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One-pot synthesis and in vivo biological evaluation of new pyrimidine privileged scaffolds as potent anti-inflammatory agents

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Abstract

A simple methodology has been developed for the synthesis of diverse members of multifunctionalized 4-hydroxy-2-methyl-6-(phenyl)pyrimidine-5-carbonitrile derivatives via multicomponent reaction of aromatic aldehydes, ethyl cyanoacetate, and acetamidine hydrochloride using a quantitative amount of NaOH in dry DMF at 80 °C in a single procedural step. The carbon skeleton of synthesized compounds resembles the bacimethrin, an antibiotic active against several yeast and bacteria. The anti-inflammatory activities of all the synthesized compounds were assessed on Wistar rats using diclofenac sodium as a standard reference. The compound AC1, 2, 5, 9, and AC10 showed promising anti-inflammatory activity (80–83 %) in comparison with diclofenac sodium (85 %) in the carrageenan-induced rat paw edema assay, which is the key finding of this article.

Graphical Abstract

The synthesized 4-hydroxy-2-methyl-6-(phenyl)pyrimidine-5-carbonitrile derivatives shown promising anti-inflammatory activity (80–83 %) in comparison with diclofenac sodium (85 %) in the carrageenan-induced rat paw edema assay.

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References

  1. H.M. Ashour, O.G. Shaaban, O.H. Rizk, I.M. El-Ashmawy, Eur. J. Med. Chem. 62, 341 (2013)

    Article  CAS  Google Scholar 

  2. P. Mc Gettigan, D. Henry, PLOS Med. 10, 1 (2013). www.plosmedicine.org

  3. C. Bombardier, L. Laine, A. Reicin, D. Shapiro, R. Burgos-Vargas, B. Davis, R. Day, M.B. Ferraz, C.J. Hawkey, M.C. Hochiberg, T.K. Kvien, T.J. Schnitzer, N. Engl, J. Med. 343, 1520 (2000)

    CAS  Google Scholar 

  4. P.J. Hashkes, R.M. Laxer, J. Am. Med. Assoc. 294, 1671 (2005)

    Article  CAS  Google Scholar 

  5. F.E. Silverstein, G. Faich, J.L. Goldstein, L.S. Simon, T. Pincus, A. Whelton, G. Makuch, G. Eisen, N.M. Agrawal, W.F. Stenson, A.M. Burr, W.W. Zhao, J.D. Kent, J.B. Lefkowith, K.M. Verburg, G.S. Geis, J. Am. Med. Assoc. 284, 1247 (2000)

    Article  CAS  Google Scholar 

  6. M.J. Langman, D.M. Jensen, D.J. Watson, S.E. Harper, P.-L. Zhao, H. Quan, J.A. Bolognese, T.J. Simon, J. Am. Med. Assoc. 282, 1929 (1999)

    Article  CAS  Google Scholar 

  7. M.C. Allison, A.G. Howatson, C.J. Torrance, F.D. Lee, R.I. Russell, N. Engl, J. Med. 327, 749 (1992)

    CAS  Google Scholar 

  8. L.J. Crofford, J. Rheumatol. 24(Suppl 49), 15 (1997)

    Google Scholar 

  9. G. Dannhardt, W. Kiefer, Eur. J. Med. Chem. 36, 109 (2001)

    Article  CAS  Google Scholar 

  10. D.A. Kujubu, B.S. Fletcher, B.C. Varnum, R.W. Lim, H.R. Herschman, J. Biol. Chem. 266, 12866 (1991)

    CAS  Google Scholar 

  11. W.C. Black, C. Bayly, M. Belley, C.C. Chan, S. Charleson, D. Denis, J.Y. Gauthier, R. Gordon, D. Guay, S. Kargman, C.K. Lau, Y. Leblanc, J. Mancini, M. Ouellet, D. Percival, P. Roy, K. Skorey, P. Tagari, P. Vickers, E. Wong, L.P. Xu, P. Prasit, Bioorg. Med. Chem. Lett. 6, 725 (1996)

