Abstract
Some isoxazole-based amides were synthesized by the reaction of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride with various aliphatic, aromatic and heterocyclic amines; characterized by analysis of spectroscopic data and evaluated for in vivo anti-inflammatory, ulcerogenic, and antimicrobial activity. Compounds A1, A7, and A10 were identified as the potent anti-inflammatory agents in carrageenan-induced albino rat paw edema assay exhibiting 92.85–93.57% edema inhibition after 5 h with lower ulcer index (2.5) than the standard diclofinac sodium (6.15). Antibacterial activity against the bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis was found to be good in comparison with the standard ampicillin in terms of minimum inhibitory concentration values. Anti-inflammatory activity results were supported by molecular docking—possible binding modes, interactions, and docking scores of titled compounds with the active site of cyclooxygenase-2 enzyme. In silico absorption, distribution, metabolism, and excretion–toxicity study was also performed to predict the preliminary pharmacological, pharmacokinetic, and toxicity profile of the synthesized anti-inflammatory agents suggesting that these derivatives have good oral drug like behavior and non-toxic nature.
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References
Abbas SE, Awadallah FM, Ibrahim NA, Gouda AM (2010) Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies. Eur J Med Chem 45:482–491
Antarkar SS, Chinwalla T, Bhatt N (1994) Anti-inflammatory activity of rubia cordifolia linn in rats. Ind J Pharm 15:185–188
Collins AH (1976) Microbiological methods, 2nd edn. Butterworth, London
Cruickshank R, Duguid JP, Marmion BP, Swain RHA eds (1975) Medicinal microbiology, 2nd edn. Churchill Livingstone, London
Duraiswamy B, Mishra SK, Subhashini V, Dhanraj SA, Suresh B (2006) Studies on the antimicrobial potential of studies on the antimicrobial potential of Mahonia Mahonia leschenaultia. Ind J Pharm Sci 68:389–391
El-Henawy AA (2013) Synthesis, characterization, AMDET and docking studies of novel diclofenac derivatives containing phenylalanine moiety acting as selective inhibitors against cyclooxygenase (COX). Chem Mater Res 3:75–89
El-Sayed NA, Awadallah FM, Ibrahim NA, El-Saadi MT (2010) Synthesis, anti-inflammatory and ulcerogenicity studies of some substituted pyrimido[1,6-a]azepine derivatives. Eur J Med Chem 45:3147–3154
Ertl P, Rohde B, Selzer P (2000) Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem 43:3714–3747
Finney DJ (1964) Statistical methods in biological assay. Charles Griffen & Company Limit, London
Gierse JK, Koboldt CM, Walker MC, Siebeil K, Isakson PC (1999) Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem J 339:607–614
Huang Y, Hickey RP, Yeh JL, Liu D, Dadak A, Young LH, Johnson RS, Giordano FJ (2004) Cardiac myocyte-specific HIF-1 alpha deletion alters vascularization, energy availability, calcium flux and contractility in the normoxic heart. Faseb J 18:1138–1140
Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuchi K (1985) Anti-inflammatory actions of ephedrines in acute inflammations. Planta Med 51:325–331
Kaur K, Kumar V, Sharma AK, Gupta GK (2014) Isoxazoline containing natural products as anticancer agents: a review. Eur J Med Chem 77:121–133
Khan ZK (1997) In: Proceedings of the international workshop UNIDO-CDRI: 210–211
Krensky AM, Bennett WM, Vincenti F (2006) Textbook of pharmacology and therapeutics, 11th Ed. McGraw-Hill, New York, NY
Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648
Lagorce D, Sperandio H, Miteva M (2008) FAF-Drugs2: Free ADME/tox filtering tool to assist drug discovery and chemical biology project. BMC Bioinform 9(396):1–10
Lipinski C, Lombardo F, Dominy B (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26
OECD (2001) Guideline for testing of chemicals-acute oral toxicity-acute toxic class method. OECD, Paris
Pancholia S, Dhameliya TM, Shah P, Jadhavar PS, Sridevi JP, Yogeshwari P, Sriram D, Chakraborti AK (2016) Eur J Med Chem 116:187–199
Porto GG, Vasconcelos BC, Gomes AC, Albert D (2007) Evaluation of lidocaine and mepivacaine for inferior third molar surgery. Med Oral Patol Oral Cir Bucal 12:E60–E64
Rajput SS, Patel SN, Jadhav NB (2015) Isoxazole—a basic aromatic heterocycle: synthesis, reactivity and biological activity. Int J Chem Tech Res 8:297–317
Rangahanumaiah P, Rai RV, Saqhib A, Jothi L, Swamy MS, Karigar CS (2016) High-throughput screening by in silico molecular docking of Eryngium Foetidum (Linn.) bioactives for cylcooxygenase-2 inhibition. Pharmacogn Commn 6:232–237
Sangshetti J, Khan F, Chouthe R, Damale M, Shinde D (2014) Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1, 2, 4-triazol-3-yl) methyl)-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine as antifungal agents. Chem Lett 25:1033–1038
Saundane AR, Rudresh K, Satynarayan ND, Hiremath SP (1989) Ind J Pharm Sci 60:379–465
Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov 15:533–550
Vincent Z et al. (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 3:01–13
Wen F, Jin H, Tao K, Hou T (2016) Design, synthesis and antifungal activity of novel furancarboxamide derivatives. Eur J Med Chem 120:244–251
Winter CA, Risely EA, Nuss GM (1962) Carrageenin-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–547
Zimhony O, Cox JS, Welch JT, Vilcheze C, Jacobs WR (2000) Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of mycobacterium tuberculosis. Nat Med 6:1043–1047
Acknowledgements
Authors are thankful to the Director, Sophisticated Analytical and Instrumentation Facility (SAIF), Panjab University Chandigarh (India) for providing spectral data and to the Director, Scan research laboratory, Bhopal for providing the results of biological activity.
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Kauthale, S., Tekale, S., Damale, M. et al. Synthesis, biological evaluation, molecular docking, and ADMET studies of some isoxazole-based amides. Med Chem Res 27, 429–441 (2018). https://doi.org/10.1007/s00044-017-2070-z
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DOI: https://doi.org/10.1007/s00044-017-2070-z