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Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Cinnamaldehyde Analogs: Docking Based Optimization, COX-2 Inhibitory In Vivo and In Vitro Studies

Author(s): Vaishali M. Patil*, Preeti Anand, Monika Bhardwaj and Neeraj Masand

Volume 17 , Issue 2 , 2020

Page: [154 - 165] Pages: 12

DOI: 10.2174/1570163816666190125153951

Price: $65

Abstract

Background: In the past decade CADD has emerged as a rational approach in drug development so with the help molecular docking approach we planned to perform virtual screening of the designed data set of Schiff bases of cinnamaldehyde. The research work will be helpful to put some light on the drug receptor interactions required for anti-inflammatory activity.

Methods: For carrying out virtual screening of the developed cinnamaldehyde Schiff base data set, AutoDock 4.0 was used. The active hits identified through in silico screening were synthesized. Anti-inflammatory evaluation was carried out using Carrageenan-induced paw oedema method.

Results: Compounds V2A44, V2A55, V2A76, V2A82, V2A119, V2A141 and V2A142 has shown highest binding energy (-4.84, -4.76, -4.59, -4.78, -4.74, -4.85 and -4.72 kcal/mol, respectively) and the binding interactions with amino acids namely, Phe478, Glu479, Lys492, Ala493, Asp497 and Ile498. Some of the analogs have shown significant activity and were comparable to Indomethacin (standard drug).

Conclusion: Five new compounds have shown significant activity and the results obtained from in silico studies are parallel to those of in vivo studies.

Keywords: Schiff bases, cinnamaldehyde, virtual screening, anti-inflammatory agent, carragenan-induced paw oedema, molecular docking.

