Computational Modeling, Docking, Synthesis, Characterization, and in vitro Cyclooxygenase Inhibitory Activity of Some Novel Non-Steroidal Anti-inflammatory Prodrugs
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed analgesic and anti-inflammatory drugs. However, inhibition of cyclooxygenase1 and acidic groups such as carboxylic groups in most NSAIDs cause gastrointestinal (GI) side effects. Therefore, masking the acidic groups till it pass through the GI tract will decrease the direct GI side effects and because N-(2,6-dimethylphenyl)-acetamide 1 also has anti-inflammatory activity so the synthesized ester prodrugs might act as mutual prodrugs.
2-Chloro-N-(2,6-dimethylphenyl)-acetamide 1 was utilized to synthesize ester prodrug of various NSAIDs 2a-e. The 2-Chloro-N-(2,6-dimethylphenyl)-acetamide 1 undergo substitution reaction at α position with various sodium carboxylate of NSAIDs 2a-e in DMSO. The constitution of the newly synthesized ester prodrugs of NSAIDs 3a-e had been confirmed depending on their IR, ¹H and ¹³C-NMR spectral analysis. The synthesized ester prodrugs 3a-e were screened for their in vitro inhibitory activities of COX-1 as well as COX-2 however, their COX inhibition activity increased compared with their starting 1 and 2a-e.
Physicochemical properties and “Lipinski’s rule of five” were assessed for compounds 3a-e, and they all satisfied the rule. Furthermore molecular docking for compounds 3a-e into COX-1 and COX-2 was done, in which they showed binding free energies ΔGb in the range of (-8.9 to -9.8 kcal/mol) when docked into COX-1 and (-10.4 to -12.4 kcal/mol) into COX-2 enzymes.
Ashraf, Z. et al. (2016) ‘Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, pharmacological investigation, and computational molecular modeling’, Drug Design, Development and Therapy. doi: 10.2147/DDDT.S109318.
Autore, G. et al. (2010) ‘Acetamide derivatives with antioxidant activity and potential anti-inflammatory activity’, Molecules. doi: 10.3390/molecules15032028.
Ayhan-Kilcigil, G. et al. (2012) ‘Synthesis and Evaluation of Antioxidant Properties of Novel 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(2-arylmethylene amino) acetamides and 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl) acetamides-I’, Chemical Biology and Drug Design. doi: 10.1111/j.1747-0285.2012.01347.x.
Le Borgne, M. et al. (2000) ‘Synthesis and biological evaluation of indole derivatives acting as anti-inflammatory or antitumoral drugs | Derives indoliques a activites anti-inflammatoire ou antitumorale’, Annales Pharmaceutiques Francaises. doi: APF-10-2000-58-5-0003-4509-101019-ART4.
Clark, D. E. and Pickett, S. D. (2000) ‘Computational methods for the prediction of “drug-likeness”’, Drug Discovery Today. doi: 10.1016/S1359-6446(99)01451-8.
Daina, A., Michielin, O. and Zoete, V. (2017) ‘SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules’, Scientific Reports. doi: 10.1038/srep42717.
Dallakyan, S. and Olson, A. J. (2015) ‘Small-molecule library screening by docking with PyRx’, Methods in Molecular Biology. doi: 10.1007/978-1-4939-2269-7_19.
Dhingra, M. S. et al. (2014) ‘Synthesis, evaluation, and molecular docking studies of cycloalkyl/aryl-3,4,5-trimethylgallates as potent non-ulcerogenic and gastroprotective anti-inflammatory agents’, Medicinal Chemistry Research. doi: 10.1007/s00044-013-0620-6.
Hamad, A. et al. (2017) ‘Synthetic Approaches and Pharmacological Evaluation of Some New Acetamide Derivatives and 5-Benzylidene-2-(2, 6-dimethyl-phenylimino)-thiazolidin-4-ones’, ZANCO Journal of Pure and Applied Sciences, (August), pp. 29(4):13–24.
Hamlin, T. A., Swart, M. and Bickelhaupt, F. M. (2018) ‘Nucleophilic Substitution (SN2): Dependence on Nucleophile, Leaving Group, Central Atom, Substituents, and Solvent’, ChemPhysChem. doi: 10.1002/cphc.201701363.
Hegazy, G. H. and Ali, H. I. (2012) ‘Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids’, Bioorganic and Medicinal Chemistry. doi: 10.1016/j.bmc.2011.12.030.
Huang, H. J. et al. (2010) ‘Current developments of computer-aided drug design’, Journal of the Taiwan Institute of Chemical Engineers. doi: 10.1016/j.jtice.2010.03.017.
Kalgutkar, A. S. et al. (2000) ‘Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors’, Journal of Medicinal Chemistry. doi: 10.1021/jm000004e.
Kuntz, I. D. et al. (1982) ‘A geometric approach to macromolecule-ligand interactions’, Journal of Molecular Biology. doi: 10.1016/0022-2836(82)90153-X.
Limongelli, V. et al. (2010) ‘Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition’, Proceedings of the National Academy of Sciences of the United States of America. doi: 10.1073/pnas.0913377107.
Lipinski, C. A. et al. (2001) ‘Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings’, Advanced Drug Delivery Reviews. doi: 10.1016/S0169-409X(00)00129-0.
Lipinski, C. A. et al. (2012) ‘Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings’, Advanced Drug Delivery Reviews. doi: 10.1016/j.addr.2012.09.019.
Makhija, D. T., Somani, R. R. and Chavan, A. V. (2013) ‘Synthesis and pharmacological evaluation of antiinflammatory mutual amide prodrugs’, Indian Journal of Pharmaceutical Sciences. doi: 10.4103/0250-474X.117399.
McConkey, B. J., Sobolev, V. and Edelman, M. (2002) ‘The performance of current methods in ligand-protein docking’, Current Science.
Nile, S. H. et al. (2016) ‘Screening of ferulic acid related compounds as inhibitors of xanthine oxidase and cyclooxygenase-2 with anti-inflammatory activity’, Brazilian Journal of Pharmacognosy. doi: 10.1016/j.bjp.2015.08.013.
Pountos, I. et al. (2011) ‘Nonsteroidal anti-inflammatory drugs: Prostaglandins, indications, and side effects’, International Journal of Interferon, Cytokine and Mediator Research. doi: 10.2147/IJICMR.S10200.
Qasir, A. J. (2013) ‘Synthesis of NSAID with Sulfonamide Conjugates as Possible Mutual Prodrugs using Amino Acid Spacer’, Der Pharma Chemica, 2(1), pp. 241–248.
Silverstein, R. M., Webster, F. X. and Kiemle, D. J. (2005) ‘Spectrometric identification of organic compounds 7ed 2005 - Silverstein, Webster & Kiemle.pdf’, Microchemical Journal. doi: 10.1016/0026-265X(76)90069-2.
Smith, M. B. and March, J. (2006) March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley-Interscience A John Wiley & Sons.
Zarghi, A. and Arfaei, S. (2011) ‘Selective COX-2 inhibitors: A review of their structure-activity relationships’, Iranian Journal of Pharmaceutical Research. doi: 10.22037/ijpr.2011.1047.
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