Skip to main content

A facile and improved synthesis of sildenafil (Viagra®) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies


Herein, the synthesis of some analogs of sildenafil (Viagra®) (21) is described, employing MW irradiations in key steps such as, SNAr reaction on important precursor bromopyrazole (7). Compound 7 was synthesized by the bromination followed by the amidation of readily available 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (5). Compounds 9 and 10 were obtained as SNAr reaction products, apparently through the proposed dipolar high-energy transition states TS-1 and TS-2 under MW irradiation, respectively. In contrast, conventional heating failed to produce similar results, even after prolonged heating. Compound 10, upon chlorosulfonation followed by the coupling of various nucleophiles, yielded a series of compounds 12–20 as analogs of sildenafil (21). Compounds 12–21 were subjected to tyrosinase inhibition studies and SAR studies were carried out. This study reflected that the inhibition was enhanced with increase of carbon chain. In case of the compound 17, the –OH group was replaced with –CH2–CH2–OH with a resulting increase in inhibition against tyrosinase. Compound 17 was found to be more potent than the potent reference inhibitor LM and KA. The 2D and 3D hydrogen bonding descriptors that help to study QSPR were also calculated. Energetically most stable conformations of these compounds were analyzed. Their kinetic, potential and total energies were also calculated through MD simulation.

This is a preview of subscription content, access via your institution.



α-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid


cyclic guanosine monophosphate


electron impact mass spectra


hydrogen bond thermodynamics


kojic acid




molecular dynamic


male erectile dysfunction


structure activity relationship


molecular mechanics


molecular mechanics force field




nuclear magnetic resonance


phosphodiesterase type 5


polyphenol oxidase


quantitative structure properties relationships


root mean square


standard error of the mean


aromatic nucleophilic substitution reaction


transition state.


  1. Mesaik, M.A., Rahat, S. Khan, K.M., Choudhary, M.I., Shahnaz, M., Ismaeil, Z., Atta-ur-Rahman, Ahmad A., Zia-Ullah, Immunomodulatory properties of synthetic oxazolone derivatives, Bioorg. Med. Chem., 12 (2004) 2049–2057, and references quoted herein.

    Google Scholar 

  2. Moreland, R.B., Goldstein, I., Kim, N.N., Traish, A., Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor, Trends Endocrinol. Metab., 10 (1999) 97–104, and references quoted herein.

    Google Scholar 

  3. Truss, M.C., Stief, C.G., Phosphodiesterase inhibitors in the treatment of erectile dysfunction, Drugs Today, 34 (1998) 805–815, and references quoted herein.

    Google Scholar 

  4. Terrett, N.K., Bell, A.S., Brown, D., Ellis, P., Sildenafil (ViagraTM), A potent and selective inhibitor of type 5 CGMP phoshphodiesterase with utility for the treatment of male erectile dysfunction, Bioorg. Med. Chem. Lett., 15 (1996) 1819–1824.

    Google Scholar 

  5. Beavo, J.A., Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms, Physiol. Rev., 75 (1995) 725-748.

    Google Scholar 

  6. Kim, D-K., Ryu, D.H., Lee, N., Lee, J.Y., Kim, J-S., Lee, S., Choi, J-Y., Ryu, J-H., Kim, N-H., Im, G-J., Choi, W-S., Kim, T-K., Synthesis and phosphodiesterase 5 inhibitory activity of new 5-phenyl-1,6-dihydro-7h-pyrazoio[4,3-d]pyrimidin-7-one derivatives containing an n-acylamido group on a phenyl ring, Bioorg. Med. Chem., 7 (2001) 1895–1899, and references quoted herein.

    Google Scholar 

  7. Texier-Boullet, F., Latouche, R., Hamelin, J., Synthesis in dry media coupled with microwave irradiation: application to the preparation of β -aminoesters and β -lactams via silyl ketene acetals and aldimines, Tetrahedron Lett., 34 (1997) 2123–2126.

    Google Scholar 

  8. Bram, G., Loupy, A., Villemin, D., Solid supports and catalysts in organic synthesis, Smith, K.(Ed) (Prentice Hall, Chichester), 1992, Chapter XII, p. 302.

    Google Scholar 

  9. Jhonson, C.R., Zhang, B., Fanartauzzi, P., Hocker, M., Yager, K.M., Libraries of n-alkylaminoheterocycles from nucleophilic aromatic substitution with purification by solid supported liquid extraction, Tetrahedron Lett., 54 (1998) 4097–4106.

    Google Scholar 

  10. Sawyer, J.S., Schmittling, E.A., Palkowitz, J.A., Smith, W.J., Synthesis of diaryl ethers, diaryl thioethers, and diarylamines mediated by potassium fluoridealumina and 18-crown-6: Expansion of scope and utility, J. Org. Chem., 63 (1998) 6338–6343.

