Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design and Synthesis of Novel Ibuprofen Derivatives as Selective COX-2 Inhibitors and Potential Anti-Inflammatory Agents: Evaluation of PGE2, TNF-α, IL-6 and Histopathological Study

Author(s): Peter Amir Halim, Hala Bakr El-Nassan* and Yara Sayed El-Dash

Volume 18, Issue 4, 2022

Published on: 09 August, 2021

Page: [427 - 443] Pages: 17

DOI: 10.2174/1573406417666210809162636

Abstract

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities.

Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups.

Methods: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity.

Results: The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent antiinflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme.

Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

Keywords: Ibuprofen, COX enzyme, docking simulation, anti-inflammatory activity, PGE2, TNF-α, IL-6, analgesic activity.

« Previous Next »
Graphical Abstract

[1]
Dannhardt, G.; Kiefer, W. Cyclooxygenase inhibitors-current status and future prospects. Eur. J. Med. Chem., 2001, 36(2), 109-126.
[http://dx.doi.org/10.1016/S0223-5234(01)01197-7] [PMID: 11311743]
[2]
Chan, F.K.L.; Graham, D.Y. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications-review and recommendations based on risk assessment. Aliment. Pharmacol. Ther., 2004, 19(10), 1051-1061.
[http://dx.doi.org/10.1111/j.1365-2036.2004.01935.x] [PMID: 15142194]
[3]
Warner, T.D.; Giuliano, F.; Vojnovic, I.; Bukasa, A.; Mitchell, J.A.; Vane, J.R. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc. Natl. Acad. Sci. USA, 1999, 96(13), 7563-7568.
[http://dx.doi.org/10.1073/pnas.96.13.7563] [PMID: 10377455]
[4]
Flower, R.J. The development of COX2 inhibitors. Nat. Rev. Drug Discov., 2003, 2(3), 179-191.
[http://dx.doi.org/10.1038/nrd1034] [PMID: 12612644]
[5]
Sharma, V.; Bhatia, P.; Alam, O.; Javed Naim, M.; Nawaz, F.; Ahmad Sheikh, A.; Jha, M. Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008-2019). Bioorg. Chem., 2019, 89, 103007.
[http://dx.doi.org/10.1016/j.bioorg.2019.103007] [PMID: 31132600]
[6]
Meek, I.L.; Van de Laar, M.A.F.J.; E Vonkeman, H. Non-steroidal anti-inflammatory drugs: an overview of cardiovascular risks. Pharmaceuticals (Basel), 2010, 3(7), 2146-2162.
[http://dx.doi.org/10.3390/ph3072146] [PMID: 27713346]
[7]
Dogné, J.M.; Supuran, C.T.; Pratico, D. Adverse cardiovascular effects of the coxibs. J. Med. Chem., 2005, 48(7), 2251-2257.
[http://dx.doi.org/10.1021/jm0402059] [PMID: 15801815]
[8]
Patrono, C. Cardiovascular effects of cyclooxygenase-2 inhibitors: a mechanistic and clinical perspective. Br. J. Clin. Pharmacol., 2016, 82(4), 957-964.
[http://dx.doi.org/10.1111/bcp.13048] [PMID: 27317138]
[9]
Arora, M.; Choudhary, S.; Singh, P.K.; Sapra, B.; Silakari, O. Structural investigation on the selective COX-2 inhibitors mediated cardiotoxicity: A review. Life Sci., 2020, 251(251), 117631.
[http://dx.doi.org/10.1016/j.lfs.2020.117631] [PMID: 32251635]
[10]
Kantor, T.G. Ibuprofen. Ann. Intern. Med., 1979, 91(6), 877-882.
[http://dx.doi.org/10.7326/0003-4819-91-6-877] [PMID: 391117]
[11]
Amir, M.; Kumar, S. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of ibuprofen derivatives. Acta Pharm., 2007, 57(1), 31-45.
[http://dx.doi.org/10.2478/v10007-007-0003-y] [PMID: 19839405]
[12]
Omar, F.; Mahfouz, N.; Rahman, M. Design, synthesis and antiinflammatory activity of some 1,3,4-oxadiazole derivatives. Eur. J. Med. Chem., 1996, 31(10), 819-825.
[http://dx.doi.org/10.1016/0223-5234(96)83976-6] [PMID: 22026938]
[13]
Sarkate, A.P.; Lokwani, D.K.; Patil, A.A.; Bhandari, S.V.; Bothara, K.G. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenicity and nitric oxide-releasing studies of novel ibuprofen analogs as nonulcerogenic derivatives. Med. Chem. Res., 2011, 20(7), 795-808.
[http://dx.doi.org/10.1007/s00044-010-9389-z]
[14]
