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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Novel Benzimidazole Derivatives: Cytotoxic and Apoptotic Properties on Lung Cancer Cell Line

Author(s): Leyla Yurttaş*, Gülşen Akalin Çiftçi, Mehmet Onur Aksoy and Şeref Demirayak

Volume 17, Issue 10, 2020

Page: [1227 - 1236] Pages: 10

DOI: 10.2174/1570180817999200513091613

Price: $65

Abstract

Background: Benzimidazole derivatives are privileged molecules known to have a wide variety of biological activities. In medicinal chemistry, due to the ring’s structural similarity to nucleotides, its derivatives were investigated as new chemotherapeutic agents. Our research group have been studying 1,2-disubstituted benzimidazoles, including thiocarbamoyl group and their potential anticancer activity. Based on previous findings, we synthesized novel 1-[2-(4-substituted phenyl-2-oxoethyl)]-2-[(2/3/4-substituted phenylpiperidin-1-yl)thiocarbamoyl]benzimidazole derivatives (3a-o).

Methods: The obtained fifteen derivatives were studied on A549 adenocarcinomic human alveolar basal epithelial cell line and mouse L929 fibroblastic cell line to determine their cytotoxic activity. These compounds were also investigated to identify their apoptotic properties.

Results and Discussion: The structures of the compounds based on three different groups differ from each other with the phenyl substituents bonded to the piperazine ring. All of the compounds showed remarkable antitumor activity, but the first five compounds bearing non-substituted phenyl moiety exhibited selective cytotoxicity when compared in terms of potencies to the normal cell line.

Conclusion: Compounds 3j, 3m and 3n were identified as the most apoptotic derivatives; however, compounds 3e and 3h provoked apoptosis with the percentages of 10.6 and 10.9% and selective cytotoxicity.

Keywords: Benzimidazole, piperazine, anticancer activity, A549 lung cancer, cytotoxicity, apoptosis.

