Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme
DOI:
https://doi.org/10.22317/jcms.v5i1.521Keywords:
Nabumetone, docking, ADMET, GOLD, Lipinski ruleAbstract
Nabumetone is a prodrug, its active metabolite 6-methoxy-2-naphthylacetic (6MNA) acid has low selectivity toward COX-2 enzyme; PLP fitness was 67.36 Kcal/Mol. A series of pyrazolines, oxazolines and pyrimidines bearing nabumetone moiety have been designed, synthesized, and evaluated as a potential cyclooxygenase-2 (COX-2) inhibitors. These new compounds were evaluated for their in vivo anti-inflammatory activity and in vitro COX-2 selectivity through molecular docking via GOLD suite v. 5.6.2. All tested compounds in molecular docking exhibited significant activities compared with diclofenac, naproxen, and 6MNA as reference drugs due to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355, and Ser530, and these results are compatible with their in vivo acute anti-inflammatory study for tested compounds. Also, ADME studies were performed to predict which of them are candidate to be given orally, site of absorption, bioavailability, topological polar surface area and drug-likeness. The ADME results showed that all synthesized compounds absorbed from GIT while, only compounds 3, 2a, 2c, and 3a -3c fulfilled the Lipinski rule.
References
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47. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein–ligand docking using GOLD. Proteins: Structure, Function, and Bioinformatics. 2003 Sep;52(4):609-23.
48. Adeniyi AA, Ajibade PA. Comparing the suitability of autodock, gold and glide for the docking and predicting the possible targets of Ru (II)-based complexes as anticancer agents. Molecules. 2013 Mar 25;18(4):3760-78.
49. Suralkar AA, Sarda PS, Ghaisas MM, Thakare VN, Deshpande AD. In-vivo animal models for evaluation of anti-inflammatory activity. Latest Rev. 2008 Mar;6(2).
2. L.J. Marnett, A.S. Kalgutkar, Current Opinion in Chemical Biology 1998, 2(4), 482-490.
3. Takahashi M, Ogawa T, Kashiwagi H, Fukushima F, Yoshitsugu M, Haba M, Hosokawa M. Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1. Bioorganic & medicinal chemistry letters. 2018 Apr 1;28(6):997-1000.
4. Mahdi MF, Mohammed MH, Jassim AA. Design, synthesis and preliminary pharmacological evaluation of new non-steroidal anti-inflammatory agents having a 4-(methylsulfonyl) aniline pharmacophore. Molecules. 2012 Feb 10;17(2):1751-63..
5. Kalgutkar AS, Rowlinson SW, Crews BC, Marnett LJ. Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorganic & medicinal chemistry letters. 2002 Feb 25;12(4):521-4.
6. Kalgutkar AS, Crews BC, Saleh S, Prudhomme D, Marnett LJ. Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors. Bioorganic & medicinal chemistry. 2005 Dec 15;13(24):6810-22.
7. Khanna S, Madan M, Vangoori A, Banerjee R, Thaimattam R, Basha SJ, Ramesh M, Casturi SR, Pal M. Evaluation of glycolamide esters of indomethacin as potential cyclooxygenase-2 (COX-2) inhibitors. Bioorganic & medicinal chemistry. 2006 Jul 15;14(14):4820-33.
8. Ermondi G, Caron G, Lawrence R, Longo D. Docking studies on NSAID/COX-2 isozyme complexes using contact statistics analysis. Journal of computer-aided molecular design. 2004 Nov 1;18(11):683-96.
9. Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural and Molecular Biology. 1996 Nov;3(11):927.
10. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996 Dec;384(6610):644.
11. Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M, Percival MD. Structure-based design of COX-2 selectivity into flurbiprofen. Bioorganic & medicinal chemistry letters. 1999 Feb 8;9(3):307-12.
12. Chakraborti AK, Garg SK, Kumar R, Motiwala HF, Jadhavar PS. Progress in COX-2 inhibitors: a journey so far. Current medicinal chemistry. 2010 May 1;17(15):1563-93.
13. Llorens O, Perez JJ, Palomer A, Mauleon D. Structural basis of the dynamic mechanism of ligand binding to cyclooxygenase. Bioorganic & medicinal chemistry letters. 1999 Oct 4;9(19):2779-84.
