Thiazole derivatives as novel influenza neuraminidase inhibitors 513
14. Russell, R.J., Haire, L.F., Stevens, D.J., Collins, P.J., Lin, Y.P.,
Blackburn, G.M., Hay, A.J., Gamblin, S.J., Skehel, J.J. estructureof
H5N1 avian influenza neuraminidase suggests new opportunities
for drug design. Nature 2006, 443, 45–49.
15. Du, Q.S., Wang, S.Q., Chou, K.C. Analogue inhibitors by modifying
oseltamivir based on the crystal neuraminidase structure for
treating drug-resistant H5N1 virus. Biochem. Biophys. Res.
Commun. 2007, 362, 525–531.
16. Mitrasinovic,P.M.Onthestructure-baseddesignofnovelinhibitors
of H5N1 influenza A virus neuraminidase (NA). Biophys. Chem.
2009, 140, 35–38.
17. Mitrasinovic, P.M. Advances in the structure-based design of the
influenza A neuraminidase inhibitors. Curr. Drug Targets 2010, 11,
315–326.
18. Abu Hammad, A.M., Afifi, F.U., Taha, M.O. Combining docking,
scoring and molecular field analyses to probe influenza
neuraminidase–ligand interactions. J. Mol. Graph. Model. 2007,
26, 443–456.
19. Wang, G.T., Chen, Y., Wang, S., Gentles, R., Sowin, T., Kati, W.,
Muchmore, S., Giranda, V., Stewart, K., Sham, H., Kempf, D.,
Laver, W.G. Design, synthesis, and structural analysis of influenza
neuraminidase inhibitors containing pyrrolidine cores. J. Med.
Chem. 2001, 44, 1192–1201.
series is compound 4d (IC50 = 3.43 μM), about 20-fold
less potent than oseltamivir.
e binding of compound 4d in the active site of NA
is shown in Figure 3. Although the four regions of the
active site of NA were not occupied as well as oselta-
mivir to establish a consistent binding orientation and
the inhibitory activity is not so potent, our study still
indicated that thiazole derivatives can show potent
NA inhibitory activity and this finding could be used
to design novel influenza NA inhibitors that exhibit
increased activity based on thiazole ring. Both NA
enzyme inhibition and X-ray crystallography data sug-
gest that the strategy of designing an inhibitor of NA
that binds to the highly conserved active site of the NA
achieves the desired goal of activity against all influenza
NA subtypes, N1–N9, and influenza B viruses.(30,31)
Declaration of interest
20. Zhang, J., Xu, W. Recent advances in anti-influenza agents with
neuraminidase as target. Mini Rev. Med. Chem. 2006, 6, 429–448.
21. Bossart-Whitaker, P., Carson, M., Babu, Y.S., Smith, C.D., Laver,
We thank the financial support from the National Natural
Science Foundation of China (Grant No. 30672541).
W.G., Air, G.M. ree-dimensional structure of influenza
A
N9 neuraminidase and its complex with the inhibitor 2-deoxy
2,3-dehydro-N-acetyl neuraminic acid. J. Mol. Biol. 1993, 232,
1069–1083.
References
1. Moscona, A. Neuraminidase inhibitors for influenza. N. Engl. J.
Med. 2005, 353, 1363–1373.
22. Babu, Y.S., Chand, P., Bantia, S., Kotian, P., Dehghani, A., El-Kattan,
Y., Lin, T.H., Hutchison, T.L., Elliott, A.J., Parker, C.D., Ananth, S.L.,
Horn, L.L., Laver, G.W., Montgomery, J.A. BCX-1812 (RWJ-270201):
discovery of a novel, highly potent, orally active, and selective
influenza neuraminidase inhibitor through structure-based drug
design. J. Med. Chem. 2000, 43, 3482–3486.
23. Zhang, J., Wang, Q., Fang, H., Xu, W., Liu, A., Du, G. Design,
synthesis, inhibitory activity, and SAR studies of pyrrolidine
derivatives as neuraminidase inhibitors. Bioorg. Med. Chem. 2007,
15, 2749–2758.
24. Zhang, J., Wang, Q., Fang, H., Xu, W., Liu, A., Du, G. Design,
synthesis, inhibitory activity, and SAR studies of hydrophobic
p-aminosalicylic acid derivatives as neuraminidase inhibitors.
