Computational Analysis and Synthesis of Syringic Acid Derivatives as Xanthine Oxidase Inhibitors

Author(s): Neelam Malik, Anurag Khatkar*, Priyanka Dhiman

Journal Name: Medicinal Chemistry

Volume 16 , Issue 5 , 2020

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Graphical Abstract:


Background: Xanthine oxidase (XO; EC has been considered as a potent drug target for the cure and management of pathological conditions prevailing due to high levels of uric acid in the bloodstream. The role of xanthine oxidase has been well established in the generation of hyperuricemia and gout due to its important role in catalytic oxidative hydroxylation of hypoxanthine to xanthine and further catalyses of xanthine to generate uric acid. In this research, syringic acid, a bioactive phenolic acid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase.

Objective: The study aimed to develop new xanthine oxidase inhibitors from natural constituents along with the antioxidant potential.

Methods: In this report, we designed and synthesized syringic acid derivatives hybridized with alcohol and amines to form ester and amide linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.

Results: Results of the study revealed that SY3 produces very good xanthine oxidase inhibitory activity. All the compounds showed very good antioxidant activity. The enzyme kinetic studies performed on syringic acid derivatives showed a potential inhibitory effect on XO ability in a competitive manner with IC50 value ranging from 07.18μM-15.60μM and SY3 was revealed as the most active derivative. Molecular simulation revealed that new syringic acid derivatives interacted with the amino acid residues SER1080, PHE798, GLN1194, ARG912, GLN 767, ALA1078 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential.

Conclusion: Molecular docking proved to be an effective and selective tool in the design of new syringic acid derivatives .This hybridization of two natural constituents could lead to desirable xanthine oxidase inhibitors with improved activity.

Keywords: Syringic acid, xanthine oxidase, molecular docking, antioxidant, hyperuricemia, uric acid.