    Article  CAS  Google Scholar 

  12. C.I. Beyly, W.C. Black, S. Leger, N. Ouimet, M. Ouellet, M.D. Percival, Bioorg. Med. Chem. Lett. 9, 307 (1999)

    Article  Google Scholar 

  13. E.A. Meade, W.L. Smith, D.L. DeWitt, J. Biol. Chem. 268, 6610 (1993)

    CAS  Google Scholar 

  14. L.J. Crofford, P.E. Lipsky, P. Brooks, S.B. Abramson, L.S. Simon, B.A. Leo, V.D. Putte, Arthritis Rheum. 43, 4 (2000)

    Article  CAS  Google Scholar 

  15. J.K. Gierse, C.M. Koboldt, M.C. Walker, K. Seibert, P.C. Isakson, Biochem. J. 339, 607 (1999)

    Article  CAS  Google Scholar 

  16. J.K. Gierse, S.D. Hauser, D.P. Creely, C. Koboldt, S.H. Rangwala, P.C. Isakson, K. Seibert, Biochem. J. 305, 479 (1995)

    Article  CAS  Google Scholar 

  17. R. Gautam, S.M. Jachak, Med. Res. Rev. 29, 767 (2009)

    Article  CAS  Google Scholar 

  18. T. Novinson, R.K. Robins, T.R. Matthews, J. Med. Chem. 20, 296 (1977)

    Article  CAS  Google Scholar 

  19. J. Matsumoto, S.J. Minami, J. Med. Chem. 18, 74 (1975)

    Article  CAS  Google Scholar 

  20. R. Aggarwal, E. Masan, P. Kaushik, D. Kaushik, C. Sharma, K.R. Aneja, J. Fluorine Chem. 168, 16 (2014)

    Article  CAS  Google Scholar 

  21. T.D. Venu, S.A. Khanum, A. Firdouse, B.K. Manuprasad, S. Shashikanth, R. Mohamed, B.S. Vishwanth, Bioorg. Med. Chem. Lett. 18, 4409 (2008)

    Article  CAS  Google Scholar 

  22. H.N. Hafez, H.A.S. Abbas, A.B.A. El-Gazzar, Acta Pharm. 58, 359 (2008)

    Article  CAS  Google Scholar 

  23. S. Valente, Y. Liu, M. Schnekenburger, C. Zwergel, S. Cosconati, C. Gros, M. Tardugno, D. Labella, C. Florean, S. Minden, H. Hashimot, Y. Chang, X. Zhang, G. Kirsch, E. Novellino, P.B. Arimondo, E. Miele, E. Ferretti, A. Gulino, M. Diederich, X. Cheng, A. Mai, J. Med. Chem. 57, 701 (2014)

    Article  CAS  Google Scholar 

  24. B. Chai, S. Wang, W. Yu, H. Li, C. Song, Y. Xu, C. Liu, J. Chang, Bioorg. Med. Chem. Lett. 23, 3505 (2013)

    Article  CAS  Google Scholar 

  25. J. Romanowska, M. Sobkowski, A. Szymanska-Michalak, K. Kozodziej, A. Dabrowska, A. Lipniacki, A. Piasek, Z.M. Pietrusiewicz, M. Figlerowicz, A. Guranowski, J. Boryski, J. Stawinski, A. Kraszewski, J. Med. Chem. 54, 6482 (2011)

    Article  CAS  Google Scholar 

  26. R.Z. Sterzycki, I. Ghazzouli, V. Brankovan, J.C. Martin, M.M. Mansuri, J. Med. Chem. 33, 2150 (1990)

    Article  CAS  Google Scholar 

  27. A.H. Bacelar, M.A. Carvalho, M.F. Proença, Eur. J. Med. Chem. 45, 3234 (2010)

    Article  CAS  Google Scholar 

  28. K. Singh, K. Singh, B. Wan, S. Franzblau, K. Chibale, J. Balzarini, Eur. J. Med. Chem. 46, 2290 (2011)

    Article  CAS  Google Scholar 

  29. I.M. Lagoja, Chem. Biodivers. Rev. 2, 1 (2005)

    Article  CAS  Google Scholar 

  30. L. Rong, H. Han, L. Gao, Y. Dai, M. Cao, S. Tu, Synth. Commun. 40, 504 (2010)

    Article  CAS  Google Scholar 

  31. B. Jiang, L.-Y. Xue, X.H. Wang, M.-S. Tu, Y.-P. Liu, S.-J. Tu, Tetrahedron Lett. 53, 1261 (2012)

    Article  CAS  Google Scholar 

  32. D.R. Fandrick, D. Reinhardt, J.-N. Desrosiers, S. Sanyal, K.R. Fandrick, S. Ma, N. Grinberg, H. Lee, J.J. Song, C.H. Senanayake, Org. Lett. 16, 2834 (2014)

