SYNTHESIS, BIOLOGICAL EVALUATION, AND DOCKING STUDY OF NOVEL 2-PHENYL-1- BENZOPYRAN-4-ONE DERIVATIVES - AS A POTENT CYCLOOXYGENASE-2 INHIBITOR
Keywords:Flavone derivatives, Cyclooxygenase-2, Antioxidant, Anti-inflammatory, Molecular docking
Objective: The inflammation and oxidative stress were related together in the generation of reactive oxygen species, which is responsible for the enhancement of inflammation associated with various chronic diseases.
Methods: The aim of this study is to synthezise and characterizes the flavones (2-phenyl-1-benzopyran-4-one) derivatives and analyzed by their docking hypothetical data as an effective anti-inflammatory mediator against cyclooxygenase-2 (COX-2) enzyme. Further, the evaluation of various in vitro antioxidant and anti-inflammatory studies was carried out.
Results: The 10 compounds were synthesized and characterized by ultraviolet, infrared, nuclear magnetic resonance, and mass spectroscopic techniques. The docking data results of these 10 flavones derivatives against COX-2 enzymes (Protein Data Bank ID: 3LN1) showed the binding energy ranging between −5.53 kcal/mol and −7.02 kcal/mol when compared with that of the standard diclofenac (−6.34 kcal/mol). The in vitro studies suggest that the lipophilic character of the side chain donor, along with the hydroxyl substituted flavones found to have significant half maximal inhibitory concentration values.
Conclusion: Based on these in silico and in vitro evaluation results, these synthesized compounds could act as a promising inhibitor to target the COX- 2 enzyme. Hence, those compounds were effective in the management of chronic diseases by exhibits free radical scavenging and anti-inflammatory property.
Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440:944-8.
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;59:365-73.
Asma M, Hamama B, Meziti H, Seoussen K, Abderrahmane S, Ibrahim D. Antioxidant and anti-inflammatory activities of Rubus fruticosus and Zizyphus vulgaris methanol extracts. Int J Pharm Pharm Sci 2017;9:69-76.
Salzano S, Checconi P, Hanschmann EM, Lillig CH, Bowler LD, Chan P, et al. Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proc Natl Acad Sci U S A 2014;111:12157-62.
Reagan LP, Magariños AM, McEwen BS. Neurological changes induced by stress in streptozotocin diabetic rats. Ann N Y Acad Sci 1999;893:126-37.
Acar A, Akil E, Alp H, Evliyaoglu O, Kibrisli E, Inal A, et al. Oxidative damage is ameliorated by curcumin treatment in brain and sciatic nerve of diabetic rats. Int J Neurosci 2012;122:367-72.
Steinmeyer J. Pharmacological basis for the therapy of pain and inflammation with nonsteroidal anti-inflammatory drugs. Arthritis Res 2000;2:379-85.
Mishra A, Sharma AK, Kumar S, Saxena AK, Pandey AK. Bauhinia variegata leaf extracts exhibit considerable antibacterial, antioxidant, and anticancer activities. Biomed Res Int 2013;2013:915436.
Kumar S, Sharma UK, Sharma AK, Pandey AK. Protective efficacy of Solanum xanthocarpum root extracts against free radical damage: Phytochemical analysis and antioxidant effect. Cell Mol Biol (Noisy-le-grand) 2012;58:174-81.
Santangelo C, Varì R, Scazzocchio B, Di Benedetto R, Filesi C, Masella R, et al. Polyphenols, intracellular signalling and inflammation. Ann Ist Super Sanita 2007;43:394-405.
Kim YS, Young MR, Bobe G, Colburn NH, Milner JA. Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev Res (Phila) 2009;2:200-8.
Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): Chemical and biomedical perspectives. Phytochemistry 2006;67:1849-55.
Park SA, Choi MS, Jung UJ, Kim MJ, Kim DJ, Park HM, et al. Eucommia ulmoides oliver leaf extract increases endogenous antioxidant activity in Type 2 diabetic mice. J Med Food 2006;9:474-9.
Tuñón MJ, García-Mediavilla MV, Sánchez-Campos S, González- Gallego J. Potential of flavonoids as anti-inflammatory agents: Modulation of pro-inflammatory gene expression and signal transduction pathways. Curr Drug Metab 2009;10:256-71.
Ribeiro D, Freitas M, Lima JL, Fernandes E. Proinflammatory pathways: The modulation by flavonoids. Med Res Rev 2015;35:877-936.
