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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

In vitro Activity of the Novel Pyrimidines and Their Condensed Derivatives Against Poliovirus

Author(s): Roman Solomyannyi*, Sergii Slivchuk, Donald Smee, Jung-ae Choi, Eduard Rusanov, Victor Zhirnov and Volodymyr Brovarets

Volume 15, Issue 5, 2019

Page: [582 - 591] Pages: 10

DOI: 10.2174/1573407214666180720120509

Price: $65

Abstract

Background: Substituted pyrimidine derivatives (non-nucleoside) are found to be associated with various biological activities. The various substituted pyrimidines are also having significant in vitro activity against different DNA and RNA viruses. The present study focuses on the anti-PV activity of new pyrimidines and their condensed derivatives.

Methods: A series of novel pyrimidines and their condensed derivatives were synthesized and their structures were confirmed by spectral data. Their antiviral activities against poliovirus type 3 (PV-3) were evaluated in vitro. In cell culture, morphological changes observed in cells infected with polioviruses, including cell rounding and detachment from the substrate, are generally termed cytopathic effects (CPE). The effects of synthetic pyrimidines on PV amplification in a culture of the heteroploid cell line, Vero 76 (African green monkey kidney cells) were investigated.

Results: Bioassays in vitro showed that one of seven synthesized compounds, 7-(Benzenesulfonyl)-5- benzyl-N-(prop-2-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, has potent antiviral activity against PV-3 (EC50 = 0.75 μM). The selectivity index of this compound is similar to that of pirodavir.

Conclusion: The need for antiviral agents to treat PV-associated diseases remains great, but few options currently exist. Here we show that substituted pyrimidine derivatives are a promising structure class of chemical compounds for the development of antiviral drugs against PV infections.

Keywords: Antiviral discovery, pyrimidine derivatives, poliovirus, Vero cells, PV amplification, CPE.

