Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

New Approaches for the Synthesis N-alkylated Benzo[b]thiophene Derivatives together with their Antiproliferative and Molecular Docking Studies

Author(s): Karam A. El-Sharkawy, Abeer A. Mohamed, Fatma O. Al Farouk and Rafat M. Mohareb*

Volume 23, Issue 12, 2023

Published on: 14 April, 2023

Page: [1429 - 1446] Pages: 18

DOI: 10.2174/1871520623666230316103419

Price: $65

Abstract

Background: 2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities.

Objective: The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship.

Methods: Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12e and 12f were studied.

Results: Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions.

Conclusion: Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12e and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds.

« Previous Next »
Graphical Abstract

[1]
Pathania, S.; Narang, R.K.; Rawal, R.K. Role of sulphur-heterocycles in medicinal chemistry: An update. Eur. J. Med. Chem., 2019, 180, 486-508.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.043] [PMID: 31330449]
[2]
Spanò, V.; Barreca, M.; Cilibrasi, V.; Genovese, M.; Renda, M.; Montalbano, A.; Galietta, L.J.V.; Barraja, P. Evaluation of fused pyrrolothiazole systems as correctors of mutant CFTR protein. Molecules, 2021, 26(5), 1275.
[http://dx.doi.org/10.3390/molecules26051275] [PMID: 33652850]
[3]
Saravanan, G.; Panneerselvam, T.; Alagarsamy, V.; Kunjiappan, S.; Parasuraman, P.; Murugan, I.; Dinesh, K.P. Design, graph theoretical analysis, density functionality theories, In silico modeling, synthesis, characterization and biological activities of novel thiazole fused quinazolinone derivatives. Drug Dev. Res., 2018, 79(6), 260-274.
[http://dx.doi.org/10.1002/ddr.21460] [PMID: 30244475]
[4]
Barreca, M.; Ingarra, A.M.; Raimondi, M.V.; Spanò, V.; De Franco, M.; Menilli, L.; Gandin, V.; Miolo, G.; Barraja, P.; Montalbano, A. Insight on pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepine systems as promising photosensitizers on malignant cells. Eur. J. Med. Chem., 2022, 237, 114399.
[http://dx.doi.org/10.1016/j.ejmech.2022.114399] [PMID: 35468516]
[5]
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]
[6]
Xu, T.; Wang, P.; Tian, J.; Qing, S.; Wang, S.; Huang, Y.; Xu, J.; Su, D.; Liu, J.; Miao, C. Pharmacological characterization of MT-1207, a novel multitarget antihypertensive agent. Acta Pharmacol. Sin., 2021, 42(6), 885-897.
[http://dx.doi.org/10.1038/s41401-021-00636-1] [PMID: 33782540]
[7]
Labbozzetta, M.; Barreca, M.; Spanò, V.; Raimondi, M.V.; Poma, P.; Notarbartolo, M.; Barraja, P.; Montalbano, A. Novel insights on [1,2]oxazolo[5,4‐e]isoindoles on multidrug resistant acute myeloid leukemia cell line. Drug Dev. Res., 2022, 83(6), 1331-1341.
[http://dx.doi.org/10.1002/ddr.21962] [PMID: 35749723]
[8]
Priestley, E.S.; Banville, J.; Deon, D.; Dubé, L.; Gagnon, M.; Guy, J.; Lapointe, P.; Lavallée, J.F.; Martel, A.; Plamondon, S.; Rémillard, R.; Ruediger, E.; Tremblay, F.; Posy, S.L.; Guarino, V.R.; Richter, J.M.; Li, J.; Gupta, A.; Vetrichelvan, M.; Balapragalathan, T.J.; Mathur, A.; Hua, J.; Callejo, M.; Guay, J.; Sum, C.S.; Cvijic, M.E.; Watson, C.; Wong, P.; Yang, J.; Bouvier, M.; Gordon, D.A.; Wexler, R.R.; Marinier, A. Discovery of two novel antiplatelet clinical candidates (BMS-986120 and BMS-986141) that antagonize protease-activated receptor 4. J. Med. Chem., 2022, 65(13), 8843-8854.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00359] [PMID: 35729784]
[9]
