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Letters in Drug Design & Discovery


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

Research Article

New 2-Oxopyridine/2-Thiopyridine Derivatives Tethered to a Benzotriazole with Cytotoxicity on MCF7 Cell Lines and with Antiviral Activities

Author(s): Adel Mahmoud Attia, Ahmed Ibrahin Khodair*, Eman Abdelnasser Gendy, Mohammed Abu El-Magd and Yaseen Ali Mosa Mohamed Elshaier*

Volume 17, Issue 2, 2020

Page: [124 - 137] Pages: 14

DOI: 10.2174/1570180816666190220123547

Price: $65


Background: Perturbation of nucleic acids structures and confirmation by small molecules through intercalation binding is an intriguing application in anticancer therapy. The planar aromatic moiety of anticancer agents was inserted between DNA base pairs leading to change in the DNA structure and subsequent functional arrest.

Objective: The final scaffold of the target compounds was annulated and linked to a benzotriazole ring. These new pharmacophoric features were examined as antiviral and anticancer agents against MCF7 and their effect on DNA damage was also assessed.

Methods: A new series of fully substituted 2-oxopyridine/2-thioxopyridine derivatives tethered to a benzotriazole moiety (4a-h) was synthesized through Michael cyclization of synthesized α,β- unsaturated compounds (3a-e) with appropriate active methylene derivatives. The DNA damage study was assessed by comet assay. In silico DNA molecular docking was performed using Open Eye software to corroborate the experimental results and to understand molecule interaction at the atomic level.

Results: The highest DNA damage was observed in Doxorubicin, followed by 4h, then, 4b, 4g, 4f, 4e, and 4d. The docking study showed that compound 4h formed Hydrogen Bonds (HBs) as a standard ligand with GSK-3. Compound 4h was the most active compound against rotavirus Wa, HAVHM175, and HSV strains with a reduction of 30%, 40%, and 70%, respectively.

Conclusion: Compound 4h was the most active compound and could act as a prospective lead molecule for anticancer agent.

Keywords: Pyridin-2-ones, pyridin-2-thiones, benzotriazole, antitumor-antiviral, DNA-docking, open eye software.