Battelli, M.G.; Bolognesi, A.; Polito, L. Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim. Biophys. Acta, 2014, 1842(9), 1502-1517.
[] [PMID: 24882753]
Okamoto, K.; Kawaguchi, Y.; Eger, B.T.; Pai, E.F.; Nishino, T. Crystal structures of urate bound form of xanthine oxidoreductase: substrate orientation and structure of the key reaction intermediate. J. Am. Chem. Soc., 2010, 132(48), 17080-17083.
[] [PMID: 21077683]
Cao, H.; Pauff, J.M.; Hille, R. X-ray crystal structure of a xanthine oxidase complex with the flavonoid inhibitor quercetin. J. Nat. Prod., 2014, 77(7), 1693-1699.
[] [PMID: 25060641]
Santi, M.D.; Paulino Zunini, M.; Vera, B.; Bouzidi, C.; Dumontet, V.; Abin-Carriquiry, A.; Grougnet, R.; Ortega, M.G. Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies. Eur. J. Med. Chem., 2018, 143, 577-582.
[] [PMID: 29207340]
Harrison, R. Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med., 2002, 33(6), 774-797.
[] [PMID: 12208366]
Urarte, E.; Esteban, R.; Moran, J.F.; Bittner, F. Established and proposed roles of xanthine oxidoreductase in oxidative and reductive pathways in plants. Reactive Oxygen and Nitrogen Species Signaling and Communication in Plants; Springer: Cham, 2015, pp. 15-42.
Maia, L.B.; Moura, J.J.G. Putting xanthine oxidoreductase and aldehyde oxidase on the NO metabolism map: Nitrite reduction by molybdoenzymes. Redox Biol., 2018, 19, 274-289.
[] [PMID: 30196191]
Fernandez, M.L.; Stupar, D.; Croll, T.; Leavesley, D.; Upton, Z. Xanthine oxidoreductase: A novel therapeutic target for the treatment of chronic wounds? Adv. Wound Care (New Rochelle), 2018, 7(3), 95-104.
[] [PMID: 29644146]
Harris, C.M.; Massey, V. The reaction of reduced xanthine dehydrogenase with molecular oxygen. Reaction kinetics and measurement of superoxide radical. J. Biol. Chem., 1997, 272(13), 8370-8379.
[] [PMID: 9079661]
Glantzounis, G.K.; Tsimoyiannis, E.C.; Kappas, A.M.; Galaris, D.A. Uric acid and oxidative stress. Curr. Pharm. Des., 2005, 11(32), 4145-4151.
[] [PMID: 16375736]
Ahmed, S.; Shaffique, S.; Asif, H.M.; Hussain, G.; Ahmad, K. Pathophysiology, clinical consequences, epidemiology and treatment of hyperurecemic gout. J. Pharm. Pharm. Sci., 2018, 6(1), 88-94.
Zhang, C.; Wang, R.; Zhang, G.; Gong, D. Mechanistic insights into the inhibition of quercetin on xanthine oxidase. Int. J. Biol. Macromol., 2018, 112, 405-412.
[] [PMID: 29410028]
Brondino, C.D.; Romão, M.J.; Moura, I.; Moura, J.J. Molybdenum and tungsten enzymes: the xanthine oxidase family. Curr. Opin. Chem. Biol., 2006, 10(2), 109-114.
[] [PMID: 16480912]
Romão, M.J.; Knäblein, J.; Huber, R.; Moura, J.J. Structure and function of molybdopterin containing enzymes. Prog. Biophys. Mol. Biol., 1997, 68(2), 121-144.
Okamoto, K.; Eger, B.T.; Nishino, T.; Pai, E.F.; Nishino, T. Mechanism of inhibition of xanthine oxidoreductase by allopurinol: crystal structure of reduced bovine milk xanthine oxidoreductase bound with oxipurinol. Nucleosides Nucleotides Nucleic Acids,, 2008, 27(6), 888-893, 888-893..
[] [PMID: 18600558]
Du, Y.; Liu, Z.; Qiao, F.; Wang, S.; Chen, K.; Zhang, X. Computational exploration of reactive fragment for mechanism-based inhibition of xanthine oxidase. J. Organomet. Chem., 2018, 864, 58-67.
Luna, G.; Dolzhenko, A.V.; Mancera, R.L. Inhibitors of xanthine oxidase: scaffold diversity and structure-based drug design. ChemMedChem, 2019, 14(7), 714-743.
Huber, R.; Hof, P.; Duarte, R.O.; Moura, J.J.; Moura, I.; Liu, M.Y.; LeGall, J.; Hille, R.; Archer, M.; Romão, M.J. A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes. Proc. Natl. Acad. Sci. USA, 1996, 93(17), 8846-8851.
