Facile heterocyclic synthesis and antimicrobial activity of polysubstituted and condensed pyrazolopyranopyrimidine and pyrazolopyranotriazine derivatives

Open access

Abstract

Reaction of 6-amino-3-methyl-4-(substituted phenyl)-1,4- dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) with triethylorthoformate followed by treatment with hydrazine hydrate, formic acid, acetic acid, phenylisocyanate, ammonium thiocyanate and formamide afforded the corresponding pyranopyrimidine derivatives 2-6. Cyclocondensation of 1 with cyclohexanone afforded pyrazolopyranoquinoline 7. One-pot process of diazotation and de-diazochlorination of 1 afforded pyrazolopyranotriazine derivative 8, which upon treatment with secondary amines afforded 9 and 10a- c. Condensation of 2 with aromatic aldehyde gave the corresponding Schiff bases 11a,b, the oxidative cyclization of the hydrazone with appropriate oxidant afforded 11-(4- fluorophenyl))- 2-(4-substituted phenyl)-10-methyl-8,11-dihydropyrazolo-[ 4’,3’:5,6]pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (12a,b). Structures of the synthesized compounds were confirmed by spectral data and elemental analysis. All synthesized compounds were evaluated for antibacterial and antifungal activities compared to norfloxacin and fluconazole as standard drugs. Compounds 9, 10c, 12a and 15 were found to be the most potent antibacterial agents, with activity equal to that of norfloxacin. On the other hand, compound 5 exhibited higher antifungal activity compared to fluconazole.

References

  • 1. A. B. A. El-Gazzar and H. N. Hafez, Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents, Bioorg. Med. Chem. Lett. 19 (2009) 3392-3397; DOI: 10.1016/j.bmcl.2009.05.044.

  • 2. F . M. A. El-Taweel, M. A. Sofan, M. A. Mashaly, M. A. Hanna and A. A. Elagamey, Synthesis of some new pyranoquinoline, pyridine and pyrone derivatives, Pharmazie 45 (1990) 671-673; DOI: 10.1002/chin.199149187.

  • 3. A. M. El-Agrody, M. S. Abd El-Latif, N. A. El- Hady, A. H. Fakery and A. H. Bedair, Heteroaromatization with 4-hydroxycoumarin Part II: Synthesis of some new pyrano[2,3-d]-pyrimidines, [1,2,4]triazolo[1,5-c]pyrimidines and pyrimido[1,6-b][1,2,4]triazine derivatives, Molecules 6 (2001) 519-527; DOI: 10.3390/60600519.

  • 4. A. H. Bedair, N. A. El-Haddy, M. S. Abd El-Latif, A. H. Fakery and A. M. El-Agrody, 4- Hydroxycoumarin in heterocyclic synthesis. Part III: Synthesis of some new pyrano[2,3-d][1,2,4]triazolo[1,5- c]pyrimidine and pyrimido[1,6-b][1,2,4]triazine derivatives, Farmaco 55 (2000) 708-714; DOI: 10.1016/S0014-827X(00)00097-5.

  • 5. A. M. El-Agrody, M. H. El-Hakim, M. S. Abd El-Latif, A. H. Fakery, E. M. El-sayed and K. A. El- Ghareab, Synthesis of pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[2,3-c] pyrimidine derivatives with promising antibacterial activities, Acta Pharm. 50 (2000) 111-120.

  • 6. A. G. Martinez and L. J. Marco, Friedlander reaction on 2-amino-3-cyano-4H-pyrans, synthesis of derivatives of 4H-pyran[2,3-b]quinoline, new tacrine analogues, Bioorg. Med. Chem. Lett. 7 (1997) 3165-3170; DOI: 10.1016/S0960-894X(97)10165-2.

  • 7. F . Eiden and F. Denk, Synthesis and CNS activity of pyrane derivatives: 6,8-dioxabicyclo(3,2,1) octanes, Arch. Pharm. (Weinheim) 324 (1991) 353-354.

  • 8. C. P. Dell and C. W. Smith, Antiproliferative derivatives of 4H-naphtho[1,2-b]pyran and process for their preparation, Eur. Pat. 537, 94, 9 21 Apr 1993; ref. Chem. Abstr. 119 (1993) 139102d.

  • 9. F . M. Abdelrazek, P. Metz, N. H. Metwally and S. F. El-Mahrouky, Synthesis and molluscicidal activity of new cinnoline and pyrano[2,3-c]pyrazole derivatives, Arch. Pharm. Chem. Life Sci. 339 (2006) 456-460.

  • 10. G. Bianchi and A. Tava, Synthesis of (2R)(+)-2,3-dihydro-2,6-dimethyl-4H-pyran-4-one, a homologue of pheromones of a species in the hepialidae family, Agr. Biol. Chem. 51 (1987) 2001-2002; DOI: 10.1271/bbb1961.51.2001.

  • 11. K. Noda, A. Nakagawa, Y. Nakajima and H. Ide, Pyrido[2,3-d]-s-triazolo[4,3-c]pyrimidine derivatives, Japan Kokai 7785, 194, 15 Jul 1977; ref. Chem. Abstr. 88 (1978) P50908q.

