Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

Author(s): Rafat M. Mohareb*, Ensaf S. Alwan

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 10 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known.

Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules.

Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied.

Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities.

Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

Keywords: Arylhydrazone, thiophene, thiazole, pyrazole, cytotoxicity, tyrosine kinases.

[1]
Thanh, N.D.V.; Patra, S.; Clive, D.L.J. Formation ofmetaarylsulfanyl- andmeta- (alkylsulfanyl)phenols fromcyclohexane- 1,3-diones. Tetrahedron, 2018, 74, 4343-4350.
[http://dx.doi.org/10.1016/j.tet.2018.06.059]
[2]
Kumar, R.; Raghuvanshi, K.; Verma, R.V.; Singh, M.S. Application of cyclic-1,3-diketones in domino and multi-componentreactions: facile route to highly functionalized chromeno[2,3-d]pyrimidinones and dihydrobenzo[b]fluorenones under solvent-free conditions. Tetrahedron Lett., 2010, 51, 5933-5936.
[http://dx.doi.org/10.1016/j.tetlet.2010.09.017]
[3]
Ashry, E.S.; Awad, L.F.; El Kilany, Y.; Ibrahim, E.I. Dimedone: A versatile precursor for annulated heterocycles. Adv. Heterocycl. Chem., 2009, 98, 1-141.
[http://dx.doi.org/10.1016/S0065-2725(09)09801-8]
[4]
Saitoh, T.; Taguchi, K.; Hiraide, M. Derivatization of formaldehyde with dimedone and subsequent sorption on sodium dodecylsulfate/ alumina admicelles for fluorometric analysis. Anal. Sci., 2002, 18(11), 1267-1268.
[http://dx.doi.org/10.2116/analsci.18.1267] [PMID: 12458715]
[5]
Guom, X.; Wei, X.R.; Sun, R.; Xu, Y.J.; Chen, Y.; Ge, J.F. The optical properties of 9-amino-9H-xanthene derivatives in different pH and their application for biomarkers in lysosome and mitochondria. Sens. Actuators B Chem., 2019, 296, 126621.
[http://dx.doi.org/10.1016/j.snb.2019.05.098]
[6]
Li, Z.; Wang, W.; Jian, H.; Li, W.; Dai, B.; He, Li. Synthesis of 9- phenol-substituted xanthenes by cascade O-insertion/1,6- conjugatead addition of benzyne with ortho-hydroxyl phenylsubstituted para-quinonem ethides. Chin. Chem. Lett., 2019, 30, 386-388.
[http://dx.doi.org/10.1016/j.cclet.2018.04.003]
[7]
Guan-Wu, W.; Chun-Bao, M. Environmentally benign one-pot multi-component approaches to the synthesis of novel unsymmetrical 4-arylacridinediones. Green Chem., 2006, 8, 1080-1085.
[http://dx.doi.org/10.1039/b604064k]
[8]
James, L.D.; Richard, A.G.; Surya, K.D. An efficient one-pot synthesis of Polyhydro-quinoline derivatives through the Hantzsch four component condensation. J. Mol. Catal. Chem., 2006, 256, 309-311.
[http://dx.doi.org/10.1016/j.molcata.2006.03.079]
[9]
Majumdar, K.C.; Samanta, S.K. Aza- claisein rearrangement: synthesis of dimedone-annaleted unusual heterocycles. Tetrahedron, 2001, 57, 4955-4958.
[http://dx.doi.org/10.1016/S0040-4020(01)00405-7]
[10]
Majumdar, K.C.; Samanta, S.K. Sulfoxide- claisein rearrangement: synthesis of dimedone-annaleted unusual heterocycles. Tetrahedron, 2002, 58, 4551-4554.
[http://dx.doi.org/10.1016/S0040-4020(02)00396-4]
[11]
Yaragorla, S.; Pareek, A.; Dada, R. Regioselective annulation of propargyl alcohols with ambident-enols: A Ca(II)-catalyzed trisubstituted benzochromene synthesis. Tetrahedron Lett., 2017, 58, 4642-4647.