    Article  CAS  Google Scholar 

  33. Y. Zhu, Y. Pan, S. Huang, Synth. Commun. 34, 3167 (2004)

    Article  CAS  Google Scholar 

  34. M.V. Reddy, J. Oh, Y.T. Jeong, C. R. Chim. 17, 484 (2014)

    Article  CAS  Google Scholar 

  35. L. Rong, S. Xia, S. Yia, S. Tao, Y. Zha, S. Tu, Res. Chem. Intermed. 39, 3699 (2013)

    Article  CAS  Google Scholar 

  36. H. Sheibani, M.A. Amrollahi, Z. Esfandiarpoor, Mol. Divers. 14, 277 (2010)

    Article  CAS  Google Scholar 

  37. P.P. Ghosh, G. Pal, S. Paul, A.R. Das, Green Chem. 14, 2691 (2012)

    Article  CAS  Google Scholar 

  38. S. Huang, H. Ying, Y. Hu, J. Heterocycl. Chem. 50, 478 (2013)

    Article  CAS  Google Scholar 

  39. A. Shaabani, M. Seyyedhamzeh, A. Maleki, F. Rezazadeh, M. Behnam, J. Comb. Chem. 11, 375 (2009)

    Article  CAS  Google Scholar 

  40. J. Zhu, Eur. J. Org. Chem. 2003, 1133 (2003)

    Article  Google Scholar 

  41. R.V.A. Orru, M. de Greef, Synthesis 10, 1471 (2003)

    Article  Google Scholar 

  42. F. Shi, X.N. Zeng, G. Zhang, N. Maa, B. Jiang, S. Tu, Bioorg. Med. Chem. Lett. 21, 7119 (2011)

    Article  CAS  Google Scholar 

  43. B.L. Li, A.G. Zhong, A.G. Ying, J. Heterocycl. Chem. 52, 445 (2015)

    Article  CAS  Google Scholar 

  44. P. Kaswan, K. Pericherla, D. Purohit, A. Kumar, Tetrahedron Lett. 56, 549 (2015)

    Article  CAS  Google Scholar 

  45. M.B. Deshmukh, S.M. Salunkhe, D.R. Patil, P.V. Anbhule, Eur. J. Med. Chem. 44, 2651 (2009)

    Article  CAS  Google Scholar 

  46. A.A. Patravale, A.H. Gore, D.R. Patil, G.B. Kolekar, M.B. Deshmukh, P.V. Anbhule, Ind. Eng. Chem. Res. 53, 16568 (2014)

    Article  CAS  Google Scholar 

  47. D.J. Finney, Statistical Method in Biological Assay, 2nd edn. (Charles Griffin and Company Limited, London, 1964)

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Acknowledgments

The author Santosh S. Undare is thankful to UGC (WRO), Pune for the award of Teacher fellowship under XII plan. The authors are thankful to SCAN Research Laboratory, Bhopal for providing anti-inflammatory activity study.

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Authors and Affiliations

  1. Medicinal Chemistry Research Laboratory, Department of Chemistry, Shivaji University, Kolhapur, M.S., 416004, India

    Santosh S. Undare, Navnath J. Valekar, Ajinkya A. Patravale, Laxman S. Walekar, Govind B. Kolekar, M. B. Deshmukh & Prashant V. Anbhule

  2. Shri Shivaji Mahavidyalaya, Barshi, M.S., India

    Dattatraya K. Jamale & Sunil S. Vibhute

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  1. Santosh S. Undare
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  2. Navnath J. Valekar
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  3. Ajinkya A. Patravale
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Correspondence to Prashant V. Anbhule.

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Undare, S.S., Valekar, N.J., Patravale, A.A. et al. One-pot synthesis and in vivo biological evaluation of new pyrimidine privileged scaffolds as potent anti-inflammatory agents. Res Chem Intermed 42, 4373–4386 (2016). https://doi.org/10.1007/s11164-015-2281-1

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  • DOI: https://doi.org/10.1007/s11164-015-2281-1

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