Login Register Cart 0
Generic placeholder image

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

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

Design, Synthesis and Pharmacological Evaluation of Gastro- Protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition

Author(s): Monika Gaba, Sarbjot Singh, Chander Mohan, Richa Dhingra , Monika Chauhan , Priyanka Rana and Neelima Dhingra*

Volume 19, Issue 3, 2020

Page: [268 - 290] Pages: 23

DOI: 10.2174/1871523018666190325155244

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration.

Objective: Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects.

Methods: In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed.

Results: Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research.

Conclusion: From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.

Keywords: Benzimidazole, cyclooxygenase, gastro protective, inflammation, oxidative stress, analgesics.

« Previous Next »
Graphical Abstract

[1]
Hassanein, A.H.; Abdelrahim, M.A.; Said, A.S.; Hussein, R.R.; Abuseif, M. The incidence of upper gastro-intestinal complications of non-steroidal anti-inflammatory drugs in elderly patients. Med. Sci., 2014, 3(1), 1032-1045.
[http://dx.doi.org/10.5455/medscience.2013.02.8105]
[2]
Gaba, M.; Mohan, C. Design, synthesis and biological evaluation of novel 1, 2, 5-substituted benzimidazole derivatives as gastroprotective anti-inflammatory and analgesic agents. Med. Chem., 2015, 5(2), 58-63.
[3]
Antunes, D.A.; Devaurs, D.; Moll, M.; Lizée, G.; Kavraki, L.E. General prediction of peptide-MHC binding modes using incremental docking: a proof of concept. Sci. Rep., 2018, 8(1), 4327-4328.
[http://dx.doi.org/10.1038/s41598-018-22173-4] [PMID: 29531253]
[4]
Ayhan-Kilcigil, G.; Kus, C.; Özdamar, E.D.; Can-Eke, B.; Iscan, M. Synthesis and antioxidant capacities of some new benzimidazole derivatives. Arch. Pharm. (Weinheim), 2007, 340(11), 607-611.
[http://dx.doi.org/10.1002/ardp.200700088] [PMID: 17994646]
[5]
Bandyopadhyay, U.; Das, D.; Banerjee, R.K. Reactive oxygen species: oxidative damage and pathogenesis. Curr. Sci., 1999, 10(5), 658-666.
[6]
Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: a review. Bioorg. Med. Chem., 2012, 20(21), 6208-6236.
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[7]
Bhattacharyya, A.; Chattopadhyay, R.; Mitra, S.; Crowe, S.E. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol. Rev., 2014, 94(2), 329-354.
[PMID: 24692350]
[8]
Benzie, I.F.; Strain, J.J. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal. Biochem., 1996, 239(1), 70-76.
[http://dx.doi.org/10.1006/abio.1996.0292] [PMID: 8660627]
[9]
Cho, K.J.; Seo, J.M.; Kim, J.H. Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species. Mol. Cells, 2011, 32(1), 1-5.
[http://dx.doi.org/10.1007/s10059-011-1021-7] [PMID: 21424583]
[10]
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]
[11]
Forli, S.; Huey, R.; Pique, M.E.; Sanner, M.F.; Goodsell, D.S.; Olson, A.J. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc., 2016, 11(5), 905-919.
[http://dx.doi.org/10.1038/nprot.2016.051] [PMID: 27077332]
[12]
Becker, J.C.; Domschke, W.; Pohle, T. Current approaches to prevent NSAID-induced gastropathy--COX selectivity and beyond. Br. J. Clin. Pharmacol., 2004, 58(6), 587-600.
[http://dx.doi.org/10.1111/j.1365-2125.2004.02198.x] [PMID: 15563357]
[13]
Gaba, M.; Gaba, P.; Uppal, D.; Dhingra, N.; Bahia, M.S.; Silakari, O.; Mohan, C. Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. Acta Pharm. Sin. B, 2015, 5(4), 337-342.