[http://dx.doi.org/10.1016/j.tetlet.2017.10.077]
[12]
Liu, H.G.; Chung-Shieh Wu, C.S.; Wang, J.F.; Yang, D.Y. Isomerization of enol esters derived from 2-acyl-1,3- cyclohexanediones: Mechanism and driving force. Tetrahedron Lett., 2003, 44, 3137-3141.
[http://dx.doi.org/10.1016/S0040-4039(03)00554-9]
[13]
Stefan Chassaing, S.; Simon Specklin, S.; Jean-Marc Weibel, J.M.; Patrick Pale, P. Vinyl triflates derived from 1,3-dicarbonyl compounds and analogs: Access and applications to organic synthesis. Tetrahedron, 2012, 68, 7245-7273.
[http://dx.doi.org/10.1016/j.tet.2012.05.107]
[14]
Feng, G.; Sun, C.; Xin, X.; Wan, R.; Liu, L. Cross-dehydrogenative coupling of 3,6-dihydro-2H-pyrans with 1,3-dicarbonyls and aryl moieties. Tetrahedron Lett., 2019, 60, 547-1550.
[http://dx.doi.org/10.1016/j.tetlet.2019.05.016]
[15]
Li, M.; Zhao, X.; Yang, W.; Zhong, F.; Yuan, L.; Ren, Q. Asymmetric synthesis and biological evaluation of 3-nitro-2H-chromenes as potential antibacterial agents. Tetrahedron Lett., 2018, 59, 3511-3515.
[http://dx.doi.org/10.1016/j.tetlet.2018.07.046]
[16]
Cui, Y.; Dang, Y.; Yang, Y.; Ji, R. Synthesis of novel oxazolidinone derivatives for antibacterial investigation. Curr. Sci., 2005, 83, 531.
[17]
Jae-Min, H.; Sung-Ho, Y.; Kang-Yeoun, J. Synthesis of oxazolidinone phosphonate derivatives, part II. Bull. Korean Chem. Soc., 2007, 28, 821-826.
[http://dx.doi.org/10.5012/bkcs.2007.28.5.821]
[18]
Jo, Y.W.; Im, W.B.; Rhee, J.K.; Shim, M.J.; Kim, W.B.; Choi, E.C. Synthesis and antibacterial activity of oxazolidinones containing pyridine substituted with heteroaromatic ring. Bioorg. Med. Chem., 2004, 12(22), 5909-5915.
[http://dx.doi.org/10.1016/j.bmc.2004.08.025] [PMID: 15498667]
[19]
Pae, A.N.; Kim, H.Y.; Joo, H.J.; Kim, B.H.; Cho, Y.S.; Choi, K.I.; Choi, J.H.; Koh, H.Y. Synthesis and in vitro activity of new oxazolidinone antibacterial agents having substituted isoxazoles. Bioorg. Med. Chem. Lett., 1999, 9(18), 2679-2684.
[http://dx.doi.org/10.1016/S0960-894X(99)00473-4] [PMID: 10509915]
[20]
Kawano, A.; Futaki, K.; Kuramochi, S.; Kazunori, K.; Tsubaki, K. Syntheses and properties of second-generation V-shaped xanthene dyes with piperidino group. Tetrahedron, 2017, 73, 7061-7066.
[http://dx.doi.org/10.1016/j.tet.2017.10.064]
[21]
Menchen, S.M.; Benson, S.C.; Lam, J.Y.L.; Zhen, W.; Sun, D.; Rosenblum, B.B.; Khan, S.H.; Taing, M. US Patent,, 2003, 6, 168.
[22]
Ahmad, M.; King, T.A.; Ko, D.K.; Cha, B.H.; Lee, J. Performance and photostability of xanthene and pyrromethene laser dyes in solgel phases. J. Phys. D Appl. Phys., 2002, 35, 1473.
[http://dx.doi.org/10.1088/0022-3727/35/13/303]
[23]
Knight, C.G.; Stephens, T. Xanthene-dye-labelled phosphatidylethanolamines as probes of interfacial pH. Studies in phospholipid vesicles. Biochem. J., 1989, 258(3), 683-687.
[http://dx.doi.org/10.1042/bj2580683] [PMID: 2471509]
[24]
Atmaca, U.; Kaya, R.; Karaman, H.S.; Çelik, M.; Gülçin, İ. Synthesis of oxazolidinone from enantiomerically enriched allylic alcohols and determination of their molecular docking and biologic activities. Bioorg. Chem., 2019, 88102980
