Analgesic Activity of Acyl-Salicylic Acid Derivatives And In Silico Docking Study For Their Potency As Cyclooxygenase-2 Inhibitors
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A series of acyl salicylic acid derivatives were screened to investigate their analgesic activities and their potency as cyclooxygenase-2 (COX-2) inhibitors. Fourteen compounds (BS1–14) were assayed by acetic acid induced writhing test. Their ability for interaction with COX-2 was studied through a docking simulation at the COX-2 active site (PDB. 5IKQ). The results of the analgesic activity test gave 3 compounds that produce ED50< 0.39 mmol/kg body weight, lower than aspirin as a positive control. The compounds BS3 and BS4 showed excellent analgesic activity and the tert-butyl substituted molecule BS3 (O-(4-tert-butylbenzoyl)-salicylic acid analog) showed the highest analgesic activity with ED50 of 0.26 mmol/kg. Based on in silico molecular docking, it is known that almost all of the tested ligands (12 compounds) showed a higher binding affinity for COX-2 than meclofenamic acid which is a COX-2 inhibitory NSAID. The results of in vivo analgesic activity were justified with the outcome of in silico investigation. Molecular docking of acyl-salicylates confirmed in vivo experiments and it was found that BS3 was the most active compound as an analgesic agent and the most potent as a COX-2 inhibitor among the evaluated compounds.
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Aronoff, D.M., Boutaud, O., Marnett, L.J., and Oates, J.A. (2003). Inhibition of Prostaglandin H2 Synthases by Salicylate is Dependent on the Oxidative State of the Enzymes. J Pharmacol Exp Ther, 304 (2), 589-595.
Amann, R., and Peskar, B.A. (2002). Review Anti-inflammatory effects of aspirin and sodium salicylate, Eur. J. Pharmacol., 447 (1), 1-9.
Bell, R., Harris, R.R., Stewart, A.O. (2003) COX-2 Inhibitors and Leucotriene Modulators. In: Abraham, D.J. (ed.) Burger's Medicinal Chemistry and Drug Discovery 6th Vol. 4: Autocoids, Diagnostics, and Drugs from New Biology John Wiley and Sons, Inc. pp. 229 – 246.
Cieslik, K.A., Zhu, Y., Shtivelband, M., Wu, K.K. (2005). Inhibition of p90 Ribosomal S6 Kinase-mediated CCAAT/Enhancer binding Protein Activation and Cyclooxygenase-2 Expression by Salicylate., J. Biol. Chem., 280 (18), 18411–18417.
Cronstein, B.N., Montesinos, M.C., Weissmann, W. (1999), Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkB. Proc. Natl. Acad. Sci., 96, 6377-6381.
Diyah, N.W., Susilowati, R., Hardjono, S. (2010). Kinetics of Degradation of Benzoylsalicylic Acid Derivatives in an Alkaline Solution. Majalah Farmasi Airlangga, 8 (2), 31-35.
Diyah, N.W., Siswandono. (2014). Docking Molekul Dan Sintesis Turunan Asam Benzoil Salisilat Tersubstitusi Klor Sebagai Penghambat Siklooksigenase-2. Berkala Ilmiah Kimia Farmasi, 3 (1), 7–15.
Diyah, N.W., Nofianti, K.A., Hakim, L. (2016). Aktivitas Antiinflamasi Turunan Asam O-Benzoilsalisilat. Berkala Ilmiah Kimia Farmasi, 5 (1), 14 – 17.
de Arriba, A.F., Fernando Cavalcanti, F., Agustí Miralles, A., Yolanda Bayón, Y., Andrés Alonso, A., Merlos, M., García-Rafanell, J., Forn, (1999). Inhibition of Cyclooxygenase-2 Expression by 4Trifluoromethyl Derivatives of Salicylate, Triflusal, and Its Deacetylated Metabolite, 2-Hydroxy-4-trifluoromethylbenzoic Acid. J Mol. Pharmacol., 55 (4), 753-760.
Hinz, B., Kraus, V., Pahl, A., Brune, K. (2000). Salicylate Metabolites Inhibit Cyclooxygenase-2-Dependent Prostaglandin E2 Synthesis in Murine Macrophages. Biochem. Biophys. Res.Commun., 274 (1), 197 – 202.
Kosinski, P., Sarzynska-Nowacka, U., Fiolna, M., Wielgos, M. (2018). The practical use of acetylsalicylic acid in the era of the ASPRE trial. Update and literature review. Ginekol Pol. 2018, 89 (2), 107-111.
Law, B.K., Waltner-Lawi, M.E., Entingh, A.J., Chytil, A., Aakre, M.E., Nùrgaard, P., Moses, H.L. (2000). Salicylate-induced Growth Arrest is Associated with Inhibition of p70 s6k and Down-regulation of c-Myc, Cyclin D1, Cyclin A, and Proliferating Cell Nuclear Antigen. J. Biol. Chem., 275 (49), 38261-38267.
Miranda, H.F., Sierralta, F., Aranda, N., et al. (2016) Pharmacological profile of dexketoprofen in oofacial pain. Pharmacol Rep, 68, 1111–1114.
Mitchell, J.A., Saunders, M., Peter J., Barnes, P.J., Newton, R., Belvisi, M.G. (1997). Sodium Salicylate Inhibits Cyclo-Oxygenase-2 Activity Independently of Transcription Factor (Nuclear Factor κB) Activation: Role of Arachidonic Acid. Mol. Pharmacol., 51 (6), 907-912.
Noriega, V., Sierralta, F., Poblete, P., Aranda, N., Sotomayor-Zarate, R., Cprieto, J., Miranda, H. F. (2020). Receptors involved in dexketoprofen analgesia in murine visceral pain. J Biosci, (2020) 45 (94 ), 1–6
Orlando, B.J., Malkowski, M.G. (2016). Substrate-selective Inhibition of Cyclooxygenase-2 by Fenamic Acid Derivatives Is Dependent on Peroxide Tone. (2016) J Biol Chem 291: 15069-15081.
Saunders, M.A., Sansores-Garcia, L., Gilroy, D.W., Wu, K.K. (2001). Selective Suppression of CCAAT/Enhancer-binding Protein Binding and Cyclooxygenase-2 Promoter Activity by Sodium Salicylate in Quiescent Human Fibroblasts. J. Biol. Chem., 276 (22), 18897-18904.
Thomsen, R., Christensen, M.H. (2006). MolDock: a new technique for high-accuracy molecular docking. J Med Chem, 49(11), 3315-3321.
Wu, K. (2003). Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med, 3 (2), 107-12.
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