Generic placeholder image

Cardiovascular & Hematological Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Research Article

Monosubstituted Coumarins Inhibit Epinephrine-induced Platelet Aggregation

Author(s): Fausto Alejandro Jiménez-Orozco*, Sergio Galicia-Zapatero, Edgar López-López, José L. Medina-Franco, Fernando León Cedeño, Mirthala Flores-García, Ana María Mejia-Domínguez and Aurora de la Peña-Díaz

Volume 20, Issue 1, 2022

Published on: 27 April, 2021

Page: [43 - 51] Pages: 9

DOI: 10.2174/1871525719666210427132808

open access plus

Abstract

Aim: The aim of this study was to evaluate the in vitro effect of coumarin and 15 monosubstituted derivatives on the inhibition of human platelet aggregation induced by various proaggregatory agonists, particularly by epinephrine.

Background: The emergence of residual platelet reactivity during the use of conventional antiplatelet agents (acetylsalicylic acid and clopidogrel) is one of the main causes of double therapy´s therapeutic failure. Platelet adrenoceptors participate in residual platelet reactivity. Therefore, it is necessary to develop new antiplatelet agents that inhibit epinephrine-induced platelet aggregation as a new therapeutic strategy. Information on the antiplatelet activity of coumarins in inhibiting epinephrine-induced aggregation is limited.

Objective: The objective of this study was to establish the structure-activity relationship (SAR) of coumarin derivatives with hydroxy, methoxy, and acetoxy groups in different positions of the coumarin nucleus to identify the most active molecules. Moreover, this study aimed to use in silico studies to suggest potential drug targets to which the molecules bind to produce antiplatelet effects.

Methods: The platelet aggregation was performed using a Lumi-aggregometer; the inhibitory activity of 16 compounds were evaluated by inducing the aggregation of human platelets (250 × 103/μl) with epinephrine (10 μM), collagen (2 μg/ml) or ADP (10 μM). The aggregation of control platelets was considered 100% of the response for each pro-aggregatory agonist.

Results: Eleven molecules inhibited epinephrine-induced aggregation, with 3-acetoxycoumarin and 7-methoxycoumarin being the most active. Only coumarin inhibited collagen-induced platelet aggregation, but no molecule showed activity when using ADP as an inducer.

Conclusions: In silico studies suggest that most active molecules might have antagonistic interactions in the α2 and β2 adrenoceptors. The antiplatelet actions of these coumarins have the potential to reduce residual platelet reactivity and thus contribute to the development of future treatments for patients who do not respond adequately to conventional agents.

Keywords: Antiplatelet agents, residual coumarin derivatives, epinephrine, molecular docking, platelet reactivity, SAR.