[http://dx.doi.org/10.1016/j.bioorg.2019.102980] [PMID: 31174010]
[25]
Wang, T.L.; Qi, H.T.; Wang, X.C.; Quan, Z.J. Iodine-catalyzed direct allylation of chiral oxazolidinones by the amide-aldehyde alkene condensation. Tetrahedron Lett., 2019, 60, 1-5.
[http://dx.doi.org/10.1016/j.tetlet.2019.07.018]
[26]
Qaddoumi, M.G.; Phillips, O.A.; Kombian, S.B. A novel oxazolidinone derivative PH192 demonstrates anticonvulsant activity in vivo in rats and mice. Eur. J. Pharm. Sci., 2019, 130, 21-26.
[http://dx.doi.org/10.1016/j.ejps.2019.01.011] [PMID: 30639401]
[27]
Dewse, C.D.; Potter, C.G. Inhibitory effect of phenylbutazone and oxyphenbutazone on DNA synthesis in normal human bone marrow cells in vitro. J. Pharm. Pharmacol., 1975, 27(7), 523-526.
[http://dx.doi.org/10.1111/j.2042-7158.1975.tb09495.x] [PMID: 239158]
[28]
Ramazani, A.; Rezaei, A. Novel one-pot, four-component condensation reaction: an efficient approach for the synthesis of 2,5- disubstituted 1,3,4-oxadiazole derivatives by a Ugi-4CR/aza-Wittig sequence. Org. Lett., 2010, 12(12), 2852-2855.
[http://dx.doi.org/10.1021/ol100931q] [PMID: 20481612]
[29]
Ramazani, A.; Karimi, Z.; Souldozi, A.; Ahmadi, Y. Four component synthesis of 1,3,4-oxadiazole derivatives from N isocyaniminotriphenylphosphorane, aromatic carboxylic acids, aromatic bisaldehydes,and secondary amines. Turk. J. Chem., 2012, 36, 81-91.
[30]
Ramazani, A.; Rouhani, M.; Rezaei, A.; Shajari, N.; Souldozi, A. The reaction of (N-Isocyanimino)triphenylphosphorane with biacetyl in the presence of aromatic carboxylic acids: efficient onepotthree- component reaction for the synthesis of 3-(5-Aryl-1,3,4-oxadiazol-2-yl)-3-hydroxybutan-2-one derivatives. Helv. Chim. Acta, 2011, 94, 282-289.
[http://dx.doi.org/10.1002/hlca.201000219]
[31]
Al-Majid, A.M.; Islam, M.S.; Barakat, A.; Al-Qahtani, N.J.; Yousuf, S.; Choudhary, M.I. Tandem Knoevenagel-Michael reactions in aqueous diethylamine medium: A greener and efficient approachtowardbis- dimedone derivatives. Arab. J. Chem., 2017, 10, 185-193.
[http://dx.doi.org/10.1016/j.arabjc.2014.04.008]
[32]
Barakat, A.; Al-Majid, A.M.; Al-Ghamdi, A.M.; Mabkhot, Y.N.; Rafiq Hussain Siddiqui, M.; Ghabbour, H.A.; Fun, H.K. Tandem Aldol-Michael reactions in aqueous diethylamine medium: A greener and efficient approach to dimedone-barbituric acid derivatives. Chem. Cent. J., 2014, 8(1), 9.
[http://dx.doi.org/10.1186/1752-153X-8-9] [PMID: 24485059]
[33]
Barakat, A.; Al-Majid, A.M. AL-Najjar, H.J.; Mabkhot, Y.N.; Ghabbour, H.A.; Fun, H.K. An efficient and green procedure for synthesis of rhodanine derivatives by aldol-thia-Michael protocol using aqueous diethylamine medium. RSC Adv., 2013, 4, 4909-4916.
[http://dx.doi.org/10.1039/c3ra46551a]
[34]
Al-Najjar, H.J.; Barakat, A.; Al-Majid, A.M. Mabkhot, Y.N.; Ghabbour, H.A.; Fun, H.K. A greener, efficient approach to Michael addition of barbituric acid to nitroalkene in aqueous diethylamine medium. Molecules, 2014, 19, 1150-1162.
[http://dx.doi.org/10.3390/molecules19011150] [PMID: 24445342]
[35]
Al-Majid, A.M.; Barakat, A.; Al-Najjar, H.J.; Mabkhot, Y.N.; Ghabbour, H.A.; Fun, H.K. Tandem aldol-Michael reactions in aqueous diethylamine medium: A greener and efficient approach to bis-pyrimidine derivatives. Int. J. Mol. Sci., 2013, 14(12), 23762-23773.