[] [PMID: 8799115]
Durak, I.; Işik, A.C.; Canbolat, O.; Akyol, O.; Kavutçu, M. Adenosine deaminase, 5′ nucleotidase, xanthine oxidase, superoxide dismutase, and catalase activities in cancerous and noncancerous human laryngeal tissues. Free Radic. Biol. Med., 1993, 15(6), 681-684.
[] [PMID: 8138195]
Ogura, J.; Kuwayama, K.; Sasaki, S.; Kaneko, C.; Koizumi, T.; Yabe, K.; Tsujimoto, T.; Takeno, R.; Takaya, A.; Kobayashi, M.; Yamaguchi, H.; Iseki, K. Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen. Biochem. Pharmacol., 2015, 97(1), 89-98.
[] [PMID: 26119820]
Doehner, W.; Jankowska, E.A.; Springer, J.; Lainscak, M.; Anker, S.D. Uric acid and xanthine oxidase in heart failure - Emerging data and therapeutic implications. Int. J. Cardiol., 2016, 213, 15-19.
[] [PMID: 26318388]
Yousef, M.I.; Hussien, H.M. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng. Food Chem. Toxicol., 2015, 78, 17-25.
[] [PMID: 25640527]
Sunagawa, S.; Shirakura, T.; Hokama, N.; Kozuka, C.; Yonamine, M.; Namba, T.; Morishima, S.; Nakachi, S.; Nishi, Y.; Ikema, T.; Okamoto, S. Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study. J. Diabetes Investig., 2018, 65-71.
[PMID: 29862667]
Liu, J.; Wang, C.; Liu, F.; Lu, Y.; Cheng, J. Metabonomics revealed xanthine oxidase-induced oxidative stress and inflammation in the pathogenesis of diabetic nephropathy. Anal. Bioanal. Chem., 2015, 407(9), 2569-2579.
[] [PMID: 25636229]
Zhang, J.; Dierckx, R.; Mohee, K.; Clark, A.L.; Cleland, J.G. Xanthine oxidase inhibition for the treatment of cardiovascular disease: an updated systematic review and meta-analysis. ESC Heart Fail., 2017, 4(1), 40-45.
[] [PMID: 28217311]
Landmesser, U.; Spiekermann, S.; Dikalov, S.; Tatge, H.; Wilke, R.; Kohler, C.; Harrison, D.G.; Hornig, B.; Drexler, H. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation, 2002, 106(24), 3073-3078.
Kim, S.C.; Schneeweiss, S.; Choudhry, N.; Liu, J.; Glynn, R.J.; Solomon, D.H. Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study. Am. J. Med., 2015, 128(6), 653.e7-653.e16.
[] [PMID: 25660249]
Ohnishi, M.; Tanaka, T.; Makita, H.; Kawamori, T.; Mori, H.; Satoh, K.; Hara, A.; Murakami, A.; Ohigashi, H.; Koshimizu, K. Chemopreventive effect of a xanthine oxidase inhibitor, 1′-acetoxychavicol acetate, on rat oral carcinogenesis. Jpn. J. Cancer Res., 1996, 87(4), 349-356.
[] [PMID: 8641965]
Lin, J.K.; Chen, P.C.; Ho, C.T.; Lin-Shiau, S.Y. Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin-3,3′-digallate, (-)-epigallocatechin-3-gallate, and propyl gallate. J. Agric. Food Chem., 2000, 48(7), 2736-2743.
[] [PMID: 10898615]
Desco, M.C.; Asensi, M.; Márquez, R.; Martínez-Valls, J.; Vento, M.; Pallardó, F.V.; Sastre, J.; Viña, J. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes, 2002, 51(4), 1118-1124.
[] [PMID: 11916934]
Sroka, Z.; Cisowski, W. Hydrogen peroxide scavenging, antioxidant and anti-radical activity of some phenolic acids. Food Chem. Toxicol., 2003, 41(6), 753-758.
[] [PMID: 12738180]
Chang, W.S.; Chang, Y.H.; Lu, F.J.; Chiang, H.C. Inhibitory effects of phenolics on xanthine oxidase. Anticancer Res., 1994, 14(2A), 501-506.
[PMID: 8017853]
Yeh, W.J.; Hsia, S.M.; Lee, W.H.; Wu, C.H. Polyphenols with antiglycation activity and mechanisms of action: A review of recent findings. Yao Wu Shi Pin Fen Xi, 2017, 25(1), 84-92.
[] [PMID: 28911546]
Schmidt, C.G.; Gonçalves, L.M.; Prietto, L.; Hackbart, H.S.; Furlong, E.B. Antioxidant activity and enzyme inhibition of phenolic acids from fermented rice bran with fungus Rizhopus oryzae. Food Chem., 2014, 146, 371-377.
[] [PMID: 24176356]