Graphical Abstract
[1]
Ding, L.; Peng, B. Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a systematic review and meta- analysis. Eur. J. Neurol., 2018, 25(10), 1276-1284.
[http://dx.doi.org/10.1111/ene.13695] [PMID: 29855121]
[2]
Fiolaki, A.; Katsanos, A.H.; Kyritsis, A.P.; Papadaki, S.; Kosmidou, M.; Moschonas, I.C.; Tselepis, A.D.; Giannopoulos, S. High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis. J. Neurol. Sci., 2017, 376, 112-116.
[http://dx.doi.org/10.1016/j.jns.2017.03.010] [PMID: 28431593]
[3]
Marketou, M.E.; Kintsurashvili, E.; Androulakis, N.E.; Kontaraki, J.; Alexandrakis, M.G.; Gavras, I.; Vardas, P.E.; Gavras, H. Blockade of platelet alpha2B-adrenergic receptors: a novel antiaggregant mechanism. Int. J. Cardiol., 2013, 168(3), 2561-2566.
[http://dx.doi.org/10.1016/j.ijcard.2013.03.051] [PMID: 23582690]
[4]
Marcinkowska, M.; Kotańska, M.; Zagórska, A.; Śniecikowska, J.; Kubacka, M.; Siwek, A.; Bucki, A.; Pawłowski, M.; Bednarski, M.; Sapa, J.; Starek, M.; Dąbrowska, M.; Kołaczkowski, M. Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 536-545.
[http://dx.doi.org/10.1080/14756366.2018.1437155] [PMID: 29482394]
[5]
Ignjatovic, V.; Pavlovic, S.; Miloradovic, V.; Andjelkovic, N.; Davidovic, G.; Djurdjevic, P.; Stolic, R.; Iric-Cupic, V.; Simic, I.; Ignjatovic, V.D.; Petrovic, N.; Smiljanic, Z.; Zdravkovic, V.; Simovic, S.; Jovanovic, D.; Nesic, J. Influence of different β-blockers on platelet aggregation in patients with coronary artery disease on dual antiplatelet therapy. J. Cardiovasc. Pharmacol. Ther., 2016, 21(1), 44-52.
[http://dx.doi.org/10.1177/1074248415581175] [PMID: 25868659]
[6]
Ilardi, F.; Gargiulo, G.; Schiattarella, G.G.; Giugliano, G.; Paolillo, R.; Menafra, G.; De Angelis, E.; Scudiero, L.; Franzone, A.; Stabile, E.; Perrino, C.; Cirillo, P.; Morisco, C.; Izzo, R.; Trimarco, V.; Esposito, G. Effects of carvedilol versus metoprolol on platelet aggregation in patients with acute coronary syndrome: The PLATE-BLOCK study. Am. J. Cardiol., 2018, 122(1), 6-11.
[http://dx.doi.org/10.1016/j.amjcard.2018.03.004] [PMID: 29747861]
[7]
Lake, B.G. Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food Chem. Toxicol., 1999, 37(4), 423-453.
[http://dx.doi.org/10.1016/S0278-6915(99)00010-1] [PMID: 10418958]
[8]
Abraham, K.; Wöhrlin, F.; Lindtner, O.; Heinemeyer, G.; Lampen, A. Toxicology and risk assessment of coumarin: focus on human data. Mol. Nutr. Food Res., 2010, 54(2), 228-239.
[http://dx.doi.org/10.1002/mnfr.200900281] [PMID: 20024932]
[9]
Raunio, H.; Rahnasto-Rilla, M. CYP2A6: genetics, structure, regulation, and function. Drug Metabol. Drug Interact., 2012, 27(2), 73-88.
[http://dx.doi.org/10.1515/dmdi-2012-0001] [PMID: 22706231]
[10]
Jiménez-Orozco, F.A.; Molina-Guarneros, J.A.; Mendoza-Patiño, N.; León-Cedeño, F.; Flores-Pérez, B.; Santos-Santos, E.; Mandoki, J.J. Cytostatic activity of coumarin metabolites and derivatives in the B16-F10 murine melanoma cell line. Melanoma Res., 1999, 9(3), 243-247.
[http://dx.doi.org/10.1097/00008390-199906000-00005] [PMID: 10465579]
[11]
Kasperkiewicz, K; Ponczek, MB; Owczarek, J; Guga, P; Elzbieta, B Antagonists of vitamin k-popular coumarin drugs and new synthetic and natural coumarin derivates. Molecules, 2020, 25(6) (1465).
[PMID: 17289685]
[12]
Zaragozá, C.; Monserrat, J.; Mantecón, C.; Villaescusa, L.; Zaragozá, F.; Álvarez-Mon, M. Antiplatelet activity of flavonoid and coumarin drugs. Vascul. Pharmacol., 2016, 87, 139-149.
[http://dx.doi.org/10.1016/j.vph.2016.09.002] [PMID: 27616636]
[13]
Chen, Y.L.; Wang, T.C.; Lee, K.H.; Tzeng, C.C. Synthesis of coumarin derivatives as inhibitors of platelet aggregation. Helv. Chim. Acta, 1996, 79, 651-657.
[http://dx.doi.org/10.1002/hlca.19960790308]
[14]
Di Braccio, M.; Grossi, G.; Roma, G.; Grazia Signorello, M.; Leoncini, G. Synthesis and in vitro inhibitory activity on human platelet aggregation of novel properly substituted 4-(1-piperazinyl)coumarins. Eur. J. Med. Chem., 2004, 39(5), 397-409.
