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Medicinal Chemistry

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

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Research Article

Chalcones as Scavengers of HOCl and Inhibitors of Oxidative Burst: Structure-Activity Relationship Studies

Author(s): Thaise Martins, Vera L.M. Silva, Artur M.S. Silva, José L.F.C. Lima, Eduarda Fernandes* and Daniela Ribeiro*

Volume 18, Issue 1, 2022

Published on: 29 December, 2020

Page: [88 - 96] Pages: 9

DOI: 10.2174/1573406417666201230093207

Abstract

Aims: This study evaluates the ability of chalcones to scavenge hypochlorous acid (HOCl) and modulate oxidative burst.

Background: The chemistry of chalcones has long been a matter of interest to the scientific community due to the phenolic groups often present and to the various replaceable hydrogens that allow the formation of a broad number of derivatives. Due to this chemical diversity, several biological activities have been attributed to chalcones, namely anti-diabetic, anti-inflammatory and antioxidant.

Objectives: Evaluate the ability of a panel of 34 structurally related chalcones to scavenge HOCl and/or suppress its production through the inhibition of human neutrophils’ oxidative burst, followed by the establishment of the respective structure-activity relationships.

Methods: The ability of chalcones to scavenge HOCl was evaluated by fluorimetric detection of the inhibition of dihydrorhodamine 123 oxidation. The ability of chalcones to inhibit neutrophils’ oxidative burst was evaluated by chemiluminometric detection of the inhibition of luminol oxidation.

Results: It was observed that the ability to scavenge HOCl depends on the position and number of hydroxy groups on both aromatic rings. Chalcone 5b was the most active with an IC50 value of 1.0 ± 0.1 μM. The ability to inhibit neutrophils’ oxidative burst depends on the presence of a 2’-hydroxy group on A-ring and on other substituents groups, e.g. methoxy, hydroxy, nitro and/or chlorine atom( s) at C-2, C-3 and/or C-4 on B-ring, as in chalcones 2d, 2f, 2j, 2i, 4b, 2n and 1d, which were the most actives with IC50 values ranging from 0.61 ± 0.02 μM to 1.7 ± 0.2 μM.

Conclusion: The studied chalcones showed high activity at a low micromolar range, indicating their potential as antioxidant agents and to be used as a molecular structural scaffold for the design of new anti-inflammatory compounds.

Keywords: Chalcones, hypochlorous acid, scavenging activity, reactive species, human neutrophils, antioxidant activity.