Malik, N.; Dhiman, P.; Khatkar, A. In-silico design and ADMET studies of natural compounds as inhibitors of Xanthine Oxidase (XO) enzyme. Curr. Drug Metab., 2017, 18(6), 577-593.
[] [PMID: 28302027]
Shi, C.; Sun, Y.; Zheng, Z.; Zhang, X.; Song, K.; Jia, Z.; Chen, Y.; Yang, M.; Liu, X.; Dong, R.; Xia, X. Antimicrobial activity of syringic acid against Cronobacter sakazakii and its effect on cell membrane. Food Chem.,, 2016, 197(Pt A), 100-106..
[] [PMID: 26616929]
Yan, S.L.; Wang, Z.H.; Yen, H.F.; Lee, Y.J.; Yin, M.C. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice. Food Chem. Toxicol.,, 2016, 98(Pt B), 119-126..
[] [PMID: 27793734]
Cikman, O.; Soylemez, O.; Ozkan, O.F.; Kiraz, H.A.; Sayar, I.; Ademoglu, S.; Taysi, S.; Karaayvaz, M. Antioxidant activity of syringic acid prevents oxidative stress in l-arginine-induced acute pancreatitis: an experimental study on rats. Int. Surg., 2015, 100(5), 891-896.
[] [PMID: 26011211]
Tanaka, T.; Kawaguchi, N.; Zaima, N.; Moriyama, T.; Fukuta, Y.; Shirasaka, N. Antiosteoporotic activity of a syringic acid diet in ovariectomized mice. J. Nat. Med., 2017, 71(4), 632-641.
[] [PMID: 28681119]
Zhou, X.; Huang, S.; Wang, P.; Luo, Q.; Huang, X.; Xu, Q.; Qin, J.; Liang, C.; Chen, X. A syringic acid derivative and two iridoid glycosides from the roots of Stachys geobombycis and their antioxidant properties. Nat. Prod. Res., 2019, 33(5), 681-686.
[PMID: 29166774]
Muthukumaran, J.; Srinivasan, S.; Venkatesan, R.S.; Ramachandran, V.; Muruganathan, U. Syringic acid, a novel natural phenolic acid, normalizes hyperglycemia with special reference to glycoprotein components in experimental diabetic rats. J. Acute Dis., 2013, 2(4), 304-309.
Feng, C.Q.; Zhang, Z.Y.; Zhu, X.J.; Lin, Y.; Chen, W.; Tang, H.; Lin, H. iTerm-PseKNC: a sequence-based tool for predicting bacterial transcriptional terminators. Bioinformatics, 2019, 35(9), 1469-1477.
Chen, W.; Lv, H.; Nie, F.; Lin, H. i6mA-Pred: identifying DNA N6-methyladenine sites in the rice genome. Bioinformatics, 2019, 35(16), 2796-2800.
Zuo, Y.C.; Peng, Y.; Liu, L.; Chen, W.; Yang, L.; Fan, G.L. Predicting peroxidase subcellular location by hybridizing different descriptors of Chou’ pseudo amino acid patterns. Anal. Biochem., 2014, 458, 14-19.
[] [PMID: 24802134]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[] [PMID: 15027865]
Zuo, Y.; Li, Y.; Chen, Y.; Li, G.; Yan, Z.; Yang, L. PseKRAAC: a flexible web server for generating pseudo K-tuple reduced amino acids composition. Bioinformatics, 2017, 33(1), 122-124.
[] [PMID: 27565583]
Zuo, Y.; Lv, Y.; Wei, Z.; Yang, L.; Li, G.; Fan, G. iDPF-PseRAAAC: a web-server for identifying the defensin peptide family and subfamily using pseudo reduced amino acid alphabet composition. PLoS One, 2015, 10(12)e0145541
[] [PMID: 26713618]
Dhiman, P.; Malik, N.; Verma, P.K.; Khatkar, A. Synthesis and biological evaluation of thiazolo and imidazo N-(4-nitrophenyl)-7-methyl-5-aryl-pyrimidine-6 carboxamide derivatives. Res. Chem. Intermed., 2015, 41(11), 8699-8711.
Patel, A.; Patel, A.; Patel, A.; Patel, N.M. Determination of polyphenols and free radical scavenging activity of Tephrosia purpurea linn leaves (Leguminosae). Pharmacognosy Res., 2010, 2(3), 152-158.
[] [PMID: 21808558]
Liu, D.; Li, G.; Zuo, Y. Function determinants of TET proteins: the arrangements of sequence motifs with specific codes. Brief. Bioinform., 2019, 20(5), 1826-1835.
[] [PMID: 29947743]

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Year: 2020
Published on: 07 August, 2020
Page: [643 - 653]
Pages: 11
DOI: 10.2174/1573406415666191004134346
Price: $65

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