Synthesis, Anti-Varicella-Zoster Virus and Anti-Cytomegalovirus Activity of 4,5-Disubstituted 1,2,3-(1H)-Triazoles

Author(s): Wei-yuan Yuan, Xue Chen, Ning-ning Liu, Yi-ning Wen, Bei Yang, Graciela Andrei, Robert Snoeck, Yu-hong Xiang, Yong-wei Wu, Zhen Jiang, Dominique Schols, Zhuo-yong Zhang, Qin-pei Wu*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug resistance. The development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action is greatly required.

Objective: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs.

Methods: A series of novel 5-(benzylamino)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were evaluated in vitro.

Results: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK− VZV strains.

Conclusion: 5-(Benzylamino)-1H-1, 2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs.

Keywords: Anti-cytomegalovirus activity, inhibitor, triazole, antiviral, cytomegalovirus, varicella-zoster virus.

[1]
Gable, J.E.; Acker, T.M.; Craik, C.S. Current and potential treatments for ubiquitous but neglected herpesvirus infections. Chem. Rev., 2014, 114, 11382-11412.
[2]
Tenney, D.J.; Yamanaka, G.; Voss, S.M.; Cianci, C.W.; Tuomari, A.V.; Sheaffer, A.K.; Alam, M.; Colonno, R.J. lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase. Antimicrob. Agent Chemother., 1997, 41, 2680-2685.
[3]
Field, H.J.; Vere Hodge, R.A. Recent developments in anti-herpesvirus drugs. Br. Med. Bull., 2013, 106, 213-249.
[4]
Andrei, G.; Snoeck, R. Advances in the treatment of varicella-zoster virus infections. Adv. Pharmacol., 2013, 67, 107-168.
[5]
Kotton, C.N.; Kumar, D.; Caliendo, A.M.; Asberg, A.; Chou, S.; Snydman, D.R.; Allen, U.; Humar, A. Transplantat Soc Int, C.M.V.C. International consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation, 2010, 89, 779-795.
[6]
Kotton, C.N.; Kumar, D.; Caliendo, A.M.; Asberg, A.; Chou, S.; Danziger-Isakov, L.; Humar, A. Transplantat Soc Int, C.M.V. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation, 2013, 96, 333-360.
[7]
Andrei, G.; De Clercq, E.; Snoeck, R. Drug targets in cytomegalovirus infection. Infect. Disord. Drug Targets, 2009, 9, 201-222.
[8]
Lurain, N.S.; Chou, S. Antiviral drug resistance of human cytomegalovirus. Clin. Microbiol. Rev., 2010, 23, 689-712.
[9]
Melendez, D.P.; Razonable, R.R. Letermovir and inhibitors of the terminase complex: A promising new class of investigational antiviral drugs against human cytomegalovirus. Infect. Drug Resist., 2015, 8, 269-277.
[10]
Marschall, M.; Stamminger, T.; Urban, A.; Wildum, S.; Ruebsamen-Schaeff, H.; Zimmermann, H.; Lischka, P. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (Letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob. Agents Chemother., 2012, 56, 1135-1137.
[11]
Kaul, D.R.; Stoelben, S.; Cober, E.; Ojo, T.; Sandusky, E.; Lischka, P.; Zimmermann, H.; Rubsamen-Schaeff, H. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am. J. Transplant., 2011, 11, 1079-1084.
[12]
Crute, J.J.; Grygon, C.A.; Hargrave, K.D.; Simoneau, B.; Faucher, A.M.; Bolger, G.; Kibler, P.; Liuzzi, M.; Cordingley, M.G. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat. Med., 2002, 8, 386-391.
[13]
Kleymann, G.; Fischer, R.; Betz, U.A.K.; Hendrix, M.; Bender, W.; Schneider, U.; Handke, G.; Eckenberg, P.; Hewlett, G.; Pevzner, V.; Baumeister, J.; Weber, O.; Henninger, K.; Keldenich, J.; Jensen, A.; Kolb, J.; Bach, U.; Popp, A.; Maben, J.; Frappa, I.; Haebich, D.; Lockhoff, O.; Rubsamen-Waigmann, H. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med., 2002, 8, 392-398.
[14]
