Login Register Cart 0
Generic placeholder image

Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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

Ex Vivo and In Vivo Evidence of Anti-Inflammatory Activity of P-aminophenol and Salicylate Derivatives

Author(s): André F. Vilvert, Marcus Vinícius P.S. Nascimento, Rosivaldo dos S. Borges and Eduardo M. Dalmarco*

Volume 16, Issue 5, 2020

Page: [593 - 605] Pages: 13

DOI: 10.2174/1573407215666190211150700

Price: $65

Abstract

Background: Paracetamol (p-aminophenol) and salicylates are nonsteroidal antiinflammatory drugs that are widely used in the general population. The adverse effects of both drugs continue to be a focus of the pharmaceutical industry in the development of new molecules that will increase treatment safety. In this context, we tested nine compounds derived from paracetamol and salicylates, synthesized in our laboratory, for their safety and ex vivo and in vivo anti-inflammatory activity.

Methods: We analyzed the cytotoxicity of the compounds in ex vivo mice neutrophils, and their ability to inhibit the production of pro-inflammatory mediators (nitric oxide and interleukin-6) after stimulating with LPS. Next, in the selected molecules, we evaluated the anti-inflammatory effect on an in vivo inflammatory model of acute lung injury in mice. All nine compounds were also submitted to the cytotoxicity assay, like the original compounds.

Results: None of the compounds showed cytotoxicity under the cells used. However, of the initial compounds, only five demonstrated anti-inflammatory effect, inhibiting Nitric Oxide (NO) and interleukin 6 (IL-6) production by neutrophils stimulated with Lipopolysaccharide (LPS). After this initial trial, four modified compounds were able to reduce leukocyte migration and fluid leakage in the bronchoalveolar lavage of mice. However, only the compound 5a1, derived from the esterification of gentisic acid, was able to significantly inhibit the levels of all pro-inflammatory cytokines and increase the levels of antiinflammatory cytokines evaluated.

Conclusion: In conclusion, all compounds showed a good safety profile, and many of them had an antiinflammatory effect. However, the compound derived from gentisic acid is highlighted for its significant effects ex vivo and in vivo and in this context, we believe that this compound is a potential candidate for the development of a new anti-inflammatory drug.

Keywords: Inflammation, salicylates, paracetamol, cytotoxicity, anti-inflammatory effect, signaling pathways, immune system.