Amir, M.; Akhter, M.W.; Alam, O. Synthesis, characterization, and biological evaluation of furoxan coupled ibuprofen derivatives as anti-inflammatory agents. Monatsh. Chem., 2016, 147(3), 493-508.
[http://dx.doi.org/10.1007/s00706-015-1557-x]
[15]
Manjunatha, K.; Poojary, B.; Lobo, P.L.; Fernandes, J.; Kumari, N.S. Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. Eur. J. Med. Chem., 2010, 45(11), 5225-5233.
[http://dx.doi.org/10.1016/j.ejmech.2010.08.039] [PMID: 20828888]
[16]
Abd-Ellah, H.S.; Abdel-Aziz, M.; Shoman, M.E.; Beshr, E.A.M.; Kaoud, T.S.; Ahmed, A.F. Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities. Bioorg. Chem., 2016, 69, 48-63.
[http://dx.doi.org/10.1016/j.bioorg.2016.09.005] [PMID: 27669120]
[17]
Al Mekhlafi, S.; Alkadi, H.; Kotb, M-I.; Sayed, E. Synthesis and anti-inflammatory activity of novel ketoprofen and ibuprofen derivatives. J. Chem. Pharm. Res., 2015, 7(2), 503-510.
[18]
Lolli, M.L.; Cena, C.; Medana, C.; Lazzarato, L.; Morini, G.; Coruzzi, G.; Manarini, S.; Fruttero, R.; Gasco, A. A new class of ibuprofen derivatives with reduced gastrotoxicity. J. Med. Chem., 2001, 44(21), 3463-3468.
[http://dx.doi.org/10.1021/jm0108799] [PMID: 11585451]
[19]
Mohamed, S.K.; Albayati, M.; Omara, W.A.M.; Abdelhamid, A.A.; Potgeiter, H.; Hameed, A.S.; Al-Janabi, K.M. Functionalization of ibuprofen core structure compound: part 1 synthesis of potential chemotherapeutic agents incorporated ibuprofen substructure and their in vitro antimicrobial study. J. Chem. Pharm. Res., 2012, 4(7), 3505-3517.
[20]
Gundogdu-Hizliates, C.; Alyuruk, H.; Gocmenturk, M.; Ergun, Y.; Cavas, L. Synthesis of new ibuprofen derivatives with their inin silico and in vitro cyclooxygenase-2 inhibitions. Bioorg. Chem., 2014, 52, 8-15.
[http://dx.doi.org/10.1016/j.bioorg.2013.10.002] [PMID: 24270352]
[21]
de Melo, T.R.F.; Chelucci, R.C.; Pires, M.E.L.; Dutra, L.A.; Barbieri, K.P.; Bosquesi, P.L.; Trossini, G.H.G.; Chung, M.C.; dos Santos, J.L. Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit. Int. J. Mol. Sci., 2014, 15(4), 5821-5837.
[http://dx.doi.org/10.3390/ijms15045821] [PMID: 24714090]
[22]
Raval, J.P.; Gandhi, A.N.; Akhaja, T.N.; Myangar, K.N.; Patel, N.H. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of new 2-(4-isobutylphenyl)propanoic acid derivatives. J. Enzyme Inhib. Med. Chem., 2012, 27(1), 110-116.
[http://dx.doi.org/10.3109/14756366.2011.578743] [PMID: 21612370]
[23]
Metwally, K.A.; Yaseen, S.H.; Lashine, S.M.; El-Fayomi, H.M.; El-Sadek, M.E. Non-carboxylic analogues of arylpropionic acids: synthesis, anti-inflammatory activity and ulcerogenic potential. Eur. J. Med. Chem., 2007, 42(2), 152-160.
[http://dx.doi.org/10.1016/j.ejmech.2006.09.001] [PMID: 17052805]
[24]
Amir, M.; Kumar, H.; Javed, S.A. Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid. Eur. J. Med. Chem., 2008, 43(10), 2056-2066.
[http://dx.doi.org/10.1016/j.ejmech.2007.09.025] [PMID: 18023930]
[25]
Rao, P.; Knaus, E.E. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J. Pharm. Pharm. Sci., 2008, 11(2), 81s-110s.
[http://dx.doi.org/10.18433/J3T886] [PMID: 19203472]
[26]
Zarghi, A.; Arfaei, S. Selective COX-2 inhibitors: A review of their structure-activity relationships. Iran. J. Pharm. Res., 2011, 10(4), 655-683.
[PMID: 24250402]
[27]
Chen, H.; Li, Q.; Yao, X.; Fan, B.; Yuan, S.; Panaye, A.; Doucet, J.P. CoMFA/CoMSIA/HQSAR and docking study of the binding mode of selective cyclooxygenase (COX-2) inhibitors. QSAR Comb. Sci., 2004, 23(1), 36-55.
[http://dx.doi.org/10.1002/qsar.200330844] [PMID: 32327948]
[28]
Orlando, B.J.; Lucido, M.J.; Malkowski, M.G. The structure of ibuprofen bound to cyclooxygenase-2. J. Struct. Biol., 2015, 189(1), 62-66.
[http://dx.doi.org/10.1016/j.jsb.2014.11.005] [PMID: 25463020]
[29]
Blobaum, A.L.; Xu, S.; Rowlinson, S.W.; Duggan, K.C.; Banerjee, S.; Kudalkar, S.N.; Birmingham, W.R.; Ghebreselasie, K.; Marnett, L.J. Action at a distance: mutations of peripheral residues transform rapid reversible inhibitors to slow, tight binders of cyclooxygenase-2. J. Biol. Chem., 2015, 290(20), 12793-12803.
