Novel Heterocyclic Hybrids Based on 2-Pyrazoline: Synthesis and Assessment of Anti-Inflammatory and Analgesic Activities

Author(s): Ahmed A.O. Abeed, Gehad A.A. Jaleel, Mohamed S.K. Youssef*.

Journal Name: Current Organic Synthesis

Volume 16 , Issue 6 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Aim and Objective: A series of new 2-pyrazoline analogues were synthesized. The structures of the synthesized compounds were elucidated by the analytical and spectroscopic data. Some selected compounds were screened for the anti-inflammatory activity by using animal model of carrageenan-induced paw edema in mice. Additionally, the analgesic and acute toxicity of these compounds were evaluated and exhibited reasonable results. The anti-oxidant and anti-inflammatory effects of these compounds were established by measuring the contents of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) in the edema paw tissue.

Materials and Methods: All chemicals and reagents used in current study were of analytical grade. Melting points were determined using APP. Digital ST 15 melting point apparatus and are uncorrected. FT-IR spectra were recorded on a Pye-Unicam SP3-100 spectrophotometer in KBr pellet. All 1H and 13C NMR spectra were recorded on AVANCE-III (400 MHz) High Performance FT-NMR Spectrometer Brucker (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (60 MHz) (USA) in CDCl3 or DMSO-d6 as solvent. Chemical shifts are reported in δ units and the coupling constants (J) are reported in hertz. C, H, N and S analyses were performed with a Vario EL C, H, N, S Analyzer. Carrageenan (product number C1013) was obtained from Sigma-Aldrich (USA).

Results: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. The results of pharmacological activity revealed that compounds 5, 6, 7, and 15 could be recognized as potential multi-potent anti-inflammatory.

Conclusion: A simple and suitable method for the synthesis of new pharmacophore was reported. We have designed nineteen heterocycles related to pyrazoline ring, and evaluated eleven of them for their antiinflammatory, analgesic and acute toxicity activities. Compounds 5, 6, 7, and 15 proved to be the interesting compounds, they have high anti-inflammatory activity. However, all the selected compounds show remarkable analgesic activity.

Keywords: 2-Pyrazoline, thiazolidinone, anti-inflammatory, analgesic, TNF-α, GSH, MDA.