Graphical Abstract
Mohamed Ahmed, M.S.; Farghaly, T.A. Antimicrobial Activity of [1, 2, 4] Triazolo [4, 3-a] pyrimidine and New Pyrido [3, 2-f][1, 4] thiazepine Derivatives. Lett. Org. Chem., 2018, 15(3), 183-190.
Lawung, R. 3-(1-adamantylthio)-4-phenylpyridine as a potential therapeutic for methicillin-resistant staphylococcus aureus. Lett. Drug Des. Discov., 2010, 7(9), 674-678.
Gottumukkala, R.V. Determination of catechin and epicatechin content in chocolates by high-performance liquid chromatography. International scholarly research n, 2014.
Chand, K. Synthesis of novel pyridin-2-(1H)-one, benzopyran-2 (1H)-one, and quinolin-2 (1H)-one derivatives & SAR study of their anticancer and antiplatelet activities. Bioorg. Med. Chem., 2013.
Abd Elhameid, M.K.; Ryad, N.; Al-Shorbagy, M.Y.; Mohammed, M.R.; Ismail, M.M.; El Meligie, S. Design, Synthesis and screening of 4,6-diaryl pyridine and pyrimidine derivatives as potential cytotoxic molecules. Chem. Pharm. Bull. (Tokyo), 2018, 66(10), 939-952.
[] [PMID: 30111667]
Ata, S.A.; Abu-Dari, K.I.; Tutunji, M.F.; Mubarak, M.S. Reversing the adverse biochemical effects in lead-intoxicated rats by N,N`- bis[(1,2-didehydro-1-hydroxy-2-thioxopyrid-4-yl)-carbonyl]- L-lysine. J. Trace Elem. Med. Biol., 2018, 50, 93-99.
[] [PMID: 30262322]
Lv, Z.; Sheng, C.; Wang, T.; Zhang, Y.; Liu, J.; Feng, J.; Sun, H.; Zhong, H.; Niu, C.; Li, K. Design, synthesis, and antihepatitis B virus activities of novel 2-pyridone derivatives. J. Med. Chem., 2010, 53(2), 660-668.
[] [PMID: 20000776]
Parreira, R.L.; Abrahão, O.r.; Galembeck, S.E. Conformational preferences of non-nucleoside HIV-1 reverse transcriptase inhibitors. Tetrahedron, 2001, 57(16), 3243-3253.
Hassan, G.S.; Kadry, H.H.; Abou-Seri, S.M.; Ali, M.M.; Mahmoud, A.E. Synthesis and in vitro cytotoxic activity of novel pyrazolo[3,4-d]pyrimidines and related pyrazole hydrazones toward breast adenocarcinoma MCF-7 cell line. Bioorg. Med. Chem., 2011, 19(22), 6808-6817.
[] [PMID: 22000322]
Cheng, Q.; Oritani, T.; Horiguchi, T.; Yamada, T.; Mong, Y. Synthesis and biological evaluation of novel 9-functional heterocyclic coupled 7-deoxy-9-dihydropaclitaxel analogue. Bioorg. Med. Chem. Lett., 2000, 10(5), 517-521.
[] [PMID: 10743961]
Li, Y-Z.; Li, C.J.; Pinto, A.V.; Pardee, A.B. Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol. Med., 1999, 5(4), 232-239.
[] [PMID: 10448645]
Abdel-Aziz, A.A. Novel and versatile methodology for synthesis of cyclic imides and evaluation of their cytotoxic, DNA binding, apoptotic inducing activities and molecular modeling study. Eur. J. Med. Chem., 2007, 42(5), 614-626.
[] [PMID: 17234303]
Ningegowda, R. Microwave-assisted solvent-free synthesis of N-alkyl benzotriazole derivatives: Antimicrobial studies. Lett. Drug Des. Discov., 2009, 6(7), 502-507.
Li, Z. Synthesis and anti-HIV evaluation of novel 1, 2, 4-triazole derivatives as potential non-nucleoside HIV-1 reverse transcriptase inhibitors. Lett. Drug Des. Discov., 2013, 10(1), 27-34.
Gado b, anticancer activity of newly designed and synthesised 5- arylidene hydantion, 2-thiohydantion derivatives MSC. THESIS, 2013.
Al Khabbas, M.H. Corrigendum to" Synthesis and characterization of new 1-hydroxy-2-pyridinethione derivatives: Their lead complexes and efficacy in the treatment of acute lead poisoning in rats"[J. Trace Elem. Med. Biol. 44 (December 2017) 209-217
Salem, M.E. Synthesis and DFT calculations of 2-thioxo-1, 2-dihydropyridine-3-carbonitrile as versatile precursors for novel pharmacophoric hybrid molecules. J. Mol. Struct., 2019, 1176, 19-30.