[http://dx.doi.org/10.3390/ijms141223762] [PMID: 24317435]
[36]
Barakat, A.; Islam, M.S.; Al-Majid, A.M.; Al-Othman, Z.A. Highly enantioselective Friedel-Craftsalkylation of indoles with a, b unsaturated ketones with simple Cu(II)-oxazoline-imidazoline catalysts. Tetrahedron, 2013, 69, 5185-5192.
[http://dx.doi.org/10.1016/j.tet.2013.04.063]
[37]
Liu, L.; Siegmund, A.; Xi, N.; Kaplan-Lefko, P.; Rex, K.; Chen, A.; Lin, J.; Moriguchi, J.; Berry, L.; Huang, L.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S.F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.; Norman, M.H.; Harmange, J.C.; Dussault, I.; Kim, T.S. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin- 4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazole- 4-carboxamide (AMG 458). J. Med. Chem., 2008, 51(13), 3688-3691.
[http://dx.doi.org/10.1021/jm800401t] [PMID: 18553959]
[38]
Peach, M.L.; Tan, N.; Choyke, S.J.; Giubellino, A.; Athauda, G.; Burke, T.R., Jr; Nicklaus, M.C.; Bottaro, D.P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem., 2009, 52(4), 943-951.
[http://dx.doi.org/10.1021/jm800791f] [PMID: 19199650]
[39]
De Bacco, F.; Luraghi, P.; Medico, E.; Reato, G.; Girolami, F.; Perera, T.; Gabriele, P.; Comoglio, P.M.; Boccaccio, C. Induction of MET by ionizing radiation and its role in radio resistance and invasive growth of cancer. J. Natl. Cancer Inst., 2011, 103(8), 645-661.
[http://dx.doi.org/10.1093/jnci/djr093] [PMID: 21464397]
[40]
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]
[41]
Fink, S.L.; Cookson, B.T. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun., 2005, 73(4), 1907-1916.
[http://dx.doi.org/10.1128/IAI.73.4.1907-1916.2005] [PMID: 15784530]
[42]
Jonathan, B.B.; Georgina, A.H. New substructure filters for removal of Pan Assay Interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 2010(53), 2719-2740.
[43]
McGovern, S.L.; Caselli, E.; Grigorieff, N.; Shoichet, B.K. A common mechanism underlying promiscuous inhibitors from virtual and high-through put screening. J. Med. Chem., 2002, 45(8), 1712-1722.
[http://dx.doi.org/10.1021/jm010533y] [PMID: 11931626]
[44]
McGovern, S.L.; Shoichet, B.K. Kinase inhibitors: Not just for kinases anymore. J. Med. Chem., 2003, 46(8), 1478-1483.
[http://dx.doi.org/10.1021/jm020427b] [PMID: 12672248]
[45]
Feng, B.Y.; Shelat, A.; Doman, T.N.; Guy, R.K.; Shoichet, B.K. High-through put assays for promiscuous inhibitors. Nat. Chem. Biol., 2005, 1(3), 146-148.
[http://dx.doi.org/10.1038/nchembio718] [PMID: 16408018]
[46]
Feng, B.Y.; Shoichet, B.K. Synergy and antagonism of promiscuous inhibition in multiple-compound mixtures. J. Med. Chem., 2006, 49(7), 2151-2154.
[http://dx.doi.org/10.1021/jm060029z] [PMID: 16570910]
[47]
Metz, J.T.; Huth, J.R.; Hajduk, P.J. Enhancement of chemical rules for predicting compound reactivity towards protein thiol groups. J. Comput. Aided Mol. Des., 2007, 21(1-3), 139-144.
[http://dx.doi.org/10.1007/s10822-007-9109-z] [PMID: 17340041]
[48]