[http://dx.doi.org/10.1016/j.ejmech.2003.12.010] [PMID: 15110966]
[15]
Kontogiorgis, C.; Nicolotti, O.; Mangiatordi, G.F.; Tognolini, M.; Karalaki, F.; Giorgio, C.; Patsilinakos, A.; Carotti, A.; Hadjipavlou-Litina, D.; Barocelli, E. Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives. J. Enzyme Inhib. Med. Chem., 2015, 30(6), 925-933.
[http://dx.doi.org/10.3109/14756366.2014.995180] [PMID: 25807297]
[16]
Macáková, K.; Řeháková, Z.; Mladěnka, P.; Karlíčková, J.; Filipský, T.; Říha, M.; Prasad, A.K.; Parmar, V.S.; Jahodář, L.; Pávek, P.; Hrdina, R.; Saso, L. In vitro platelet antiaggregatory properties of 4-methylcoumarins. Biochimie, 2012, 94(12), 2681-2686.
[http://dx.doi.org/10.1016/j.biochi.2012.09.006] [PMID: 22996069]
[17]
Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C.T. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J. Med. Chem., 2010, 53(1), 335-344.
[http://dx.doi.org/10.1021/jm901287j] [PMID: 19911821]
[18]
Jakubowski, M.; Szahidewicz-Krupska, E.; Doroszko, A. The human carbonic anhydrase II in platelets: an underestimated field of its activity. BioMed Res. Int., 2018, 20184548353
[http://dx.doi.org/10.1155/2018/4548353] [PMID: 30050931]
[19]
Spalding, A.; Vaitkevicius, H.; Dill, S.; MacKenzie, S.; Schmaier, A.; Lockette, W. Mechanism of epinephrine-induced platelet aggregation. Hypertension, 1998, 31(2), 603-607.
[http://dx.doi.org/10.1161/01.HYP.31.2.603] [PMID: 9461228]
[20]
Woodman, R.; Brown, C.; Lockette, W. Chlorthalidone decreases platelet aggregation and vascular permeability and promotes angiogenesis. Hypertension, 2010, 56(3), 463-470.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.154476] [PMID: 20625077]
[21]
Prieto-Martinez, F.D.; López-López, E.; Juárez-Mercado, E.K.; Medina-Franco, J.L. Computational drug design methods- current and future perspectives. In Silico drug design; Elsevier, 2019, pp. 19-44.
[http://dx.doi.org/10.1016/B978-0-12-816125-8.00002-X]
[22]
Flores-García, M.; Fernández-G, J.M.; León-Martínez, M.; Hernández-Ortega, S.; Pérez-Méndez, O.; Correa-Basurto, J.; Carreón-Torres, E.; Tolentino-López, L.E.; Ceballos-Reyes, G.M.; de la Peña-Díaz, A. The structures and inhibitory effects of Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-butylamine] and Diebud [N,N′-bis-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-1,4-butanediamine] on platelet aggregation. Steroids, 2012, 77(5), 512-520.
[http://dx.doi.org/10.1016/j.steroids.2012.01.010] [PMID: 22326683]
[23]
Burley, S.K.; Berman, H.M.; Bhikadiya, C.; Bi, C.; Chen, L.; Di Costanzo, L.; Christie, C.; Dalenberg, K.; Duarte, J.M.; Dutta, S.; Feng, Z.; Ghosh, S.; Goodsell, D.S.; Green, R.K.; Guranovic, V.; Guzenko, D.; Hudson, B.P.; Kalro, T.; Liang, Y.; Lowe, R.; Namkoong, H.; Peisach, E.; Periskova, I.; Prlic, A.; Randle, C.; Rose, A.; Rose, P.; Sala, R.; Sekharan, M.; Shao, C.; Tan, L.; Tao, Y.P.; Valasatava, Y.; Voigt, M.; Westbrook, J.; Woo, J.; Yang, H.; Young, J.; Zhuravleva, M.; Zardecki, C. RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res., 2019, 47(D1), D464-D474.
[http://dx.doi.org/10.1093/nar/gky1004] [PMID: 30357411]
[24]
Jones, D.T. Protein secondary structure prediction based on position-specific scoring matrices. J. Mol. Biol., 1999, 292(2), 195-202.
[http://dx.doi.org/10.1006/jmbi.1999.3091] [PMID: 10493868]
[25]
Hooft, R.W.; Vriend, G.; Sander, C.; Abola, E.E. Errors in protein structures. Nature, 1996, 381(6580), 272.
[http://dx.doi.org/10.1038/381272a0] [PMID: 8692262]
[26]
Michalsky, E.; Goede, A.; Preissner, R. Loops In Proteins (LIP)- a comprehensive loop database for homology modelling. Protein Eng., 2003, 16(12), 979-985.
[http://dx.doi.org/10.1093/protein/gzg119] [PMID: 14983078]
[27]
