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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Benzazole Substituted Iminocoumarins as Potential Antioxidants with Antiproliferative Activity

Author(s): Nataša Perin, Maja Cindrić, Peter Vervaeke, Sandra Liekens, Tomislav Mašek, Kristina Starčević* and Marijana Hranjec*

Volume 17, Issue 1, 2021

Published on: 18 December, 2019

Page: [13 - 20] Pages: 8

DOI: 10.2174/1573406416666191218101427

Price: $65

Abstract

Background: Benzazole and coumarin derivatives are one of the most privileged heterocyclic substructures in the medicinal chemistry with well-known biological features, which include a wide range of versatile biological activities as well as excellent spectroscopic characteristics thus offering their potential application in many research fields.

Objective: The prepared iminocoumarins were synthesized to evaluate their antioxidative potential by using ABTS and FRAP assays and in vitro antiproliferative activity.

Methods: A series of coumarin derivatives containing a 2-benzazole motif were synthesized and evaluated for their antioxidative capacity and antiproliferative activity. Their molecular structure incorporates a push-pull functionality: an electron donor donating group at the 7-position with an electron-withdrawing group, such as benzimidazole, benzothiazole and imidazopyridine fragment at the 3-position.

Results: The iminocoumarins bearing different substituents on 7-position were evaluated for their antiproliferative activity on tree cancer cells with only 4 compounds showing the antiproliferative activity. The most active derivative was N,N-diethylamino substituted benzimidazole derivative 4d and imidazo[4,5-b]pyridine analogue 6b, both also displayed selective activity toward CEM with submicromolar inhibitory concentration (0.059 μM; 0.17 ± 0.09, respectively). The inhibitory effect of 4d and 6b derivatives on the cell-cycle progression of HeLa cells was studied. A flow cytometric analysis of the HeLa cells indicated an appreciable cell-cycle arrest in a dose-dependent manner. Antioxidant properties were studied by ABTS and FRAP assays and obtained results revealed that the most promising antioxidant has proven to be compound 3b while other compounds, in general, showed moderate to very low antioxidative capacity in both assays.

Conclusion: Unsubstituted benzimidazole derivatives bearing hydroxyl group on iminocoumarin nuclei exhibited the most prominent antioxidant potential in ABTS assay (3b; 40.5 ± 0.01). The most significant and selective antiproliferative activity was displayed by compounds 4d and 6b (0.059 μM; 0.17 ± 0.09, respectively), which were chosen as lead compounds for further optimization and rational design to obtain more active and selective antiproliferative agents.

Keywords: Antioxidative capacity, antiproliferative activity, benzimidazoles, benzotiazoles, imidazo[4, 5-b]pyridines, iminocoumarins, spectroscopy.

