Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus

Open access


New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

1. J. S. Au and P. J. Pockros, Novel therapeutic approaches for hepatitis C, Clin. Pharmacol. Ther. 95 (2014) 78–88; DOI: 10.1038/clpt.2013.206.

2. M. P. Manns, J. G. McHutchison, S. C. Gordon, V. K. Rustgi, M. Shiffman, R. Reindollar, Z. D. Goodman, K. Koury, M. Ling and J. K. Albrecht, Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial, Lancet 358 (2001) 958–965.

3. M. W. Fried, M. L. Shiffman, K. R. Reddy, C. Smith, G. Marinos, F. L. Gonçales Jr., D. Häussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffman and J. Yu, Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, N. Engl. J. Med. 347 (2002) 975–982; DOI: 10.1056/NEJMoa020047.

4. Y. Bansal and O. Silakari, The therapeutic journey of benzimidazoles: A review, Bioorg. Med. Chem. 20 (2012) 6208–6236; DOI: 10.1016/j.bmc.2012.09.013.

5. V. Boido, G. Paglietti, M. Tonelli and G. Vitale, Non-nucleoside Benzimidazoles as Antiviral Drugs Against HCV and RSV Infections, in RNA-Viruses. Enzymatic and Receptoral Inhibitors (Ed. A. Carta), Research Signpost, Kerala 2009, pp. 41–93.

6. B. A. Katz, J. Clark, J. Finer-Moore, T. Jenkins, C. Johnson, M. Ross, C. Luong, W. Moore and R. Stroud, Design of potent selective zinc-mediated serine protease inhibitors, Nature 391 (1998) 608–612; DOI: 10.1038/35422.

7. D. Sperandio, A. R. Gangloff, J. Litvak, R. Goldsmith, J. M. Hataye, V. R. Wang, E. J. Shelton, K. Elrod, J. W. Janc, J. M. Clark, K. Rice, S. Weinheimer, K. Yeung, N. A. Meanwell, D. Hernandez, A. J. Staab, B. L. Venables and J. R. Spencer, Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease, Bioorg. Med. Chem. Lett. 12 (2002) 3129–3133; DOI: 10.1016/S0960-894X(02)00680-7.

8. H. I. El Diwani, H. T. Abdel-Mohsen, I. Salama, F. A.-F. Ragab, M. M. Ramla, S. A. Galal, M. M. Abdalla, A. Abdel-Wahab and M. A. El Demellawy, Synthesis, molecular modeling, and biological evaluation of novel benzimidazole derivatives as inhibitors of hepatitis C virus RNA replication, Chem. Pharm. Bull. 62 (2014) 856–866; DOI: 10.1248/cpb.c13-01009.

9. L. Garuti, M. Roberti and G. Gentilomi, Synthesis and antiviral assays of some 2-substituted benzimidazole-N-carbamates, Farmaco 55 (2000) 35–39; DOI: 10.1016/S0014-827X(99)00117-2.

10. S. Budow, M. Kozlowska, A. Gorska, Z. Kazimierczuk, H. Eickmeier, P. La Colla, G. Gosselin and F. Seela, Substituted benzimidazole: antivral activity and synthesis of nucleosides, ARKIVOC iii (2009) 225–250; DOI: 10.3998/ark.5550190.0010.319.

11. M. F. Tonelli, F. Novelli, B. Tasso, I. Vazzana, A. Sparatore, V. Boido, F. Sparatore, P. La Colla, G. Sanna, G. Giliberti, B. Busonera, P. Farci, C. Ibba and R. Loddo, Antiviral activity of benzimidazole derivatives. III. Novel anti-CVB-5, anti-RSV and anti-Sb-1 agents, Bioorg. Med. Chem. 22 (2014) 4893–4909; DOI: 10.1016/j.bmc.2014.06.043.

12. Y. Saito, V. Escuret, D. Durantel, F. Zoulim, R. F. Schinazic and L. A. Agrofoglio, Synthesis of 1,2,3-triazolo-carbanucleoside analogues of ribavirin targeting an HCV in replicon, Bioorg. Med. Chem. 11 (2003) 3633–3639; DOI: 10.1016/S0968-0896(03)00349-3.

