Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

Nashwa Hafez Zaher 1 , Mohammed Ismail Mostafa 2 ,  und Abdullah Yousef Altaher 3
  • 1 Radiation Drug Research Department National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
  • 2 Department of Pharmacology, College of Veterinary Medicine, Cairo University, Gizah, Egypt
  • 3 Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, King Faisal University Alhasa


Middle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.

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  • 1. R. L. Graham, E. F. Donaldson and R. S. Baric, A decade after SARS: strategies for controlling emerging coronaviruses, Nat. Rev. Microbiol. 11 (2013) 836–848;

  • 2. V. S. Raj, H. Mou, S. L. Smits, D. H. Dekkers, M. A. Müller, R. Dijkman, D. Muth, J. A. Demmers, A. Zaki, R. A. Fouchier, V. Thiel, C. Drosten, P. J. Rottier, A. D. Osterhaus, B. J. Bosch and B. L. Haagmans, Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC, Nature 495 (2013) 251–254;

  • 3. A. M. Zaki, S. V. Boheemen, T. M. Bestebroer, A. D. Osterhaus and R. A. Fouchier, Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia, N. Engl. J. Med. 367 (2012) 1814–1820;

  • 4. P. A. Rota, M. S. Oberste, S. S. Monroe, W. A. Nix, R. Campagnoli, J. P. Icenogle, S. Peñaranda, B. Bankamp, K. Maher, M. H. Chen, S. Tong, A. Tamin, L. Lowe, M. Frace, J. L. DeRisi, Q. Chen, D. Wang, D. D. Erdman, T. C. Peret, C. Burns, T. G. Ksiazek, P. E. Rollin, A. Sanchez, S. Liffick, B. Holloway, J. Limor, K. McCaustland, M. Olsen-Rasmussen, R. Fouchier, S. Günther, A. D. Osterhaus, C. Drosten, M. A. Pallansch, L. J. Andersonthe and W. J. Bellini, Characterization of a novel coronavirus associated with severe acute respiratory syndrome, Science 300 (2003) 1394–1399;

  • 5. J. S. M. Peiris, K. Y. Yuen, A. D. M. E. Osterhaus and K. Stöhr, The severe acute respiratory syndrome, N. Engl. J. Med. 349 (2003) 2431–2441;

  • 6. P. M. Penttinen, K. Kaasik-Aaslav, A. Friaux, A. Donachie, B. Sudre, A. J. Amato-Gauci, Z. A. Memish and D. Coulombier, Taking stock of the first 133 MER S coronavirus cases globally – Is the epidemic changing? Euro Surveill. 18 (2013) 1–5;

  • 7. World Health Organization, MERS-CoV Global Summary and Assessment of Risk, (WHO/MERS/RA/August18), WHO, Geneva 2018

  • 8. A. O. Adedeji and S. G. Sarafianos, Antiviral drugs specific for coronaviruses in preclinical development, Curr. Opin. Virol. 8 (2014) 45–53;

  • 9. L. J. Stockman, R. Bellamy and P. Garner, SARS: Systematic review of treatment effects, PLoS Med. 3 (2006) 1525–1531;

  • 10. R. Y. Kao, W. H. Tsui, T. S. Lee, J. A. Tanner, R. M. Watt, J. D. Huang, L. Hu, G. Chen, Z. Chen, L. Zhang, T. He, K. H. Chan, H. Tse, A. P. To, L. W. Ng, B. C. Wong, H. W. Tsoi, D. Yang, D. D. Ho and K. Y. Yuen, Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics, Chem. Biol. 11 (2004) 1293–1299;

  • 11. D. N. Frick and A. M. I. Lam, Understanding helicases as a means of virus control, Curr. Pharm. Des. 12 (2006) 1315–1338;

  • 12. W. Hao, J. A. Wojdyla, R. Zhao, R. Han, R. Das, I. Zlatev, M. Manoharan, M. Wang and S. Cui, Crystal structure of Middle East respiratory syndrome coronavirus helicase, PLoS Pathog. 13 (2017) e1006474 (19 pages);

  • 13. A. O. Adedeji and H. Lazarus, Biochemical characterization of Middle East respiratory syndrome coronavirus helicase, mSphere 1 (2016) e00235-16 (14 pages);

  • 14. D. Dheer, V. Singh and R. Shankar, Medicinal attributes of 1,2,3-triazoles: Current developments, Bioorg. Chem. 71 (2017) 30–54;

  • 15. Y. W. He, C. Z. Dong, J. Y. Zhao, L. Ma, Y. H. Li and H. A. Aisa, 1,2,3-Triazole-containing derivatives of rupestonic acid: Click-chemical synthesis and antiviral activities against influenza viruses, Eur. J. Med. Chem. 76 (2014) 245–255;

  • 16. J. Zhao and H. A. Aisa, Synthesis and anti-influenza activity of aminoalkyl rupestonates, Bioorg. Med. Chem. Lett. 22 (2012) 2321–2325;

  • 17. A. O. Adedeji, K. Singh, N. E. Calcaterra, M. L. DeDiego, L. Enjuanes, S. Weiss and S. G. Sarafianos, Antimicrob. Agents Chemother. 56 (2012) 4718–4728;

  • 18. A. O. Adedeji, K. Singh, A. Kassim, C. M. Coleman, R. Elliott, S. R. Weiss, M. B. Frieman and S. G. Sarafianos, Evaluation of SSYA10-001 as a replication inhibitor of SARS, MHV and MERS corona-viruses, Antimicrob. Agents Chemother. 58 (2014) 4894–898;

  • 19. A. A. Fadda, S. Bondock, R. Rabie and H. A. Etman, Cyanoacetamide derivatives as synthons in heterocyclic synthesis, Turk. J. Chem. 32 (2008) 259–286;

  • 20. J. A. Tanner, R. M. Watt, Y. B. Chai, L. Y. Lu, M. C. Lin, J. S. Peiris, L. L. Poon, H. F. Kung and J. D. Huang, The severe acute respiratory syndrome (SARS) coronavirus NTPase/helicase belongs to a distinct class of 5’ to 3’ viral helicases, J. Biol. Chem. 278 (2003) 39578–39582;

  • 21. D. J. T. Porter, Inhibition of the hepatitis C virus helicase-associated ATPase activity by the combination of ADP, NaF, MgCl2, and poly(rU) – Two ADP binding sites on the enzyme-nucleic acid complex, J. Biol. Chem. 273 (1998) 7390–7396;

  • 22. A. M. Boguszewska-Chachulska, M. Krawczyk, A. Stankiewicz, A. Gozdek, A-L. Haenni and L. Strokovskaya, Direct fluorometric measurement of hepatitis C virus helicase activity, FEBS Lett. 567 (2004) 253–258;

  • 23. M. K. Abdel-Hamid, A. A. Abdel-Hafez, N. A. El-Koussi, N. M. Mahfouz, A. Innocenti and C. T. Supuran, Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity, Bioorg. Med. Chem. 15 (2007) 6975–6984;

  • 24. J. A. Tanner, B. J. Zheng, J. Zhou, R. M. Watt, J. Q. Jiang, K. L. Wong, Y. P. Lin, L.Y. Lu, M. L. He, H. F. Kung, A. J. Kesel and J. D. Huang, The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus, Chem. Biol. 12 (2005) 303–311;

  • 25. Z-Y. Wu, N. Liu, B. Qin, L. Huang, F. Yu, K. Qian, S. L. Morris-Natschke, S. Jiang, C. H. Chen, K-H. Lee and L. Xie, Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS, ChemMedChem 9 (2014) 1546–1555;


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