Huth, J.R.; Song, D.; Mendoza, R.R.; Black-Schaefer, C.L.; Mack, J.C.; Dorwin, S.A.; Ladror, U.S.; Severin, J.M.; Walter, K.A.; Bartley, D.M.; Hajduk, P.J. Toxicological evaluation of thiol reactive compounds identified using a la assay to detect reactive molecules by nuclear magnetic resonance. Chem. Res. Toxicol., 2007, 20(12), 1752-1759.
[http://dx.doi.org/10.1021/tx700319t] [PMID: 18001056]
[49]
Baell, J.; Walters, M.A. Chemistry: Chemical con artists foil drug discovery. Nature, 2014, 513(7519), 481-483.
[http://dx.doi.org/10.1038/513481a] [PMID: 25254460]
[50]
Dahlin, J.L.; Walters, M.A. The essential roles of chemistry in high-through put screening triage. Future Med. Chem., 2014, 6(11), 1265-1290.
[http://dx.doi.org/10.4155/fmc.14.60] [PMID: 25163000]
[51]
Pouliot, M.; Jeanmart, S. Pan assay interference compounds (PAINS) and other promiscuous compounds in antifungal research. J. Med. Chem., 2016, 59(2), 497-503.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00361] [PMID: 26313340]
[52]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. SAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[http://dx.doi.org/10.1021/ci300367a] [PMID: 23092397]
[53]
Verma, G.; Marella, A.; Shaquiquzzaman, M.; Akhtar, M.; Ali, M.R.; Alam, M.M. A review exploring biological activities of hydrazones. J. Pharm. Bioallied Sci., 2014, 6(2), 69-80.
[http://dx.doi.org/10.4103/0975-7406.129170] [PMID: 24741273]
[54]
Rollas, S.; Küçükgüzel, S.G. Biological activities of hydrazone derivatives. Molecules, 2007, 12(8), 1910-1939.
[http://dx.doi.org/10.3390/12081910] [PMID: 17960096]
[55]
de Miranda, A.S.; Bispo Júnior, W.; da Silva, Y.K.; Alexandre- Moreira, M.S.; Castro, R.P.; Sabino, J.R.; Lião, L.M.; Lima, L.M.; Barreiro, E.J. Design, synthesis, antinociceptive and anti inflammatory activities of novel piroxicam analogues. Molecules, 2012, 17(12), 14126-14145.
[http://dx.doi.org/10.3390/molecules171214126] [PMID: 23192189]
[56]
Gökçe, M.; Utku, S.; Küpeli, E. Synthesis and analgesic and anti inflammatory activities 6-substituted-3(2H)-pyridazinone-2-acetyl- 2-(p-substituted/nonsubstituted benzal)hydrazone derivatives. Eur. J. Med. Chem., 2009, 44(9), 3760-3764.
[http://dx.doi.org/10.1016/j.ejmech.2009.04.048] [PMID: 19535179]
[57]
Mohareb, R.M.; Abdallah, A.E.M. New approaches for the synthesis of pyrazole, thiophene, thieno[2,3-b]pyridine and thiazole derivatives together with their anti-tumor evaluations. Med. Chem. Res., 2014, 23, 564-579.
[http://dx.doi.org/10.1007/s00044-013-0664-7]
[58]
Mohareb, R.M.; Wardakhan, W.W.; Hamid, F.I. Synthesis and cytotoxicity of fused thiophene and pyrazole derivatives derived from 2-N-acetyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene. Med. Chem. Res., 2015, 24, 2043-2054.
[http://dx.doi.org/10.1007/s00044-014-1273-9]
[59]
Mohareb, R.M.; Zaki, M.Y.; Abbas, N.S. Synthesis, anti inflammatory and anti-ulcer evaluations of thiazole, thiophene, pyridine and pyran derivatives derived from androstenedione. Steroids, 2015, 98, 80-91.
[http://dx.doi.org/10.1016/j.steroids.2015.03.001] [PMID: 25759119]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 10
Year: 2020
Published on: 20 August, 2020
Page: [1209 - 1220]
Pages: 12
DOI: 10.2174/1871520620666200310093911
Price: $65

Article Metrics

PDF: 26
HTML: 1