13. F. D. Da Silva, M. C. B. V. de Souza, I. I. P. Frugulhetti, H. C. Castro, S. L. D Souza, T. M. L. de Souza, D. Q. Rodrigues, A. M. T. Souza, P. A. Abreu, F. Passamani, C. R. Rodrigues and V. F. Ferreira, Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates, Eur. J. Med. Chem. 44 (2009) 373–383; DOI: 10.1016/j.ejmech.2008.02.047.

14. D. K. Mohapatra, P. K. Maity, M. Shabab and M. I. Khan, Click chemistry based rapid one-pot synthesis and evaluation for protease inhibition of new tetracyclic triazole fused benzodiazepine derivatives, Bioorg. Med. Chem. 19 (2009) 5241–5245; DOI: 10.1016/j.bmcl.2009.06.107.

15. T. O. Olomola, R. Klein, K. A. Lobb, Y. Sayed and P. T. Kaye, Synthesis and evaluation of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors, Bioorg. Med. Chem. 21 (2013) 1964–1971; DOI: 10.1016/j.bmc.2013.01.025.

16. M. M. Heravi, A. Keivanloo, M. Rahimizadeh, M. Bakavoli and M. Ghassemzadeh, Pd–Cu catalyzed heterocyclization during Sonogashira coupling: synthesis of 3-benzylthiazolo[3,2-a]benzimidazole, Tetrahedron Lett. 45 (2004) 5747–5749; DOI: 10.1016/j.tetlet.2004.05.094.

17. K.-C. Tiew, D. Dou, T. Teramoto, H. Lai, K. R. Alliston, G. H. Lushington, R. Padmanabhan and W. C. Groutas, Inhibition of Dengue virus and West Nile virus proteases by click chemistry-derived benz[d] isothiazol-3(2H)-one derivatives, Bioorg. Med. Chem. 20 (2012) 1213–1221; DOI: 10.1016/j.bmc.2011.12.047.

18. C. Baba, K. Yanagida, T. Kanzaki and M. Baba, Colorimetric lactate dehydrogenase (LDH) assay for evaluation of antiviral activity against bovine viral diarrhoea virus (BVDV) in vitro, Antivir. Chem. Chemother. 16 (2005) 33–39; DOI: 10.1016/j.biomaterials.2014.01.054.

19. K. Sako, H. Aoyama, S. Sato, Y. Hashimoto and M. Baba, γ-carboline derivatives with anti-bovine viral diarrhea virus (BVDV) activity, Bioorg. Med. Chem. 16 (2008) 3780–3790; DOI: 10.1016/j.bmc.2008.01.052.

20. H. C. Kolb, M. G. Finn and K. B. Sharpless, Click chemistry: Diverse chemical function from a few good reactions, Angew. Chem. Int. Ed. 40 (2001) 2004–2021; DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5.

21. J. E. Moses and A. D. Moorhouse, The growing applications of click chemistry, Chem. Soc. Rev. 36 (2007) 1249–1262; DOI: 10.1039/b613014n.

22. S. G. Agalave, S. R. Maujan and V. S. Pore, Click chemistry: 1,2,3-Triazoles as pharmacophores, Chem. Asian J. 6 (2011) 2696–2718; DOI: 10.1002/asia.201100432.

23. J.-F. Lutz and Z. Zarafshani, Efficient construction of therapeutics, bioconjugates, biomaterials and bioactive surfaces using azide-alkyne “click” chemistry, Adv. Drug Deliv. Rev. 60 (2008) 958–970; DOI: 10.1016/j.addr.2008.02.004.

24. K. Lin, R. B. Perni, A. D. Kwong and c. Lin, VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells, Antimicrob. Agents. Cli. 50 (2006) 1813–1822; DOI: 10.1128/AAC.50.5.1813-1822.2006.

25. J. G. Topliss, Utilization of operational schemes for analog synthesis in drug design, J. Med. Chem. 15 (1972) 1006–1011; DOI: 10.1021/jm00280a002.

26. J. G. Topliss, A manual method for applying the Hansch approach to drug design, J. Med. Chem. 20 (1977) 463–469; DOI: 10.1021/jm00214a001.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information

IMPACT FACTOR 2017: 1.071
5-year IMPACT FACTOR: 1.623

CiteScore 2017: 1.46

SCImago Journal Rank (SJR) 2017: 0.362
Source Normalized Impact per Paper (SNIP) 2017: 0.642

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 214 214 29
PDF Downloads 93 93 14