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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

Design, Synthesis, Biological Evaluation and In Silico Studies of Few Novel 2-Substituted Benzothiazole Derivatives as Potential EGFR Inhibitors

Author(s): Muhammad Mubeen, Suvarna Ganesh Kini*, Avinash Kumar and Karkala Sreedhara Ranganath Pai

Volume 16, Issue 8, 2019

Page: [961 - 971] Pages: 11

DOI: 10.2174/1570180816666181108112228

Price: $65

Abstract

Background: There is a great unmet medical need for new anticancer small molecule therapeutics. Exhaustive literature review suggests that benzothiazole derivatives have good potential to exhibit anticancer activity. Compounds that inhibit the kinase activity of EGFR are of potential interest as new antitumor agent.

Objective: To design, synthesize and carry out in silico along with biological evaluation of 2- substituted benzothiazole compounds with EGFR inhibitory activity.

Methods: Benzothiazole derivatives designed from molecular docking method for potential EGFR tyrosine kinase inhibition have been synthesized based on the docking results and characterized. Insilico studies were carried out to understand the mode of EGFR enzyme inhibition by our molecules. As a preliminary study, these compounds were first screened for antioxidant activity and then for anticancer activity against MCF-7 cell lines and A549 cell line.

Results: Compound B5 showed potent anticancer activity on MCF-7 cell line with IC50 value of 9.7µM and compound B8 showed significant anticancer activity on A549 cell line with IC50 value of 49.7μM in comparison with the standard drug Doxorubicin (IC50 = 1.4µM on MCF-7 and 1.0µM on A549 cell lines). In EGFR inhibitory activity B8 showed maximum activity on A549 cell line by inactivating 69.10% of EGFR phosphorylation and B7 showed maximum activity on MCF-7 cell line by inactivating 41.90% of EGFR phosphorylation in comparison with the reference drug Gefitinib. Molecular dynamics simulation studies suggest that benzothiazole derivative could also bind to allosteric site and inhibit the EGFR enzyme activity.

Conclusion: Reported compounds have shown potent anticancer activity through EGFR inhibition by possibly binding at allosteric site.

Keywords: Benzothiazole, synthesis, docking, antioxidant, anticancer, EGFR, breast cancer, MCF-7.