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[1]
Swain, S.D.; Rohn, T.T.; Quinn, M.T. Neutrophil priming in host defense: role of oxidants as priming agents. Antioxid. Redox Signal., 2002, 4(1), 69-83.
[http://dx.doi.org/10.1089/152308602753625870] [PMID: 11970845]
[2]
Winterbourn, C.C.; Kettle, A.J.; Hampton, M.B. Reactive oxygen species and neutrophil function. Annu. Rev. Biochem., 2016, 85(1), 765-792.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014442] [PMID: 27050287]
[3]
Kolaczkowska, E.; Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol., 2013, 13(3), 159-175.
[http://dx.doi.org/10.1038/nri3399] [PMID: 23435331]
[4]
Dinauer, M.C. Neutrophil Defects and Diagnosis Disorders of Neutrophil Function: An OverviewNeutrophil: Methods and Protocols, 3ed; Quinn, M.T.; DeLeo, F.R.: Humana: New York 2014, pp. 11-29.
[5]
Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik, A.B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal., 2014, 20(7), 1126-1167.
[http://dx.doi.org/10.1089/ars.2012.5149] [PMID: 23991888]
[6]
Aratani, Y. Myeloperoxidase: Its role for host defense, inflammation, and neutrophil function. Arch. Biochem. Biophys., 2018, 640, 47-52.
[http://dx.doi.org/10.1016/j.abb.2018.01.004] [PMID: 29336940]
[7]
Hampton, M.B.; Kettle, A.J.; Winterbourn, C.C. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood, 1998, 92(9), 3007-3017.
[http://dx.doi.org/10.1182/blood.V92.9.3007] [PMID: 9787133]
[8]
Di Meo, S.; Reed, T.T.; Venditti, P.; Victor, V.M. Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell. Longev., 2016.20161245049
[http://dx.doi.org/10.1155/2016/1245049] [PMID: 27478531]
[9]
Chelombitko, M.A. Role of reactive oxygen species in inflammation: A minireview. Moscow Univ. Biol. Sci. Bull., 2018, 73(4), 199-202.
[http://dx.doi.org/10.3103/S009639251804003X]
[10]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev., 2017, 117(12), 7762-7810.
[http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]
[11]
Leopoldini, M.; Russo, N.; Toscano, M. The molecular basis of working mechanism of natural polyphenolic antioxidants. Food Chem., 2011, 125(2), 288-306.
[http://dx.doi.org/10.1016/j.foodchem.2010.08.012]
[12]
Gomes, M.N.; Muratov, E.N.; Pereira, M.; Peixoto, J.C.; Rosseto, L.P.; Cravo, P.V.L.; Andrade, C.H.; Neves, B.J. Chalcone derivatives: Promising starting points for drug design. Molecules, 2017, 22(8), 25.
[http://dx.doi.org/10.3390/molecules22081210] [PMID: 28757583]
[13]
Rioux, B.; Pouget, C.; Fidanzi-Dugas, C.; Gamond, A.; Laurent, A.; Semaan, J.; Pinon, A.; Champavier, Y.; Léger, D.Y.; Liagre, B.; Duroux, J.L.; Fagnère, C.; Sol, V. Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents. Bioorg. Med. Chem. Lett., 2017, 27(18), 4354-4357.
[http://dx.doi.org/10.1016/j.bmcl.2017.08.024] [PMID: 28838697]
[14]
Rocha, S.; Sousa, A.; Ribeiro, D.; Correia, C.M.; Silva, V.L.M.; Santos, C.M.M.; Silva, A.M.S.; Araújo, A.N.; Fernandes, E.; Freitas, M. A study towards drug discovery for the management of type 2 diabetes mellitus through inhibition of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase by chalcone derivatives. Food Funct., 2019, 10(9), 5510-5520.
[http://dx.doi.org/10.1039/C9FO01298B] [PMID: 31414099]
[15]
Chu, W.C.; Bai, P.Y.; Yang, Z.Q.; Cui, D.Y.; Hua, Y.G.; Yang, Y.; Yang, Q.Q.; Zhang, E.; Qin, S. Synthesis and antibacterial evaluation of novel cationic chalcone derivatives possessing broad spectrum antibacterial activity. Eur. J. Med. Chem., 2018, 143, 905-921.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.009] [PMID: 29227931]
[16]
Mahapatra, D.K.; Bharti, S.K.; Asati, V. Chalcone derivatives: Anti-inflammatory potential and molecular targets perspectives. Curr. Top. Med. Chem., 2017, 17(28), 3146-3169.
[http://dx.doi.org/10.2174/1568026617666170914160446] [PMID: 28914193]
[17]
Sökmen, M.; Akram Khan, M. The antioxidant activity of some curcuminoids and chalcones. Inflammopharmacology, 2016, 24(2-3), 81-86.
[http://dx.doi.org/10.1007/s10787-016-0264-5] [PMID: 27188988]
[18]
Araico, A.; Terencio, M.C.; Alcaraz, M.J.; Domínguez, J.N.; León, C.; Ferrándiz, M.L. Phenylsulphonyl urenyl chalcone derivatives as dual inhibitors of cyclo-oxygenase-2 and 5-lipoxygenase. Life Sci., 2006, 78(25), 2911-2918.
[http://dx.doi.org/10.1016/j.lfs.2005.11.017] [PMID: 16360707]
[19]
Zeraik, M.L.; Ximenes, V.F.; Regasini, L.O.; Dutra, L.A.; Silva, D.H.S.; Fonseca, L.M.; Coelho, D.; Machado, S.A.S.; Bolzani, V.S. 4′-Aminochalcones as novel inhibitors of the chlorinating activity of myeloperoxidase. Curr. Med. Chem., 2012, 19(31), 5405-5413.
[http://dx.doi.org/10.2174/092986712803833344] [PMID: 22963624]
[20]
Bukhari, S.N.A.; Tajuddin, Y.; Benedict, V.J.; Lam, K.W.; Jantan, I.; Jalil, J.; Jasamai, M. Synthesis and evaluation of chalcone derivatives as inhibitors of neutrophils’ chemotaxis, phagocytosis and production of reactive oxygen species. Chem. Biol. Drug Des., 2014, 83(2), 198-206.