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[1]
Torre, L.A.; Siegel, R.L.; Jemal, A. Lung Cancer Statistics. Lung Cancer and Personalized Medicine: Current Knowledge and Therapies; Ahmad, A; Gadgeel, S., Ed.; Springer International Publishing: Cham, 2016, pp. 1-19.
[http://dx.doi.org/10.1007/978-3-319-24223-1_1]
[2]
Herbst, R.S.; Morgensztern, D.; Boshoff, C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689), 446-454.
[http://dx.doi.org/10.1038/nature25183] [PMID: 29364287]
[3]
Hirsch, F.R.; Scagliotti, G.V.; Mulshine, J.L.; Kwon, R.; Curran, W.J., Jr; Wu, Y-L.; Paz-Ares, L. Lung cancer: Current therapies and new targeted treatments. Lancet, 2017, 389(10066), 299-311.
[http://dx.doi.org/10.1016/S0140-6736(16)30958-8] [PMID: 27574741]
[4]
Mariappan, G.; Hazarika, R.; Alam, F.; Karki, R.; Patangia, U.; Nath, S. Synthesis and biological evaluation of 2-substituted benzimidazole derivatives. Arab. J. Chem., 2015, 8(5), 715-719.
[http://dx.doi.org/10.1016/j.arabjc.2011.11.008]
[5]
El Rashedy, A.A.; Aboul-Enein, H.Y. Benzimidazole derivatives as potential anticancer agents. Mini Rev. Med. Chem., 2013, 13(3), 399-407.
[PMID: 23190032]
[6]
Anand, K.; Wakode, S. Development of drugs based on benzimidazole heterocycle: Recent advancement and insights. IJCS, 2017, 5(2), 350-362.
[7]
Gaba, M.; Mohan, C. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: Recent advances and future directions. Med. Chem. Res., 2015, 25(2), 173-210.
[http://dx.doi.org/10.1007/s00044-015-1495-5]
[8]
Salahuddin; Shaharyar, M.; Mazumder, A., Benzimidazoles: A biologically active compounds. Arab. J. Chem., 2017, 10, S157-S173.
[http://dx.doi.org/10.1016/j.arabjc.2012.07.017]
[9]
Alaqeel, S.I. Synthetic approaches to benzimidazoles from o-phenylenediamine: A literature review. J. Saudi Chem. Soc., 2017, 21(2), 229-237.
[http://dx.doi.org/10.1016/j.jscs.2016.08.001]
[10]
Walia, R.; Hedaitullah, M.; Naaz, S.F.; Iqbal, K.; Lamba, H. Benzimidazole derivatives–an overview. IJRPC, 2011, 1(3), 565-574.
[11]
Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: A review. Bioorg. Med. Chem., 2012, 20(21), 6208-6236.
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[12]
Galal, S.A.; Abdelsamie, A.S.; Rodriguez, M.L.; Kerwin, S.M.; El Diwani, H.I. Synthesis and studying the antitumor activity of novel 5-(2-methylbenzimidazol-5-yl)-1, 3, 4-oxadiazole-2 (3H)-thiones. Eur. J. Chem., 2010, 1(2), 67-72.
[http://dx.doi.org/10.5155/eurjchem.1.2.67-72.1]
[13]
Sun, Y.; Gou, S.; Yin, R.; Jiang, P. Synthesis, antiproliferative activity and DNA binding study of mixed ammine/cyclohexylamine platinum(II) complexes with 1-(substituted benzyl) azetidine-3, 3-dicarboxylates. Eur. J. Med. Chem., 2011, 46(10), 5146-5153.
[http://dx.doi.org/10.1016/j.ejmech.2011.08.029] [PMID: 21875765]
[14]
Refaat, H.M. Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives. Eur. J. Med. Chem., 2010, 45(7), 2949-2956.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.022] [PMID: 20399544]
[15]
Yadav, S.; Narasimhan, B. Perspectives of benzimidazole derivatives as anticancer agents in the new era. Anticancer. Agents Med. Chem., 2016, 16(11), 1403-1425.
[http://dx.doi.org/10.2174/1871520616666151103113412]
[16]
Spasov, A.; Yozhitsa, I.; Bugaeva, L.; Anisimova, V. Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties (a review). Pharm. Chem. J., 1999, 33(5), 232-243.
[http://dx.doi.org/10.1007/BF02510042]
[17]
Purushottamachar, P.; Ramalingam, S.; Njar, V.C. Development of Benzimidazole Compounds for Cancer Therapy. In Chemistry and applications of benzimidazole and its derivatives; IntechOpen, 2019.
[18]
Narasimhan, B.; Sharma, D.; Kumar, P. Benzimidazole: A medicinally important heterocyclic moiety. Med. Chem. Res., 2010, 21(3), 269-283.
[http://dx.doi.org/10.1007/s00044-010-9533-9]
[19]
Arulmurugan, S.P.; Kavitha, H.; Sathishkumar, S.; Arulmozhi, R. Biologically active benzimidazole derivatives. Mini Rev. Org. Chem., 2015, 12(2), 178-195.
[http://dx.doi.org/10.2174/1570193X1202150225153403]
[20]
Barot, K.P.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Novel research strategies of benzimidazole derivatives: A review. Mini Rev. Med. Chem., 2013, 13(10), 1421-1447.