Graphical Abstract

[1]
Washington, D.C. Exploring the role of antiviral drugs in the eradication of polio: workshop report; The National Academies Press: Washington, DC, 2006.
[2]
Oberste, M.S.; Moore, D.; Anderson, B.; Pallansch, M.A.; Pevear, D.C.; Collett, M.S. In vitro antiviral activity of V-073 against polioviruses. Antimicrob. Agents Chemother., 2009, 53(10), 4501-4503.
[http://dx.doi.org/10.1128/AAC.00671-09] [PMID: 19635956]
[3]
Collett, M.S.; Neyts, J.; Modlin, J.F. A case for developing antiviral drugs against polio. Antiviral Res., 2008, 79(3), 179-187.
[http://dx.doi.org/10.1016/j.antiviral.2008.04.002] [PMID: 18513807]
[4]
Bordería, A.V.; Stapleford, K.A.; Vignuzzi, M. RNA virus population diversity: Implications for inter-species transmission. Curr. Opin. Virol., 2011, 1(6), 643-648.
[http://dx.doi.org/10.1016/j.coviro.2011.09.012] [PMID: 22440922]
[5]
Viktorova, E.G.; Nchoutmboube, J.; Ford-Siltz, L.A.; Belov, G.A. Cell-specific establishment of poliovirus resistance to an inhibitor targeting a cellular protein. J. Virol., 2015, 89(8), 4372-4386.
[http://dx.doi.org/10.1128/JVI.00055-15] [PMID: 25653442]
[6]
Crotty, S.; Cameron, C.E.; Andino, R. RNA virus error catastrophe: Direct molecular test by using ribavirin. Proc. Natl. Acad. Sci. USA, 2001, 98(12), 6895-6900.
[http://dx.doi.org/10.1073/pnas.111085598] [PMID: 11371613]
[7]
Lenarcic, E.M.; Landry, D.M.; Greco, T.M.; Cristea, I.M.; Thompson, S.R. Thiouracil cross-linking mass spectrometry: A cell-based method to identify host factors involved in viral amplification. J. Virol., 2013, 87(15), 8697-8712.
[http://dx.doi.org/10.1128/JVI.00950-13] [PMID: 23740976]
[8]
Dhongade, H.J.; Dansena, D.H.; Chandrakar, K. Pharmacological potentials of pyrimidine derivative: A review. Asian J. Pharm. Clin. Res., 2015, 8, 171-177.
[9]
Deep, A.; Narasimhan, B.; Kumar, S. A review on synthesis, anticancer and antiviral potentials of pyrimidine derivatives. Curr. Bioact. Compd., 2018, 14.
[http://dx.doi.org/10.2174/1573407214666180124160405]
[10]
De Clercq, E.; Sakuma, T.; Baba, M.; Pauwels, R.; Balzarini, J.; Rosenberg, I.; Holý, A. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res., 1987, 8(5-6), 261-272.
[http://dx.doi.org/10.1016/S0166-3542(87)80004-9] [PMID: 3451698]
[11]
Hocková, D.; Holý, A.; Masojídková, M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds. Bioorg. Med. Chem., 2004, 12(12), 3197-3202.
[http://dx.doi.org/10.1016/j.bmc.2004.04.002] [PMID: 15158787]
[12]
Summa, V.; Petrocchi, A.; Matassa, V.G.; Taliani, M.; Laufer, R.; De Francesco, R.; Altamura, S.; Pace, P. HCV NS5b RNA-dependent RNA polymerase inhibitors: From α,γ-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecar-boxylic acids. Design and synthesis. J. Med. Chem., 2004, 47(22), 5336-5339.
[http://dx.doi.org/10.1021/jm0494669] [PMID: 15481971]
[13]
Koch, U.; Attenni, B.; Malancona, S.; Colarusso, S.; Conte, I.; Di Filippo, M.; Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.; Tomei, L.; De Francesco, R.; Altamura, S.; Matassa, V.G.; Narjes, F. 2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: Discovery, SAR, modeling, and mutagenesis. J. Med. Chem., 2006, 49(5), 1693-1705.
[http://dx.doi.org/10.1021/jm051064t] [PMID: 16509585]
[14]
Prekupec, S.; Makuc, D.; Plavec, J.; Suman, L.; Kralj, M.; Pavelić, K.; Balzarini, J.; Clercq, E.D.; Mintas, M.; Raić-Malić, S. Novel C-6 fluorinated acyclic side chain pyrimidine derivatives: Synthesis, (1)H and (13)C NMR conformational studies, and antiviral and cytostatic evaluations. J. Med. Chem., 2007, 50(13), 3037-3045.
[http://dx.doi.org/10.1021/jm0614329] [PMID: 17539622]
[15]
Ravendra Babu, K.; Rao, V.K.; Nanda Kumar, Y.; Polireddy, K.; Venkata Subbaiah, K.; Bhaskar, M.; Lokanatha, V.; Naga Raju, C. Identification of substituted [3, 2-a] pyrimidines as selective antiviral agents: molecular modeling study. Antiviral Res., 2012, 95(2), 118-127.
