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
General Research Article

ROS Inhibitory Activity and Cytotoxicity Evaluation of Benzoyl, Acetyl, Alkyl Ester, and Sulfonate Ester Substituted Coumarin Derivatives

Author(s): Uzma Salar, Khalid M. Khan*, Almas Jabeen, Aisha Faheem, Farwa Naqvi, Shakil Ahmed, Erum Iqbal, Farman Ali, Kanwal and Shahnaz Perveen

Volume 16, Issue 8, 2020

Page: [1099 - 1111] Pages: 13

DOI: 10.2174/1573406415666190826153001

Price: $65

Abstract

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist.

Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique.

Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM).

Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

Keywords: Coumarin, ROS, antiinflammatory, ibuprofen, structure-activity relationship, cytotoxicity.

« Previous Next »
Graphical Abstract

[1]
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and antiinflammatory activity of coumarin derivatives. J. Med. Chem., 2005, 48(20), 6400-6408.
[http://dx.doi.org/10.1021/jm0580149] [PMID: 16190766]
[2]
Chang-Hui, L.; Yen-Ju, H.; Yin-Chou, L. Celecoxib simulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for β 2-integrin expression on human neutrophils. Eur. J. Pharmacol., 2004, 484(1), 29-39.
[http://dx.doi.org/10.1016/j.ejphar.2003.10.054] [PMID: 14729379]
[3]
Narayanan, P.K.; Carter, W.O.; Ganey, P.E.; Roth, R.A.; Voytik-Harbin, S.L.; Robinson, J.P. Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity. J. Leukoc. Biol., 1998, 63(2), 216-224.
[http://dx.doi.org/10.1002/jlb.63.2.216] [PMID: 9468280]
[4]
Khan, K.M.; Khan, M.; Ali, M.; Qadir, M.I.; Parveen, S.; Karim, A.; Choudhary, M.I. Superoxide respiratory burst inhibitory activity of Bis-Schiff bases of isatins. J. Chem. Soc. Pak., 2013, 35, 987-993.
[5]
Payá, M.; Halliwell, B.; Hoult, J.R.S. Interactions of a series of coumarins with reactive oxygen species. Scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochem. Pharmacol., 1992, 44(2), 205-214.
[http://dx.doi.org/10.1016/0006-2952(92)90002-Z] [PMID: 1322662]
[6]
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]
[7]
Schoen, R.T.; Vender, R.J. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am. J. Med., 1989, 86(4), 449-458.
[http://dx.doi.org/10.1016/0002-9343(89)90344-6] [PMID: 2648824]
[8]
Lombardino, J.G.; Wiseman, E.H. Preparation and antiinflammatory activity of some nonacidic trisubstituted imidazoles. J. Med. Chem., 1974, 17(11), 1182-1188.
[http://dx.doi.org/10.1021/jm00257a011] [PMID: 4415171]
[9]
Hiller, K.O.; Hodd, P.L.; Willson, R.L. Antiinflammatory drugs: protection of a bacterial virus as an in vitro biological measure of free radical activity. Chem. Biol. Interact., 1983, 47(3), 293-305.
[http://dx.doi.org/10.1016/0009-2797(83)90165-5] [PMID: 6317211]
[10]
Kumar, P.V.; Reddy, K.M.; Rao, V.R. Synthesis of some 7-methyl-3-(2-oxo-2H-chromen-3-yl)-5H [1, 3] thiazolo [3, 2-a]-pyrimidin-5-ones. Indian J. Chem. Sect. B, 2008, 47, 759-763.
[http://dx.doi.org/10.1002/chin.200836168]
[11]
Hoult, J.R.S.; Payá, M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen. Pharmacol., 1996, 27(4), 713-722.
[http://dx.doi.org/10.1016/0306-3623(95)02112-4] [PMID: 8853310]
[12]
Sashidhara, K.V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett., 2010, 20(24), 7205-7211.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.116] [PMID: 21071221]
[13]
Kidane, A.G.; Salacinski, H.; Tiwari, A.; Bruckdorfer, K.R.; Seifalian, A.M. Anticoagulant and antiplatelet agents: their clinical and device application(s) together with usages to engineer surfaces. Biomacromolecules, 2004, 5(3), 798-813.
[http://dx.doi.org/10.1021/bm0344553] [PMID: 15132664]
[14]
Ma, T.; Liu, L.; Xue, H.; Li, L.; Han, C.; Wang, L.; Chen, Z.; Liu, G. Chemical library and structure-activity relationships of 11-demethyl-12-oxo calanolide A analogues as anti-HIV-1 agents. J. Med. Chem., 2008, 51(5), 1432-1446.
[http://dx.doi.org/10.1021/jm701405p] [PMID: 18284187]
[15]
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. Bioorg. Med. Chem. Lett., 2004, 14(3), 611-614.
[http://dx.doi.org/10.1016/j.bmcl.2003.11.060] [PMID: 14741253]
[16]
Appendino, G.; Mercalli, E.; Fuzzati, N.; Arnoldi, L.; Stavri, M.; Gibbons, S.; Ballero, M.; Maxia, A. Antimycobacterial coumarins from the sardinian giant fennel (Ferula communis). J. Nat. Prod., 2004, 67(12), 2108-2110.
[http://dx.doi.org/10.1021/np049706n] [PMID: 15620264]
[17]
