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Current Enzyme Inhibition

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ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

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Research Article

Anti-inflammatory Activity of Pyrazole Analogues Deduced from Bioactive Piperine: Synthesis, In silico, and In vitro Evaluation

Author(s): Lilbet Mathew, Murugesan sankaranarayanan and Ilango Kaliappan*

Volume 19, Issue 2, 2023

Published on: 10 May, 2023

Page: [125 - 135] Pages: 11

DOI: 10.2174/1573408019666230303143432

Price: $65

Abstract

Background: Around ten novel pyrazoline and pyrazolidine derivatives were designed and synthesized by the condensation of piperine, hydrazine hydrate, phenylhydrazine, aromatic carboxylic acid, and ethanol.

Methods: The synthesized compounds (2, 3, 4a-d, and 5a-d) were characterized by FTIR, 1HNMR, mass spectral, and elemental analysis. Pharmacokinetic, physicochemical, drug-likeness, and medicinal chemistry friendliness parameters were also predicted by in silico methods.

Results: Furthermore, compounds were screened for in vitro anti-inflammatory activity by the HRBC membrane stabilization method using diclofenac sodium as the standard drug. The tested compounds showed moderate anti-inflammatory activity compared to the standard drug. The molecular docking studies of significantly active (4d) and least active compounds (5d) were also carried out in the active sites of an arachidonate-12-lipoxygenase target in order to study the putative binding pattern of the study compounds.

Conclusion: According to the findings of this study, further lead identification as well as lead optimization techniques will be required in the near future in order to get potent analogues.