Mohsin, N.U.; Seebacher, W.; Faist, J.; Hochegger, P.; Kaiser, M.; Mäser, P.; Belaj, F.; Saf, R.; Kretschmer, N.; Alajlani, M.; Turek, I.; Brantner, A.; Bauer, R.; Bucar, F.; Weis, R. Synthesis of new 1-benzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities. Eur. J. Med. Chem., 2018, 143, 97-106.
[] [PMID: 29172086]
Elgemeie, G.H.; Fathy, N.M.; Farag, A.B.; Alkhursani, S.A. Design, synthesis, molecular docking and anti-hepatocellular carcinoma evaluation of novel acyclic pyridine thioglycosides. Nucleosides Nucleotides Nucleic Acids, 2018, 37(3), 186-198.
[] [PMID: 29608403]
Salem, M.E.; Darweesh, A.F.; Elwahy, A.H. 2-Mercapto-4, 6-disubstituted nicotinonitriles: Versatile precursors for novel mono-and bis. thienopyridines J. Sulfur Chem., 2018, 1-19.
Kumar, S. Design, synthesis and in vitro evaluation of novel anti- HIV 3-pyrazol-3-yl-pyridin-2-one analogs. In: Medicinal chemistry (Shariqah (United Arab Emirates)); , 2018.
Fearon, D.; Westwood, I.M.; van Montfort, R.L.M.; Bayliss, R.; Jones, K.; Bavetsias, V. Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition. Bioorg. Med. Chem., 2018, 26(11), 3021-3029.
[] [PMID: 29764757]
Heravi, M.M.; Hamidi, H. Recent advances in synthesis of 2-pyridones: A key heterocycle is revisited. J. Indian Chem. Soc., 2013, 10(2), 265-273.
Cantrell, W.R., Jr; Bauta, W.E.; Engles, T. Hydrogen peroxide promoted hydroxylation of haloarenes and heteroarenes. Tetrahedron Lett., 2006, 47(25), 4249-4251.
Earl, R.A.; Vollhardt, K.P.C. The preparation of 2 (1H)-pyridinones and 2, 3-dihydro-5 (1H)-indolizinones via transition metal mediated cocyclization of alkynes and isocyanates. A novel construction of the antitumor agent camptothecin. J. Org. Chem., 1984, 49(25), 4786-4800.
Heravi, M.M. 1, 4‐Diaza‐bicyclo [2, 2, 2] octane as a Novel and Efficient Catalyst for the Synthesis of 3, 4, 6‐Trisubstituted 2-Pyridone Derivatives. Chin. J. Chem., 2010, 28(4), 670-672.
Hosseini, H.; Bayat, M. Cyanoacetohydrazides in Synthesis of Heterocyclic Compounds. Top. Curr. Chem. (Cham), 2018, 376(6), 40.
[] [PMID: 30306359]
Dyachenko, V.D.; Dyachenko, I.V.; Nenajdenko, V.G. Cyanothioacetamide: a polyfunctional reagent with broad synthetic utility. Russ. Chem. Rev., 2018, 87(1), 1.
Luo, J. Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett., 2009, 273(2), 194-200.
[] [PMID: 18606491]
Shakoori, A.; Ougolkov, A.; Yu, Z.W.; Zhang, B.; Modarressi, M.H.; Billadeau, D.D.; Mai, M.; Takahashi, Y.; Minamoto, T. Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem. Biophys. Res. Commun., 2005, 334(4), 1365-1373.
[] [PMID: 16043125]
Ougolkov, A.V.; Fernandez-Zapico, M.E.; Savoy, D.N.; Urrutia, R.A.; Billadeau, D.D. Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res., 2005, 65, 2076-2081.
[ 10.1158/0008-5472.CAN-04-3642] [PMID: 15781615]
Zhou, W.; Wang, L.; Gou, S.M.; Wang, T.L.; Zhang, M.; Liu, T.; Wang, C.Y. shRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Lett., 2012, 316, 178-186.
[] [PMID: 22100174]
Farago, M.; Dominguez, I.; Landesman-Bollag, E.; Xu, X.; Rosner, A.; Cardiff, R.D.; Seldin, D.C. Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis. Cancer Res., 2005, 65(13), 5792-5801.
[] [PMID: 15994955]
McCubrey, J.A.; Steelman, L.S.; Bertrand, F.E.; Davis, N.M.; Sokolosky, M.; Abrams, S.L.; Montalto, G.; D’Assoro, A.B.; Libra, M.; Nicoletti, F.; Maestro, R.; Basecke, J.; Rakus, D.; Gizak, A.; Demidenko, Z.; Cocco, L.; Martelli, A.M. Cervello. M. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget, 2014, 5(10), 2881-2911.
