Issue

Vol. 30 No. 9 (2018): Vol 30 Issue 9

Copyright (c) 2018 AJC

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

3-Methyl-4-substituted Benzylidene Pyrazol-5-ones: Synthesis, Evaluation of Antinociceptive Activities and in silico Studies

https://doi.org/10.14233/ajchem.2018.21464
B. Swapna
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati-517 502, India
Shaheen Begum
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati-517 502, India
Arifa Begum
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati-517 502, India
K. Bharathi
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati-517 502, India
D. Sujatha
Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati-517 502, India

Corresponding Author(s) : B. Swapna

shaheen.pharmchem@gmail.com

Asian Journal of Chemistry, Vol. 30 No. 9 (2018): Vol 30 Issue 9

Abstract

A series of 3-methyl-4-substituted benzylidene pyrazol-5-ones were subjected to molecular docking studies using targets involved in nociception such as COX-2, TRPV1, P2X3 and glutamate to explore the structural features necessary for interactions with the active site of amino acids in various biological targets. Molecular docking studies showed that the introduction of electron releasing groups on benzylidene ring seem to enhance the binding affinity of pyrazolones. Compounds M2 (4-hydroxy) and M8 (3,4-dimethoxy) showed good binding affinity for TRPV1 and P2X3 receptors, whereas compound M9 (3,4,5-trimethoxy) was found to be favorable for COX-2 and glutamate receptors. These compounds were synthesized and evaluated using capsaicin, ATP and glutamate induced nociception to study the effect of title compounds on TRPV1, purinergic and glutamate receptors, respectively at a dose of 150 mg/kg body weight. Compounds M6 (3,4-dichlro) and M8 (3,4-dimethoxy) displayed good antinociceptive activity in TRPV1 and ATP induced nociception models whereas, compound M9 (3,4,5-trimethoxy) exhibited promising activity in glutamate-induced nociception. Some of the synthesized compounds bearing unsubstituted 4-hydroxy-2,3-dimethoxy and 4-dimethylamino benzylidene ring (M1-M4) have been earlier reported for their antinociceptive activity in acetic acid induced writhing and tail immersion methods. The results of the present study implicated that the compounds possessing 4-hydroxy and 4-dimethylamino groups showed good antinociceptive activity in all the models. The results might be useful to design and develop pyrazolones as potential antinociceptive agents.