[1]
Ferrero-Miliani, L.; Nielsen, O.H.; Andersen, P.S.; Girardin, S.E. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation. Clin. Exp. Immunol., 2007, 147(2), 227-235.
[PMID: 17223962]
[2]
Jachak, S.M. Cyclooxygenase inhibitory natural products: Current status. Curr. Med. Chem., 2006, 13(6), 659-678.
[http://dx.doi.org/10.2174/092986706776055698] [PMID: 16529558]
[3]
Black, J.G. Microbiology Principles and Exploration, 6th ed; John Wiley and Sons, Inc.: New York, 2005, p. 446.
[4]
Lacerda, R.B.; de Lima, C.K.; da Silva, L.L.; Romeiro, N.C.; Miranda, A.L.; Barreiro, E.J.; Fraga, C.A. Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes. Bioorg. Med. Chem., 2009, 17(1), 74-84.
[http://dx.doi.org/10.1016/j.bmc.2008.11.018] [PMID: 19059783]
[5]
Szabó, G.; Fischer, J.; Kis-Varga, A.; Gyires, K. New celecoxib derivatives as anti-inflammatory agents. J. Med. Chem., 2008, 51(1), 142-147.
[http://dx.doi.org/10.1021/jm070821f] [PMID: 18072726]
[6]
Zebardast, T.; Zarghi, A.; Daraie, B.; Hedayati, M.; Dadrass, O.G. Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(12), 3162-3165.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.125] [PMID: 19447036]
[7]
Laufer, S.; Luik, S. Different methods for testing potential cyclooxygenase-1 and cyclooxygenase-2 inhibitors. Methods Mol. Biol., 2010, 644, 91-116.
[http://dx.doi.org/10.1007/978-1-59745-364-6_8] [PMID: 20645167]
[8]
Al-Hourani, B.J.; Sharma, S.K.; Mane, J.Y.; Tuszynski, J.; Baracos, V.; Kniess, T.; Suresh, M.; Pietzsch, J.; Wuest, F. Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(6), 1823-1826.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.057] [PMID: 21316237]
[9]
Abbas, S.E.; Awadallah, F.M.; Ibrahim, N.A.; Gouda, A.M. Novel substituted and fused pyrrolizine derivatives: Synthesis, anti-inflammatory and ulcerogenecity studies. Eur. J. Med. Chem., 2010, 45(2), 482-491.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.031] [PMID: 19913956]
[10]
Gawad, N.M.; Georgey, H.H.; Ibrahim, N.A.; Amin, N.H.; Abdelsalam, R.M. Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents. Arch. Pharm. Res., 2012, 35(5), 807-821.
[http://dx.doi.org/10.1007/s12272-012-0507-y] [PMID: 22644849]
[11]
Abdellatif, K.R.A.; Abdelgawad, M.A.; Elshemy, H.A.H.; Alsayed, S.S.R.; Kamel, G. Synthesis and anti-inflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing an aminosulphonyl pharmacophore. Arch. Pharm. Res., 2015, 38(11), 1932-1942.
[http://dx.doi.org/10.1007/s12272-015-0606-7] [PMID: 25904239]
[12]
Ramiz, M.M.; El-Sayed, W.A.; El-Tantawy, A.I.; Abdel-Rahman, A.A. Antimicrobial activity of new 4,6-disubstituted pyrimidine, pyrazoline, and pyran derivatives. Arch. Pharm. Res., 2010, 33(5), 647-654.
[http://dx.doi.org/10.1007/s12272-010-0501-1] [PMID: 20512460]
[13]
Shubhalaxmi, P.L.; Ananda, K.; Bhat, S. Synthesis of focused library of novel aryloxyacids and pyrazoline dserivatives; Molecular docking studies and antimicrobial investigation. Cogent. Chem., 2016, 2, 2-18.
[http://dx.doi.org/10.1080/23312009.2016.1141388]
[14]
Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Lesyk, R. Synthesis, anticancer and antiviral activities of 2-pyrazoline substituted 4-thiazolidinones. J. Heterocycl. Chem., 2013, 50, E55-E62.
[http://dx.doi.org/10.1002/jhet.1056]
[15]
Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity. J. Med. Chem., 2012, 55(20), 8630-8641.
[http://dx.doi.org/10.1021/jm300789g] [PMID: 22992049]
[16]
Bekhit, A.A.; Ashour, H.M.A.; Abdel Ghany, Y.S. Bekhit, Ael-D.; Baraka, A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur. J. Med. Chem., 2008, 43(3), 456-463.
[http://dx.doi.org/10.1016/j.ejmech.2007.03.030] [PMID: 17532544]
[17]
Ottanà, R.; Maccari, R.; Barreca, M.L.; Bruno, G.; Rotondo, A.; Rossi, A.; Chiricosta, G.; Di Paola, R.; Sautebin, L.; Cuzzocrea, S.; Vigorita, M.G. 5-Arylidene-2-imino-4-thiazolidinones: Design and synthesis of novel anti-inflammatory agents. Bioorg. Med. Chem., 2005, 13(13), 4243-4252.
[http://dx.doi.org/10.1016/j.bmc.2005.04.058] [PMID: 15905093]
[18]
Omar, Y.M.; Abdu-Allah, H.H.M.; Abdel-Moty, S.G. Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg. Chem., 2018, 80, 461-471.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.036] [PMID: 29986191]
[19]
Tageldin, G.N.; Fahmy, S.M.; Ashour, H.M.; Khalil, M.A.; Nassra, R.A.; Labouta, I.M. Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidine derivatives bearing thiazolidinone moiety as anti-inflammatory agents. Bioorg. Chem., 2018, 80, 164-173.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.013] [PMID: 29929077]
[20]
Narasimhan, B.; Saharan, R.; Kumar, P.H. Hansch analysis of anti-inflammatory and analgesic activities of substituted 1-alkyl/aryl-3-ethoxy carbonyl-5-hydroxy-2-methyl indoles. Acta. Pharm. Sci., 2011, 53, 117-126.
