Novel Dual COX-2/5-LOX Inhibitory Activity by Chalcone Derivatives: A Safe and Efficacious Anti-Inflammatory Agent

Roopal      Mittal; Shailesh      Sharma; Amit      Mittal; Ajay   Singh   Kushwah

doi:10.2174/0118715230301176240605072113

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Abstract

Background: Non-communicable diseases are chronic systemic inflammation in humans that occurs because of enhanced inflammatory mediators of the arachidonic acid cas-cade. We aimed to explore whether the lead chalcone compounds could exhibit anti-inflam-matory activity via dual blockage of COX-2/5-LOX enzymes and their regulatory mechanism.

Methods: RAW 264.7 macrophages were collected from NCC, Pune, for in-vitro experiments. The IC50 values of chalcone compounds C45 and C64 were calculated. RAW 264.7 macro-phages were treated with C45 and C64 (10%, 5%, 2.5%, 0.125%, and 0.0625% concentration). The cell viability was carried out with an MTT assay. The COX-1, COX-2, 5-LOX, PGE2, and LTB4 levels were detected by ELISA-based kits. The in-vivo evaluation was carried out in Male Wistar rats (250-300 g, 7-8 weeks old) with acute and chronic anti-inflammatory models and histopathological studies on the stomach, liver, and kidney.

Results: The present study described the in-vitro and in-vivo biological evaluation of dual COX-2/5-LOX inhibitors in chalcone derivatives (C45 and C64) compounds showed the most effective COX-2 and 5-LOX inhibition with IC50 values 0.092 and 0.136μM respectively. Simultaneously, compound C64 showed comparable selectivity towards COX-2 with a Selec-tivity Index (SI) of 68.43 compared to etoricoxib, with an SI of 89.32. In-vivo carrageenan-induced rat paw oedema activity, the compound C64 showed a significant reduction in oedema with 78.28% compared to indomethacin with 88.07% inhibition. Furthermore, cotton pellet-induced granuloma activity revealed that compound C64 significantly reduced 32.85% com-pared with standard 40.13% granuloma inhibition.

Conclusion: The chalcone compound C64, (E)-1-(4-Amino-2-hydroxyphenyl)-3-(3,4,5-tri-methoxyphenyl)-prop-2-en-1-one was proved to be a potent and novel Dual COX-2/5-LOX inhibitor with improved gastric safety profiling.

[1]
Hariharan, R.; Odjidja, E.N.; Scott, D.; Shivappa, N.; Hébert, J.R.; Hodge, A.; de Courten, B. The dietary inflammatory index, obesity, type 2 diabetes, and cardiovascular risk factors and diseases. Obes. Rev.,  2022, 23(1), e13349.
 [http://dx.doi.org/10.1111/obr.13349] [PMID: 34708499]

[2]
Roth, G. Global burden of disease study 2017 (GBD 2017) results. Seattle, United States: Institute for Health Metrics and Evaluation (IHME), 2018. Lancet,  2018, 392, 1736-1788.
 [http://dx.doi.org/10.1016/S0140-6736(18)32203-7]

[3]
Phillips, C.M.; Chen, L.W.; Heude, B.; Bernard, J.Y.; Harvey, N.C.; Duijts, L.; Mensink-Bout, S.M.; Polanska, K.; Mancano, G.; Suderman, M.; Shivappa, N.; Hébert, J.R. Dietary inflammatory index and non-communicable disease risk: A narrative review. Nutrients,  2019, 11(8), 1873.
 [http://dx.doi.org/10.3390/nu11081873] [PMID: 31408965]

[4]
Harizi, H.; Corcuff, J.B.; Gualde, N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol. Med.,  2008, 14(10), 461-469.
 [http://dx.doi.org/10.1016/j.molmed.2008.08.005] [PMID: 18774339]

[5]
de Gaetano, G.; Donati, M.B.; Cerletti, C. Prevention of thrombosis and vascular inflammation: Benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. Trends Pharmacol. Sci.,  2003, 24(5), 245-252.
 [http://dx.doi.org/10.1016/S0165-6147(03)00077-4] [PMID: 12767724]