[http://dx.doi.org/10.1016/j.apsb.2015.05.003] [PMID: 26579464]
[14]
Giardina, C.; Inan, M.S. Nonsteroidal anti-inflammatory drugs, short-chain fatty acids, and reactive oxygen metabolism in human colorectal cancer cells. Biochim. Biophys. Acta, 1998, 1401(3), 277-288.
[http://dx.doi.org/10.1016/S0167-4889(97)00140-7] [PMID: 9540818]
[15]
Hassan, A.; Martin, E.; Puig-Parellada, P. Role of antioxidants in gastric mucosal damage induced by indomethacin in rats. Methods Find. Exp. Clin. Pharmacol., 1998, 20(10), 849-854.
[http://dx.doi.org/10.1358/mf.1998.20.10.487540] [PMID: 10091221]
[16]
Singh, P.; Shaveta, S.S.; Bhatti, R. Rationally designed hybrid molecules with appreciable COX-2 inhibitory and anti-nociceptive activities. Bioorg. Med. Chem. Lett., 2014, 24(1), 77-82.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.080] [PMID: 24332492]
[17]
Kitchen, D.B.; Decornez, H.; Furr, J.R.; Bajorath, J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug Discov., 2004, 3(11), 935-949.
[http://dx.doi.org/10.1038/nrd1549] [PMID: 15520816]
[18]
Koster, R. Acetic acid for analgesic screening. Fed. Proc., 1959, 18, 412-413.
[19]
Ou-Yang, S.S.; Lu, J.Y.; Kong, X.Q.; Liang, Z.J.; Luo, C.; Jiang, H. Computational drug discovery. Acta Pharmacol. Sin., 2012, 33(9), 1131-1140.
[http://dx.doi.org/10.1038/aps.2012.109] [PMID: 22922346]
[20]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[21]
Pradelles, P.; Grassi, J.; Maclouf, J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal. Chem., 1985, 57(7), 1170-1173.
[http://dx.doi.org/10.1021/ac00284a003] [PMID: 3898913]
[22]
Rainsford, K.D. Leukotrienes in the pathogenesis of NSAID-induced gastric and intestinal mucosal damage. Agents Actions, 1993, 39, 24-26.
[23]
Ghosh, R.; Alajbegovic, A.; Gomes, A.V. NSAIDs and cardiovascular diseases: role of reactive oxygen species. Oxid. Med. Cell. Longev., 2015, 3, 1-25.
[24]
Nile, S.H.; Kumar, B.; Park, S.W. In vitro evaluation of selected benzimidazole derivatives as an antioxidant and xanthine oxidase inhibitors. Chem. Biol. Drug Des., 2013, 82(3), 290-295.
[http://dx.doi.org/10.1111/cbdd.12141] [PMID: 23581708]
[25]
Schneider, G. Automating drug discovery. Nat. Rev. Drug Discov., 2018, 17(2), 97-113.
[http://dx.doi.org/10.1038/nrd.2017.232] [PMID: 29242609]
[26]
Kirchmair, J.; Göller, A.H.; Lang, D.; Kunze, J.; Testa, B.; Wilson, I.D.; Glen, R.C.; Schneider, G. Predicting drug metabolism: experiment and/or computation? Nat. Rev. Drug Discov., 2015, 14(6), 387-404.
[http://dx.doi.org/10.1038/nrd4581] [PMID: 25907346]
[27]
Robinson, M.G. Griffin, Jr.; Bowers. J. Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal anti-inflammatory drugs. Dig. Dis. Sci., 1989, 34(3), 424-428.
[http://dx.doi.org/10.1007/BF01536266] [PMID: 2646087]
[28]
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(3), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[29]
Wolfe, M.M.; Lichtenstein, D.R.; Singh, G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N. Engl. J. Med., 1999, 340(24), 1888-1899.
[http://dx.doi.org/10.1056/NEJM199906173402407] [PMID: 10369853]
[30]
Zhou, B.; Li, B.; Yi, W.; Bu, X.; Ma, L. Synthesis, antioxidant, and antimicrobial evaluation of some 2-arylbenzimidazole derivatives. Bioorg. Med. Chem. Lett., 2013, 23(13), 3759-3763.
[http://dx.doi.org/10.1016/j.bmcl.2013.05.004] [PMID: 23711920]

Rights & Permissions Print Cite
Article Metrics
16
© 2024 Bentham Science Publishers | Privacy Policy