Novel piperazine substituted indole derivatives: Synthesis, anti-inflammatory and antioxidant activities and molecular docking

Year 2020, Volume: 24 Issue: 3, 350 - 360, 27.06.2025

Gul Altuntas-dınlen , Gul Altuntas-dınlen , Zuhal Kılıç Kurt , Cemre Acar Sezen Yılmaz Sarıaltın , Tülay Çoban

https://doi.org/10.35333/jrp.2020.157

Cited By: 2

Abstract

In this work, a series of piperazine substituted indole derivatives were synthesized and evaluated for their in vitro antioxidant and anti-inflammatory activities. The results of antioxidant activity showed that compounds 2 (81.63%) and 11 (85.63%) had comparable DPPH free radical scavenging activity to Vit E (88.6%). The in vitro antiinflammatory assays indicated that most of the compounds had more higher anti-inflammatory activities than standart ASA. Docking results revealed that compound 11 possessing the strongest anti-inflammatory activities showed the Hbond interactions with the key residues of COX-2 active site. It suggested that the anti-inflammatory activity of the compounds might result from COX-2 inhibition. It will be verified with further enzyme inhibition assays.

Keywords

Anti-inflammatory activity , antioxidant activity , COX-2 , piperazine , indole

References

• [1] Kumar R, Clermont G, Vodovotz Y, Chow CC. The dynamics of acute inflammation. J Theor Biol. 2004; 230: 145-155. [CrossRef]
• [2] Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006; 6: 772-783. [CrossRef]
• [3] Biswas SK. Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxid Med Cell Longev. 2016; 5698931. [CrossRef]
• [4] Weber V, Rubat C, Duroux E, Lartigue C, Madesclaire M, Coudert P. New 3- and 4-hydroxyfuranones as antioxidants and anti-inflammatory agents. Bioorg Med Chem. 2005; 13: 4552-4564. [CrossRef]
• [5] Geronikaki AA, Lagunin AA, Hadjipavlou-Litina DI, Eleftheriou PT, Filimonov DA, Poroikov VV, Alam I, Saxena AK. Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition. J Med Chem. 2008; 51: 1601-1609. [CrossRef]
• [6] Suthar SK, Jaiswal V, Lohan S, Bansal S, Chaudhary A, Tiwari A, Alex AT, Joesph A. Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening. Eur J Med Chem. 2013; 63: 589-602. [CrossRef]
• [7] Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, Yuan Q, Yu H, Xu W, Xie X. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 2019; 20: 247-260. [CrossRef]
• [8] Mahat RK, Singh N, Rathore V, Arora M, Yadav T. Cross-sectional correlates of oxidative stress and inflammation with glucose intolerance in prediabetes. Diabetes Metab Syndr. 2019; 13: 616-621. [CrossRef]
• [9] Cachofeiro V, Goicochea M, de Vinuesa SG, Oubina P, Lahera V, Luno J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease: New strategies to prevent cardiovascular risk in chronic kidney disease. Kidney Int. 2008; 74: S4-S9. [CrossRef]
• [10] Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006; 97: 1634-1658. [CrossRef]
• [11] Lindqvist D, Dhabhar FS, James SJ, Hough CM, Jain FA, Bersani FS, Reus VI, Verhoeven JE, Epel ES, Mahan L, Rosser R, Wolkowitz OM, Mellon SH. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology. 2017; 76: 197-205. [CrossRef]
• [12] Ambade A, Mandrekar P. Oxidative stress and ınflammation: essential partners in alcoholic liver disease. Int J Hepatol. ArticleID 853175, 2012. [CrossRef]
• [13] Tucker PS, Scanlan AT, Dalbo VJ. Chronic kidney disease ınfluences multiple systems: describing the relationship between oxidative stress, ınflammation, kidney damage, and concomitant disease. Oxid Med Cell Longev. ArticleID 806358, 2015. [CrossRef]
• [14] Biswas SK, De Faria JBL. Which comes first: Renal inflammation or oxidative stress in spontaneously hypertensive rats? Free Radic Res. 2007; 41: 216-224. [CrossRef] [15] Chadha N, Silakari O. Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view. Eur J Med Chem. 2017; 134: 159-184. [CrossRef] [16] Estevão MS, Carvalho LC, Ribeiro D, Couto D, Freitas M, Gomes A, Ferreira LM, Fernandes E, Marques MM. Antioxidant activity of unexplored indole derivatives: Synthesis and screening. Eur J Med Chem. 2010; 45: 4869-4878. [CrossRef]
• [17] Moore PF, Larson DL, Otterness IG, Weissman A, Kadin SB, Sweeney FJ, Eskara JD, Nagahisa A, Sakakibara M, Carty TJ. Tenidap, a structurally novel drug for the treatment of arthritis: Antiinflammatory and analgesic properties. Inflamm Res. 1996; 45: 54-61. [CrossRef]
• [18] Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol. 1971; 231: 237-239. [CrossRef]
• [19] Simon LS. Actions and toxicity of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol. 1996; 8: 169-175. [CrossRef]