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[1]
Ferla, J.; Soerjomataram, I.; Ervik, M.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet].
[2]
Mortimer, G.C.; Wells, G.; Crochard, J.; Stone, L.E.; Bradshaw, D.T.; Stevens, F.G.M.; Westwell, D.A. Antitumor benzothiazoles. 261. 2-(3,4-dimethoxyphenyl)-5- fluorobenzothiazole (GW 610, NSC 721648), a simple fluorinated 2-arylbenzothiazole, shows potent and selective inhibitory activity against lung, colon, and breast cancer cell lines. J. Med. Chem., 2006, 49, 179-185.
[3]
Brantley, E.; Antony, S.; Kohlhagen, G.; Meng, H.L.; Agama, K.; Stinson, F.S.; Sausville, A.E.; Pommier, Y. Anti-tumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 breast cancer cells. Cancer Chemother. Pharmacol., 2006, 58, 62-72.
[4]
Liona, J.C.; Matthewsa, S.C.; Wellsa, G.; Bradshawa, D.T.; Stevensa, F.G.M.; Westwell, D.A. Antitumour properties of fluorinated benzothiazole-substituted hydroxycyclohexa-2,5- dienones (‘quinols’). Bioorg. Med. Chem. Lett., 2006, 16, 5005-5008.
[5]
Huanga, T.S.; Hseib, J.I.; Chen, C. Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles. Bioorg. Med. Chem., 2006, 14, 6106-6119.
[6]
O’Brien, E.S.; Browne, L.H.; Bradshaw, D.T.; Westwell, D.A.; Stevensa, F.G.M.; Laughton, A.C. Antitumor benzothiazoles. Frontier molecular orbital analysis predicts bioactivation of 2-(4- aminophenyl)benzothiazoles to reactive intermediates by cytochrome P4501A1. Org. Biomol. Chem., 2003, 1, 493-497.
[7]
Saeeda, S.; Rashida, N.; Jonesb, G.P.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem., 2010, 45, 1323-1331.
[8]
Elzahabi, S.A.H. Synthesis, characterization of some benzazoles bearing pyridine moiety: Search for novel anticancer agents. Eur. J. Med. Chem., 2011, 46, 4025-4036.
[9]
Hutchinson, I.; Bradshaw, T.D.; Matthews, C.S.; Stevens, M.F.G.; Westwell, A.D. Antitumour benzothiazoles. Part 20:† 3′cyano and 3′-alkynyl-substituted 2-(4′-aminophenyl)benzothiazoles as new potent and selective analogues. Bioorg. Med. Chem. Lett., 2003, 13(3), 471-474.
[10]
Gabr, T.M.; El-Gohary, S.N.; El-Bendary, R.E. El-Kerdawy. EGFR tyrosine kinase targeted compounds: In vitro antitumor activity and molecular modeling studies of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives. EXCLI J., 2014, 13, 573-585.
[11]
Easmon, J.; Purstinger, G.; Thies, K.S.; Heinisch, G. Synthesis, structure−activity relationships, and antitumor studies of 2- benzoxazolyl hydrazones derived from alpha-(n)-acyl heteroaromatics. J. Med. Chem., 2006, 49, 6343-6350.
[12]
Okaniwa, M.; Hirose, M.; Arita, T.; Yabuki, M.; Nakamura, A.; Takagi, T.; Kawamoto, T.; Uchiyama, N.; Sumita, A.; Tsutsumi, S.; Tottori, T.; Inui, Y.; Sang, B.C.; Yano, J.; Aertgeerts, K.; Yoshida, S.; Ishikawa, T. Discovery of a selective kinase inhibitor (TAK-632) targeting Pan-RAF inhibition: Design, synthesis, and biological evaluation of c-7-substituted 1,3-benzothiazole derivatives. J. Med. Chem., 2013, 56, 6478-6494.
[13]
D’Angelo, N.D.; Kim, T.S.; Andrews, K.; Booker, S.K.; Caenepeel, S.; Chen, K.; D’ Amico, D.; Freeman, D.; Jiang, J.; Liu, L.; McCarter, J.D.; San Miguel, T. Mullady, E.L.; Schrag, M.; Subramanian, R.; Tang, J.; Wahl, R.C.; Wang, L.; Whittington, D.A.; Wu, T.; Xi, N.; Xu, Y.; Yakowec, P.; Yang, K.; Zalameda, L.P.; Zhang, N.; Hughes, P.; Norman, M.H. Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem., 2011, 54, 1789-1811.
[14]
Liu, C.; Lin, J.; Pitt, S.; Zhang, R.F.; Sack, J.S.; Keifer, S.E.; Kish, K.; Doweyko, A.M.; Zhang, H.; Marathe, P.H.; Trzastos, J.; Mckinnon, M.; Dodd, J.H.; Barrish, J.C.; Schieven, G.L.; Leftheris, K. Benzothiazole based inhibitors of p38α MAP kinase. Bioorg. Med. Chem. Lett., 2008, 18, 1874-1879.
[15]
Noolvi, M.N.; Patel, H.M. Kaur. Benzothiazoles: Search for anticancer agents. Eur. J. Med. Chem., 2012, 54, 447-462.
[16]
El-Gohary, S.N.; El-Bendary, R.E.; El-Kerdawy, M.M.; Gabr, T.M. New series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives: Synthesis, antitumor activity, EGFR tyrosine kinase inhibitory activity and molecular modeling studies. Med. Chem. Res., 2015, 24, 860-878.
[17]
Singh, M.; Singh, K.M.; Thakur, B.; Ray, P.; Singh, K.S. Design and synthesis of novel schiff base-benzothiazole hybrids as potential epidermal growth factor receptor (EGFR) inhibitors. Anticancer. Agents Med. Chem., 2016, 16, 722-739.
[18]
Zhang, L.; Deng, S.X.; Zhang, C.; Meng, G.; Wu, J.F.; Li, X.S.; Zhao, C.Q.; Hu, C. Design, synthesis and cytotoxic evaluation of a novel series of benz[d]thiazole-2-carboxamide derivatives as potential EGFR inhibitors. Med. Chem. Res., 2017, 26, 2180-2189.
[19]
Singh, Y.; Kaur, B.; Kaur, A.; Gupta, K.V.; Gupta, M. Synthesis, spectral studies and biological activity of 2, 3-disubstituted imidazo [2, 1-b] benzothiazole derivatives. Indian J. Pharm. Biol. Res., 2018, 6(1), 1-8.
[20]
Yarden, Y.; Schlessinger, J. Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor. Biochemistry, 1987, 26(5), 1443-1451.
[21]
Martin, L.A. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaption of MCF-7 cells to long term estrogen deprivation. J. Biol. Chem., 2003, 278(33), 30458-30468.
[22]
Swain, S.P.; Gandhi, A.M.; Kini, G.S. Synthesis and evaluation of novel benzothiazole derivatives against human cervical cancer cell lines. Indian J. Pharm. Sci., 2007, 69(1), 46-50.
[23]
Choudhary, S.; Kini, G.S.; Mubeen, M. Antioxidant activity of novel coumarin substituted benzothiazole derivatives. Pharma Chem., 2013, 5, 213-222.
[24]
Dua, K.; Gude, R.P. Antiproliferative and antiproteolytic activity of pentoxifylline in cultures of B16F10 melanoma cells. Cancer Chemother. Pharmacol., 2006, 58, 195-202.
[25]
Likhar, R.; Perumal, P.; Kolhe, N.; Bhaskar, H.V.; Daroi, P. Synthesis and antioxidant activity of novel 2-aryl substituted benzothiazole derivatives. Int. J. Curr. Pharm. Res., 2015, 7(4), 34-37.
[26]
Hiyoshi, H.; Goto, N.; Tsuchiya, M.; Iida, K.; Nakajima, Y.; Hirata, N.; Kanda, Y.; Nagasawa, K.; Yanagisawa, J. 2-(4- Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase. Sci. Rep., 2014, 4, 7095.
[27]
Bhuva, H.A.; Kini, S.G. Synthesis, anticancer activity and docking of some substituted benzothiazoles as tyrosine kinase inhibitors. J. Mol. Graph. Model., 2010, 29(1), 32-37.
[28]
Devmurari, V.P.; Pandey, S.; Goyani, M.B.; Nandanwar, R.R.; Jivani, N.P.; Perumal, P. Synthesis and anticancer activity of some novel 2-substituted benzothiazole derivatives. Int. J. Chemtech Res., 2010, 2(1), 681-689.

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