[6]
Hawkey, C.J. COX-2 inhibitors. Lancet,  1999, 353(9149), 307-314.
 [http://dx.doi.org/10.1016/S0140-6736(98)12154-2] [PMID: 9929039]

[7]
Fiorucci, S.; Meli, R.; Bucci, M.; Cirino, G. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? 1 1Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; COX, cyclooxygenase; LT, leukotriene; 5-LOX, 5-lipoxygenase; PG, prostaglandin; DFU, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsuphonyl)-phenyl-2(5H)-furanone; and DFP, diisopropyl fluorophosphate. Biochem. Pharmacol.,  2001, 62(11), 1433-1438.
 [http://dx.doi.org/10.1016/S0006-2952(01)00747-X] [PMID: 11728379]

[8]
Charlier, C.; Michaux, C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur. J. Med. Chem.,  2003, 38(7-8), 645-659.
 [http://dx.doi.org/10.1016/S0223-5234(03)00115-6] [PMID: 12932896]

[9]
Julémont, F.; Dogné, J.M.; Pirotte, B.; Leval, X. Recent development in the field of dual COX / 5-LOX inhibitors. Mini Rev. Med. Chem.,  2004, 4(6), 633-638.
 [http://dx.doi.org/10.2174/1389557043403747] [PMID: 15279597]

[10]
Zhang, J.M.; An, J. Cytokines, inflammation, and pain. Int. Anesthesiol. Clin.,  2007, 45(2), 27-37.
 [http://dx.doi.org/10.1097/AIA.0b013e318034194e] [PMID: 17426506]

[11]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev.,  2017, 117(12), 7762-7810.
 [http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]

[12]
Rozmer, Z.; Perjési, P. Naturally occurring chalcones and their biological activities. Phytochem. Rev.,  2016, 15(1), 87-120.
 [http://dx.doi.org/10.1007/s11101-014-9387-8]

[13]
Kostanecki, V.S.; Tambor, J. About the six isomeric monooxybenzalacetophenones (monooxychalcones). Ber. Dtsch. Chem. Ges.,  1899, 32(2), 1921-1926.
 [http://dx.doi.org/10.1002/cber.18990320293]

[14]
Singhal, M.; Paul, A.; Singh, H. Synthesis and characterization of some novel chalcone derivatives: An intermediate for various heterocyclic compounds. Int. J. Pharm. Investig.,  2011, 1(1), 1-7.
 [PMID: 23071911]

[15]
Díaz-Tielas, C.; Graña, E.; Reigosa, M.J.; Sánchez-Moreiras, A.M. Biological activities and novel applications of chalcones. Planta Daninha,  2016, 34(3), 607-616.
 [http://dx.doi.org/10.1590/s0100-83582016340300022]

[16]
Prashar, H.; Chawla, A.; Sharma, A.K.; Kharb, R. Chalcone as a versatile moiety for diverse pharmacological activities. Int. J. Pharm. Sci. Res.,  2012, 3(7), 1913.

[17]
Awaad, A.S.; El-Meligy, R.M.; Soliman, G.A. Natural products in treatment of ulcerative colitis and peptic ulcer. J. Saudi Chem. Soc.,  2013, 17(1), 101-124.
 [http://dx.doi.org/10.1016/j.jscs.2012.03.002]

[18]
ur Rashid, H.; Xu, Y.; Ahmad, N.; Muhammad, Y.; Wang, L. Promising anti-inflammatory effects of chalcones via inhibition of cyclooxygenase, prostaglandin E2, inducible NO synthase and nuclear factor κb activities. Bioorg. Chem.,  2019, 87, 335-365.
 [http://dx.doi.org/10.1016/j.bioorg.2019.03.033] [PMID: 30921740]

[19]
Mittal, R.; Sharma, S.; Mittal, A.; Kumar, S.; Kushwah, A.S. Virtual screening, molecular docking, and physiochemical analysis of novel 1,3-diphenyl-2-propene-1-one as dual COX-2/5-LOX inhibitors. Lett. Drug Des. Discov.,  2024, 21(2), 270-288.
 [http://dx.doi.org/10.2174/1570180819666220523093435]

