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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3β Enzyme Inhibition

Author(s): Carla S. Francisco, Clara L. Javarini, Iatahanderson de S. Barcelos , Pedro A.B. Morais, Heberth de Paula, Warley de S. Borges, Álvaro Cunha Neto and Valdemar Lacerda*

Volume 20, Issue 2, 2020

Page: [153 - 160] Pages: 8

DOI: 10.2174/1568026619666191019105349

Price: $65

Abstract

Background: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD.

Objective: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors.

Methods: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D].

Results: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97–49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224–6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity.

Conclusion: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

Keywords: Coumarin, Coumarin derivatives, Biological activity, GSK-3β, Enzymatic inhibition, Molecular docking.

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[1]
Kim, J.; Movassaghi, M. Biogenetically inspired syntheses of alkaloid natural products. Chem. Soc. Rev., 2009, 38(11), 3035-3050.
[http://dx.doi.org/10.1039/b819925f] [PMID: 19847339]
[2]
Gadakh, S.K.; Dey, S.; Sudalai, A. Rh-Catalyzed synthesis of coumarin derivatives from phenolic acetates and acrylates via C-H bond activation. J. Org. Chem., 2015, 80(22), 11544-11550.
[http://dx.doi.org/10.1021/acs.joc.5b01713] [PMID: 26509478]
[3]
Hamulakova, S.; Kozurkova, M.; Kuca, K. Coumarin derivatives in pharmacotherapy of alzheimer’s disease. Curr. Org. Chem., 2017, 21(7), 602-612.
[http://dx.doi.org/10.2174/1385272820666160601155411]
[4]
Matos, M.J.; Pérez-Cruz, F.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L.; Borges, F.; Olea-Azar, C. Remarkable antioxidant properties of a series of hydroxy-3-arylcoumarins. Bioorg. Med. Chem., 2013, 21(13), 3900-3906.
[http://dx.doi.org/10.1016/j.bmc.2013.04.015] [PMID: 23673214]
[5]
Sridhar Reddy, M.; Thirupathi, N.; Babu, M.H. Synthesis of substituted coumarins and 2-quinolinones by cycloisomerisation of (Hydroxy/Aminophenyl)Propargyl alcohols. European. J. Org. Chem., 2012, 29, 5803-5809.
[6]
Anand, P.; Singh, B.; Singh, N. A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg. Med. Chem., 2012, 20(3), 1175-1180.
[http://dx.doi.org/10.1016/j.bmc.2011.12.042] [PMID: 22257528]
[7]
Ghanei-Nasab, S.; Khoobi, M.; Hadizadeh, F.; Marjani, A.; Moradi, A.; Nadri, H.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and anticholinesterase activity of coumarin-3-carboxamides bearing tryptamine moiety. Eur. J. Med. Chem., 2016, 121, 40-46.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.014] [PMID: 27214510]
[8]
Vafadarnejad, F.; Mahdavi, M.; Karimpour-Razkenari, E.; Edraki, N.; Sameem, B.; Khanavi, M.; Saeedi, M.; Akbarzadeh, T. Design and synthesis of novel coumarin-pyridinium hybrids: In vitro cholinesterase inhibitory activity. Bioorg. Chem., 2018, 77, 311-319.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.013] [PMID: 29421707]
[9]
Karakaya, S.; Koca, M.; Sytar, O.; Dursunoglu, B.; Ozbek, H.; Duman, H.; Guvenalp, Z.; Kılıc, C.S. Antioxidant and anticholinesterase potential of ferulago cassia with farther bio-guided isolation of active coumarin constituents. S. Afr. J. Bot., 2019, 121, 536-542.