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[1]
Bleicher KH, Böhm HJ, Müller K, Alanine AI. Hit and lead generation: Beyond high-throughput screening. Nat Rev Drug Discov 2003; 2(5): 369-78.
[http://dx.doi.org/10.1038/nrd1086] [PMID: 12750740]
[2]
Lewis RA. A general method for exploiting QSAR models in lead optimization. J Med Chem 2005; 48(5): 1638-48.
[http://dx.doi.org/10.1021/jm049228d] [PMID: 15743205]
[3]
Kalra BS, Tekur U, Lahoti A. Evaluation of the analgesic and anti-inflammatory activity of fixed dose combination: Non-steroidal anti-inflammatory drugs in experimental animals. Indian J Dent Res 2014; 25(5): 551-4.
[http://dx.doi.org/10.4103/0970-9290.147071] [PMID: 25511049]
[4]
Luci DK, Jameson JB II, Yasgar A, et al. Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase. J Med Chem 2014; 57(2): 495-506.
[http://dx.doi.org/10.1021/jm4016476] [PMID: 24393039]
[5]
Kenyon V, Rai G, Jadhav A, et al. Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase. J Med Chem 2011; 54(15): 5485-97.
[http://dx.doi.org/10.1021/jm2005089] [PMID: 21739938]
[6]
Block JH, Beale JM. Wilson & Giswold’s Text Book of Organic Medicinal Chemistry and Pharmaceutical Chemistry. (11th ed.). Lippincott Williams & Wilkins 2004; pp. 1-2.
[7]
Brahmbhatt H, Molnar M. Pavić V. Pyrazole nucleus fused tri-substituted imidazole derivatives as antioxidant and antibacterial agents. Karbala Int J Mod Sci 2018; 4(2): 200-6.
[http://dx.doi.org/10.1016/j.kijoms.2018.01.006]
[8]
El-Shoukrofy MS, Abd El Razik HA. AboulWafa OM, Bayad AE, El-Ashmawy IM. Pyrazoles containing thiophene, thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design, synthesis, in vivo anti-inflammatory activity, docking and in silico chemo-informatic studies. Bioorg Chem 2019; 85: 541-57.
[http://dx.doi.org/10.1016/j.bioorg.2019.02.036] [PMID: 30807897]
[9]
Aly AA, Sayed SM, Abdelhafez ESMN, et al. New quinoline-2-one/pyrazole derivatives; design, synthesis, molecular docking, anti-apoptotic evaluation, and caspase-3 inhibition assay. Bioorg Chem 2020; 94: 103348.
[http://dx.doi.org/10.1016/j.bioorg.2019.103348] [PMID: 31699387]
[10]
Bhagat SS, Ghotekar DS, Badadhe PV, Chavan NM, Dixit PP, Gill CH. Synthesis and antimicrobial screening of pyrazolines and benzothiazepines incorporated with thiophene. Indian J Chem 2011; 20: 355-8.
[http://dx.doi.org/10.15680/IJIRSET.2015.0402027]
[11]
Shankaraiah GK, Bhaskar SD. Synthesis and antimicrobial properties of some new imidazole containing 2-pyrazoline derivatives. Indian J Chem 2010; 20: 153-6. http://dx.doi.org/10.5155
[12]
Ghotekar DS, Mandhane PG, Joshi RS, Bhagat SS, Gill CH. Synthesis of chromones and pyrazolines as antimicrobial and antifungal agents. Indian J Chem 2010; 19: 341-4.
[13]
Joshi RS, Mandhane PG, Diwakar SD, Dabhade SK, Gill CH. Synthesis, analgesic and anti-inflammatory activities of some novel pyrazolines derivatives. Bioorg Med Chem Lett 2010; 20(12): 3721-5.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.082] [PMID: 20529688]
[14]
Sahu SK, Banerjee M, Samantray A, Behera C, Azam MA. Synthesis, analgesic, anti-inflammatory and antimicrobial activities of some novel pyrazoline derivatives. Trop J Pharm Res 2008; 7(2): 961-8.
[http://dx.doi.org/10.4314/tjpr.v7i2.14664]
[15]
Arunkumar S, Ilango K, Manikandan RS, Ramalakshmi N. Synthesis and anti-inflammatory activity of some novel pyrazole derivatives of gallic acid. E-J Chem 2009; 6(s1): S123-8.
[http://dx.doi.org/10.1155/2009/128586]
[16]
Bang JS, Oh DH, Choi HM, et al. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther 2009; 11(2): R49.
[http://dx.doi.org/10.1186/ar2662] [PMID: 19327174]
[17]
Kumar AD, Prabhudeva MG, Bharath S, Kumara K, Lokanath NK, Kumar KA. Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole carboxamides that potently inhibit Phospholipase A2 by binding to an allosteric site on the enzyme. Bioorg Chem 2018; 80: 444-52.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.023] [PMID: 29986189]
[18]
Kaplancıklı ZA, Özdemir A, Turan-Zitouni G, Altıntop MD, Can ÖD. New pyrazoline derivatives and their antidepressant activity. Eur J Med Chem 2010; 45(9): 4383-7.
[http://dx.doi.org/10.1016/j.ejmech.2010.06.011] [PMID: 20587366]
[19]
Rajendra Prasad Y, Lakshmana Rao A, Prasoona L, Murali K, Ravi Kumar P. Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2″-hydroxy naphthalen-1″-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 2005; 15(22): 5030-4.
[http://dx.doi.org/10.1016/j.bmcl.2005.08.040] [PMID: 16168645]
[20]
Chimenti F, Bizzarri B, Manna F, et al. Synthesis and in vitro selective anti-Helicobacter pylori activity of pyrazoline derivatives. Bioorg Med Chem Lett 2005; 15(3): 603-7.
[http://dx.doi.org/10.1016/j.bmcl.2004.11.042] [PMID: 15664821]
[21]
Rostom SAF. Polysubstituted pyrazoles, part 6. Synthesis of some 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring systems as potential antitumor agents. Bioorg Med Chem 2010; 18(7): 2767-76.
[http://dx.doi.org/10.1016/j.bmc.2010.02.006] [PMID: 20207545]
[22]
Insuasty B, Tigreros A, Orozco F, et al. Synthesis of novel pyrazolic analogues of chalcones and their 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antitumor agents. Bioorg Med Chem 2010; 18(14): 4965-74.
[http://dx.doi.org/10.1016/j.bmc.2010.06.013] [PMID: 20594863]
[23]
Acharya BN, Saraswat D, Tiwari M, et al. Synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines. Eur J Med Chem 2010; 45(2): 430-8.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.023] [PMID: 19926176]
[24]