Wald, A.; Corey, L.; Timmler, B.; Magaret, A.; Warren, T.; Tyring, S.; Johnston, C.; Kriesel, J.; Fife, K.; Galitz, L.; Stoelben, S.; Huang, M-L.; Selke, S.; Stobernack, H-P.; Ruebsamen-Schaeff, H.; Birkmann, A. Helicase-primase inhibitor pritelivir for HSV-2 infection. Eng. J. Med., 2014, 370, 201-210.
[15]
Reefschlaeger, J.; Bender, W.; Hallenberger, S.; Weber, O.; Eckenberg, P.; Goldmann, S.; Haerter, M.; Buerger, I.; Trappe, J.; Herrington, J.A.; Haebich, D.; Ruebsamen-Waigmann, H. Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): In vitro and in vivo antiviral activity and mechanism of action. J. Antimicrob. Chemother., 2001, 48, 757-767.
[16]
Underwood, M.R.; Ferris, R.G.; Selleseth, D.W.; Davis, M.G.; Drach, J.C.; Townsend, L.B.; Biron, K.K.; Boyd, F.L. Mechanism of action of the ribopyranoside benzimidazole GW275175X against human cytomegalovirus. Antimicrob. Agents Chemother., 2004, 48, 1647-1651.
[17]
Ogilvie, W.; Bailey, M.; Poupart, M.A.; Abraham, A.; Bhavsar, A.; Bonneau, P.; Bordeleau, J.; Bousquet, Y.; Chabot, C.; Duceppe, J.S.; Fazal, G.; Goulet, S.; Grandmaitre, C.; Guse, I.; Halmos, T.; Lavallee, P.; Leach, M.; Malenfant, E.; Omeara, J.; Plante, R.; Plouffe, C.; Poirier, M.; Soucy, F.; Yoakim, C.; Deziel, R. Peptidomimetic inhibitors of the human cytomegalovirus protease. J. Med. Chem., 1997, 40, 4113-4135.
[18]
Di Grandi, M.J.; Curran, K.J.; Baum, E.Z.; Bebernitz, G.; Ellestad, G.A.; Ding, W.D.; Lang, S.A.; Rossi, M.; Bloom, J.D. Pyrimido[1,2-b]-1,2,4,5-tetrazin-6-ones as HCMV protease inhibitors: A new class of heterocycles with flavin-like redox properties. Bioorg. Med. Chem. Lett., 2003, 13, 3483-3486.
[19]
Jordao, A.K.; Ferreira, V.F.; Souza, T.M.L.; de Souza, F.G.G.; Machado, V.; Abrantes, J.L.; de Souza, M.C.B.V.; Cunha, A.C. Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives. Bioorg. Med. Chem., 2011, 19, 1860-1865.
[20]
Jordao, A.K.; Afonso, P.P.; Ferreira, V.F.; de Souza, M.C.B.V.; Almeida, M.C.B.; Beltrame, C.O.; Paiva, D.P.; Wardell, S.M.S.V.; Wardell, J.L.; Tiekink, E.R.T.; Damaso, C.R.; Cunha, A.C. Antiviral evaluation of N-amino-1,2,3-triazoles against Cantagalo virus replication in cell culture. Eur. J. Med. Chem., 2009, 44, 3777-3783.
[21]
Wen, Y-N.; Zhang, Z-F.; Liu, N-N.; Andrei, G.; Snoeck, R.; Xiang, Y-H.; Schols, D.; Chen, X.; Zhang, Z-Y.; Zhang, Q-S.; Wu, Q-P. Synthesis and antiviral activity of 5-(benzylthio)-4- carbamyl-1,2,3-triazoles against human cytomegalovirus (CMV) and varicella-zoster virus (VZV). Med. Chem., 2017, 13, 453-464.
[22]
Wen, Y-N.; Zhang, Z-F.; Liu, N-N.; Xiang, Y-H.; Zhang, Z-Y.; Andrei, G.; Snoeck, R.; Schols, D.; Zhang, Q-S.; Wu, Q-P. Synthesis and bioactivity of novel trisubstituted triazole nucleosides. Nucleosid. Nucleotid. Nucl. Acid, 2016, 35, 147-160.
[23]
Wen, Y.; Yuan, W.; Wu, Y.; Chen, X.; Xiang, Y.; Zhang, Zh.; Liu, N.; Andrei, G.; Snoeck, R.; Schols, D.; Wu, Q. Synthesis and antiviral activity of 1,2,3-triazoles. Chin. J. Med. Chem., 2016, 26, 18-24.
[24]
Wen, Y.; Liu, N.; Zhang, Z.; Chen, X.; Yuan, W.; Zhang, Q.; Wu, Q. Synthesis and antitumor activity of multisubstituted triazole derivatives. Chin. J. Med. Chem., 2015, 25, 348-354.
[25]
Gomes, A.T.P.C.; Martins, P.R.C.; Rocha, D.R.; Neves, M.G.P.M.S.; Ferreira, V.F.; Silva, A.M.S.; Cavaleiro, J.A.S.; da Silva, F.D.C. Consecutive tandem cycloaddition between nitriles and azides; synthesis of 5-amino-1H-[1, 2, 3]-triazoles. Synlett, 2013, 24, 41-44.
[26]
Dieudonne-Vatran, A.; Azoulay, M.; Florent, J-C. A new access to 3-substituted-1(2H) -isoquinolone by tandem palladium-catalyzed intramolecular aminocarbonylation annulation. Org. Biomol. Chem., 2012, 10, 2683-2691.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [801 - 812]
Pages: 12
DOI: 10.2174/1573406414666181109095239
Price: $65

Article Metrics

PDF: 22
HTML: 3