[] [PMID: 24931005]
Kubic, J.D.; Mascarenhas, J.B.; Iizuka, T.; Wolfgeher, D.; Lang, D. GSK-3 promotes cell survival, growth, and PAX3 levels in human melanoma cells. Mol. Cancer Res., 2012, 10(8), 1065-1076.
[] [PMID: 22679108]
Dickey, A.; Schleicher, S.; Leahy, K.; Hu, R.; Hallahan, D.; Thotala, D.K. GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. J. Neurooncol., 2011, 104(1), 145-153.
[] [PMID: 21161565]
Beurel, E.; Blivet-Van Eggelpoël, MJ.; Kornprobst, M.; Moritz, S.; Delelo, R.; Paye, F.; Housset, C.; Desbois-Mouthon, C. Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochem. Pharmacol., 2009, 77(1), 54-65.
[ bcp.2008.09.026]
Ghattas, A.E-B.A.G.; Khodairy, A.; Moustafa, H.M.; Hussein, B.R.M. Synthesis and biological evaluation of some novel thienopyridines. J. Pharm. Appl. Chem., 2015, 1(1), 21-26.
Litvinov, V.P. The chemistry of 3-cyanopyridine-2 (1H)-chalcogenones. Russ. Chem. Rev., 2006, 75(7), 577-599.
Elgemeie, G.E.H.; Sherif, S.M.; Abd-el Al, F.A.E.M.; Elnagdi, M.H. Nitriles in heterocyclic synthesis: novel synthesis of 4H-thiopyran and of 2-hydroxy-6-pyridine thione derivatives. Zeitschrift für Naturforschung, 1986, 41(6), 781-783.
Geies, A.A.E.; Monem, M. Reinvestigation of the reaction of arylidene malononitrile with cyanothioacetamide: new approach for the synthesis of pyridine derivatives. Zeitschrift für Naturforschung. B, 1992, 47(10), 1438-1440.
Beak, P.; Covington, J.B.; Smith, S.G.; White, M.; Zeigler, J.M. Displacement of protomeric equilibriums by self-association: hydroxypyridine-pyridone and mercaptopyridine-thiopyridone isomer pairs. J. Org. Chem., 1980, 45(8), 1354-1362.
M., Flefel E.; Abbas, S.H.A.; Mageid, E.A, R.; A Zaghary W. Synthesis and cytotoxic effect of some novel 1, 2-dihydropyridin-3-carbonitrile and nicotinonitrile derivatives. Molecules, 2015, 21(1), 30.
[PMID: 26729087]
Elansary, A.K.; Moneer, A.A.; Kadry, H.H.; Gedawy, E.M. Synthesis and anticancer activity of some novel fused pyridine ring system. Arch. Pharm. Res., 2012, 35(11), 1909.
[] [PMID: 23212632]
Mohamed, M.S.; Zohny, Y.M.; El-Senousy, W.M.; El-Elaa, A.M.A. Synthesis and biological screening of novel pyrazoles and their precursors as potential antiviral agents. Pharmacophore, 2018, 9(1), 126-139.
Aguilar-Morante, D.; Morales-Garcia, J.A.; Sanz-SanCristobal, M.; Garcia-Cabezas, M.A.; Santos, A.; Perez-Castillo, A. Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8. PLoS One, 2010, 5(11) e13879
Ohishi, K.; Toume, K.; Arai, M.A.; Sadhu, S.K.; Ahmed, F.; Mizoguchi, T.; Itoh, M.; Ishibashi, M. Ricinine: A pyridone alkaloid from Ricinus communis that activates the Wnt signaling pathway through casein kinase 1α. Bio Org. Med. Chem., 2014, 22(17), 4597-4601.
[] [PMID: 25124862]
Maria, M.; Bargiotti, A.; Berthelsen, J.; Bertrand, J.A.; Bossi, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.; Croci, V.; D’Alessio, R.; Fasolini, M.; Fiorentini, F.; Forte, B.; Isacchi, A.; Martina, K.; Molinari, A.; Montagnoli, A.; Orsini, P.; Orzi, F.; Pesenti, E.; Pezetta, D.; Pillan, A.; Poggesi, I.; Roletto, F.; Scolaro, A.; Tato, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C.; Vanotti, E. First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J. Med. Chem., 2008, 52(2), 293-307.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[] [PMID: 2359136]
Simões, C.; Amoros, M.; Girre, L. Mechanism of antiviral activity of triterpenoid saponins. Phytother. Res., 1999, 13(4), 323-328.