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[1]
Murray, R.D.H.; Mendez, J.; Brown, S.A. The Natural Coumarins. Ocurrence, Chemistry and Biochemistry; Wiley: Chichester, 1982.
[2]
Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr. Med. Chem., 2005, 12(8), 887-916.
[http://dx.doi.org/10.2174/0929867053507315] [PMID: 15853704]
[3]
Kennedy, O´. R.; Thornes, R.D. Coumarins. Biology, applications and mode of action; John Wiley and Sons: Chichester, 1997.
[4]
Roussaki, M.; Kontogiorgis, C.A.; Hadjipavlou-Litina, D.; Hamilakis, S.; Detsi, A. A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant and lipoxygenase inhibitory activity. Bioorg. Med. Chem. Lett., 2010, 20(13), 3889-3892.
[http://dx.doi.org/10.1016/j.bmcl.2010.05.022] [PMID: 20627725]
[5]
Rice-Evans, C.A.; Miller, N.J.; Paganga, G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med., 1996, 20(7), 933-956.
[http://dx.doi.org/10.1016/0891-5849(95)02227-9] [PMID: 8743980]
[6]
Kostova, I. Synthetic and natural coumarins as cytotoxic agents. Curr. Med. Chem. Anticancer Agents, 2005, 5(1), 29-46.
[http://dx.doi.org/10.2174/1568011053352550] [PMID: 15720259]
[7]
Khan, K.M.; Iqbal, S.; Lodhi, M.A.; Maharvi, G.M.; Ullah, Z.; Choudhary, M.I.; Rahman, A.U.; Perveen, S. Biscoumarin: new class of urease inhibitors; economical synthesis and activity. Bioorg. Med. Chem., 2004, 12(8), 1963-1968.
[http://dx.doi.org/10.1016/j.bmc.2004.01.010] [PMID: 15051064]
[8]
Hwu, J.R.; Singha, R.; Hong, S.C.; Chang, Y.H.; Das, A.R.; Vliegen, I.; De Clercq, E.; Neyts, J. Synthesis of new benzimidazole-coumarin conjugates as anti-hepatitis C virus agents. Antiviral Res., 2008, 77(2), 157-162.
[http://dx.doi.org/10.1016/j.antiviral.2007.09.003] [PMID: 17977606]
[9]
Nagashima, R.; Levy, G.; Sarcione, E.J. Comparative pharmacokinetics of coumarin anticoagulants. 3. Factors affecting the distribution and elimination of bishydroxycoumarin (BHC) in isolated liver perfusion studies. J. Pharm. Sci., 1968, 57(11), 1881-1888.
[http://dx.doi.org/10.1002/jps.2600571112] [PMID: 4177835]
[10]
Yim, D.; Singh, R.P.; Agarwal, C.; Lee, S.; Chi, H.; Agarwal, R. A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells. Cancer Res., 2005, 65(3), 1035-1044.
[PMID: 15705905]
[11]
Payne, S.L.; Rodriguez-Aristegui, S.; Bardos, J.; Cano, C.; Golding, B.T.; Hardcastle, I.R.; Peacock, M.; Parveen, N.; Griffin, R.J. Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(12), 3649-3653.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.102] [PMID: 20472428]
[12]
Starcević, S.; Brožič, P.; Turk, S.; Cesar, J.; Rižner, T.L.; Gobec, S. Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1. J. Med. Chem., 2011, 54(1), 248-261.
[http://dx.doi.org/10.1021/jm101104z] [PMID: 21138273]
[13]
Kim, S.N.; Kim, N.H.; Park, Y.S.; Kim, H.; Lee, S.; Wang, Q.; Kim, Y.K. 7-Diethylamino-3(2′-benzoxazolyl)-coumarin is a novel microtubule inhibitor with antimitotic activity in multidrug resistant cancer cells. Biochem. Pharmacol., 2009, 77(12), 1773-1779.
[http://dx.doi.org/10.1016/j.bcp.2009.03.007] [PMID: 19428332]
[14]
Cao, D.; Liu, Y.; Yan, W.; Wang, C.; Bai, P.; Wang, T.; Tang, M.; Wang, X.; Yang, Z.; Ma, B.; Ma, L.; Lei, L.; Wang, F.; Xu, B.; Zhou, Y.; Yang, T.; Chen, L. Design, synthesis, and evaluation of in vitro and in vivo anticancer activity of 4-substituted coumarins: A novel class of potent tubulin polymerization inhibitors. J. Med. Chem., 2016, 59(12), 5721-5739.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00158] [PMID: 27213819]
[15]
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]
[16]
Sharma, P.C.; Sinhmar, A.; Sharma, A.; Rajak, H.; Pathak, D.P. Medicinal significance of benzothiazole scaffold: an insight view. J. Enzyme Inhib. Med. Chem., 2013, 28(2), 240-266.
[http://dx.doi.org/10.3109/14756366.2012.720572] [PMID: 23030043]
[17]
Racané, L.; Tralić-Kulenović, V.; Kraljević Pavelić, S.; Ratkaj, I.; Peixoto, P.; Nhili, R.; Depauw, S.; Hildebrand, M.P.; David-Cordonnier, M.H.; Pavelić, K.; Karminski-Zamola, G. Novel diamidino-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes: synthesis, antiproliferative and DNA binding properties. J. Med. Chem., 2010, 53(6), 2418-2432.
[http://dx.doi.org/10.1021/jm901441b] [PMID: 20170096]
[18]
Perin, N.; Nhili, R.; Cindrić, M.; Bertoša, B.; Vušak, D.; Martin-Kleiner, I.; Laine, W.; Karminski-Zamola, G.; Kralj, M.; David-Cordonnier, M.H.; Hranjec, M. Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties. Eur. J. Med. Chem., 2016, 122, 530-545.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.007] [PMID: 27448912]
[19]
Gorobets, N.Yu.; Abakumov, V.V.; Borisov, A.V.; Nikitchenko, V.M. Novel Aspects of the Reaction of 3-(Benzimidazol-2-yl)-2-iminocoumarins with Aromatic Aldehydes. Chem. Het. Comp., 2004, 40(3), 334-342.
[http://dx.doi.org/10.1023/B:COHC.0000028630.64934.8c]
[20]
Kovalenko, S.N.; Vasil’ev, M.V.; Sorokina, I.V.; Chernykh, V.P.; Turov, A.V.; Rudnev, S.A. Recyclization of 2-imino-2H-1-benzopyrans using nucleophilic reagents 3. Reaction of 2-iminocoumarin-3-carboxamides with o-phenylenediamines and o-amino(thio)-phenols. Chem. Het. Comp., 1999, 34(12), 1412-1415.
[http://dx.doi.org/10.1007/BF02317811]
[21]
Hammad, A.; El-Sayed, A.S.; Islam, I.E.; Shafik, N. Synthesis of 3-(2-benzimidazolyl)coumarins of anticipated biological activity. J. Chem. Soc. Pak., 1990, 12(4), 292-296.
[22]
Perin, N.; Alić, J.; Liekens, S.; Van Aerschot, A.; Vervaeke, P.; Gadakh, B.; Hranjec, M. Different positions of amide side chains on the benzimidazo[1,2-a]quinoline skeleton strongly influenced biological activity. New J. Chem., 2018, 42, 7096-7104.
[http://dx.doi.org/10.1039/C8NJ00416A]
[23]
Gülçin, I.; Huyut, Z.; Elmastas, M.; Aboul-Enein, H.Y. Radical scavenging and antioxidant activity of tannic acid. Arab. J. Chem., 2014, 3, 43-53.
[http://dx.doi.org/10.1016/j.arabjc.2009.12.008]
[24]
Tireli, M.; Starčević, K.; Martinović, T.; Pavelić, S.K.; Karminski-Zamola, G.; Hranjec, M. Antioxidative and antiproliferative activities of novel pyrido[1,2-a]benzimidazoles. Mol. Divers., 2017, 21(1), 201-210.
[http://dx.doi.org/10.1007/s11030-016-9702-y] [PMID: 27677735]
[25]
Benzie, I.F.F.; Strain, J.J. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal. Biochem., 1996, 239(1), 70-76.
[http://dx.doi.org/10.1006/abio.1996.0292] [PMID: 8660627]
[26]
Perin, N.; Roškarić, P.; Sović, I.; Boček, I.; Starčević, K.; Hranjec, M.; Vianello, R. Amino-substituted benzamide derivatives as promising antioxidant agents: a combined experimental and computational study. Chem. Res. Toxicol., 2018, 31(9), 974-984.
[http://dx.doi.org/10.1021/acs.chemrestox.8b00175] [PMID: 30109922]

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