    Google Scholar 

  11. Damien, P., Gilbert, K., Jean, N.F., Efficient synthesis of N,N-disubstituted 5-aminothiophene-2-carboxaldehydes by nucleophilic aromatic substitution in water, Syn. Lett., 4 (1998) 383–384.

    Google Scholar 

  12. Cirrincione, G., Almerico, A.M., Passannanti, A., Diana, P., Mingoia, F., Nucleophilic reactions in the pyrrole series: Displacement of halogen as a tool to functionalize the pyrrole nucleus, Synthesis, (1997) 1169–1174.

  13. Ohmori, J., Sasamata, S.M., Okada, M., Sakamoto, S., Novel AMPA Receptor antagonists: synthesis and structure-activity relationships of 1-Hydroxy-7-(1H-Imidazol-1-Yl)-6-Nitro-2,3(1H,4H)- Quinoxalinedione and related compounds, J. Med. Chem., 39 (1996) 3971–3979.

    Google Scholar 

  14. Napoli, L.D., Messere, A., Montesarchio, D., Piccialli, G., Synthesis of [1-15N]-labeled 2′-deoxyinosine and 2′-deoxyadenosine, J. Org. Chem., 60 (1995) 2251–2253.

    Google Scholar 

  15. Kiyomori, A., Marcoux, J.F., Buchwald, S.L., An efficient copper-catalyzed coupling of aryl halides with imidazoles, Tetrahedron Lett., 40 (1999) 2657–2660.

    Google Scholar 

  16. Shakespeare, W.C., Palladium-catalyzed coupling of lactams with bromobenzenes, Tetrahedron Lett., 40 (1999) 2035-2038.

    Google Scholar 

  17. Shiino, M., Watanabe, Y., Umezawa, K., Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase, Bioorg. Med. Chem., 9 (2001) 1233–1240.

    Google Scholar 

  18. Lee, H.S., Tyrosinase inhibitors of pulsatilla cernua root-derived materials, J. Agric. Food Chem., 50 (2002) 1400–1403.

    Google Scholar 

  19. Burch, H.A., Acylpyruvates as potential antifungal agents, J. Med. Chem., 15 (1972) 429–431.

    Google Scholar 

  20. Habraken, C., Moore, J.A., Heterocyclic Studies. XVI. The assignment of isomeric and tautomeric structures of pyrazoles by nuclear magnetic resonance, J. Org. Chem., 30 (1965) 1889–1896.

    Google Scholar 

  21. Hamilton H.W., Ortwine, D.F., Worth, D.F., Bristol, J.A., Synthesis and structure-activity relationships of pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists, J. Med. Chem., 30 (1987) 91–96.

    Google Scholar 

  22. von Auwers, K., Hollman, H., Über die isomerie-verhältnisse in der pyrazol-reihe, VI.: über alkylderivative der 3,5-methyl-pyrazol-carbonsäure und des 3(5)-methyl-pyrazols, Ber., 59 (1926) 601–607.

    Google Scholar 

  23. Bell, A.S., Brown, D., Terrett, N.K., US Patent 5,346,901 (1994).

  24. Chen, J., Wei, C., Marshall, M., Inhibition Mechanism of Kojic Acid on polyphenol oxidase, J. Agric. Food Chem., 39 (1991) 1897–1901.

    Google Scholar 

  25. Cabanes, J., García-Cánovas, F., Tudela, J., Lozano, J., and García-Carmona, F.: l-mimosine, a slow-binding inhibitor of mushroom tyrosinase, Phytochem, 26 (1987) 917–919.

    Google Scholar 

  26. Hearing, V.J., Methods in Enzymology, Academic Press, New York, 142 (1987) pp. 154–165.

  27. McEachern, M.J., Krauskopf, A., Blackburn, E.H., Telomeres and their control, Annu. Rev. Genet., 34 (2000) 331–358.

    Google Scholar 

  28. Ren, J., Qu, X., Dattagupta, N., Chaires, J.B., Molecular recognition of a RNA:DNA hybrid structure, J. Am. Chem. Soc., 123 (2001) 6742–6743.

    Google Scholar 

  29. Raevsky, O.A., Molecular structure descriptors in the computer-aided design of biologically active compounds, Russ. Chem. Rev., 68 (1999) 505–524.

    Google Scholar 

  30. Raevsky, O.A., Skvortsov, V.S., 3D Hydrogen Bond Thermodynamics (HYBOT) Potentials in Molecular Modeling, Comp.-Aided Mol. Des., 16 (2002) 1–10.

    Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Khalid M. Khan.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Khan, K.M., Maharvi, G.M., Khan, M.T.H. et al. A facile and improved synthesis of sildenafil (Viagra®) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies. Mol Divers 9, 15–26 (2005).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:


  • bromination
  • energy minimization
  • hydrogen bonding
  • molecular modeling
  • sildenafil
  • solid state
  • tyrosinase