Graphical Abstract
[1]
Schiff H. Mittheilungen aus dem universita¨ tslaboratorium in Pisa: Eine neue reihe organischer basen. Justus Liebigs Ann Chem 1864; 131: 118-9.
[http://dx.doi.org/10.1002/jlac.18641310113]
[2]
Shah S, Vyas R, Mehta RH. Synthesis, characterization and antibacterial activities of some new Schiff base compounds. J Indian Chem Soc 1992; 69: 590-6.
[3]
Pandeya SN, Sriram D, Neath G, Clercq ED. Synthesis and antimicrobial activity of Schiff base and Mannich base of isatin and their derivatives with pyrimidine. Eur J Pharm Sci 1999; 9: 25-32.
[http://dx.doi.org/10.1016/S0928-0987(99)00038-X] [PMID: 10493993]
[4]
More PG, Bhalvankar RB, Patter SC. Schiff bases derived from substituted-2-aminothiazole and substituted salicylaldehyde and 2-hydroxy-1-napthaldehyde exhibits antibacterial and antifungal activity. J Indian Chem Soc 2001; 78: 474-5.
[5]
Kuz’min VE, Artemenko AG, Lozytska RN, et al. Investigation of anticancer activity of macrocyclic Schiff bases by means of 4D-QSAR based on simplex representation of molecular structure. SAR QSAR Environ Res 2005; 16(3): 219-30.
[http://dx.doi.org/10.1080/10659360500037206] [PMID: 15804810]
[6]
Dhar DN, Taploo CL. Schiff bases and their applications. J Sci Ind Res (India) 1982; 41: 501-6.
[7]
Bondock S, Khalifa W, Fadda AA. Synthesis and antimicrobial activity of some new 4-hetarylpyrazole and furo[2,3-c]pyrazole derivatives. Eur J Med Chem 2011; 46(6): 2555-61.
[http://dx.doi.org/10.1016/j.ejmech.2011.03.045] [PMID: 21489661]
[8]
Shi L, Ge HM, Tan SH, et al. Synthesis and antimicrobial activities of Schiff bases derived from 5-chloro-salicylaldehyde. Eur J Med Chem 2007; 42(4): 558-64.
[http://dx.doi.org/10.1016/j.ejmech.2006.11.010] [PMID: 17194508]
[9]
Sridhar SK, Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives. Biol Pharm Bull 2001; 24(10): 1149-52.
[http://dx.doi.org/10.1248/bpb.24.1149] [PMID: 11642321]
[10]
Kaplan JP, Raizon BM, Desarmenien M, et al. New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide. J Med Chem 1980; 23(6): 702-4.
[http://dx.doi.org/10.1021/jm00180a029] [PMID: 7392039]
[11]
Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ. Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg Med Chem 2008; 16(4): 1822-31.
[http://dx.doi.org/10.1016/j.bmc.2007.11.014] [PMID: 18248993]
[12]
Patole J, Shingnapurkar D, Padhye S, Ratledge C. Schiff base conjugates of p-aminosalicylic acid as antimycobacterial agents. Bioorg Med Chem Lett 2006; 16(6): 1514-7.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.035] [PMID: 16413184]
[13]
Hearn MJ, Cynamon MH. Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base. J Antimicrob Chemother 2004; 53(2): 185-91.
[http://dx.doi.org/10.1093/jac/dkh041] [PMID: 14688045]
[14]
Ren S, Wang R, Komatsu K, et al. Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. J Med Chem 2002; 45(2): 410-9.
[http://dx.doi.org/10.1021/jm010252q] [PMID: 11784145]
[15]
Przybylski P, Huczynski A, Pyta K, Brzezinski B, Bartl F. Biological properties of schiff bases and azo derivatives of phenols. Curr Org Chem 2009; 13: 124-48.
[http://dx.doi.org/10.2174/138527209787193774]
[16]
Nogardy T, Weaver DF. Medicinal Chemistry: A Molecular and Biochemical Approach Oxford University Press. New York 2005.
[17]
DaSilva M, DaSilva L, Fatima MARM. Schiff bases: A short review of their antimicrobial activities. J Adv Res 2011; 2: 1-8.
[http://dx.doi.org/10.1016/j.jare.2010.05.004]
[18]
Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS. Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kappaB activation: effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 2008; 229(2): 161-71.
[http://dx.doi.org/10.1016/j.taap.2008.01.021] [PMID: 18304597]
[19]
Hong CH, Hur SK, Oh OJ, Kim SS, Nam KA, Lee SK. Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells. J Ethnopharmacol 2002; 83(1-2): 153-9.
[http://dx.doi.org/10.1016/S0378-8741(02)00205-2] [PMID: 12413723]
[20]
Seo UK, Lee YJ, Kim JK, et al. Large-scale and effective screening of Korean medicinal plants for inhibitory activity on matrix metalloproteinase-9. J Ethnopharmacol 2005; 97(1): 101-6.
[http://dx.doi.org/10.1016/j.jep.2004.10.022] [PMID: 15652283]
[21]
Lou ZQ, Qin B. Species systematization and quality evaluation of commonly used Chinese traditional drugs, In: Beijing University Medical Press, Beijing, China. 1985; 1: pp. 1-8. In:
[22]
Lim CS, Kim EY, Lee HS, et al. Protective effects of Cinnamomum cassia Blume in the fibrogenesis of activated HSC-T6 cells and dimethylnitrosamine-induced acute liver injury in SD rats. Biosci Biotechnol Biochem 2010; 74(3): 477-83.
[http://dx.doi.org/10.1271/bbb.90435] [PMID: 20208363]
[23]
Verspohl EJ, Bauer K, Neddermann E. Antidiabetic effect of Cinnamomum cassia and Cinnamomum zeylanicum in vivo and in vitro. Phytother Res 2005; 19(3): 203-6.
[http://dx.doi.org/10.1002/ptr.1643] [PMID: 15934022]
[24]
He ZD, Qiao CF, Han QB, et al. Authentication and quantitative analysis on the chemical profile of cassia bark (cortex cinnamomi) by high-pressure liquid chromatography. J Agric Food Chem 2005; 53(7): 2424-8.
[http://dx.doi.org/10.1021/jf048116s] [PMID: 15796573]
[25]
Chang ST, Chen PF, Chang SC. Antibacterial activity of leaf essential oils and their constituents from Cinnamomum osmophloeum. J Ethnopharmacol 2001; 77(1): 123-7.
[http://dx.doi.org/10.1016/S0378-8741(01)00273-2] [PMID: 11483389]
[26]