Graphical Abstract

[1]
Ashley, N.T.; Weil, Z.M.; Nelson, R. J. Inflammation: Mechanisms, costs and natural variation. Annu. Rev. Ecol. Evol. Syst., 2012, 43, 385-406.
[http://dx.doi.org/10.1146/annurev-ecolsys-040212-092530]
[2]
Medzhitov, R. Origin and physiological roles of inflammation. Nature, 2008, 454(7203), 428-435.
[http://dx.doi.org/10.1038/nature07201] [PMID: 18650913]
[3]
Medzhitov, R.; Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol., 2009, 9(10), 692-703.
[http://dx.doi.org/10.1038/nri2634] [PMID: 19859064]
[4]
Hanke, T.; Merk, D.; Steinhilber, D.; Geisslinger, G.; Schubert-Zsilavecz, M. Small molecules with anti-inflammatory properties in clinical development. Pharmacol. Ther., 2016, 157, 163-187.
[http://dx.doi.org/10.1016/j.pharmthera.2015.11.011] [PMID: 26627986]
[5]
Borges, R.S.; Pereira, G.A.N.; Vale, J.K.L.; França, L.C.; Monteiro, M.C.; Alves, C.N.; da Silva, A.B. Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger. Chem. Biol. Drug Des., 2013, 81(3), 414-419.
[http://dx.doi.org/10.1111/cbdd.12096] [PMID: 23405943]
[6]
Tomáśová, H.; Nevoral, J.; Pachl, J.; Kincl, V. Aspirin esterase activity and Reye’s syndrome. Lancet, 1984, 2(8393), 43.
[http://dx.doi.org/10.1016/S0140-6736(84)92030-0] [PMID: 6145962]
[7]
Bertolini, A.; Ferrari, A.; Ottani, A.; Guerzoni, S.; Tacchi, R.; Leone, S. Paracetamol: new vistas of an old drug. CNS Drug Rev., 2006, 12(3-4), 250-275.
[http://dx.doi.org/10.1111/j.1527-3458.2006.00250.x] [PMID: 17227290]
[8]
Diniz, J.E.M.; Borges, R.S.; Alves, C.N. A DFT study for paracetamol and 3,5-disubstituted analogues. J. Mol. Struct., 2004, 673, 93-97.
[http://dx.doi.org/10.1016/j.theochem.2003.12.002]
[9]
Borges, R.S. A computational study for the antioxidant capacity increasesin hydroxy-derivatives of paracetamol and salicylic acid. Med. Chem. Res., 2015, 24, 3453-3459.
[http://dx.doi.org/10.1007/s00044-015-1393-x]
[10]
Borges, R.S.; Castle, S.L. The antioxidant properties of salicylate derivatives: A possible new mechanism of anti-inflammatory activity. Bioorg. Med. Chem. Lett., 2015, 25(21), 4808-4811.
[http://dx.doi.org/10.1016/j.bmcl.2015.07.001] [PMID: 26183083]
[11]
Silva, A.M.O.; Machado, I.D.; Santin, J.R.; de Melo, I.L.; Pedrosa, G.V.; Genovese, M.I.; Farsky, S.H.; Mancini-Filho, J. Aqueous extract of Rosmarinus officinalis L. inhibits neutrophil influx and cytokine secretion. Phytother. Res., 2015, 29(1), 125-133.
[http://dx.doi.org/10.1002/ptr.5238] [PMID: 25319517]
[12]
Flecknell, P. Replacement, reduction and refinement. ALTEX, 2002, 19(2), 73-78.
[PMID: 12098013]
[13]
Szarka, R.J.; Wang, N.; Gordon, L.; Nation, P.N.; Smith, R.H. A murine model of pulmonary damage induced by lipopolysaccharide via intranasal instillation. J. Immunol. Methods, 1997, 202(1), 49-57.
[http://dx.doi.org/10.1016/S0022-1759(96)00236-0] [PMID: 9075771]
[14]
Dalmarco, E.M.; Budni, P.; Parisotto, E.B.; Wilhelm Filho, D.; Fröde, T.S. Antioxidant effects of mycophenolate mofetil in a murine pleurisy model. Transpl. Immunol., 2009, 22(1-2), 12-17.
[http://dx.doi.org/10.1016/j.trim.2009.09.005] [PMID: 19778612]
[15]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 1951, 193(1), 265-275.
[PMID: 14907713]
[16]
Netea, M.G.; Balkwill, F.; Chonchol, M.; Cominelli, F.; Donath, M.Y.; Giamarellos-Bourboulis, E.J.; Golenbock, D.; Gresnigt, M.S.; Heneka, M.T.; Hoffman, H.M.; Hotchkiss, R.; Joosten, L.A.B.; Kastner, D.L.; Korte, M.; Latz, E.; Libby, P.; Mandrup-Poulsen, T.; Mantovani, A.; Mills, K.H.G.; Nowak, K.L.; O’Neill, L.A.; Pickkers, P.; van der Poll, T.; Ridker, P.M.; Schalkwijk, J.; Schwartz, D.A.; Siegmund, B.; Steer, C.J.; Tilg, H.; van der Meer, J.W.M.; van de Veerdonk, F.L.; Dinarello, C.A. A guiding map for inflammation. Nat. Immunol., 2017, 18(8), 826-831.