[PMID: 10404540]
Mehdizadeh, S. Understanding cell toxicology: Principles and practice. E. Walum, K. Stenberg and D. Jenssen. Series in Biochemistry and Biotechnology. Ellis Horwood Ltd.: Chichester, England, 206. (1990), 1991, Wiley Online Library.
Wilson, A.P. Cytotoxicity and viability assays. Vol. 1. 2000: Oxford University Press, Oxford.
Schmidtke, M.; Knorre, C.; Blei, L.; Stelzner, A.; Birch-Hirschfeld, E. Penetration and antiviral activity of Coxsackievirus B3 (CVB3)-specific phosphorothioate oligodeoxynucleotides (PS-ODN). Nucleosides & nucleotides, 1998, 17(9-11), 1557-1566.
Forlani, L.; Cristoni, G.; Boga, C.; Todesco, P.E.; Vecchio, E.D.; Selva, S.; Monari, M. Reinvestigation of the tautomerism of some substituted 2-hydroxypyridines. ARKIVOC, 2002, 11, 198-215.
Vögeli, U.; Philipsborn, W.V. 13C and 1H NMR spectroscopic studies on the structure of N-methyl-3-pyridone and 3ë hydroxypyridine. Mag. Res. Chem., 1973, 5(12), 551-559.
Albert, A.; and Phillips, J.N. 264. Ionization constants of heterocyclic substances. Part II. Hydroxy-derivatives of nitrogenous six-membered ring-compounds. J. Chem. Soc.(Resumed), 1956, 1294-1304.
Frank, J.; Katritzky, A.R. Tautomeric pyridines. Part XV. Pyridone-hydroxypyridine equilibria in solvents of differing polarity. J. Chem. Soc., Perkin Trans. 2, 1976, (12), 1428-1431.
Penfold, B.R. The electron distribution in crystalline α-pyridone. Acta Crystallographica., 1953, 6(7), 591-600.
Ohms, U.; Guth, H.; Hellner, E.; Dannohl, H.; Schweig, A. 2-Pyridone, C5H5NO, crystal structure refinements at 295 K and 120 K, experimental and theoretical deformation density studies. Zeitschrift für Kristallographie-Crystalline Materials., 1984, 169(1-4), 185-200.
Aue, D.H.; Betowski, L.D.; Davidson, W.R.; Bowers, M.T.; Beak, P.; Lee, J. Gas-phase basicities of amides and imidates. Estimation of protomeric equilibrium constants by the basicity method in the gas phase. J. Amer. Chem. Soc., 1979, 101(6), 1361-1368.
Aksnes, D.W.; Kryvi, H. Substituent and solvent effects in the proton magnetic resonance (PMR) spectra of six 2-substituted pyridines. Acta Chem. Scand., 1972, 26(6), 2255-2266.
Cox, R.H.; Bothner-By, A.A. Proton magnetic resonance spectra of tautomeric substituted pyridines and their conjugate acids. J. Phys. Chem., 1969, 73(8), 2465-2468.
Gilad, Y.; Senderowitz, H. Docking studies on DNA intercalators. J. Chem. Inf. Model., 2013, 54(1), 96-107.
[] [PMID: 24303988]
Berger, I.; Su, L.; Spitzner, J.R.; Kang, C.; Burke, T.G.; and A., Rich Molecular structure of the halogenated anti-cancer drug iododoxorubicin complexed with d (TGTACA) and d (CGATCG). Nucleic Acids Res., 1995, 23(21), 4488-4494.
Colgrave, M.L.; Williams, H.E.; Searle, M.S. Structure of a drugë induced DNA të bulge: Implications for DNA frameshift mutations. Angew. Chem. Int. Ed. Engl., 2002, 41(24), 4754-4756.
[] [PMID: 12481349]
Williams, H.E.; Colgrave, M.L.; Searle, M.S. Drug recognition of a DNA single strand break. Eur. J. Biochem., 2002, 269(6), 1726-1733.
Adams, A.; Guss, J.M.; Collyer, C.A.; Denny, W.A.; Wakelin, L.P. Crystal structure of the topoisomerase II poison 9-amino-[N-(2-dimethylamino) ethyl] acridine-4-carboxamide bound to the DNA hexanucleotide d (CGTACG) 2. Biochemistry, 1999, 38(29), 9221-9233.
[] [PMID: 10413496]
(OpenEye Scientific Software, I.A.L.A.F.o.P., Al-Azhar university, Assuit, Egypt, PI: Yaseen A. M. M. Elshaier).

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