[20]
Kang, S.R.; Han, D.Y.; Park, K.I.; Park, H.S. Suppressive effect on lipopolysaccharide-induced proinflammatory mediators by citrus aurantium L. in macrophage RAW 264.7 cells via NF-B signal pathway. Evid. Based Complement. Alternat. Med.,  2011, 248592
 [http://dx.doi.org/10.1155/2011/248592]

[21]
Yoon, S.B.; Lee, Y.J.; Park, S.K.; Kim, H.C.; Bae, H.; Kim, H.M.; Ko, S.G.; Choi, H.Y.; Oh, M.S.; Park, W. Anti-inflammatory effects of Scutellaria baicalensis water extract on LPS-activated RAW 264.7 macrophages. J. Ethnopharmacol.,  2009, 125(2), 286-290.
 [http://dx.doi.org/10.1016/j.jep.2009.06.027] [PMID: 19577625]

[22]
Karki, R.; Park, C.H.; Kim, D.W. Extract of buckwheat sprouts scavenges oxidation and inhibits pro-inflammatory mediators in lipopolysaccharide-stimulated macrophages (RAW264.7). J. Integr. Med.,  2013, 11(4), 246-252.
 [http://dx.doi.org/10.3736/jintegrmed2013036] [PMID: 23867243]

[23]
Lee, M.Y.; Park, B.Y.; Kwon, O.K.; Yuk, J.E.; Oh, S.R.; Kim, H.S.; Lee, H.K.; Ahn, K.S. Anti-inflammatory activity of (−)-aptosimon isolated from Daphne genkwa in RAW264.7 cells. Int. Immunopharmacol.,  2009, 9(7-8), 878-885.
 [http://dx.doi.org/10.1016/j.intimp.2009.03.012] [PMID: 19328870]

[24]
Wu, L.; Fan, N.; Lin, M.; Chu, I.; Huang, S.; Hu, C.Y.; Han, S. Anti-inflammatory effect of spilanthol from Spilanthes acmella on murine macrophage by down-regulating LPS-induced inflammatory mediators. J. Agric. Food Chem.,  2008, 56(7), 2341-2349.
 [http://dx.doi.org/10.1021/jf073057e] [PMID: 18321049]

[25]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Exp. Biol. Med.,  1962, 111(3), 544-547.
 [http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]

[26]
Abdelrahman, M.H.; Youssif, B.G.M.; abdelgawad, M.A.; Abdelazeem, A.H.; Ibrahim, H.M.; Moustafa, A.E.G.A.; Treamblu, L.; Bukhari, S.N.A. Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity. Eur. J. Med. Chem.,  2017, 127, 972-985.
 [http://dx.doi.org/10.1016/j.ejmech.2016.11.006] [PMID: 27837994]

[27]
George, L.; Ramasamy, T.; Manickam, V.; Iyer, S.K.; Radhakrishnan, V. Novel phenanthridine (PHE-4i) derivative inhibits carrageenan-induced rat hind paw oedema through suppression of hydrogen sulfide. Inflammopharmacology,  2016, 24(4), 173-180.
 [http://dx.doi.org/10.1007/s10787-016-0273-4] [PMID: 27380491]

[28]
Xu, G.L.; Liu, F.; Ao, G.Z.; He, S.Y.; Ju, M.; Zhao, Y.; Xue, T. Anti-inflammatory effects and gastrointestinal safety of NNU-hdpa, a novel dual COX/5-LOX inhibitor. Eur. J. Pharmacol.,  2009, 611(1-3), 100-106.
 [http://dx.doi.org/10.1016/j.ejphar.2009.03.062] [PMID: 19345206]

[29]
Sabiu, S.; Garuba, T.; Sunmonu, T.; Ajani, E.; Sulyman, A.; Nurain, I.; Balogun, A. Indomethacin-induced gastric ulceration in rats: Protective roles of Spondias mombin a nd Ficus exasperata. Toxicol. Rep.,  2015, 2, 261-267.
 [http://dx.doi.org/10.1016/j.toxrep.2015.01.002] [PMID: 28962358]