[http://dx.doi.org/10.1111/cbdd.12226] [PMID: 24433224]
[21]
Yuandani; Jantan, I.; Husain, K. 4,5,4′-Trihydroxychalcone, 8,8′-(ethene-1,2-diyl)-dinaphtalene-1,4,5-triol and rutin from Gynura segetum inhibit phagocytosis, lymphocyte proliferation, cytokine release and nitric oxide production from phagocytic cells. BMC Complement. Altern. Med., 2017, 17(1), 211.
[http://dx.doi.org/10.1186/s12906-017-1726-z] [PMID: 28399868]
[22]
Brito, C.M.; Pinto, D.C.G.A.; Silva, A.M.S.; Silva, A.M.G.; Tomé, A.C.; Cavaleiro, J.A.S. Diels–Alder reactions of 2′-hydroxychalcones with ortho-benzoquino-dimethane: A new synthesis of 3-aryl-2-naphthyl 2-hydroxyphenyl ketones. Eur. J. Org. Chem., 2006, (11), 2558-2569.
[http://dx.doi.org/10.1002/ejoc.200500872]
[23]
Barros, A.I.R.N.A.; Dias, A.R.F.; Silva, A.M.S. Reductive coupling reactions of 2-nitrochalcones and their β-hydroxy-analogues: New syntheses of 2-arylquinoline and 2-aryl-4-hydroxyquinoline derivatives. Monatsh. Chem., 2007, 138(6), 585-594.
[http://dx.doi.org/10.1007/s00706-007-0647-9]
[24]
Barros, A.I.R.N.A.; Nunes, F.M.; Barros, C.; Silva, A.M.S.; Domingues, M.R.M. Structural characterization of nitrated 2′-hydroxychalcones by electrospray ionization tandem mass spectrometry. Eur J Mass Spectrom (Chichester), 2009, 15(5), 605-616.
[http://dx.doi.org/10.1255/ejms.1020] [PMID: 19679941]
[25]
Rosa, G.P.; Seca, A.M.L.; Barreto, M.C.; Silva, A.M.S.; Pinto, D.C.G.A. Chalcones and flavanones bearing hydroxyl and/or methoxyl groups: Synthesis and biological assessments. Appl. Sci. (Basel), 2019, 9(14), 17.
[http://dx.doi.org/10.3390/app9142846]
[26]
Proença, C.; Albuquerque, H.M.T.; Ribeiro, D.; Freitas, M.; Santos, C.M.M.; Silva, A.M.S.; Fernandes, E. Novel chromone and xanthone derivatives: Synthesis and ROS/RNS scavenging activities. Eur. J. Med. Chem., 2016, 115, 381-392.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.043] [PMID: 27031214]
[27]
Freitas, M.; Porto, G.; Lima, J.L.F.C.; Fernandes, E. Isolation and activation of human neutrophils in vitro. The importance of the anticoagulant used during blood collection. Clin. Biochem., 2008, 41(7-8), 570-575.
[http://dx.doi.org/10.1016/j.clinbiochem.2007.12.021] [PMID: 18226596]
[28]
Freitas, M.; Lima, J.L.F.C.; Fernandes, E. Optical probes for detection and quantification of neutrophils’ oxidative burst. A review. Anal. Chim. Acta, 2009, 649(1), 8-23.
[http://dx.doi.org/10.1016/j.aca.2009.06.063] [PMID: 19664458]
[29]
Degrossoli, A.; Müller, A.; Xie, K.; Schneider, J.F.; Bader, V.; Winklhofer, K.F.; Meyer, A.J.; Leichert, L.I. Neutrophil-generated HOCl leads to non-specific thiol oxidation in phagocytized bacteria. eLife, 2018, 7, 26.
[http://dx.doi.org/10.7554/eLife.32288] [PMID: 29506649]
[30]
Casciaro, M.; Di Salvo, E.; Pace, E.; Ventura-Spagnolo, E.; Navarra, M.; Gangemi, S. Chlorinative stress in age-related diseases: a literature review. Immun. Ageing, 2017, 14(21), 21.
[http://dx.doi.org/10.1186/s12979-017-0104-5] [PMID: 29163665]
[31]
Perjési, P.; Rozmer, Z. Kinetic analysis of some chalcones and synthetic chalcone analogues on the fenton-reaction initiated deoxyribose degradation assay. Open Med. Chem. J., 2011, 5, 61-67.
[http://dx.doi.org/10.2174/1874104501105010061] [PMID: 21804900]
[32]
Xue, Y.; Zheng, Y.; Zhang, L.; Wu, W.; Yu, D.; Liu, Y. Theoretical study on the antioxidant properties of 2′-hydroxychalcones: H-atom vs. electron transfer mechanism. J. Mol. Model., 2013, 19(9), 3851-3862.
[http://dx.doi.org/10.1007/s00894-013-1921-x] [PMID: 23801254]
[33]
Kozlowski, D.; Trouillas, P.; Calliste, C.; Marsal, P.; Lazzaroni, R.; Duroux, J-L. Density functional theory study of the conformational, electronic, and antioxidant properties of natural chalcones. J. Phys. Chem. A, 2007, 111(6), 1138-1145.
[http://dx.doi.org/10.1021/jp066496+] [PMID: 17253666]
[34]
Detsi, A.; Majdalani, M.; Kontogiorgis, C.A.; Hadjipavlou-Litina, D.; Kefalas, P. Natural and synthetic 2′-hydroxy-chalcones and aurones: synthesis, characterization and evaluation of the antioxidant and soybean lipoxygenase inhibitory activity. Bioorg. Med. Chem., 2009, 17(23), 8073-8085.
[http://dx.doi.org/10.1016/j.bmc.2009.10.002] [PMID: 19853459]
[35]
Sivakumar, P.M.; Prabhakar, P.K.; Doble, M. Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones. Med. Chem. Res., 2011, 20(4), 482-492.
[http://dx.doi.org/10.1007/s00044-010-9342-1]
[36]
Naumann, K. Influence of chlorine substituents on biological activity of chemicals. J. Prakt. Chem., 1999, 341(5), 417-435.
[http://dx.doi.org/10.1002/(SICI)1521-3897(199907)341:5<417:AID-PRAC417>3.0.CO;2-A]
[37]
Constantinescu, T.; Lungu, C.N.; Lung, I. Lipophilicity as a central component of drug-like properties of chalchones and flavonoid derivatives. Molecules, 2019, 24(8), 11.
[http://dx.doi.org/10.3390/molecules24081505] [PMID: 30999606]

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