[http://dx.doi.org/10.1016/j.sajb.2019.01.020]
[10]
Tripathi, A.C.; Upadhyay, S.; Paliwal, S.; Saraf, S.K. Privileged scaffolds as MAO inhibitors: Retrospect and prospects. Eur. J. Med. Chem., 2018, 145, 445-497.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.003] [PMID: 29335210]
[11]
Tao, D.; Wang, Y.; Bao, X.Q.; Yang, B.B.; Gao, F.; Wang, L.; Zhang, D.; Li, L. Discovery of coumarin Mannich base derivatives as multifunctional agents against monoamine oxidase B and neuroinflammation for the treatment of Parkinson’s disease. Eur. J. Med. Chem., 2019, 173, 203-212.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.016] [PMID: 31005056]
[12]
Forde, J.E.; Dale, T.C. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell. Mol. Life Sci., 2007, 64(15), 1930-1944.
[http://dx.doi.org/10.1007/s00018-007-7045-7] [PMID: 17530463]
[13]
Kockeritz, L.; Doble, B.; Patel, S.; Woodgett, J.R. Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Curr. Drug Targets, 2006, 7(11), 1377-1388.
[http://dx.doi.org/10.2174/1389450110607011377] [PMID: 17100578]
[14]
Jope, R.S.; Johnson, G.V.W. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci., 2004, 29(2), 95-102.
[http://dx.doi.org/10.1016/j.tibs.2003.12.004] [PMID: 15102436]
[15]
Cohen, P.; Goedert, M. GSK3 inhibitors: development and therapeutic potential. Nat. Rev. Drug Discov., 2004, 3(6), 479-487.
[http://dx.doi.org/10.1038/nrd1415] [PMID: 15173837]
[16]
Gao, M.; Wang, M.; Zheng, Q.H. Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2017, 27(4), 740-743.
[http://dx.doi.org/10.1016/j.bmcl.2017.01.041] [PMID: 28119025]
[17]
He, Q.; Liu, J.; Lan, J.S.; Ding, J.; Sun, Y.; Fang, Y.; Jiang, N.; Yang, Z.; Sun, L.; Jin, Y.; Xie, S.S. Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation. Bioorg. Chem., 2018, 81, 512-528.
[http://dx.doi.org/10.1016/j.bioorg.2018.09.010] [PMID: 30245233]
[18]
Shi, X.L.; Wu, J.D.; Liu, P.; Liu, Z.P. Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer’s disease. Eur. J. Med. Chem., 2019, 167, 211-225.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.001] [PMID: 30772605]
[19]
Karami, B.; Kiani, M. ZrOCl2.8H2O/SiO2: An efficient and recyclable catalyst for the preparation of coumarin derivatives by pechmann condensation reaction. Catal. Commun., 2011, 14(1), 62-67.
[http://dx.doi.org/10.1016/j.catcom.2011.07.002]
[20]
Keri, R.S.; Hosamani, K.M.; Reddy, H.R.S. A solvent-free synthesis of coumarins using phosphotungstic acid as catalyst. Catal. Lett., 2009, 131(1–2), 321-327.
[http://dx.doi.org/10.1007/s10562-009-9940-z]
[21]
Santos-Contreras, R.J.; Martínez-Martínez, F.J.; García-Báez, E.V.; Padilla-Martínez, I.I.; Peraza, A.L.; Höpfl, H. carbonyl-carbonyl, carbon-yl-π and carbon-yl-halogen dipolar inter-actions as the directing motifs of the supra-molecular structure of ethyl 6-chloro-2- oxo-2h-chromene-3-carboxyl-ate and ethyl 6-bromo-2-oxo-2hchromene- 3- carboxyl-ate. acta crystallogr. Sect. C. Cryst. Struct. Commun., 2007, 63(4), 0239-0242.
[http://dx.doi.org/10.1107/S0108270107008712]
[22]