[30]
Lee, E.S.; Park, B.C.; Paek, S.H.; Lee, Y.S.; Basnet, A.; Jin, D.Q.; Choi, H.G.; Yong, C.S.; Kim, J.A. Potent analgesic and anti-inflammatory activities of 1-furan-2-yl-3-pyridin-2-yl-propenone with gastric ulcer sparing effect. Biol. Pharm. Bull.,  2006, 29(2), 361-364.
 [http://dx.doi.org/10.1248/bpb.29.361] [PMID: 16462046]

[31]
Zhao, J.; Maitituersun, A.; Li, C.; Li, Q.; Xu, F.; Liu, T. Evaluation on analgesic and anti-inflammatory activities of total flavonoids from Juniperus sabina. Evid. Based Complement. Alternat. Med.,  2018, 2018, 1-9.
 [http://dx.doi.org/10.1155/2018/7965306] [PMID: 30069226]

[32]
Chen, S.; Mukoyama, T.; Sato, N.; Yamagata, S.I.; Arai, Y.; Satoh, N.; Ueda, S. Induction of nephrotoxic serum nephritis in inbred mice and suppressive effect of colchicine on the development of this nephritis. Pharmacol. Res.,  2002, 45(4), 319-324.
 [http://dx.doi.org/10.1006/phrs.2002.0948] [PMID: 12030796]

[33]
Naz, M.; Rehman, N.; Nazam Ansari, M.; Kamal, M.; Ganaie, M.A.; Awaad, A.S.; Alqasoumi, S.I. Comparative study of subchronic toxicities of mosquito repellents (coils, mats and liquids) on vital organs in Swiss albino mice. Saudi Pharm. J.,  2019, 27(3), 348-353.
 [http://dx.doi.org/10.1016/j.jsps.2018.12.002] [PMID: 30976177]

[34]
Shrivastava, S.K.; Srivastava, P.; Bandresh, R.; Tripathi, P.N.; Tripathi, A. Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity. Bioorg. Med. Chem.,  2017, 25(16), 4424-4432.
 [http://dx.doi.org/10.1016/j.bmc.2017.06.027] [PMID: 28669741]

[35]
Ganguly, A.K. A method for quantitative assessment of experimentally produced ulcers in the stomach of albino rats. Experientia,  1969, 25(11), 1224-1224.
 [http://dx.doi.org/10.1007/BF01900290] [PMID: 5357845]

[36]
Kamil, M.; Fatima, A.; Ullah, S.; Ali, G.; Khan, R.; Ismail, N.; Qayum, M.; Irimie, M.; Dinu, C.G.; Ahmedah, H.T.; Cocuz, M.E. Toxicological evaluation of novel cyclohexenone derivative in an animal model through histopathological and biochemical techniques. Toxics,  2021, 9(6), 119.
 [http://dx.doi.org/10.3390/toxics9060119] [PMID: 34070633]

[37]
Tasneem, S.; Liu, B.; Li, B.; Choudhary, M.I.; Wang, W. Molecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agents. Pharmacol. Res.,  2019, 139, 126-140.
 [http://dx.doi.org/10.1016/j.phrs.2018.11.001] [PMID: 30395947]

[38]
Ong, C.K.S.; Lirk, P.; Tan, C.H.; Seymour, R.A. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin. Med. Res.,  2007, 5(1), 19-34.
 [http://dx.doi.org/10.3121/cmr.2007.698] [PMID: 17456832]

[39]
Sostres, C.; Gargallo, C.J.; Arroyo, M.T.; Lanas, A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract. Res. Clin. Gastroenterol.,  2010, 24(2), 121-132.
 [http://dx.doi.org/10.1016/j.bpg.2009.11.005] [PMID: 20227026]

[40]
Xu, G.L.; Liu, F.; Zhao, Y.; Ao, G.Z.; Xi, L.; Ju, M.; Xue, T. Biological evaluation of 2-(4-amino-phenyl)-3-(3,5-dihydroxylphenyl) propenoic acid. Basic Clin. Pharmacol. Toxicol.,  2009, 105(5), 350-356.
 [http://dx.doi.org/10.1111/j.1742-7843.2009.00463.x] [PMID: 19744157]