Koh WS, Yoon SY, Kwon BM, Jeong TC, Nam KS, Han MY. Cinnamaldehyde inhibits lymphocyte proliferation and modulates T-cell differentiation. Int J Immunopharmacol 1998; 20(11): 643-60.
[http://dx.doi.org/10.1016/S0192-0561(98)00064-2] [PMID: 9848396]
[27]
Kwon BM, Lee SH, Choi SU, et al. Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor cells. Arch Pharm Res 1998; 21(2): 147-52.
[http://dx.doi.org/10.1007/BF02974019] [PMID: 9875422]
[28]
Shaughnessy DT, Setzer RW, DeMarini DM. The antimutagenic effect of vanillin and cinnamaldehyde on spontaneous mutation at GC but not AT sites. Mutat Res 2001; 48: 55-69.
[http://dx.doi.org/10.1016/S0027-5107(01)00169-5] [PMID: 11506799]
[29]
Fang SH, Rao YK, Tzeng YM. Cytotoxic effect of trans-Cinnamaldehyde from Cinnamomum osmophloeum leaves on human cancer cell lines. Internat J Appl Sci Eng 2004; 2: 136-47.
[30]
Chao LK, Hua KF, Hsu HY, et al. Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling. Food Chem Toxicol 2008; 46(1): 220-31.
[http://dx.doi.org/10.1016/j.fct.2007.07.016] [PMID: 17868967]
[31]
Lee HS, Kim BS, Kim MK. Suppression effect of Cinnamomum cassia bark-derived component on nitric oxide synthase. J Agric Food Chem 2002; 50(26): 7700-3.
[http://dx.doi.org/10.1021/jf020751f] [PMID: 12475291]
[32]
Lin CC, Wu SJ, Chang CH, Ng LT. Antioxidant activity of Cinnamomum cassia. Phytother Res 2003; 17(7): 726-30.
[http://dx.doi.org/10.1002/ptr.1190] [PMID: 12916067]
[33]
Cheng SS, Liu JY, Tsai KH, Chen WJ, Chang ST. Chemical composition and mosquito larvicidal activity of essential oils from leaves of different Cinnamomum osmophloeum provenances. J Agric Food Chem 2004; 52(14): 4395-400.
[http://dx.doi.org/10.1021/jf0497152] [PMID: 15237942]
[34]
Kim HO, Park SW, Park HD. Inactivation of Escherichia coli O157:H7 by cinnamic aldehyde purified from Cinnamomum cassia shoot. Food Microbiol 2004; 21: 105-10.
[http://dx.doi.org/10.1016/S0740-0020(03)00010-8]
[35]
Ng LT, Wu SJ. Antiproliferative Activity of Cinnamomum cassia Constituents and effects of pifithrin-alpha on their apoptotic signaling pathways in Hep G2 Cells. Evid Based Complement Alternat Med 2011; 2011492148
[http://dx.doi.org/10.1093/ecam/nep220] [PMID: 20038571]
[36]
Huss U, Ringbom T, Perera P, Bohlin L, Vasänge M. Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay. J Nat Prod 2002; 65(11): 1517-21.
[http://dx.doi.org/10.1021/np020023m] [PMID: 12444669]
[37]
Sayed NA, Awadallah FM, Ibrahim NA, Saadi MT. Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives. Med Chem Res 2012; 21: 395-405.
[http://dx.doi.org/10.1007/s00044-010-9545-5]
[38]
Hegazy GH, Ali HI. Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids. Bioorg Med Chem 2012; 20(3): 1259-70.
[http://dx.doi.org/10.1016/j.bmc.2011.12.030] [PMID: 22225915]
[39]
Kulkarni SK. Practical Pharmacology and Clinical Pharmacy. Vallabh Publications 2009; pp. 250-2.
[40]
Morris GM, Goodsell DS, Halliday RS, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19: 1639-48.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639:AID-JCC10>3.0.CO;2-B]
[41]
Mukherjee A, Sarkar A. New pyrazole-tethered Schiff bases as ligands for the Suzuki reaction. Tetrahedron Lett 2005; 46: 15-8.
[http://dx.doi.org/10.1016/j.tetlet.2004.11.051]
[42]
Shin DS, Kim J, Han DC, et al. Synthesis and biological evaluation of cinnamyl compounds as potent antitumor agents. Bioorg Med Chem Lett 2007; 17(19): 5423-7.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.033] [PMID: 17683933]
[43]
Khan KM, Ambreen N, Mughal UR, Jalil S, Perveen S, Choudhary MI. 3-Formylchromones: Potential anti-inflammatory agent, H E J Research Institute of Chemistry, In: International Center for Chemical and Biological Sciences, University of Karachi, Ka-rachi-75270, Pakistan,. 2010.
[44]
Kaur J, Bhardwaj A, Huang Z, Knaus EE. N-1 and C-3 substituted indole Schiff bases as selective COX-2 inhibitors: synthesis and biological evaluation. Bioorg Med Chem Lett 2012; 22(6): 2154-9.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.130] [PMID: 22361134]
[45]
Armitage P. Statistical Methods in Medical Research, 1st ed , Blackwell: In: Scientific, Oxford, London 1971; pp. 158-62. In:
[46]
Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 1962; 111: 544-7.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[47]
Dannhardt G, Kiefer W, Krämer G, Maehrlein S, Nowe U, Fiebich B. The pyrrole moiety as a template for COX-1/COX-2 inhibitors. Eur J Med Chem 2000; 35(5): 499-510.
[http://dx.doi.org/10.1016/S0223-5234(00)00150-1] [PMID: 10889329]
[48]
Copeland RA, Williams JM, Giannaras J, et al. Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase. Proc Natl Acad Sci USA 1994; 91(23): 11202-6.
[http://dx.doi.org/10.1073/pnas.91.23.11202] [PMID: 7972034]
[49]
Pagels WR, Sachs RJ, Marnett LJ, Dewitt DL, Day JS, Smith WL. Immunochemical evidence for the involvement of prostaglandin H synthase in hydroperoxide-dependent oxidations by ram seminal vesicle microsomes. J Biol Chem 1983; 258(10): 6517-23.
[PMID: 6406484]
[50]
Egan RW, Paxton J, Kuehl FA Jr. Mechanism for irreversible self-deactivation of prostaglandin synthetase. J Biol Chem 1976; 251(23): 7329-35.
[PMID: 826527]
[51]
Tewari AK, Singh VP, Yadav P, et al. Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Bioorg Chem 2014; 56: 8-15.
[http://dx.doi.org/10.1016/j.bioorg.2014.05.004] [PMID: 24893208]

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