[http://dx.doi.org/10.1016/j.antiviral.2012.05.010] [PMID: 22659095]
[16]
Yamazi, Y.; Takahashi, M.; Todome, Y. Inhibition of poliovirus by effect of a methylthiopyrimidine derivative. Proc. Soc. Exp. Biol. Med., 1970, 133(2), 674-677.
[http://dx.doi.org/10.3181/00379727-133-34542] [PMID: 4313152]
[17]
La Colla, P.; Marcialis, M.A.; Mereu, G.P.; Loddo, B. Specific inhibition of poliovirus induced blockade of cell protein synthesis by a thiopyrimidine derivative. J. Gen. Virol., 1972, 17(1), 13-18.
[http://dx.doi.org/10.1099/0022-1317-17-1-13] [PMID: 4343527]
[18]
Marcialis, M.A.; Schivo, M.L.; Uccheddu, P.; Garzia, A.; Loddo, B. Inhibition of poliovirus growth by 2-amino-4,6-dichloropyrimidine. Experientia, 1973, 29, 1442-1443.
[http://dx.doi.org/10.1007/BF01922867]
[19]
La Colla, P.; Marcialis, M.A.; Flore, O.; Sau, M.; Garzia, A.; Loddo, B. Specific inhibition of virus multiplication by bichlorinated pyrimidines. Ann. N. Y. Acad. Sci., 1977, 284, 294-304.
[http://dx.doi.org/10.1111/j.1749-6632.1977.tb21964.x] [PMID: 280138]
[20]
Loddo, B.; Garzia, A.; Ferrari, W. In vitro polio virus inhibition by two guanidino-pyrimidines. Experientia, 1964, 20(1), 12-13.
[http://dx.doi.org/10.1007/BF02146013] [PMID: 4285064]
[21]
Lunt, E.; Newton, C.G.; Smith, C.; Stevens, G.P.; Stevens, M.F.G.; Straw, C.G.; Walsh, R.J.A.; Warren, P.J.; Fizames, C.; Lavelle, F.; Langdon, F.P.; Vickers, L.M. Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones. J. Med. Chem., 1987, 30(2), 357-366.
[http://dx.doi.org/10.1021/jm00385a018] [PMID: 3806616]
[22]
Pigošová, J.; Gatial, A.; Milata, V.; Černuchová, P.; Prónayová, N.; Liptaj, T.; Matějka, P. The isomers and conformers of some push-pull enamines studied by vibrational and NMR spectroscopy and by ab initio calculations. J. Mol. Struct., 2005, 744-747, 315-324.
[http://dx.doi.org/10.1016/j.molstruc.2004.10.053]
[23]
Shaaban, M.R. Synthesis and antimicrobial evaluation of novel pyrazolo[1,5-a]pyrimidine, pyrimido[1,2-a]benzimidazole, triazolo[4,3-a]pyrimidine and pyrido[1,2-a]benzimidazole derivatives incorporated phenylsulfonyl moiety. Heterocycles, 2008, 75, 3005-3014.
[http://dx.doi.org/10.3987/COM-08-11471]
[24]
Tominagava, Y.; Sakai, S.; Kohra, S.; Tsuka, J.; Matsuda, Y.; Kobayashi, G. Pyrimidine and fused pyrimidine derivatives. III. Synthesis of s-triazolo[1,5-a]pyrimidine derivatives by using ketene dithioacetals. Chem. Pharm. Bull. (Tokyo), 1985, 33, 962-970.
[http://dx.doi.org/10.1248/cpb.33.962]
[25]
Le Goff, R.; Martel, A.; Sanselme, M.; Lawson, A.M.; Daïch, A.; Comesse, S. Simple access to highly functional bicyclic γ- and δ-lactams: Origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT. Chemistry, 2015, 21(7), 2966-2979.
[http://dx.doi.org/10.1002/chem.201405094] [PMID: 25524225]
[26]
Solomyannyi, R.N.; Slivchuk, S.R.; Vasilenko, A.N.; Rusanov, E.B.; Brovarets, V.S. Synthesis of 3-Amino-1-benzyl-4-benzenesulfonyl-2-carbonitrilo-1H-pyrrole and preparation of related pyrrolo[3,2-d]pyrimidines. Russ. J. Gen. Chem., 2012, 82, 317-322.
[http://dx.doi.org/10.1134/S1070363212020235]
[27]
Solomyannyi, R.N.; Slivchuk, S.R.; Brovarets, V.S. New approach of 4-phosphorylated 1,2,3-trisubstituted pyrroles. Russ. J. Gen. Chem., 2010, 80, 2259-2262.
[http://dx.doi.org/10.1134/S107036321011006X]
[28]
Andries, K.; Dewindt, B.; Snoeks, J.; Willebrords, R.; van Eemeren, K.; Stokbroekx, R.; Janssen, P.A. In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity. Antimicrob. Agents Chemother., 1992, 36(1), 100-107.
[http://dx.doi.org/10.1128/AAC.36.1.100] [PMID: 1317142]
[29]
Reed, L.J.; Muench, H. A simple method of estimating fifty percent endpoints. Am. J. Hyg., 1938, 27, 493-497.
[30]
Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. A, 2008, 64(Pt 1), 112-122.
[http://dx.doi.org/10.1107/S0108767307043930] [PMID: 18156677]

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