[21]
Collin, X.; Robert, J.; Wielgosz, G.; Le Baut, G.; Bobin-Dubigeon, C.; Grimaud, N.; Petit, J. New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-α production inhibitors. Eur. J. Med. Chem., 2001, 36(7-8), 639-649.
[http://dx.doi.org/10.1016/S0223-5234(01)01254-5] [PMID: 11600233]
[22]
Sarigol, D.; Uzgoren-Baran, A.; Tel, B.C.; Somuncuoglu, E.I.; Kazkayasi, I.; Ozadali-Sari, K.; Unsal-Tan, O.; Okay, G.; Ertan, M.; Tozkoparan, B. Novel thiazolo[3,2-b]1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: Synthesis, biological evaluation and molecular modeling studies. Bioorg. Med. Chem., 2015, 23, 2518-2528.
[http://dx.doi.org/10.1016/j.bmc.2015.03.049] [PMID: 25868745]
[23]
Abeed, A.A.O.; Abdel Mohsen, Sh.A. Synthesis, characterization and antimicrobial activity of new thiadiazoles, thiazolidines, and spiro (indole-azoles). Eur. J. Sci. Res., 2013, 108, 279-294.
[24]
Youssef, M.S.K.; Omar, A.A. Synthesis and reactions of 5-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile. Monatsh. Chem., 2007, 138, 989-995.
[http://dx.doi.org/10.1007/s00706-007-0703-5]
[25]
Youssef, M.S.K.; Abeed, A.A.O. Synthesis, characterization and pharmacological activities of pyrimidine derivatives containing 2-pyrazolin-5-one. Int. J. Pharm. Sci. Res., 2014, 5, 1705-1720.
[26]
Youssef, M.S.K.; Abbady, M.S.; Ahmed, R.A.; Omar, A.A. Synthesis of some new heterocycles derived from ethyl 7-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-aryl-5H-thiazolo[3,2-a] pyrimidine-6-carboxylate of biological importance. J. Heterocycl. Chem., 2013, 50, 179-187.
[http://dx.doi.org/10.1002/jhet.735]
[27]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenan-induced oedema in hind paws on the rat as an assay for anti-inflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111, 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[28]
Abdel Jaleel, G.A.R.; Abdallah, H.M.I.; Gomaa, N.E.L.S. Pharmacological effects of ethanol extract of Egyptian Artemisia herba-alba in rats and mice. Asian Pac. J. Trop. Biomed., 2016, 6, 44-49.
[http://dx.doi.org/10.1016/j.apjtb.2015.10.005]
[29]
Selvam, T.P.; Kumar, P.V.; Saravanan, G.; Prakash, C.R. Microwave-assisted synthesis, characterization and biological activity of novel pyrazole derivatives. J. Saudi Chem. Soc., 2014, 18, 1015-1020.
[http://dx.doi.org/10.1016/j.jscs.2011.12.006]
[30]
Alam, M.J.; Alam, O.; Khan, S.A.; Naim, M.J.; Islamuddin, M.; Deora, G.S. Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues. Drug Des. Devel. Ther., 2016, 10, 3529-3543.
[http://dx.doi.org/10.2147/DDDT.S118297] [PMID: 27826185]
[31]
Sorg, D.A.; Buckner, B. A simple method of obtaining venous blood animals. Proc. Soc. Exp. Biol. Med., 1964, 115, 1131-1132.
[http://dx.doi.org/10.3181/00379727-115-29134] [PMID: 14166577]
[32]
Beutler, E.; Duron, O.; Kelly, B.M. Improved method for the determination of blood glutathione. J. Lab. Clin. Med., 1963, 61, 882-888.
[PMID: 13967893]
[33]
Miranda, K.M.; Espey, M.E.; Wink, D.A. Rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Biol. Chem., 2001, 5, 62-71.
[34]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[35]
Tarpey, M.M.; Wink, D.A.; Grisham, M.B. Methods for detection of reactive metabolites of oxygen and nitrogen: In vitro and in vivo considerations. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2004, 286(3), R431-R444.
[http://dx.doi.org/10.1152/ajpregu.00361.2003] [PMID: 14761864]
[36]
Bonavida, B. Immunomodulatory effect of tumor necrosis factor. Biotherapy, 1991, 3(2), 127-133.
[http://dx.doi.org/10.1007/BF02172085] [PMID: 2054253]
[37]
Laviola, G.; Alleva, E. Ontogeny of muscimol effects on locomotor activity, habituation, and pain reactivity in mice. Psychopharmacology (Berl.), 1990, 102(1), 41-48.
[http://dx.doi.org/10.1007/BF02245742] [PMID: 2392506]
[38]
Silva, J.; Abebe, W.; Sousa, S.M.; Duarte, V.G.; Machado, M.I.; Matos, F.J. Analgesic and anti-inflammatory effects of essential oils of Eucalyptus. J. Ethnopharmacol., 2003, 89(2-3), 277-283.
[http://dx.doi.org/10.1016/j.jep.2003.09.007] [PMID: 14611892]
[39]
Buck, W.B.; Osweiler, G.D.; Van Gelder, G.A. Clinical and Diagnostic Veterinary Toxicology; Kendall/Hunt Publ. Co.: Dubuque, Iowa, 1976.
[40]
Dunn, O.J. Multiple comparisons using rank sums. Technometrics, 1964, 6, 241-252.
[http://dx.doi.org/10.1080/00401706.1964.10490181]
[41]
Abeed, A.A.O.; El-Emary, T.I.; Youssef, M.S.K. A facile synthesis and reactions of some novel pyrazole-based heterocycles. Curr. Org. Synth., 2019, 16, 405-412.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 6
Year: 2019
Page: [921 - 930]
Pages: 10
DOI: 10.2174/1570179416666190703115133
Price: $58

Article Metrics

PDF: 17
HTML: 2

Special-new-year-discount