George RF, Kandeel M, El-Ansary DY, El Kerdawy AM. Some 1,3,5-trisubstituted pyrazoline derivatives targeting breast cancer: Design, synthesis, cytotoxic activity, EGFR inhibition and molecular docking. Bioorg Chem 2020; 99: 103780.
[http://dx.doi.org/10.1016/j.bioorg.2020.103780] [PMID: 32224337]
[25]
Burguete A, Pontiki E, Hadjipavlou-Litina D, et al. Synthesis and anti-inflammatory/antioxidant activities of some new ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues. Bioorg Med Chem Lett 2007; 17(23): 6439-43.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.002] [PMID: 17942306]
[26]
Shoman ME, Abdel-Aziz M, Aly OM, Farag HH, Morsy MA. Synthesis and investigation of anti-inflammatory activity and gastric ulcerogenicity of novel nitric oxide-donating pyrazoline derivatives. Eur J Med Chem 2009; 44(7): 3068-76.
[http://dx.doi.org/10.1016/j.ejmech.2008.07.008] [PMID: 18722034]
[27]
Chimenti F, Carradori S, Secci D, et al. Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1 H)-pyrazole derivatives. Eur J Med Chem 2010; 45(2): 800-4.
[http://dx.doi.org/10.1016/j.ejmech.2009.11.003] [PMID: 19926363]
[28]
Chimenti F, Fioravanti R, Bolasco A, et al. Synthesis, molecular modeling studies and selective inhibitory activity against MAO of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. Eur J Med Chem 2008; 43(10): 2262-7.
[http://dx.doi.org/10.1016/j.ejmech.2007.12.026] [PMID: 18281126]
[29]
Lévai A. Jekő J. Synthesis of carboxylic acid derivatives of 2-pyrazolines. ARKIVOC 2007; 2007(1): 134-45.
[http://dx.doi.org/10.3998/ark.5550190.0008.114]
[30]
van de Waterbeemd H, Gifford E. ADMET in silico modelling: Towards prediction paradise? Nat Rev Drug Discov 2003; 2(3): 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID: 12612645]
[31]
Thomas D, Karle C, Kiehn J. The cardiac hERG/IKr potassium channel as pharmacological target: Structure, function, regulation, and clinical applications. Curr Pharm Des 2006; 12(18): 2271-83.
[http://dx.doi.org/10.2174/138161206777585102] [PMID: 16787254]
[32]
Cusan C, Spalluto G, Prato M, et al. Synthesis and biological evaluation of a new class of acyl derivatives of 3-amino-1-phenyl-4,5-dihydro-1H-pyrazol-5-one as potential dual cyclooxygenase (COX-1 and COX-2) and human lipoxygenase (5-LOX) inhibitors. Farmaco 2005; 60(4): 327-32.
[http://dx.doi.org/10.1016/j.farmac.2004.12.009] [PMID: 15848208]
[33]
Eissa AAM, Farag NAH, Soliman GAH. Synthesis, biological evaluation and docking studies of novel benzopyranone congeners for their expected activity as anti-inflammatory, analgesic and antipyretic agents. Bioorg Med Chem 2009; 17(14): 5059-70.
[http://dx.doi.org/10.1016/j.bmc.2009.05.073] [PMID: 19527932]
[34]
Velankar AD, Quintini G, Prabhu A, et al. Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK). Bioorg Med Chem 2010; 18(12): 4547-59.
[http://dx.doi.org/10.1016/j.bmc.2010.04.056] [PMID: 20472447]
[35]
Zhong LG, Liang WZ, Bao XZ, et al. The synthesis, X-ray crystal structure and optical properties of novel 1,3,5-triaryl pyrazoline derivatives. Photochem Photobio Chem 2010; 209: 49-55.
[http://dx.doi.org/10.1016/j.jphotochem.2009.10.007]
[36]
Gautam N, Chourasia OP. Synthesis, antimicrobial and insecticidal activity of some new cinnoline based chalcones and cinnoline based pyrazoline derivatives. Indian J Chem 2010; 49B: 830-5.
[http://dx.doi.org/10.1002/chin.201044161]
[37]
Raffa D, Daidone G, Maggio B, Cascioferro S, Plescia F, Schillaci D. Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones. Farmaco 2004; 59(3): 215-21.
[http://dx.doi.org/10.1016/j.farmac.2003.10.004] [PMID: 14987985]
[38]
Dikmen M, Özturk N, Özturk Y. The antioxidant potency of Punica granatum L. Fruit peel reduces cell proliferation and induces apoptosis on breast cancer. J Med Food 2011; 14(12): 1638-46.
[http://dx.doi.org/10.1089/jmf.2011.0062] [PMID: 21861726]
[39]
Larregieu CA, Benet LZ. Distinguishing between the permeability relationships with absorption and metabolism to improve BCS and BDDCS predictions in early drug discovery. Mol Pharm 2014; 11(4): 1335-44.
[http://dx.doi.org/10.1021/mp4007858] [PMID: 24628254]
[40]
DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: New estimates of drug development costs. J Health Econ 2003; 22(2): 151-85.
[http://dx.doi.org/10.1016/S0167-6296(02)00126-1] [PMID: 12606142]
[41]
Chander S, Wang P, Ashok P, Yang LM, Zheng YT, Sankaranarayanan M. Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives. Bioorg Med Chem Lett 2017; 27(1): 61-5.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.030] [PMID: 27894873]
[42]
Lagorce D, Douguet D, Miteva MA, Villoutreix BO. Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. Sci Rep 2017; 7(1): 46277.
[http://dx.doi.org/10.1038/srep46277] [PMID: 28397808]
[43]
Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 2015; 58(9): 4066-72.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00104] [PMID: 25860834]
[44]
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7(1): 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[45]
Cheng F, Li W, Zhou Y, et al. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 2012; 52(11): 3099-105.
[http://dx.doi.org/10.1021/ci300367a] [PMID: 23092397]
[46]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[47]
Berman HM, Westbrook J, Feng Z, et al. The protein data bank nucleic acids research. 2000; 28: 235-42.
[http://dx.doi.org/10.1093/nar/28.1.235]
[48]
Banks JL, Beard HS, Cao Y, et al. Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem 2005; 26(16): 1752-80.
[http://dx.doi.org/10.1002/jcc.20292] [PMID: 16211539]

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