14. Friedman HL. Influence of isosteric replacements upon biological activity. Nasnrs. 1951;206:295-358.
15. Lolli ML, Cena C, Medana C, Lazzarato L, Morini G, Coruzzi G, Manarini S, Fruttero R, Gasco A. A new class of ibuprofen derivatives with reduced gastrotoxicity. Journal of medicinal chemistry. 2001 Oct 11;44(21):3463-8.
16. Prabhakar C, Reddy GB, Reddy CM, Nageshwar D, Devi AS, Babu JM, Vyas K, Sarma MR, Reddy GO. Process research and structural studies on nabumetone. Organic Process Research & Development. 1999 Mar 19;3(2):121-5.
17. Kachroo M, Panda R, Yadav Y. Synthesis and biological activities of some new pyrimidine derivatives from chalcones. Pharm Chem. 2014;6(2):352.
18. Aksöz BE, Ertan R. Chemical and structural properties of chalcones I. FABAD J Pharm Sci. 2011;36:223-42.
19. Israf DA, Khaizurin TA, Syahida A, Lajis NH, Khozirah S. Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-κB nuclear translocation and Iκ-B phosphorylation in RAW 264.7 macrophage cells. Molecular immunology. 2007 Feb 1;44(5):673-9.
20. Kim DW, Curtis-Long MJ, Yuk HJ, Wang Y, Song YH, Jeong SH, Park KH. Quantitative analysis of phenolic metabolites from different parts of Angelica keiskei by HPLC–ESI MS/MS and their xanthine oxidase inhibition. Food chemistry. 2014 Jun 15;153:20-7.
21. Yamamoto T, Yoshimura M, Yamaguchi F, Kouchi T, Tsuji R, Saito M, Obata A, Kikuchi M. Anti-allergic activity of naringenin chalcone from a tomato skin extract. Bioscience, biotechnology, and biochemistry. 2004 Jan 1;68(8):1706-11.
22. Aoki N, Muko M, Ohta E, Ohta S. C-geranylated chalcones from the stems of Angelica keiskei with superoxide-scavenging activity. Journal of natural products. 2008 Jun 18;71(7):1308-10.
23. Birari RB, Gupta S, Mohan CG, Bhutani KK. Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: experimental and computational studies. Phytomedicine. 2011 Jun 15;18(8-9):795-801.
24. Chen M, Christensen SB, Blom J, Lemmich E, Nadelmann L, Fich K, Theander TG, Kharazmi A. Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania. Antimicrobial agents and chemotherapy. 1993 Dec 1;37(12):2550-6.
25. Cho S, Kim S, Jin Z, Yang H, Han D, Baek NI, Jo J, Cho CW, Park JH, Shimizu M, Jin YH. Isoliquiritigenin, a chalcone compound, is a positive allosteric modulator of GABA A receptors and shows hypnotic effects. Biochemical and biophysical research communications. 2011 Oct 7;413(4):637-42.
26. Siddiqui N, Alam P, Ahsan W. Design, Synthesis, and Inâ€Vivo Pharmacological Screening of N, 3â€(Substituted Diphenyl)â€5â€phenylâ€1Hâ€pyrazolineâ€1â€carbothioamide Derivatives. Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry. 2009 Mar;342(3):173-81.
27. Mahdi MF, Raauf AM, Mohammed NM. Synthesis, characterization and preliminary pharmacological evaluation of new non-steroidal anti-inflammatory pyrazoline derivatives. European Journal of Chemistry. 2015 Dec 31;6(4):461-7.
28. Trivedi AR, Dodiya DK, Ravat NR, Shah VH. Synthesis and biological evaluation of some new pyrimidines via a novel chalcone series. Arkivoc. 2008 Jan 1;11:131-41.
29. Khoje AD, Kulendrn A, Charnock C, Wan B, Franzblau S, Gundersen LL. Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring. Bioorganic & medicinal chemistry. 2010 Oct 15;18(20):7274-82.