[http://dx.doi.org/10.2174/13895575113139990072] [PMID: 23544603]
[21]
Wang, H.; Yu, N.; Song, H.; Chen, D.; Zou, Y.; Deng, W.; Lye, P.L.; Chang, J.; Ng, M.; Sun, E.T.; Sangthongpitag, K.; Wang, X.; Wu, X.; Khng, H.H.; Fang, L.; Goh, S.K.; Ong, W.C.; Bonday, Z.; Stünkel, W.; Poulsen, A.; Entzeroth, M. N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: Design, synthesis, SAR studies, and in vivo antitumor activity. Bioorg. Med. Chem. Lett., 2009, 19(5), 1403-1408.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.041] [PMID: 19181524]
[22]
Liu, T.; Sun, C.; Xing, X.; Jing, L.; Tan, R.; Luo, Y.; Huang, W.; Song, H.; Li, Z.; Zhao, Y. Synthesis and evaluation of 2-[2-(phenylthiomethyl)-1H-benzo[d] imidazol-1-yl)acetohydrazide derivatives as antitumor agents. Bioorg. Med. Chem. Lett., 2012, 22(9), 3122-3125.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.061] [PMID: 22483608]
[23]
Sondhi, S.M.; Rani, R.; Singh, J.; Roy, P.; Agrawal, S.K.; Saxena, A.K. Solvent free synthesis, anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives. Bioorg. Med. Chem. Lett., 2010, 20(7), 2306-2310.
[http://dx.doi.org/10.1016/j.bmcl.2010.01.147] [PMID: 20188544]
[24]
Herbert, W. Benzimidazoles for the treatment of cancer.pdf. EP 2 698 367 Al., , 2010.
[25]
Yadav, G.; Ganguly, S. Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. Eur. J. Med. Chem., 2015, 97, 419-443.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.053] [PMID: 25479684]
[26]
Yurttas, L.; Demirayak, S.; Ciftci, G.A. cytotoxic, antiproliferative and apoptotic effects of new benzimidazole derivatives on A549 lung carcinoma and C6 glioma cell lines. Anticancer. Agents Med. Chem., 2015, 15(9), 1174-1184.
[http://dx.doi.org/10.2174/1871520615666150703122625] [PMID: 26138412]
[27]
Demirayak, Ş.; Yurttaş, L. Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives. J. Enzyme Inhib. Med. Chem., 2014, 29(6), 811-822.
[http://dx.doi.org/10.3109/14756366.2013.858142] [PMID: 24456294]
[28]
Demirayak, S.; Kayagil, I.; Yurttas, L. Synthesis of some 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives and investigation their anticancer activities. Drugs Future, 2007, 32, 109-110.
[29]
Demirayak, S.; Kayagil, I.; Yurttas, L. Microwave supported synthesis of some novel 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives and investigation of their anticancer activities. Eur. J. Med. Chem., 2011, 46(1), 411-416.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.007] [PMID: 21122952]
[30]
Yurttaş, L.; Demirayak, Ş.; Çiftçi, G.A.; Yıldırım, S.U.; Kaplancıklı, Z.A. Synthesis and biological evaluation of some 1,2-disubstituted benzimidazole derivatives as new potential anticancer agents. Arch. Pharm. (Weinheim), 2013, 346(5), 403-414.
[http://dx.doi.org/10.1002/ardp.201200452] [PMID: 23526768]
[31]
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]
[32]
Shrivastava, N.; Naim, M.J.; Alam, M.J.; Nawaz, F.; Ahmed, S.; Alam, O. Benzimidazole scaffold as anticancer agent: Synthetic approaches and structure-activity relationship. Arch. Pharm. (Weinheim), 2017, 350(6), e201700040
[http://dx.doi.org/10.1002/ardp.201700040] [PMID: 28544162]
[33]
Rashid, M.; Husain, A.; Shaharyar, M.; Sarafroz, M. Anticancer activity of new compounds using benzimidazole as a scaffold. Anticancer. Agents Med. Chem., 2014, 14(7), 1003-1018.
[http://dx.doi.org/10.2174/1871520614666140509153021]
[34]
Kanwal, A.; Saddique, F.A.; Aslam, S.; Ahmad, M.; Zahoor, A.F. benzimidazole ring system as a privileged template for anticancer agents. Pharm. Chem. J., 2018, 51(12), 1068-1077.
[http://dx.doi.org/10.1007/s11094-018-1742-4]
[35]
Akhtar, M.J.; Shahar Yar, M.; Sharma, V.K.; Khan, A.A.; Ali, Z.; Haider, M.R.; Pathak, A. Recent progress of benzimidazole hybrids for anticancer potential. Curr. Med. Chem., 2019, 26, 1-44.
[http://dx.doi.org/10.2174/0929867326666190808122929] [PMID: 31393240]
[36]
Singh, I.; Luxami, V.; Paul, K. Effective synthesis of benzimidazoles-imidazo[1,2-a]pyrazine conjugates: A comparative study of mono-and bis-benzimidazoles for antitumor activity. Eur. J. Med. Chem., 2019, 180, 546-561.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.042] [PMID: 31344614]

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