[http://dx.doi.org/10.1038/ni.3790] [PMID: 28722720]
[17]
Eltzschig, H.K.; Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med., 2011, 17364(7), 656-665.
[http://dx.doi.org/10.1056/NEJMra0910283]
[18]
Toner, P.; McAuley, D.F.; Shyamsundar, M. Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome. Crit. Care, 2015, 19, 374.
[http://dx.doi.org/10.1186/s13054-015-1091-6] [PMID: 26494395]
[19]
Ahmad, T.B.; Rudd, D.; Benkendorff, K.; Mahdi, L.K.; Pratt, K.A.; Dooley, L.; Wei, C.; Kotiw, M. Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury. PLoS One, 2017, 2612(10) e0186904
[http://dx.doi.org/10.1371/journal.pone.0186904]
[20]
Smith, J.B.; Willis, A.L. Aspirin selectively inhibits prostaglandin production in human platelets. Nat. New Biol., 1971, 231(25), 235-237.
[http://dx.doi.org/10.1038/newbio231235a0] [PMID: 5284361]
[21]
Moncada, S.; Needleman, P.; Bunting, S.; Vane, J.R. Prostaglandin endoperoxide and thromboxane generating systems and their selective inhibition. Prostaglandins, 1976, 12(3), 323-335.
[http://dx.doi.org/10.1016/0090-6980(76)90014-9] [PMID: 968048]
[22]
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature, 2011, 469(7329), 221-225.
[http://dx.doi.org/10.1038/nature09663] [PMID: 21124315]
[23]
De-Simone, F.I.; Sariyer, R.; Otalora, Y.L.; Yarandi, S.; Craigie, M.; Gordon, J.; Sariyer, I.K. IFN-gamma inhibits JC virus replication in glial cells by suppressing T-antigen expression. PLoS One, 2015, 10(6)e0129694
[http://dx.doi.org/10.1371/journal.pone.0129694] [PMID: 26061652]
[24]
Frantz, B.; O’Neill, E.A. The effect of sodium salicylate and aspirin on NF-kappa B. Science, 1995, 270(5244), 2017-2019.
[http://dx.doi.org/10.1126/science.270.5244.2017] [PMID: 8533099]
[25]
Whiteley, W.; Jackson, C.; Lewis, S.; Lowe, G.; Rumley, A.; Sandercock, P.; Wardlaw, J.; Dennis, M.; Sudlow, C. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med., 2009, 6(9)e1000145
[http://dx.doi.org/10.1371/journal.pmed.1000145] [PMID: 19901973]
[26]
Olefsky, J.M.; Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol., 2010, 72, 219-246.
[http://dx.doi.org/10.1146/annurev-physiol-021909-135846] [PMID: 20148674]
[27]
Kata, D.; Földesi, I.; Feher, L.Z.; Hackler, L., Jr; Puskas, L.G.; Gulya, K. A novel pleiotropic effect of aspirin: Beneficial regulation of pro- and anti-inflammatory mechanisms in microglial cells. Brain Res. Bull., 2017, 132, 61-74.
[http://dx.doi.org/10.1016/j.brainresbull.2017.05.009] [PMID: 28528204]
[28]
Ouyang, W.; Rutz, S.; Crellin, N.K.; Valdez, P.A.; Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol., 2011, 29, 71-109.
[http://dx.doi.org/10.1146/annurev-immunol-031210-101312] [PMID: 21166540]
[29]
Qu, T.; Wang, E.; Jin, B.; Li, W.; Liu, R.; Zhao, Z.B. 5-Aminosalicylic acid inhibits inflammatory responses by suppressing JNK and p38 activity in murine macrophages. Immunopharmacol. Immunotoxicol., 2017, 39(1), 45-53.
[http://dx.doi.org/10.1080/08923973.2016.1274997] [PMID: 28071183]
[30]
Whitehouse, M.W.; Rainsford, K.D. Esterification of acidic anti-inflammatory drugs suppresses their gastrotoxicity without adversely affecting their anti-inflammatory activity in rats. J. Pharm. Pharmacol., 1980, 32(11), 795-796.
[http://dx.doi.org/10.1111/j.2042-7158.1980.tb13073.x] [PMID: 6110734]
[31]
Vasconcelos, R.M.; Leite, F.C.; Leite, J.A.; Rodrigues Mascarenhas, S.; Rodrigues, L.C.; Piuvezam, M.R. Synthesis, acute toxicity and anti-inflammatory effect of bornyl salicylate, a salicylic acid derivative. Immunopharmacol. Immunotoxicol., 2012, 34(6), 1028-1038.
[http://dx.doi.org/10.3109/08923973.2012.694891] [PMID: 22712758]

Rights & Permissions Print Cite
Article Metrics
18
World Immunization Week
© 2024 Bentham Science Publishers | Privacy Policy