Quezada, E.; Delogu, G.; Picciau, C.; Santana, L.; Podda, G.; Borges, F.; García-Morales, V.; Viña, D.; Orallo, F. Synthesis and vasorelaxant and platelet antiaggregatory activities of a new series of 6-halo-3-phenylcoumarins. Molecules, 2010, 15(1), 270-279.
[http://dx.doi.org/10.3390/molecules15010270] [PMID: 20110890]
[23]
Matos, M.J.; Terán, C.; Pérez-Castillo, Y.; Uriarte, E.; Santana, L.; Viña, D. Synthesis and study of a series of 3-arylcoumarins as potent and selective monoamine oxidase B inhibitors. J. Med. Chem., 2011, 54(20), 7127-7137.
[http://dx.doi.org/10.1021/jm200716y] [PMID: 21923181]
[24]
Francisco, C.S.; Rodrigues, L.R.; Cerqueira, N.M.F.S.A.; Oliveira-Campos, A.M.F.; Rodrigues, L.M.; Esteves, A.P. Synthesis of novel psoralen analogues and their in vitro antitumor activity. Bioorg. Med. Chem., 2013, 21(17), 5047-5053.
[http://dx.doi.org/10.1016/j.bmc.2013.06.049] [PMID: 23886808]
[25]
Francisco, C.S.; Rodrigues, L.R.; Cerqueira, N.M.F.S.A.; Oliveira-Campos, A.M.F.; Esteves, A.P. Novel benzopsoralen analogues: synthesis, biological activity and molecular docking studies. Eur. J. Med. Chem., 2014, 87, 298-305.
[http://dx.doi.org/10.1016/j.ejmech.2014.09.066] [PMID: 25262050]
[26]
Francisco, C.S.; Rodrigues, L.R.; Cerqueira, N.M.F.S.A.; Oliveira-Campos, A.M.F.; Rodrigues, L.M. Synthesis of novel benzofurocoumarin analogues and their anti-proliferative effect on human cancer cell lines. Eur. J. Med. Chem., 2012, 47(1), 370-376.
[http://dx.doi.org/10.1016/j.ejmech.2011.11.005] [PMID: 22119152]
[27]
Kudale, A.A.; Kendall, J.; Warford, C.C.; Wilkins, N.D.; Bodwell, G.J. Hydrolysis-free synthesis of 3-aminocoumarins. Tetrahedron Lett., 2007, 48(29), 5077-5080.
[http://dx.doi.org/10.1016/j.tetlet.2007.05.088]
[28]
Tighe, A.; Ray-Sinha, A.; Staples, O.D.; Taylor, S.S. GSK-3 inhibitors induce chromosome instability. BMC Cell Biol., 2007, 8, 34.
[http://dx.doi.org/10.1186/1471-2121-8-34] [PMID: 17697341]
[29]
Martinez, A. Preclinical efficacy on GSK-3 inhibitors: towards a future generation of powerful drugs. Med. Res. Rev., 2008, 28(5), 773-796.
[http://dx.doi.org/10.1002/med.20119] [PMID: 18271054]
[30]
Lamers, M.B.A.C.; Antson, A.A.; Hubbard, R.E.; Scott, R.K.; Williams, D.H. Structure of the protein tyrosine kinase domain of C-terminal SRC kinase (CSK) in complex with staurosporine. J. Mol. Biol., 1999, 285(2), 713-725.
[31]
Bertrand, J.A.; Thieffine, S.; Vulpetti, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H.M.; Flocco, M. Structural characterization of the GSK-3β active site using selective and non-selective ATP-mimetic inhibitors. J. Mol. Biol., 2003, 333(2), 393-407.
[http://dx.doi.org/10.1016/j.jmb.2003.08.031] [PMID: 14529625]
[32]
Leclerc, S.; Garnier, M.; Hoessel, R.; Marko, D.; Bibb, J.A.; Snyder, G.L.; Greengard, P.; Biernat, J.; Wu, Y.Z.; Mandelkow, E.M.; Eisenbrand, G.; Meijer, L. Indirubins inhibit glycogen synthase kinase-3 β and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J. Biol. Chem., 2001, 276(1), 251-260.
[http://dx.doi.org/10.1074/jbc.M002466200] [PMID: 11013232]
[33]
Pandey, M.K.; DeGrado, T.R. Glycogen synthase kinase-3 (GSK-3)-targeted therapy and imaging. Theranostics, 2016, 6(4), 571-593.
[http://dx.doi.org/10.7150/thno.14334] [PMID: 26941849]

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