Atassi, G.; Tagnon, H.J. R17934-NSC 238159: A new antitumor drug-I. Effect on experimental tumors and factors influencing effectiveness. Eur. J. Cancer, 1975, 11(9), 599-607.
[http://dx.doi.org/10.1016/0014-2964(75)90092-4] [PMID: 1220975]
[10]
Ye, L.; He, J.; Hu, Z.; Dong, Q.; Wang, H.; Fu, F.; Tian, J. Antitumor effect and toxicity of Lipusu in rat ovarian cancer xenografts. Food Chem. Toxicol., 2013, 52, 200-206.
[http://dx.doi.org/10.1016/j.fct.2012.11.004] [PMID: 23149094]
[11]
Hama, S.; Utsumi, S.; Fukuda, Y.; Nakayama, K.; Okamura, Y.; Tsuchiya, H.; Fukuzawa, K.; Harashima, H.; Kogure, K. Development of a novel drug delivery system consisting of an antitumor agent tocopheryl succinate. J. Control. Release, 2012, 161(3), 843-851.
[http://dx.doi.org/10.1016/j.jconrel.2012.05.031] [PMID: 22634091]
[12]
Fakhr, I.M.I.; Radwan, M.A.A.; El-Batran, S.; Abd El-Salam, O.M.E.; El-Shenawy, S.M. Synthesis and pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2009, 44(4), 1718-1725.
[http://dx.doi.org/10.1016/j.ejmech.2008.02.034] [PMID: 18433939]
[13]
Bondock, S.; Fadaly, W.; Metwally, M.A. Synthesis and antimicrobial activity of some new thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety. Eur. J. Med. Chem., 2010, 45(9), 3692-3701.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.018] [PMID: 20605657]
[14]
Ryu, C.K.; Lee, S.K.; Han, J.Y.; Jung, O.J.; Lee, J.Y.; Jeong, S.H. Synthesis and antifungal activity of 5-arylamino-4,7-dioxobenzo[b]thiophenes. Bioorg. Med. Chem. Lett., 2005, 15(10), 2617-2620.
[http://dx.doi.org/10.1016/j.bmcl.2005.03.042] [PMID: 15863328]
[15]
Athri, P.; Wenzler, T.; Ruiz, P.; Brun, R.; Boykin, D.W.; Tidwell, R.; Wilson, W.D. 3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity. Bioorg. Med. Chem., 2010, 45, 1718-1725.
[PMID: 16442293]
[16]
Hudson, J.B.; Graham, E.A.; Miki, N.; Towers, G.H.N.; Hudson, L.L.; Rossi, R.; Carpita, A.; Neri, D. Photoactive antiviral and cytotoxic activities of synthetic thiophenes and their acetylenic derivatives. Chemosphere, 1989, 19(8-9), 1329-1343.
[http://dx.doi.org/10.1016/0045-6535(89)90080-5]
[17]
Molvi, K.I.; Vasu, K.K.; Yerande, S.G.; Sudarsanam, V.; Haque, N. Syntheses of new tetrasubstituted thiophenes as novel anti-inflammatory agents. Eur. J. Med. Chem., 2007, 42(8), 1049-1058.
[http://dx.doi.org/10.1016/j.ejmech.2007.01.007] [PMID: 17336429]
[18]
Kulandasamy, R.; Adhikari, A.V.; Stables, J.P. A new class of anticonvulsants possessing 6Hz activity: 3,4-Dialkyloxy thiophene bishydrazones. Eur. J. Med. Chem., 2009, 44(11), 4376-4384.
[http://dx.doi.org/10.1016/j.ejmech.2009.05.026] [PMID: 19556038]
[19]
Jung, H.J.; Song, Y.S.; Lim, C.J.; Park, E.H. Anti-inflammatory, anti-angiogenic and anti-nociceptive activities of an ethanol extract of Salvia plebeia R. Brown. J. Ethnopharmacol., 2009, 126(2), 355-360.
[http://dx.doi.org/10.1016/j.jep.2009.08.031] [PMID: 19715750]
[20]
Chi, W.O.; Hong-Chang, L. Antitumor antibiotics drug design. Part II. Synthesis of 4-ethylamido [5,(2′-thienyl)-2-thiophene] imidazole iron(II) complex, a new N2S2-metallocycle with a ‘built in’ intercalating moiety which causes DNA scissioning in vitro. Inorg. Chim. Acta, 1986, 125(4), 203-206.
[http://dx.doi.org/10.1016/S0020-1693(00)81212-8]
[21]
Friedman, D.C.S.; Friedman, P. A theoretical study of 2,2′;5′,2″-terthiophene (α-T) and its analogs. Part 1. Correlation of electronic structure and energies with herbicidal phototoxicity. J. Mol. Struct. theochem., 1995, 333(1-2), 71-78.
[http://dx.doi.org/10.1016/0166-1280(94)03930-J]
[22]