• [20] Wada Y, Nakamura M, Kogo H, Aizawa Y. Inhibitory effect of acemetacin, a prodrug of indomethacin, on prostaglandin E2 release from inflamed synovial tissue. Jpn J Pharmacol. 1984; 34: 468-470. [CrossRef]
• [21] Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C. Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem. 1983; 26: 1778- 1780. [CrossRef].
• [22] Costa D, Gomes A, Reis S, Lima JLFC, Fernandes E. Hydrogen peroxide scavenging activity by non-steroidal antiinflammatory drugs. Life Sci. 2005; 76: 2841-2848. [CrossRef]
• [23] Reiter RJ, Tan DX, Cabrera J, D'Arpa D, Sainz RM, Mayo JC, Ramos S. The oxidant/antioxidant network: Role of melatonin. Biol Signals Recept. 1999; 8: 56-63. [CrossRef]
• [24] Elisabetsky E, Costa-Campos L. The alkaloid alstonine: A review of its pharmacological properties. Evid Based Complement Alternat Med. 2006; 3: 39-48. [CrossRef]
• [25] Kruk I, Aboul‐Enein HY, Michalska T, Lichszteld K, Kubasik‐Kladna K, Ölgen S. In vitro scavenging activity for reactive oxygen species by N‐substituted indole‐2‐carboxylic acid esters. J Lumin. 2007; 22: 379-386. [CrossRef]
• [26] Andreadou I, Tsantili-Kakoulidou A, Spyropoulou E, Siatra T. Reactions of indole derivatives with cardioprotective activity with reactive oxygen species. Comparison with melatonin. Chem Pharm Bull. 2003; 51: 1128-1131. [CrossRef]
• [27] Aboul-Enein HY, Kladna A, Kruk I, Lichszteld K, Michalska T, Olgen S. Scavenging of reactive oxygen species by novel indolin‐2‐one and indoline‐2‐thione derivatives. Biopolymers. 2005; 78: 171-178. [CrossRef]
• [28] Suzen S, Bozkaya P, Coban T, Nebioglu D. Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin. J Enzym Inhib Med Chem. 2006; 21: 405-411. [CrossRef].
• [29] Misik V, Ondrias K, Stasko A. EPR spectroscopy of free radical intermediates of antiarrhythmic-antihypoxic drug stobadine, a pyridoindole derivative. Life Sci. 1999; 65: 1879-1881. [CrossRef]
• [30] Cano A, Alcaraz O, Arnao MB. Free radical-scavenging activity of indolic compounds in aqueous and ethanolic media. Anal Bioanal Chem. 2003; 376: 33-37. [CrossRef]
• [31] Sharath V, Kumar HV, Naik N. Synthesis of novel indole based scaffolds holding pyrazole ring as anti-inflammatory and antioxidant agents. J Pharm Res. 2013; 6: 785-790. [CrossRef]
• [32] Suzen S. Melatonin and synthetic analogs as antioxidants. Curr Drug Delivery. 2013; 10: 71-75. [CrossRef]
• [33] Altuntas TG, Yılmaz N, Çoban T, Ölgen S. Synthesis and antioxidant activity of indole derivatives containing 4- substituted piperazine moieties. Lett Drug Des Discov. 2017; 14: 380-386. [CrossRef]
• [34] Bhandari K, Murti V, Aruna J, Padam C, Anand N. Agents acting on the central nervous system: Part XXXIII. Synthesis of 1,2,3,4,6,7,8,12-octahydropyrazino [2',1':2,1]pyrido[4,3-b]indole and some 2-substituted aminoalkylindoles. Ind J Chem Sect B. 1979; 17B(3): 246-249.
• [35] Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, Marnett LJ. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. Biol Chem. 2010; 285: 34950-34959. [CrossRef]
• [36] Molinspiration Cheminformatics, Bratislava, Slovak Republic. http://www.molinspiration.com/services/properties.html (accessed on 18 August 2019).
• [37] Lipinski CA, Lombardo L, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46: 3-26. [CrossRef]
• [38] Zhao YH, Abraham MH, Lee J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper I. Rate-limited steps of human oral absorption and QSAR studies. Pharm Res. 2002; 19: 1446-1457. [CrossRef]
• [39] Mc Cord JM, Fridovich I. Superoxide dismutase, an enzymic function for erythrocuprein (Hemocuprein). J Biol Chem. 1969; 243: 6049-6055.
• [40] Xie J, Schaich KM. Re-evaluation of the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) assay for antioxidant activity. J Agric Food Chem. 2014; 62: 4251-4260. [CrossRef]
• [41] Mihara M, Uchiyama M, Fuzukawa K. Thiobarbituric acid value on fresh homogenate of rat as a parameter of lipid peroxidation in aging, CCl4 intoxication, and vitamin E deficiency. Biochem Med. 1980; 23: 302-311. [CrossRef]
• [42] Anosike CA, Obidoa O, Ezeanyika LU. Membrane stabilization as a mechanism of the anti-inflammatory activity of methanol extract of garden egg (Solanum aethiopicum). Daru. 2012; 20: 76-83. [CrossRef] [43] Debnath PC, Das A, Islam A, Islam MA, Hassan MM, Uddin SMG. Membrane stabilization – A possible mechanism of action for the anti-inflammatory activity of a Bangladeshi medicinal plant: Erioglossum rubiginosum (Bara Harina). Pharmacogn J. 2013; 5: 104-107. [CrossRef]