  • 12. H. N. Hafez, H. A. S. Abbas and A. B. A. El-Gazzar, Synthesis and evaluation of analgesic, antiinflammatory and ulcerogenic activities of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines, Acta. Pharm. 58 (2008) 359-378; DOI: 10.2478/v10007-008-0024-1.

  • 13. A. B. A. El-Gazzar, H. A. R. Hossein and H. N. Hafez, Synthesis and biological evaluation of thieno[2,3-d]pyrimidines derivatives as anti-inflammatory, analgesic and ulcerogenic activity, Acta. Pharm. 57 (2007) 395-411; DOI: 10.2478/v10007-007-0032-6.

  • 14. A. B. A. El-Gazzar, H. N. Hafez and G. M. Nawwar, New acyclic nucleosides analogues as potential analgesic, anti-inflammatory, anti-oxidant and anti-microbial derived from pyrimido[4,5-b] quinolines, Eur. Med. Chem. 44 (2009) 1427-1436; DOI: 10.1016/j.ejmech. 2008.09.030.

  • 15. L . P. Prikazchikova, B. M. Khutova, I. F. Vladimirtsev, I. V. Boldyrev and N. I. Zhuravskaya, stimulating activity of mono- and diketone pyrimidine derivatives, Fiziol. Akt. Veshchestva 7 (1975) 84-87; ref. Chem. Abstr. 83 (1975) 127346m.

  • 16. D . J. Brown, Pyrimidines and Their Benzo Derivatives, in Comprehensive Heterocyclic Chemistry (Eds. A. R. Katritzky and C. W. Rees), Vol. 3, Pergamon Press, Oxford 1984, p. 443.

  • 17. S. M. Yu, S. C. Kuo, L. J. Huang, S. S. M. Sun, T. F. Huang and C. M. Teng, Vasorelaxation of rat thoracic aorta caused by two Ca2+-channel blockers, HA-22 and HA-23, J. Pharm. Pharmacol. 44 (1992) 667-671; DOI: 10.1111/j.2042-7158.1992.tb05491.x.

  • 18. D . Catarzi, L. Cecchi, V. Colotta, G. Filacchioni, C. Martini, P. Tacchi and A. Lucacchini, Tricyclic heteroaromatic systems. Synthesis and A1 and A2a adenosine binding activities of some 1-aryl-1,4-dihydro-3-methyl[1]benzopyrano[2,3-c]pyrazol-4-ones, 1-aryl-4,9-dihydro-3-methyl-1Hpyrazolo[ 3,4-b]quinolin-4-ones, and 1-aryl-1H-imidazo[4,5-b]quinoxalines, J. Med. Chem. 38 (1995) 1330-1336.

  • 19. N . Foloppe, L. M. Fisher, R. Howes, A. Potter, A. G. S. Robertson and A. E. Surgenor, Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening, Bioorg. Med. Chem. 14 (14) (2006) 4792-4802; DOI: 10.1016/j.bmc.2006.03.021.

  • 20. H. M. Al-Matar, K. D. Khalil, A. Y. Adam and M. H. Elnagdi, Green one pot solvent-free synthesis of pyrano[2,3-c]pyrazoles and pyrazolo[1,5-a]pyrimidines, Molecules 15 (2010) 6619-6629; DOI: 10.3390/molecules15096619.

  • 21. S. R. Jain and A. Kar, The antibacterial activity of some essential oils and their combination, Planta Med. 20 (1971) 118-123; DOI: 10.1055/s-0028-109967.

  • 22. H. Naeimi, Z. S. Nazifi, S. M. Amininezhad and M. Amouheidari, Synthesis, characterization and in vitro antimicrobial activity of some new Schiff bases and their complexes, J. Antibiot. 66 (2013) 687-689; DOI: 10.1038/ja.2013.73.

  • 23. M . B. Madhusudana Reddy, V. P. Jayashankara and M. A. Pasha, Glycine-catalyzed efficient synthesis of pyranopyrazoles via one-pot multicomponent reaction, Synth. Commun. 40 (2010) 2930-2934; DOI: 10.1080/00397910903340686.

  • 24. D . Thomae, G. Kirsch and P. Seck, Synthesis of selenophene analogues of the tacrine series: comparison of classical route and microwave irradiation, Synthesis 10 (2008) 1600-1606; DOI: 10.1055/s-2008-1067001.

  • 25. N . Galic, B. Peric, B. Kojic-Prodic and Z. Cimerman, Structural and spectroscopic characteristics of aroylhydrazones derived from nicotinic acid hydrazide, J. Mol. Struct. 559 (2001) 187-194; DOI: 10.10.1016/S0022-2860(00)00703-1.

  • 26. V. Klimesova, L. Zahajska, K. Waisser, J. Kaustova and U. Mollmann, Synthesis and antimycobacterial activity of 1, 2, 4-triazole 3-benzylsulfanyl derivatives, Farmaco 59 (2004) 279-288; DOI: 10.1016/j.farmac.2004.01.006.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information


IMPACT FACTOR 2016: 1.288
5-year IMPACT FACTOR: 1.600

CiteScore 2016: 1.55

SCImago Journal Rank (SJR) 2016: 0.353
Source Normalized Impact per Paper (SNIP) 2016: 0.854

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 22 22 14
PDF Downloads 7 7 6