Canutescu, A.A.; Shelenkov, A.A.; Dunbrack, R.L., Jr A graph-theory algorithm for rapid protein side-chain prediction. Protein Sci., 2003, 12(9), 2001-2014.
[http://dx.doi.org/10.1110/ps.03154503] [PMID: 12930999]
[28]
López-López, E.; Barrientos-Salcedo, C.; Prieto-Martínez, F.D.; Medina-Franco, J.L. In silico tools to study molecular targets of neglected diseases: inhibition of TcSir2rp3, an epigenetic enzyme of Trypanosoma cruzi. Adv. Protein Chem. Struct. Biol., 2020, 122, 203-229.
[http://dx.doi.org/10.1016/bs.apcsb.2020.04.001] [PMID: 32951812]
[29]
Rasmussen, S.G.; DeVree, B.T.; Zou, Y.; Kruse, A.C.; Chung, K.Y.; Kobilka, T.S.; Thian, F.S.; Chae, P.S.; Pardon, E.; Calinski, D.; Mathiesen, J.M.; Shah, S.T.; Lyons, J.A.; Caffrey, M.; Gellman, S.H.; Steyaert, J.; Skiniotis, G.; Weis, W.I.; Sunahara, R.K.; Kobilka, B.K. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature, 2011, 477(7366), 549-555.
[http://dx.doi.org/10.1038/nature10361] [PMID: 21772288]
[30]
Taylor, L.; Vasudevan, S.R.; Jones, C.I.; Gibbins, J.M.; Churchill, G.C.; Campbell, R.D.; Coxon, C.H. Discovery of novel GPVI receptor antagonists by structure-based repurposing. PLoS One, 2014, 9(6)e101209
[http://dx.doi.org/10.1371/journal.pone.0101209] [PMID: 24971515]
[31]
Zhang, K.; Zhang, J.; Gao, Z.G.; Zhang, D.; Zhu, L.; Han, G.W.; Moss, S.M.; Paoletta, S.; Kiselev, E.; Lu, W.; Fenalti, G.; Zhang, W.; Müller, C.E.; Yang, H.; Jiang, H.; Cherezov, V.; Katritch, V.; Jacobson, K.A.; Stevens, R.C.; Wu, B.; Zhao, Q. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature, 2014, 509(7498), 115-118.
[http://dx.doi.org/10.1038/nature13083] [PMID: 24670650]
[32]
Chemical Computing Group Inc. Molecular Operating Environment (MOE), 2020. Available from: https://www.chemcomp.com/
[33]
Cho, A.E.; Guallar, V.; Berne, B.J.; Friesner, R. Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach. J. Comput. Chem., 2005, 26(9), 915-931.
[http://dx.doi.org/10.1002/jcc.20222] [PMID: 15841474]
[34]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[35]
Cherezov, V.; Rosenbaum, D.M.; Hanson, M.A.; Rasmussen, S.G.; Thian, F.S.; Kobilka, T.S.; Choi, H.J.; Kuhn, P.; Weis, W.I.; Kobilka, B.K.; Stevens, R.C. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science, 2007, 318(5854), 1258-1265.
[http://dx.doi.org/10.1126/science.1150577] [PMID: 17962520]
[36]
Zhang, J.; Zhang, K.; Gao, Z.G.; Paoletta, S.; Zhang, D.; Han, G.W.; Li, T.; Ma, L.; Zhang, W.; Müller, C.E.; Yang, H.; Jiang, H.; Cherezov, V.; Katritch, V.; Jacobson, K.A.; Stevens, R.C.; Wu, B.; Zhao, Q. Agonist-bound structure of the human P2Y12 receptor. Nature, 2014, 509(7498), 119-122.
[http://dx.doi.org/10.1038/nature13288] [PMID: 24784220]
[37]
Steer, M.L.; Atlas, D. Demonstration of human platelet β-adrenergic receptors using 125I-labeled cyanopindolol and 125I-labeled hydroxybenzylpindolol. Biochim. Biophys. Acta, 1982, 686(2), 240-244.
[http://dx.doi.org/10.1016/0005-2736(82)90118-3] [PMID: 6282327]
[38]
Anfossi, G.; Trovati, M. Role of catecholamines in platelet function: pathophysiological and clinical significance. Eur. J. Clin. Invest., 1996, 26(5), 353-370.
[http://dx.doi.org/10.1046/j.1365-2362.1996.150293.x] [PMID: 8796362]
[39]
Noé, L.; Peeters, K.; Izzi, B.; Van Geet, C.; Freson, K. Regulators of platelet cAMP levels: clinical and therapeutic implications. Curr. Med. Chem., 2010, 17(26), 2897-2905.
[http://dx.doi.org/10.2174/092986710792065018] [PMID: 20858171]
[40]
Broos, K.; Feys, H.B.; De Meyer, S.F.; Vanhoorelbeke, K.; Deckmyn, H. Platelets at work in primary hemostasis. Blood Rev., 2011, 25(4), 155-167.
[http://dx.doi.org/10.1016/j.blre.2011.03.002] [PMID: 21496978]
[41]
López-López, E.; Bajorath, J.; Medina-Franco, J.L.; Medina-Franco, J.L. Informatics for chemistry, biology, and biomedical sciences. J. Chem. Inf. Model., 2021, 61(1), 26-35.
[http://dx.doi.org/10.1021/acs.jcim.0c01301] [PMID: 33382611]

© 2024 Bentham Science Publishers | Privacy Policy