884]
[39]
Pundeer, R.; Ranjan, P.; Pannu, K.; Prakash, O. One-pot synthesis of some new semicarbazone, thiosemicarbazone and hydrazone derivatives of 1-phenyl-3-arylpyrazole-4-carboxaldehyde from acetophenone phenylhydrazones using Vilsmeier-Haack reagent. Synth. Commun., 2009, 39(2), 316-324.
[http://dx.doi.org/10.1080/00397910802372582]
[40]
Kaushik, D.; Khan, S.A.; Chawla, G. Design & synthesis of 2-(substituted aryloxy)-5-(substituted benzylidene)-3-phenyl-2,5-dihydro-1H-[1,2,4] triazin-6-one as potential anticonvulsant agents. Eur. J. Med. Chem., 2010, 45(9), 3960-3969.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.051 ] [PMID: 20573424]
[41]
Sharma, C.; Thadhaney, B.; Pemawat, G.; Talesara, G.L. Synthesis of some novel hoxyphthalimide derivatives of pyrazolo[3,4-c]pyrazoles. Indian J. Chem., 2008, 47B(12), 1892-1897.
[42]
Datterl, B.; Tröstner, N.; Kucharski, D.; Holzer, W. Heterocyclic analogues of xanthone and xanthione. 1H-pyrano[2,3-c:6,5-c]dipyrazol-4(7H)-ones and thiones: synthesis and NMR data. Molecules, 2010, 15(9), 6106-6126.
[http://dx.doi.org/10.3390/molecules15096106 ] [PMID: 20877210]
[43]
Higashi, Y.; Jitsuiki, D.; Chayama, K.; Yoshizumi, M. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases. Recent Pat. Cardiovasc. Drug Discov., 2006, 1(1), 85-93.
[http://dx.doi.org/10.2174/157489006775244191 ] [PMID: 18221078]
[44]
Ahasan, N.B.; Islam, M.R. Cytotoxicity study of pyrazole derivatives. Bangladesh J. Pharmacol., 2007, 2(2), 81-87.
[45]
Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G. Tatchell, A.R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed; Longman Publisher: Singapore, 1996.
[46]
Kaushik, D.; Khan, S.A.; Chawla, G.; Kumar, S.N. ′-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] 2/4-substituted hydrazides: Synthesis and anticonvulsant activity. Eur. J. Med. Chem., 2010, 45(9), 3943-3949.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.049 ] [PMID: 20573423]
[47]
Prakash, O.; Pannu, K.; Naithania, R.; Kaur, H. One-pot synthesis of oxime derivatives of 1,3-diphenylpyrazole-4-carboxaldehydes from acetophenone phenylhydrazones using Vilsmeier-Haack reagent. Synth. Commun., 2006, 36(23), 3479-3485.
[http://dx.doi.org/10.1080/00397910600942941]
[48]
Kaushik, D.; Khan, S.A.; Chawla, G. Synthesis of (substituted benzamidostyryl) lH-benzimidazoles and their screening for antiinflammatory activity. Med. Chem. Res.,.
[http://dx.doi.org/10.1007/s00044-011-9552-1]

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