Keywords

Pyrazolones COX-2 P2X3 Capsaicin model ATP-induced nociception Glutamate induced model
Swapna, B., Begum, S., Begum, A., Bharathi, K., & Sujatha, D. (2018). 3-Methyl-4-substituted Benzylidene Pyrazol-5-ones: Synthesis, Evaluation of Antinociceptive Activities and in silico Studies. Asian Journal of Chemistry, 30(9), 2107–2115. https://doi.org/10.14233/ajchem.2018.21464
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. J.X. Li and Y. Zhang, Eur. J. Pharmacol., 681, 1 (2012); https://doi.org/10.1016/j.ejphar.2012.01.017.
  2. G.R. Tibbs, D.J. Posson and P.A. Goldstein, Trends Pharmacol. Sci., 37, 522 (2016); https://doi.org/10.1016/j.tips.2016.05.002.
  3. A.P. Ford, Purinergic Signal., 8, S3 (2012); https://doi.org/10.1007/s11302-011-9271-6.
  4. A.S. Yekkirala, D.P. Roberson, B.P. Bean and C.J. Woolf, Nat. Rev. Drug Discov., 16, 810 (2017); https://doi.org/10.1038/nrd.2017.87.
  5. G. Labar, J. Wouters and D.M. Lambert, Curr. Med. Chem., 17, 2588 (2010); https://doi.org/10.2174/092986710791859414.
  6. S.M. Saario and J.T. Laitinen, Basic Clin. Pharmacol. Toxicol., 101, 287 (2007); https://doi.org/10.1111/j.1742-7843.2007.00130.x.
  7. S. Hua and P.J. Cabot, Front. Pharmacol., 5, 211 (2014); https://doi.org/10.3389/fphar.2014.00211.
  8. T.L. Yaksh, S.A. Woller, R. Ramachandran and L.S. Sorkin, F1000Prime Rep., 7, 1 (2015); https://doi.org/10.12703/P7-56.
  9. J. Barclay, S. Patel, G. Dorn, G. Wotherspoon, S. Moffatt, L. Eunson, S. Abdel’al, F. Natt, J. Hall, J. Winter, S. Bevan, W. Wishart, A. Fox and P. Ganju, J. Neurosci., 22, 8139 (2002); https://doi.org/10.1523/JNEUROSCI.22-18-08139.2002.
  10. I. Kissin, Anesth. Analg., 110, 780 (2010); https://doi.org/10.1213/ANE.0b013e3181cde882.
  11. K. Lalit, T. Chandresh and S. Vivek, Int. J. Res. Pharm. Sci., 2, 13 (2012).
  12. R. Ramajayam, K.P. Tan, H.G. Liu and P.H. Liang, Bioorg. Med. Chem., 18, 7849 (2010); https://doi.org/10.1016/j.bmc.2010.09.050.
  13. R. Prajuli, J. Banerjee and H. Khanal, Orient. J. Chem., 31, 2099 (2015); https://doi.org/10.13005/ojc/310430.
  14. G. Mariyappan, B.P. Saha, L. Sutharson and A. Haldar, Indian J. Chem., 49B, 1671 (2010).
  15. G. Mariappan, B.P. Saha, L. Sutharson, A. Singh, S. Garg, L. Pandey and D. Kumar, Saudi Pharm. J., 19, 115 (2011); https://doi.org/10.1016/j.jsps.2011.01.003.
  16. R. Nassini, C. Fusi, S. Materazzi, E. Coppi, T. Tuccinardi, I.M. Marone, F. De Logu, D. Preti, R. Tonello, A. Chiarugi, R. Patacchini, P. Geppetti and S. Benemei, Br. J. Pharmacol., 172, 3397 (2015); https://doi.org/10.1111/bph.13129.
  17. S.E. Gulmez, H. Gurdal and F.C. Tulunay, Pharmacology, 78, 202 (2006); https://doi.org/10.1159/000096688.
  18. P. Vicini, F. Zani, P. Cozzini and I. Doytchinova, Eur. J. Med. Chem., 37, 553 (2002); https://doi.org/10.1016/S0223-5234(02)01378-8.
  19. R. Ottanà, R. Maccari, M.L. Barreca, G. Bruno, A. Rotondo, A. Rossi, G. Chiricosta, R. Di Paola, L. Sautebin, S. Cuzzocrea and M.G. Vigorita, Bioorg. Med. Chem., 13, 4243 (2005); https://doi.org/10.1016/j.bmc.2005.04.058.
  20. A.A. Chavan and N.R. Pai, ARKIVOC, 148 (2007); https://doi.org/10.3998/ark.5550190.0008.g16.
  21. A. Grosdidier, V. Zoete and O. Michielin, J. Comput. Chem., 32, 2149 (2011); https://doi.org/10.1002/jcc.21797.
  22. H. Knotkova, M. Pappagallo and A. Szallasi, Clin. J. Pain, 24, 142 (2008); https://doi.org/10.1097/AJP.0b013e318158ed9e.
  23. S.G. Hamilton, A. Wade and S.B. McMahon, Br. J. Pharmacol., 126, 326 (1999); https://doi.org/10.1038/sj.bjp.0702258.
  24. J. Du, M. Koltzenburg and S.M. Carlton, Pain, 89, 187 (2001); https://doi.org/10.1016/S0304-3959(00)00362-6.
  25. A.G. Nerkar, S.A. Kudale, P.P. Joshi and H.U. Chikhale, Int. J. Pharm. Pharm. Sci., 4, 449 (2012).
  26. M.Y. Zhao, M.H. Abraham, J. Le, A. Hersey, C.N. Luscombe, G. Beck, B. Sherborne and I. Cooper, Pharm. Res., 19, 1446 (2002); https://doi.org/10.1023/A:1020444330011.
  27. P.N. Dube, S.S. Bule, S.N. Mokale, M.R. Kumbhare, P.R. Dighe and Y.V. Ushir, Chem. Biol. Drug Des., 84, 409 (2014); https://doi.org/10.1111/cbdd.12324.
  28. R. Giniatullin and A. Nistri, Front. Cell. Neurosci., 7, 1 (2013); https://doi.org/10.3389/fncel.2013.00245.
  29. L.A. Alves, J.H.M. da Silva, D.N.M. Ferreira, A.A. Fidalgo-Neto, P.C.N. Teixeira, C. de Souza, E. Caffarena and M. de Freitas, Int. J. Mol. Sci., 15, 4531 (2014); https://doi.org/10.3390/ijms15034531.
  30. Z. Wang, L. Sun, H. Yu, Y. Zhang, W. Gong, H. Jin, L. Zhang and H. Liang, Int. J. Mol. Sci., 13, 8958 (2012); https://doi.org/10.3390/ijms13078958.
  31. A. Szallasi, D.N. Cortright, C.A. Blum and S.R. Eid, Nat. Rev. Drug Discov., 6, 357 (2007); https://doi.org/10.1038/nrd2280.
  32. K. Elokely, P. Velisetty, L. Delemotte, E. Palovcak, M.L. Klein, T. Rohacs and V. Carnevale, Proc. Natl. Acad. Sci., 113, E137 (2016); https://doi.org/10.1073/pnas.1517288113.
  33. K.M. Wozniak, C. Rojas, Y. Wu and S.B. Slusher, Curr. Med. Chem., 19, 1323 (2012); https://doi.org/10.2174/092986712799462630.
  34. D. Bleakman, A. Alt and E.S. Nisenbaum, Semin. Cell. Dev. Biol., 17, 592 (2006); https://doi.org/10.1016/j.semcdb.2006.10.008.
  35. M. Balestra, H. Bunting, D. Chen, I. Egle, J. Forst, J. Frey, M. Isaac, F. Ma, D. Nugiel, A. Slassi, G. Steelman, G.R. Sun, R. Ukkiramapandian, B. Sundar, R.A. Urbanek and S. Walsh, Pyrazolone Compounds as Metabotropic Glutamate Receptor Agonists for the Treatment of Neurological and Psychiatric Disorders, WO Application, W02006071730A1 (2005).
  36. P.A. Bland-Ward and P.P.A. Humphrey, Br. J. Pharmacol., 122, 365 (1997); https://doi.org/10.1038/sj.bjp.0701371.
Read More
Author biographies is not available.
Download
PDF
Statistic
Read Counter : 0 Download : 0