30. Chaudhari PK, Pandey A, Shah VH. Synthesis and biological studies of 1, 2, 3, 4-tetrahydro pyrimidine derivatives. Oriental Journal of Chemistry. 2010;26(4):1377.
31. Shmalenyuk ER, Kochetkov SN, Alexandrova LA. Novel inhibitors of Mycobacterium tuberculosis growth based on modified pyrimidine nucleosides and their analogues. Russian Chemical Reviews. 2013;82(9):896.
32. Doan TN, Tran DT. Synthesis, antioxidant and antimicrobial activities of a novel series of chalcones, pyrazolic chalcones, and allylic chalcones. Pharmacology & Pharmacy. 2011 Oct 19;2(04):282.
33. Jyothi MV, Prasad YR, Venkatesh P, Sureshreddy M. Synthesis and antimicrobial activity of some novel chalcones of 3-acetyl pyridine and their pyrimidine derivatives. Chem Sci Trans. 2012;1(3):716-22.
34. Rao NS, Kistareddy C, Balram B, Ram B. Synthesis and antibacterial activity of novel imidazo [1, 2-a] pyrimidine and imidazo [1, 2-a] pyridine chalcones derivatives. Der Pharma Chemica. 2012;4(6):2408-15.
35. Sato Y, He JX, Nagai H, Tani T, Akao T. Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine. Biological and Pharmaceutical Bulletin. 2007;30(1):145-9.
36. Patel VG, Goswami TK. Synthesis, Spectral Characterization and Biological Evaluation of Some Novel Pyrazolines. Journal of Chemical, Biological and Physical Sciences (JCBPS). 2014 Aug 1;4(4):3070.
37. Asiri AM, Marwani HM, Alamry KA, Al-Amoudi MS, Khan SA, El-Daly SA. Green synthesis, characterization, photophysical and electrochemical properties of bis-chalcones. Int J Electrochem Sci. 2014 Feb 1;9:799-809..
38. MA B, MJ A. Synthesis of chalcone 1-(2, 4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl) prop-2-en-1-one via conventional and sonochemical methods: a comparative study. International Journal of Biology, Pharmacy and Allied Science. 2014 May; 3(5): 705-717.
39. Balaji P, Ranganayakulu D, Ramyayadav K, jayamma J, Reddykumar S, Sivaramaiah C. Anthelmintic and Anti-microbial Activities of Synthesized Heterocyclic Pyrazole and Its Derivatives from Fluoro Substituted Hydrazino Benzothiazole. International Journal of PharmTech Research. 2014 Nov; Vol.6 (7): pp. 1970-1975.
40. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports. 2017 Mar 3;7:42717.
41. Daina A, Zoete V. A BOILEDâ€Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016 Jun 6;11(11):1117-21
42. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. Journal of molecular biology. 1997 Apr 4;267(3):727-48.
43. Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. Journal of molecular biology. 1995 Jan 1;245(1):43-53.
44. Huang SY, Zou X. Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking. Proteins: Structure, Function, and Bioinformatics. 2007 Feb 1;66(2):399-421.
45. Webb EF, Griswold DE. Microprocessor-assisted plethysmograph for the measurment of mouse paw volume. Journal of pharmacological methods. 1984 Sep 1;12(2):149-53.
46. Palm K, Stenberg P, Luthman K, Artursson P. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharmaceutical research. 1997 May 1;14(5):568-71.
47. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein–ligand docking using GOLD. Proteins: Structure, Function, and Bioinformatics. 2003 Sep;52(4):609-23.
48. Adeniyi AA, Ajibade PA. Comparing the suitability of autodock, gold and glide for the docking and predicting the possible targets of Ru (II)-based complexes as anticancer agents. Molecules. 2013 Mar 25;18(4):3760-78.
49. Suralkar AA, Sarda PS, Ghaisas MM, Thakare VN, Deshpande AD. In-vivo animal models for evaluation of anti-inflammatory activity. Latest Rev. 2008 Mar;6(2).
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Published
2019-02-26
How to Cite
Yousif, O. A., Mahdi, M. F., & Raauf, A. M. R. (2019). Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme. Journal of Contemporary Medical Sciences, 5(1), 41–50. https://doi.org/10.22317/jcms.v5i1.521
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