Cole AL, Hossain S, Cole AM, Phanstiel O 4th. Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents. Bioorg Med Chem 2016;24:2768-76.
Pramod S, Dasharath D, Ravi V, Pudukulathan K, Cyclization of 2?-hydroxychalcones to flavones using ammonium iodide as an iodine source-an eco-friendly approach. J Serb Chem Soc 2013;78:909-16.
Ammar T, Ruplal Choudhary C. Determination of antioxidant activity in different kinds of plants in-Vivo and in-Vitro by using diverse technical methods. J Nutr Food Sci 2013;3:1-9.
Zhao H, Fan W, Dong J, Lu J, Chen J, Fan W, et al. Evaluation of antioxidant activities and total phenolic contents of typical malting barley varieties. Food Chem 2008;107:296-304.
Klein SM, Cohen G, Cederbaum AI. Production of formaldehyde during metabolism of dimethyl sulfoxide by hydroxyl radical generating systems. Biochemistry 1981;20:6006-12.
Marcocci L, Maguire JJ, Droy-Lefaix MT, Packer L. The nitric oxide-scavenging properties of Ginkgo biloba extract EGb 761. Biochem Biophys Res Commun 1994;201:748-55.
Alhakmani F, Khan SA, Ahmad A. Determination of total phenolic, in-vitro antioxidant and anti-inflammatory activity of seeds and fruits of Zizyphus spina-Christi grown in Oman. Asian Pac J Trop Biomed 2014;4:656-60.
Shinde UA, Phadke AS, Nair AM, Mugantiwar AA, Dikshit VJ, Saraf VO. Membrane stabilizing activity-a possible mechanism of action for the anti-inflammatory activity of Cedrus deodara wood oil. Fitoterapia 1999;70:251-7.
Gandhidasan R, Thamaraichelvan A. Antiinflamattory action of Lanea coromondelica by HRBC membarane stabilisation. Fitotherapia 1991;62:82-3.
Abdellatif KR, Chowdhury MA, Dong Y, Velázquez C, Das D, Suresh MR, et al. Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)- 3-trifluoromethyl-1H-pyrazole and its methanesulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem 2008;16:9694-8.
Abdellatif KR, Chowdhury MA, Dong Y, Das D, Yu G, Velázquez C, et al. Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-carboxymethylphenyl)-1-(4-methanesulfonylphenyl)-3- trifluoromethyl-1H-pyrazole and its aminosulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem 2009;17:5182-8.
Nagmoti DM, Khatri DK, Juvekar PR, Juvekar AR. Antioxidant activity and free radical-scavenging potential of Pithecellobium dulce Benth seed extracts. Free Radic Antioxid 2011;2:37-43.
Prapurnachandra Y, Viswanathswamy AH. In-vitro Antioxidant and cytotoxic activity of rutin and piperine and their synergistic effect. Int J Pharm Pharm Sci 2016;8:78-82.
Taylor BS, Kim YM, Wang Q, Shapiro RA, Billiar TR, Geller DA, et al. Nitric oxide down-regulates hepatocyte-inducible nitric oxide synthase gene expression. Arch Surg 1997;132:1177-83.
Turkoglu A, Duru ME, Mercan N, Kivrak I, Gezer K. Antioxidant and antimicrobial activities of Laetiporus sulphurous (Bull) Murrill. Food Chem 2007;101:267-73.
Mizushima Y, Kobayashi M. Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins. J Pharm Pharmacol 1968;20:169-73.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231:232-5.
Anonymous. New Medical Dictionary. New Delhi: Oxford and IBH Publishing Co. Pvt. Ltd.; 2007. p. 376.
Tripathi KD. Essentials of Medical Pharmacology. New Delhi: Jaypee Brothers Medical Publishers Ltd.; 2008. p. 189.
Opie EL. On the relation of necrosis and inflammation to denaturation of proteins. J Exp Med 1962;115:597-608.
Umapathy E, Ndebia EJ, Meeme A, Adam B, Menziwa P, Nkeh- Chungag BN, et al. An experimental evaluation of Albuca setosa aqueous extract on membrane stabilization, protein denaturation and white blood cell migration during acute inflammation. J Med Plants Res 2010;4:789-95.
Murugesh N, Vembar S, Damodaran C. Studies on erythrocyte membrane IV: In vitro haemolytic activity of oleander extract. Toxicol Lett 1981;8:33-8.
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