Parai, M.K.; Panda, G.; Chaturvedi, V.; Manju, Y.K.; Sinha, S. Thiophene containing triarylmethanes as antitubercular agents. Bioorg. Med. Chem. Lett., 2008, 18(1), 289-292.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.083] [PMID: 17997304]
[23]
Caridha, D.; Kathcart, A.K.; Jirage, D.; Waters, N.C. Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases. Bioorg. Med. Chem. Lett., 2010, 20(13), 3863-3867.
[http://dx.doi.org/10.1016/j.bmcl.2010.05.039] [PMID: 20627564]
[24]
Fear, G.; Komarnytsky, S.; Raskin, I. Protease inhibitors and their peptidomimetic derivatives as potential drugs. Pharmacol. Ther., 2007, 113(2), 354-368.
[http://dx.doi.org/10.1016/j.pharmthera.2006.09.001] [PMID: 17098288]
[25]
Al-Najjar, B.O.; Wahab, H.A.; Tengku, M.T.S.; Shu-Chien, A.C.; Ahmad, N.N.A.; Taha, M.O. Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling. Eur. J. Med. Chem., 2011, 46(6), 2513-2529.
[http://dx.doi.org/10.1016/j.ejmech.2011.03.040] [PMID: 21482446]
[26]
Mohareb, R.M.; Abbas, N.S.; Ibrahim, R.A. New approaches for the synthesis of thiophene derivatives with anti-tumor activities. Acta Chim. Slov., 2013, 60(3), 583-594.
[PMID: 24169713]
[27]
Mohareb, R.M.; El-Arab, E.Z.; El-Sharkawy, K.A. The reaction of cyanoacetic acid hydrazide with 2-acetylfuran: Synthesis of coumarin, pyridine, thiophene and thiazole derivatives with potential antimicrobial activities. Sci. Pharm., 2009, 77(2), 355-366.
[http://dx.doi.org/10.3797/scipharm.0901-20]
[28]
El-Sayed, N.N.E.; Abdelaziz, M.A.; Wardakhan, W.W.; Mohareb, R.M. The Knoevenagel reaction of cyanoacetylhydrazine with pregnenolone: Synthesis of thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole, pyran and pyridine derivatives with anti-inflammatory and anti-ulcer activities. Steroids, 2016, 107, 98-111.
[http://dx.doi.org/10.1016/j.steroids.2015.12.023] [PMID: 26772772]
[29]
Mohareb, R.M.; Megally Abdo, N.Y. Synthesis and cytotoxic evaluation of pyran, dihydropyridine and thiophene derivatives of 3-acetylcoumarin. Chem. Pharm. Bull., 2015, 63(9), 678-687.
[http://dx.doi.org/10.1248/cpb.c15-00115] [PMID: 26329861]
[30]
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]
[31]
Al-Suwaidan, I.A.; Abdel-Aziz, N.I.; El-Azab, A.S.; El-Sayed, M.A.A.; Alanazi, A.M.; El-Ashmawy, M.B.; Abdel-Aziz, A.A.M. Antitumor evaluation and molecular docking study of substituted 2-benzylidenebutane-1,3-dione, 2-hydrazonobutane-1,3-dione and trifluoromethyl-1H-pyrazole analogues. J. Enzyme Inhib. Med. Chem., 2015, 30(4), 679-687.
[http://dx.doi.org/10.3109/14756366.2014.960863] [PMID: 25472776]
[32]
Pogacic, V.; Bullock, A.N.; Fedorov, O.; Filippakopoulos, P.; Gasser, C.; Biondi, A.; Meyer-Monard, S.; Knapp, S.; Schwaller, J. Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity. Cancer Res., 2007, 67(14), 6916-6924.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0320] [PMID: 17638903]
[33]
Cheney, I.W.; Yan, S.; Appleby, T.; Walker, H.; Vo, T.; Yao, N.; Hamatake, R.; Hong, Z.; Wu, J.Z. Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorg. Med. Chem. Lett., 2007, 17(6), 1679-1683.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.086] [PMID: 17251021]
[34]
Mohareb, R.M.; Hassaneen, H.M.; Ahmed, N.A.M. New approaches for the synthesis thiophene, thiazole, pyran derivatives and their antitumor evaluations. Jacob J. Org. Chem., 2016, 1, 1-13.
[35]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34(2), 91-109.
[http://dx.doi.org/10.1002/ddr.430340203]
[36]
Boyd, M.R. Cancer Drug Discovery and Development, 2; Teicher, B.A., Ed.; Humana Press: Totowa, New Jersey, united states, 1997, pp. 23-43.
[37]