Reddy, N.S.; Mallireddigari, M.R.; Cosenza, S.; Gumireddy, K.; Bell, S.C.; Reddy, E.P.; Reddy, M.V.R. Synthesis of new coumarin 3-(N-aryl) sulfonamides and their anticancer activity. Bioorg. Med. Chem. Lett., 2004, 14(15), 4093-4097.
[http://dx.doi.org/10.1016/j.bmcl.2004.05.016] [PMID: 15225733]
[18]
Kempen, I.; Papapostolou, D.; Thierry, N.; Pochet, L.; Counerotte, S.; Masereel, B.; Foidart, J.M.; Reboud-Ravaux, M.; Noël, A.; Pirotte, B. 3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo. Br. J. Cancer, 2003, 88(7), 1111-1118.
[http://dx.doi.org/10.1038/sj.bjc.6600856] [PMID: 12671713]
[19]
Sashidhara, K.V.; Rosaiah, J.N.; Kumar, A.; Bhatia, G.; Khanna, A.K. Synthesis of novel benzocoumarin derivatives as lipid lowering agents. Bioorg. Med. Chem. Lett., 2010, 20(10), 3065-3069.
[http://dx.doi.org/10.1016/j.bmcl.2010.03.103] [PMID: 20399654]
[20]
Kostova, I. Synthetic and natural coumarins as cytotoxic agents. Curr. Med. Chem. Anticancer Agents, 2005, 5(1), 29-46.
[http://dx.doi.org/10.2174/1568011053352550] [PMID: 15720259]
[21]
Musa, M.A.; Cooperwood, J.S.; Khan, M.O. A review of coumarin derivatives in pharmacotherapy of breast cancer. Curr. Med. Chem., 2008, 15(26), 2664-2679.
[http://dx.doi.org/10.2174/092986708786242877] [PMID: 18991629]
[22]
Khan, K.M.; Ambreen, N.; Mughal, U.R.; Jalil, S.; Perveen, S.; Choudhary, M.I. 3-Formylchromones: potential antiinflammatory agents. Eur. J. Med. Chem., 2010, 45(9), 4058-4064.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.065] [PMID: 20576329]
[23]
Salar, U.; Khan, K.M.; Jabeen, A.; Faheem, A.; Taha, M.; Ali, F.; Syed, S.; Haider, S.M.; Perveen, S. Anti-inflammatory activity of 3-thiazolyl coumarins. J. Chem. Soc. Pak., 2017, 39, 578-585.
[24]
Salar, U.; Khan, K.M.; Jabeen, A.; Faheem, A.; Fakhri, M.I.; Saad, S.M.; Perveen, S.; Taha, M.; Hameed, A. Coumarin sulfonates: As potential leads for ROS inhibition. Bioorg. Chem., 2016, 69, 37-47.
[http://dx.doi.org/10.1016/j.bioorg.2016.09.006] [PMID: 27669119]
[25]
Salar, U.; Khan, K.M.; Muhammad, H.; Fakhri, M.I. Sanaullah; Perveen, S.; Choudhary, M.I. Anti-MRSA (Multidrug resistant Staphylococcus aureus) activity of 3-substituted coumarins. Lett. Drug Des. Discov., 2018, 15, 353-362.
[http://dx.doi.org/10.2174/1570180814666170619121844]
[26]
Salar, U.; Khan, K.M.; Iqbal, J.; Ejaz, S.A.; Hameed, A.; Al-Rashida, M.; Perveen, S.; Tahir, M.N. Coumarin sulfonates: New alkaline phosphatase inhibitors; in vitro and in silico studies. Eur. J. Med. Chem., 2017, 131, 29-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.003] [PMID: 28288318]
[27]
Helfand, S.L.; Werkmeister, J.; Roder, J.C. Chemiluminescence response of human natural killer cells. I. The relationship between target cell binding, chemiluminescence, and cytolysis. J. Exp. Med., 1982, 156(2), 492-505.
[http://dx.doi.org/10.1084/jem.156.2.492] [PMID: 6178787]
[28]
Jabeen, A.; Mesaik, M.A.; Simjee, S.U. Lubna; Bano, S.; Faizi, S. Anti-TNF-α and antiarthritic effect of patuletin: A rare flavonoid from Tagetes patula. Int. Immunopharmacol., 2016, 36, 232.
[http://dx.doi.org/10.1016/j.intimp.2016.04.034] [PMID: 27177082]
[29]
Brandes, R.P.; Janiszewski, M. Direct detection of reactive oxygen species ex vivo. Kidney Int., 2005, 67(5), 1662-1664.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00258.x] [PMID: 15840007]
[30]
Pavelkova, M.; Kubala, L. Luminol-, isoluminol- and lucigenin-enhanced chemiluminescence of rat blood phagocytes stimulated with different activators. Luminescence, 2004, 19(1), 37-42.
[http://dx.doi.org/10.1002/bio.754] [PMID: 14981645]
[31]
Vicidomini, C.; Cioffi, F.; Broersen, K.; Roviello, V.; Riccardi, C.; Montesarchio, D.; Capasso, D.; Gaetano, S.D.; Musumeci, D.; Roviello, G.N. Benzodifurans for biomedical applications: BZ4, a selective anti-proliferative and anti-amyloid lead compound. Future Med. Chem., 2019, 11, 285-302.
[http://dx.doi.org/10.4155/fmc-2018-0473] [PMID: 30801198]
[32]
Carella, A.; Roviello, V.; Iannitti, R.; Palumbo, R.; La Manna, S.; Marasco, D.; Trifuoggi, M.; Diana, R.; Roviello, G.N. Evaluating the biological properties of synthetic 4-nitrophenyl functionalized benzofuran derivatives with telomeric DNA binding and antiproliferative activities. Int. J. Biol. Macromol., 2019, 121, 77-88.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.09.153] [PMID: 30261256]

Rights & Permissions Print Cite
Article Metrics
43
© 2024 Bentham Science Publishers | Privacy Policy