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.
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α-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid
cyclic guanosine monophosphate
electron impact mass spectra
hydrogen bond thermodynamics
male erectile dysfunction
structure activity relationship
molecular mechanics force field
nuclear magnetic resonance
phosphodiesterase type 5
quantitative structure properties relationships
root mean square
standard error of the mean
aromatic nucleophilic substitution reaction
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.
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.
Truss, M.C., Stief, C.G., Phosphodiesterase inhibitors in the treatment of erectile dysfunction, Drugs Today, 34 (1998) 805–815, and references quoted herein.
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.
Beavo, J.A., Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms, Physiol. Rev., 75 (1995) 725-748.
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.
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.
Bram, G., Loupy, A., Villemin, D., Solid supports and catalysts in organic synthesis, Smith, K.(Ed) (Prentice Hall, Chichester), 1992, Chapter XII, p. 302.
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.
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.
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.
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.
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.
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.
Kiyomori, A., Marcoux, J.F., Buchwald, S.L., An efficient copper-catalyzed coupling of aryl halides with imidazoles, Tetrahedron Lett., 40 (1999) 2657–2660.
Shakespeare, W.C., Palladium-catalyzed coupling of lactams with bromobenzenes, Tetrahedron Lett., 40 (1999) 2035-2038.
Shiino, M., Watanabe, Y., Umezawa, K., Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase, Bioorg. Med. Chem., 9 (2001) 1233–1240.
Lee, H.S., Tyrosinase inhibitors of pulsatilla cernua root-derived materials, J. Agric. Food Chem., 50 (2002) 1400–1403.
Burch, H.A., Acylpyruvates as potential antifungal agents, J. Med. Chem., 15 (1972) 429–431.
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.
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.
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.
Bell, A.S., Brown, D., Terrett, N.K., US Patent 5,346,901 (1994).
Chen, J., Wei, C., Marshall, M., Inhibition Mechanism of Kojic Acid on polyphenol oxidase, J. Agric. Food Chem., 39 (1991) 1897–1901.
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.
Hearing, V.J., Methods in Enzymology, Academic Press, New York, 142 (1987) pp. 154–165.
McEachern, M.J., Krauskopf, A., Blackburn, E.H., Telomeres and their control, Annu. Rev. Genet., 34 (2000) 331–358.
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.
Raevsky, O.A., Molecular structure descriptors in the computer-aided design of biologically active compounds, Russ. Chem. Rev., 68 (1999) 505–524.
Raevsky, O.A., Skvortsov, V.S., 3D Hydrogen Bond Thermodynamics (HYBOT) Potentials in Molecular Modeling, Comp.-Aided Mol. Des., 16 (2002) 1–10.
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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). https://doi.org/10.1007/s11030-005-1299-5
- energy minimization
- hydrogen bonding
- molecular modeling
- solid state