Garofalo, S.; Rosa, R.; Bianco, R.; Tortora, G. EGFR-targeting agents in oncology. Expert Opin. Ther. Pat., 2008, 18(8), 889-901.
[http://dx.doi.org/10.1517/13543776.18.8.889]
[38]
Abdel-Fattah, M.A.; El-Naggar, M.A.M.; Rashied, R.M.H.; Gary, B.D.; Piazza, G.A.; Abadi, A.H. Four-component synthesis of 1,2-dihydropyridine derivatives and their evaluation as anticancer agents. Med. Chem., 2012, 8(3), 392-400.
[http://dx.doi.org/10.2174/1573406411208030392] [PMID: 22530887]
[39]
Han, X.; Alu, A.; Liu, H.; Shi, Y.; Wei, X.; Cai, L.; Wei, Y. Biomaterial-assisted biotherapy: A brief review of biomaterials used in drug delivery, vaccine development, gene therapy, and stem cell therapy. Bioact. Mater., 2022, 17, 29-48.
[http://dx.doi.org/10.1016/j.bioactmat.2022.01.011] [PMID: 35386442]
[40]
Mendieta, I.; Rodríguez-Nieto, M.; Nuñez-Anita, R.E.; Menchaca-Arredondo, J.L.; García-Alcocer, G.; Berumen, L.C.; Laura Berumen, C. Ultrastructural changes associated to the neuroendocrine transdifferentiation of the lung adenocarcinoma cell line A549. Acta Histochem., 2021, 123(8), 151797.
[http://dx.doi.org/10.1016/j.acthis.2021.151797] [PMID: 34688180]
[41]
Gao, J.; Zhao, Y.; Wang, C.; Ji, H.; Yu, J.; Liu, C.; Liu, A. A novel synthetic chitosan selenate (CS) induces apoptosis in A549 lung cancer cells via the Fas/FasL pathway. Int. J. Biol. Macromol., 2020, 158, 689-697.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.05.016] [PMID: 32387597]
[42]
Nunhart, P.; Konkoľová, E.; Janovec, L.; Jendželovský, R.; Vargová, J.; Ševc, J.; Matejová, M.; Miltáková, B.; Fedoročko, P.; Kozurkova, M. Fluorinated 3,6,9-trisubstituted acridine derivatives as DNA interacting agents and topoisomerase inhibitors with A549 antiproliferative activity. Bioorg. Chem., 2020, 94, 103393.
[http://dx.doi.org/10.1016/j.bioorg.2019.103393] [PMID: 31679839]
[43]
Mohareb, R.M.; Samir, E.M.; Halim, P.A. Synthesis, and anti-proliferative, Pim-1 kinase inhibitors and molecular docking of thiophenes derived from estrone. Bioorg. Chem., 2019, 83, 402-413.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.067] [PMID: 30415021]
[44]
Javadi, F.; Tayebee, R. Preparation and characterization of ZnO/nanoclinoptilolite as a new nanocomposite and studying its catalytic performance in the synthesis of 2-aminothiophenes via Gewald reaction. Micropor. Mesopor. Mater., 2016, 231, 100-109.
[http://dx.doi.org/10.1016/j.micromeso.2016.05.025]
[45]
Han, Y.; Tang, W-Q.; Yan, C-G. Gewald-type reaction of double activated 2,3-diarylcyclopropanes with elemental sulfur for synthesis of polysubstituted 2-aminothiophenes. Tetrahedron Lett., 2014, 55(8), 1441-1443.
[http://dx.doi.org/10.1016/j.tetlet.2014.01.043]
[46]
Puterová, Z.; Krutošíková, A.; Végh, D. Gewald reaction: Synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC, 2010, 2010(1), 209-246.
[http://dx.doi.org/10.3998/ark.5550190.0011.105]
[47]
Mohareb, R.M.; Sherif, S.M.; Sami, A.M. Heterocyclic synthesis with isothiocyanates: A convenien synthesis of polyfunctionally substituted 2,3-dihydrothiazole, 2-(Pyrazol-4′-yl)-Thaizole, 5-(Thiazol-2′-yl)pyrimidine and Thiazolo-[3,2-a]pyridine derivatives. Phosphorous. Sulfur Silicon, 1995, 101, 57-65.
[http://dx.doi.org/10.1080/10426509508042499]
[48]
Mohareb, R.M.; Zohdi, H.F. Heterocyclic synthesis with isothiocyanate: An expeditious synthetic route for polyfunctionally substituted 3-(thiazol-2′-ylidene)pyridines and their fused derivatives. Tetrahedron, 1994, 50, 5807-5820.
[http://dx.doi.org/10.1016/S0040-4020(01)85648-9]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy