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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

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ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

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Research Article

Molecular Modelling, Synthesis and Evaluation of Flavone and Flavanone Scaffolds as Anti-inflammatory Agents

Author(s): Natarajan Kiruthiga*, Manikandan Alagumuthu, Chellappa Selvinthanuja, Kulandaivel Srinivasan and Thangavel Sivakumar

Volume 20, Issue 1, 2021

Published on: 02 January, 2020

Page: [20 - 38] Pages: 19

DOI: 10.2174/1871523019666200102112017

Price: $65

Abstract

Objective: The objective of the study was to develop new Cyclooxygenase-2 inhibitors as anti-inflammatory agents from the synthetic route.

Materials and Methods: The 2-phenyl-4H-chromen-4-one and 2-phenyl-2,3-dihydro-4H-chromenone hybrids were synthesised and characterised by using UV, IR, 1H-NMR, and mass spectrometry. An attempt was made for consolidated lead flavones and flavanones scaffolds by determining ADME/ T properties. Molecular docking simulations were performed by using Autodock.4 to understand the binding interaction over the targeted enzyme Cyclooxygenase-2. The titled compounds were evaluated for various in-vitro models for antioxidant and anti-inflammatory activities and based upon the IC50 values, the selected compounds were screened for in vivo anti-inflammatory activity by both acute and chronic models.

Results and Discussion: Twenty titled compounds were synthesised and elucidated their structure for confirmation of their functional groups by various spectroscopic techniques. Among the synthesized compounds, flavone derivatives such as HFc (7-hydroxy-3-(4-methoxy phenyl)-4H-chromen-4- one), HFd (2-(2,4-di methoxy-phenyl)-7-hydroxy-4H-chromen-4-one) and HFe (7-hydroxy-2- (thiophen-2-yl)-4H-chromen-4-one) produced higher potency. Flavanone derivatives HFAc (7- hydroxy-2-(4-hydroxy-3-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one), HFAb (7-hydroxy-2-(4- methoxy phenyl)-2,3-dihydro-4H-chromen-4-one) and HFAd (7-hydroxy-2-(thiophen-2-yl)-2,3- dihydro-4H-chromen-4-one) showed significant anti-inflammatory activity compared to the standard COX-2 inhibitors.

Conclusion: The flavone and flavanone scaffolds possess their excellent inhibitory action over the Cyclooxygenase-2 and act as a potential anti-inflammatory agent. The results of computational studies were also significantly correlated and concluded that those naturally mimicking flavonoid analogues were tremendous candidates to fight against the inflammatory diseases in drug discovery.

Keywords: Antioxidant, carrageenan, cyclooxygenase-2, flavonoid derivatives, molecular docking, serotonin.

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[1]
Zengin, G.; Aktumsek, A.; Guler, G.O.; Cakmak, Y.S.; Yildiztugay, E. Antioxidant properties of methanolic extract and fatty acid composition of Centaurea urvillei DC. subsp. Hayekiana wagenitz. Rec. Nat. Prod., 2011, 5(2), 123-132.
[2]
Kurumbail, R.G.; Stevens, A.M.; Gierse, J.K.; McDonald, J.J.; Stegeman, R.A.; Pak, J.Y.; Gildehaus, D.; Miyashiro, J.M.; Penning, T.D.; Seibert, K.; Isakson, P.C.; Stallings, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 1996, 384(6610), 644-648.
[http://dx.doi.org/10.1038/384644a0] [PMID: 8967954]
[3]
Herschman, H.R. Prostaglandin synthase 2. Biochim. Biophys. Acta Lipids Lipid Metab., 1996, 1299(1), 125-140.
[http://dx.doi.org/10.1016/0005-2760(95)00194-8]
[4]
Dewitt, D.L.; Meade, E.A.; Smith, W.L. PGH Synthase isoenzyme selectivity: the potential for safer non steroidal anti-inflammatory drugs. Am. J. Med., 1993, 95(2), 2A40S-2A44S.
[5]
Xie, W.; Robertson, D.L.; Simmons, D.L. Mitogen inducible prostaglandin G/H synthase: A new target for NSAID. Drug Dev. Res., 1992, 25(4), 249-265.
[http://dx.doi.org/10.1002/ddr.430250402]
[6]
Chandra, K.; Salman, A.S.; Mohd, A.; Sweety, R. Protection against FCA induced oxidative stress induced DNA damage as a model of arthritis and in vitro anti-arthritic potential of Costus speciosus rhizome extract. Int. J. Pharmaceut. Phytochem. Res., 2015, 7(2), 383-389.
[7]
Hollis, F.; Kanellopoulos, A.K.; Bagni, C. Mitochondrial dysfunction in autism spectrum disorder: clinical features and perspectives. Curr. Opin. Neurobiol., 2017, 45, 178-187.
[http://dx.doi.org/10.1016/j.conb.2017.05.018] [PMID: 28628841]
[8]
Haider, L.; Fischer, M.T.; Frischer, J.M.; Bauer, J.; Höftberger, R.; Botond, G.; Esterbauer, H.; Binder, C.J.; Witztum, J.L.; Lassmann, H. Oxidative damage in multiple sclerosis lesions. Brain, 2011, 134(Pt 7), 1914-1924.
[http://dx.doi.org/10.1093/brain/awr128 ] [PMID: 21653539]
[9]
Patel, V.P.; Chu, C.T. Nuclear transport, oxidative stress, and neurodegeneration. Int. J. Clin. Exp. Pathol., 2011, 4(3), 215-229.
[PMID: 21487518]
[10]
Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M.C.; Rahu, N. Nuclear transport, oxidative stress, and neurodegeneration. Int. J. Clin. Exp. Pathology, 2016, 4(3), 215.
[11]
Houstis, N.; Rosen, E.D.; Lander, E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature, 2006, 440(7086), 944-948.
[http://dx.doi.org/10.1038/nature04634] [PMID: 16612386]
[12]
Rahimi, R.; Nikfar, S.; Larijani, B.; Abdollahi, M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed. Pharmacother., 2005, 59(7), 365-373.
[http://dx.doi.org/10.1016/j.biopha.2005.07.002] [PMID: 16081237]
[13]
Zhong, J.Q.; Li, B.; Jia, Q.; Li, Y.M.; Zhu, W.L.; Chen, K.X. Advances in the structure-activity relationship study of natural flavonoids and its derivatives. Yao Xue Xue Bao, 2011, 46(6), 622-630.
[PMID: 21882520]
[14]
Bhavana, S.; Agrawal, S.C.; Gupta, K.C. Colour reactions of chalcones and their mechanism (a review). Orient. J. Chem., 2008, 24(1), 289-294.
[15]
Wagner, H.; Farkas, L. Synthesis of flavonoids. The flavanoids; Springer: US, 1975.
[16]
Cole, A.L.; Hossain, S.; Cole, A.M.; Phanstiel, O IV Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents. Bioorg. Med. Chem., 2016, 24(12), 2768-2776.
[http://dx.doi.org/10.1016/j.bmc.2016.04.045] [PMID: 27161874]
[17]
Kulkarni, P.S.; Kondhare, D.D.; Varala, R.; Zubaidha, P.K. Cyclization of 2′-hydroxychalcones to flavones using ammonium iodide as an iodine source: An eco-friendly approach. J. Serb. Chem. Soc., 2013, 78(7), 909-916.
[http://dx.doi.org/10.2298/JSC120901119K]
[18]
Ahmad, F.; Idris, M.S.; Adib, A.M. Synthesis and characterization some flavonoids derivatives. Research vote 75148, Univ. Tech. Malaysia Instit. Reposit., 2006, 1-29.http://eprints.utm.my/id/eprint/2881/1/75148.pdf
[19]
Ma, X.L.; Chen, C.; Yang, J. Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacol. Sin., 2005, 26(4), 500-512.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00068.x ] [PMID: 15780201]
[20]
Mannhold, R. Molecular drug properties: Measurement and prediction wiley-vhc verlag gmbh Co. KGaA : Weinheim, Germany,, 2008.
[21]
Zhao, Y.H.; Le, J.; Abraham, M.H.; Hersey, A.; Eddershaw, P.J.; Luscombe, C.N.; Butina, D.; Beck, G.; Sherborne, B.; Cooper, I.; Platts, J.A. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci., 2001, 90(6), 749-784.
[http://dx.doi.org/10.1002/jps.1031] [PMID: 11357178]
[22]
Hou, T.J.; Zhang, W.; Xia, K.; Qiao, X.B.; Xu, X.J. ADME evaluation in drug discovery. 5. Correlation of Caco-2 permeation with simple molecular properties. J. Chem. Inf. Comput. Sci., 2004, 44(5), 1585-1600.
[http://dx.doi.org/10.1021/ci049884m] [PMID: 15446816]
[23]
Irvine, J.D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J.W.; Selick, H.E.; Grove, J.R. MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. J. Pharm. Sci., 1999, 88(1), 28-33.
[http://dx.doi.org/10.1021/js9803205] [PMID: 9874698]
[24]
Ames, B.N.; Gurney, E.G.; Miller, J.A.; Bartsch, H. Carcinogens as frameshift mutagens: metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens. Proc. Natl. Acad. Sci. USA, 1972, 69(11), 3128-3132.
[http://dx.doi.org/10.1073/pnas.69.11.3128 ] [PMID: 4564203]
[25]
Klein, S.M.; Cohen, G.; Cederbaum, A.I. Production of formaldehyde during metabolism of dimethyl sulfoxide by hydroxyl radical generating systems. Biochemistry, 1981, 20(21), 6006-6012.
[http://dx.doi.org/10.1021/bi00524a013 ] [PMID: 6272833]
[26]
Al-Temimi, A.; Choudhary, R. Determination of antioxidant activity in different kinds of plants in-vivo and in-vitro by using diverse technical methods. Nutr. Food Sci., 2013, 3(1), 184.
[http://dx.doi.org/10.4172/2155-9600.1000184]
[27]
Zhao, H.; Fan, W.; Dong, J.; Lu, J. Evaluation of antioxidant activities and total phenolic contents of typical malting barley varieties. Food Chem., 2008, 107(1), 296-304.
[http://dx.doi.org/10.1016/j.foodchem.2007.08.018]
[28]
Shinde, U.A.; Phadke, A.S.; Nair, A.M.; Mugantiwar, A.A.; Dikshit, V.J.; Saraf, V.O. Membrane stabilizing activity -a possible mechanism of action for the anti-inflammatory activity of Cedrusdeodarawood oil. Fitoterapia, 1999, 70(3), 251-257.
[http://dx.doi.org/10.1016/S0367-326X(99)00030-1]
[29]
Gandhidasan, R.; Thamaraichelvan, A. Antiinflamattory action of Laneacoromondelica by HRBC membarane stabilisation. Fitotherapia, 1991, 62(1), 82-83.
[30]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111(3), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[31]
Nsonde Ntandou, G.F.; Banzouzi, J.T.; Mbatchi, B.; Elion-Itou, R.D.; Etou-Ossibi, A.W.; Ramos, S.; Benoit-Vical, F.; Abena, A.A.; Ouamba, J.M. Analgesic and anti-inflammatory effects of Cassia siamea Lam. stem bark extracts. J. Ethnopharmacol., 2010, 127(1), 108-111.
[http://dx.doi.org/10.1016/j.jep.2009.09.040] [PMID: 19799981]
[32]
Goyal, M.; Ghosh, M.; Nagori, B.P.; Sasmal, D. Analgesic and anti-inflammatory studies of cyclopeptide alkaloid fraction of leaves of Ziziyphus nummularia. Saudi J. Biol. Sci., 2013, 20(4), 365-371.
[http://dx.doi.org/10.1016/j.sjbs.2013.04.003] [PMID: 24235873]
[33]
Samy, R.P.; Gopalakrishnakone, P.; Houghton, P.; Thwin, M.M.; Ignacimuthu, S. Effect of aqueous extract of Tragia involucrata Linn. on acute and subacute inflammation. Phytother. Res., 2006, 20(4), 310-312.
[http://dx.doi.org/10.1002/ptr.1845] [PMID: 16557620]
[34]
Park, E.K.; Rhee, H.I.; Jung, H.S.; Ju, S.M.; Lee, Y.A.; Lee, S.H.; Hong, S.J.; Yang, H.I.; Yoo, M.C.; Kim, K.S. Antiinflammatory effects of a combined herbal preparation (RAH13) of Phellodendron amurense and Coptis chinensis in animal models of inflammation. Phytother. Res., 2007, 21(8), 746-750.
[http://dx.doi.org/10.1002/ptr.2156] [PMID: 17450506]
[35]
Alegaon, S.G.; Alagawadi, K.R.; Sonkusare, P.V.; Chaudhary, S.M.; Dadwe, D.H.; Shah, A.S.; Shah, A.S. Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents. Bioorg. Med. Chem. Lett., 2012, 22(5), 1917-1921.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.052] [PMID: 22325950]
[36]
Parepally, J.M.; Mandula, H.; Smith, Q.R. Brain uptake of nonsteroidal anti-inflammatory drugs: Ibuprofen, flurbiprofen, and indomethacin. Pharm. Res., 2006, 23(5), 873-881.
[http://dx.doi.org/10.1007/s11095-006-9905-5] [PMID: 16715377]
[37]
Mounnissamy, V.M.; Kavimani, S.; Balu, V.; Drlin, Q.S. Evaluation of anti-inflammatory and membrane stabilizing properties of ethanol extract of Canjerarehedi. Iranian J. Pharmacol. Therap., 2008, 6(2), 235-237.
[38]
Halliwell, B.; Whiteman, M. Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean? Br. J. Pharmacol., 2004, 142(2), 231-255.
[http://dx.doi.org/10.1038/sj.bjp.0705776] [PMID: 15155533]
[39]
Di Rosa, M.; Giroud, J.P.; Willoughby, D.A. Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J. Pathol., 1971, 104(1), 15-29.
[http://dx.doi.org/10.1002/path.1711040103] [PMID: 4398139]
[40]
Vinegar, R.; Schreiber, W.; Hugo, R. Biphasic development of carrageenin edema in rats. J. Pharmacol. Exp. Ther., 1969, 166(1), 96-103.
[PMID: 5776026]
[41]
Salvemini, D.; Wang, Z.Q.; Wyatt, P.S.; Bourdon, D.M.; Marino, M.H.; Manning, P.T.; Currie, M.G. Nitric oxide: A key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br. J. Pharmacol., 1996, 118(4), 829-838.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15475.x ] [PMID: 8799551]
[42]
Baruah, C.C.; Gupta, P.P.; Patnaik, G.K.; Dubey, M.P.; Goel, R.K.; Dhawan, B.N. Comparative study of the anti-PCA and mast-cell stabilizing activity fractions of Albizzia lebbeck: A traditional medicinal plant. J. Med. Aromat. Plants Sci., 2000, 22, 59-63.
[43]
Nurul, I.M.; Mizuguchi, H.; Shahriar, M.; Venkatesh, P.; Maeyama, K.; Mukherjee, P.K.; Hattori, M.; Choudhuri, M.S.; Takeda, N.; Fukui, H. Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions. Int. Immunopharmacol., 2011, 11(11), 1766-1772.
[44]
Gupta, M.; Mazumder, U.K.; Kumar, R.S.; Gomathi, P.; Rajeshwar, Y.; Kakoti, B.B.; Selven, V.T. Anti-inflammatory, analgesic and antipyretic effects of methanol extract from Bauhinia racemosa stem bark in animal models. J. Ethnopharmacol., 2005, 98(3), 267-273.
[http://dx.doi.org/10.1016/j.jep.2005.01.018] [PMID: 15814258]
[45]
Almawi, W.Y.; Melemedjian, O.K. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J. Mol. Endocrinol., 2002, 28(2), 69-78.
[http://dx.doi.org/10.1677/jme.0.0280069] [PMID: 11932204]
[46]
Pramanik, K.C.; Bhattacharya, P.; Chatterjee, T.K.; Mandal, S.C. Anti-inflammatory activity of methanol extract of Albizzia lebbeck (Mimosaceae) bark. Eur. Bullet. Drug Res., 2005, 13, 71-75.
[47]
Swingle, K.F.; Shideman, F.E. Phases of the inflammatory response to subcutaneous implantation of a cotton pellet and their modification by certain anti-inflammatory agents. J. Pharmacol. Exp. Ther., 1972, 183(1), 226-234.
[PMID: 4562620]
[48]
Snedegard, G. Mediators of vascular permeability in inflammation. Pro. Appl. Microcir., 1985, 7, 96-112.
[http://dx.doi.org/10.1159/000411530]
[49]
Serhan, C.N.; Savill, J. Resolution of inflammation: The beginning programs the end. Nat. Immunol., 2005, 6(12), 1191-1197.
[http://dx.doi.org/10.1038/ni1276] [PMID: 16369558]
[50]
Hadjipavlou-Litina, D. Quantitative structure--activity relationship (QSAR) studies on non steroidal anti-inflammatory drugs (NSAIDs). Curr. Med. Chem., 2000, 7(4), 375-388.
[http://dx.doi.org/10.2174/0929867003375128] [PMID: 10702615]
[51]
Khan, A.A.; Iadarola, M.; Yang, H.Y.; Dionne, R.A. Expression of COX-1 and COX-2 in a clinical model of acute inflammation. J. Pain, 2007, 8(4), 349-354.
[http://dx.doi.org/10.1016/j.jpain.2006.10.004] [PMID: 17270500]

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