[http://dx.doi.org/10.1074/jbc.M114.635987] [PMID: 25825493]
[30]
Kansara, S.G.; Pandit, R.D.; Bhawe, V.G. Synthesis of some new ibuprofen derivatives containing chief heterocyclic moiety like s-triazine and evaluated for their analgesic activity. Rasayan J. Chem., 2009, 2(3), 699-705.
[31]
Mohamed, S.K.; Albayati, M.R.; Younes, S.H.H. Functionalization of ibuprofen core structure compound : synthesis of new potential chemotherapeutic agents incorporating ibuprofen substructure. Chem. Sci. J., 2013, 2013, CSJ-97.
[32]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111(111), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[33]
Manivannan, E.; Chaturvedi, S.C. Analogue-based design, synthesis and molecular docking analysis of 2,3-diaryl quinazolinones as non-ulcerogenic anti-inflammatory agents. Bioorg. Med. Chem., 2011, 19(15), 4520-4528.
[http://dx.doi.org/10.1016/j.bmc.2011.06.019] [PMID: 21724403]
[34]
Cho, C.H.I.H.; Ogle, C.W. Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1-and H2-receptor activation in stress ulceration in rats. Eur. J. Pharmacol., 1979, 55(1), 23-33.
[http://dx.doi.org/10.1016/0014-2999(79)90144-4] [PMID: 436942]
[35]
Culling, C.F.A. Handbook of histopathological and histochemical techniques, 3rd; Elsevier Academic Press, 1974.
[36]
Fakhr, I.M.I.; Radwan, M.A.A.; el-Batran, S.; Abd el-Salam, O.M.E.; el-Shenawy, S.M. Synthesis and pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2009, 44(4), 1718-1725.
[http://dx.doi.org/10.1016/j.ejmech.2008.02.034] [PMID: 18433939]
[37]
Nakanishi, M.; Rosenberg, D.W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol., 2013, 35(2), 123-137.
[http://dx.doi.org/10.1007/s00281-012-0342-8] [PMID: 22996682]
[38]
Kawahara, K.; Hohjoh, H.; Inazumi, T.; Tsuchiya, S.; Sugimoto, Y. Prostaglandin E2-induced inflammation: relevance of prostaglandin e receptors.Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids; Elsevier B.V., 2015, pp. 414-421.
[39]
Idriss, H.T.; Naismith, J.H. TNF α and the TNF receptor superfamily: structure-function relationship(s). Microsc. Res. Tech., 2000, 50(3), 184-195.
[http://dx.doi.org/10.1002/1097-0029(20000801)50:3<184:AID-JEMT2>3.0.CO;2-H] [PMID: 10891884]
[40]
Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 2014, 6(10), a016295.
[http://dx.doi.org/10.1101/cshperspect.a016295] [PMID: 25190079]
[41]
Labib, M.B.; Fayez, A.M.; El-Nahass, E.S.; Awadallah, M.; Halim, P.A. Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study. Bioorg. Chem., 2020, 104, 104308.
[http://dx.doi.org/10.1016/j.bioorg.2020.104308] [PMID: 33011534]
[42]
Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.; Browner, M.F. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol., 1996, 3(11), 927-933.
[http://dx.doi.org/10.1038/nsb1196-927] [PMID: 8901870]
[43]
Rowlinson, S.W.; Kiefer, J.R.; Prusakiewicz, J.J.; Pawlitz, J.L.; Kozak, K.R.; Kalgutkar, A.S.; Stallings, W.C.; Kurumbail, R.G.; Marnett, L.J. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J. Biol. Chem., 2003, 278(46), 45763-45769.
[http://dx.doi.org/10.1074/jbc.M305481200] [PMID: 12925531]
[44]
Moneer, A.A.; Mohammed, K.O.; El-Nassan, H.B. Synthesis of novel substituted thiourea and benzimidazole derivatives containing a pyrazolone ring as anti-inflammatory agents. Chem. Biol. Drug Des., 2016, 87(5), 784-793.
[http://dx.doi.org/10.1111/cbdd.12712] [PMID: 26684979]
[45]
Kurumbail, R.G.; Stevens, A.M.; Gierse, J.K.; McDonald, J.J.; Stegeman, R.A.; Pak, J.Y.; Gildehaus, D.; Miyashiro, J.M.; Penning, T.D.; Seibert, K.; Isakson, P.C.; Stallings, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 1996, 384(6610), 644-648.
[http://dx.doi.org/10.1038/384644a0] [PMID: 8967954]

Rights & Permissions Print Cite
Article Metrics
28
1
© 2024 Bentham Science Publishers | Privacy Policy