[41]
Yang, J.; Li, S.; Xie, C.; Ye, H.; Tang, H.; Chen, L.; Peng, A. Anti-inflammatory activity of ethyl acetate fraction of the seeds of Brucea Javanica. J. Ethnopharmacol.,  2013, 147(2), 442-446.
 [http://dx.doi.org/10.1016/j.jep.2013.03.034] [PMID: 23538165]

[42]
Karim, N.; Khan, I.; Khan, W.; Khan, I.; Khan, A.; Halim, S.A.; Khan, H.; Hussain, J.; Al-Harrasi, A. Anti-nociceptive and anti-inflammatory activities of asparacosin a involve selective cyclooxygenase 2 and inflammatory cytokines inhibition: An in-vitro, in-vivo, and in-silico approach. Front. Immunol.,  2019, 10, 581.
 [http://dx.doi.org/10.3389/fimmu.2019.00581] [PMID: 30972073]

[43]
Negi, P.; Agarwal, S.; Garg, P.; Ali, A.; Kulshrestha, S. In vivo models of understanding inflammation (in vivo methods for inflammation) In: Recent Developments in Anti-Inflammatory Therapy; , 2023; pp. 315-330.
 [http://dx.doi.org/10.1016/B978-0-323-99988-5.00017-6]

[44]
Sengar, N.; Joshi, A.; Prasad, S.K.; Hemalatha, S. Anti-inflammatory, analgesic and anti-pyretic activities of standardized root extract of Jasminum sambac. J. Ethnopharmacol.,  2015, 160, 140-148.
 [http://dx.doi.org/10.1016/j.jep.2014.11.039] [PMID: 25479154]

[45]
Solanki, H.K.; Shah, D.A.; Maheriya, P.M.; Patel, C.A. Evaluation of anti-inflammatory activity of probiotic on carrageenan-induced paw edema in Wistar rats. Int. J. Biol. Macromol.,  2015, 72, 1277-1282.
 [http://dx.doi.org/10.1016/j.ijbiomac.2014.09.059] [PMID: 25316426]

[46]
Cong, H.H.; Khaziakhmetova, V.N.; Zigashina, L.E. Rat paw oedema modeling and NSAIDs: Timing of effects. Int. J. Risk Saf. Med.,  2015, 27(s1)(Suppl. 1), S76-S77.
 [http://dx.doi.org/10.3233/JRS-150697] [PMID: 26639722]

[47]
Spector, W.G. The granulomatous inflammatory exudate. Int. Rev. Exp. Pathol.,  1969, 8, 1-55.
 [PMID: 4904706]

[48]
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]

[49]
Li, W.; Huang, H.; Zhang, Y.; Fan, T.; Liu, X.; Xing, W.; Niu, X. Anti-inflammatory effect of tetrahydrocoptisine from Corydalis impatiens is a function of possible inhibition of TNF-α, IL-6 and NO production in lipopolysaccharide-stimulated peritoneal macrophages through inhibiting NF-κB activation and MAPK pathway. Eur. J. Pharmacol.,  2013, 715(1-3), 62-71.
 [http://dx.doi.org/10.1016/j.ejphar.2013.06.017] [PMID: 23810685]

[50]
Liao, J.C.; Tsai, J.C.; Peng, W.H.; Chiu, Y.J.; Sung, P.J.; Tsuzoki, M.; Kuo, Y.H. Anti-inflammatory activity of N-(3-florophenyl)ethylcaffeamide in mice. Int. J. Mol. Sci.,  2013, 14(8), 15199-15211.
 [http://dx.doi.org/10.3390/ijms140815199] [PMID: 23887648]

[51]
Vysakh, A.; Jayesh, K.; Helen, L.R.; Jyothis, M.; Latha, M.S. Acute oral toxicity and anti-inflammatory evaluation of methanolic extract of Rotula aquatica roots in Wistar rats. J. Ayurveda Integr. Med.,  2020, 11(1), 45-52.
 [http://dx.doi.org/10.1016/j.jaim.2017.09.007] [PMID: 30120055]

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DOI https://dx.doi.org/10.2174/0118715230301176240605072113	Print ISSN 1871-5230
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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Novel Dual COX-2/5-LOX Inhibitory Activity by Chalcone Derivatives: A Safe and Efficacious Anti-Inflammatory Agent

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