Bioorg. Med. Chem. 2008, 16, 3839–3847.
25. Nielsen, P.E., Haaina, G., Lohse, A., Buchardt, O. Peptide nucleic
acids (PNAs) containing thymine monomers derived from
chiral amino acids: hybridization and solubility properties of
d-lysine PNA. Angew Chem. Int. Ed. Engl. Comm. 1995, 35,
1939–1942.
2. Gong, J., Xu, W., Zhang, J. Structure and functions of influenza
virus neuraminidase. Curr. Med. Chem. 2007, 14, 113–122.
3. Chong, A.K., Pegg, M.S., Taylor, N.R., von Itzstein, M. Evidence
for a sialosyl cation transition-state complex in the reaction of
sialidase from influenza virus. Eur. J. Biochem. 1992, 207, 335–343.
4. Liu, Y., Zhang, J., Xu, W. Recent progress in rational drug design of
neuraminidase inhibitors. Curr. Med. Chem. 2007, 14, 2872–2891.
5. Oxford, J.S., Novelli, P., Sefton, A., Lambkin, R. New millennium
antivirals against pandemic and epidemic influenza: the
neuraminidase inhibitors. Antivir. Chem. Chemother. 2002, 13,
205–217.
6. Wilson, J.C., von Itzstein, M. Recent strategies in the search for
new anti-influenza therapies. Curr. Drug Targets 2003, 4, 389–408.
7. Dreitlein,W.B.,Maratos,J.,Brocavich,J.Zanamivirandoseltamivir:
two new options for the treatment and prevention of influenza.
Clin. er. 2001, 23, 327–355.
8. Collins, P.J., Haire, L.F., Lin, Y.P., Liu, J., Russell, R.J., Walker, P.A.,
Skehel, J.J., Martin, S.R., Hay, A.J., Gamblin, S.J. Crystal structures
of oseltamivir-resistant influenza virus neuraminidase mutants.
Nature 2008, 453, 1258–1261.
9. Moscona,A.Globaltransmissionofoseltamivir-resistantinfluenza.
N. Engl. J. Med. 2009, 360, 953–956.
26. Lindegårdh, N., Hien, T.T., Farrar, J., Singhasivanon, P., White, N.J.,
Day, N.P. A simple and rapid liquid chromatographic assay for
evaluation of potentially counterfeit Tamiflu. J. Pharm. Biomed.
Anal. 2006, 42, 430–433.
10. Mihajlovic, M.L., Mitrasinovic, P.M. Another look at the
molecular mechanism of the resistance of H5N1 influenza A virus
neuraminidase (NA) to oseltamivir (OTV). Biophys. Chem. 2008,
136, 152–158.
28. Wang, T., Wade, R.C. Comparative binding energy (COMBINE)
analysis of influenza neuraminidase–inhibitor complexes. J. Med.
Chem. 2001, 44, 961–971.
11. Mihajlovic, M.L., Mitrasinovic, P.M. Some novel insights into the
binding of oseltamivir and zanamivir to H5N1 and N9 influenza
virus neuraminidases: a homology modeling and flexible docking
study. J. Serb. Chem. Soc. 2009, 74, 1–13.
12. Mihajlovic, M.L., Mitrasinovic, P.M. Applications of the ArgusLab4/
AScore protocol in the structure-based binding affinity prediction
of various inhibitors of group-1 and group-2 influenza virus
neuraminidases (NAs). Mol Simulat 2009, 35, 311–324.
13. Wang, M.Z., Tai, C.Y., Mendel, D.B. Mechanism by which mutations
at his274 alter sensitivity of influenza a virus n1 neuraminidase
to oseltamivir carboxylate and zanamivir. Antimicrob. Agents
Chemother. 2002, 46, 3809–3816.
29. Ortiz, A.R., Pisabarro, M.T., Gago, F., Wade, R.C. Prediction of drug
binding affinities by comparative binding energy analysis. J. Med.
Chem. 1995, 38, 2681–2691.
30. Govorkova, E.A., Leneva, I.A., Goloubeva, O.G., Bush, K.,
Webster, R.G. Comparison of efficacies of RWJ-270201,
zanamivir, and oseltamivir against H5N1, H9N2, and other
avian influenza viruses. Antimicrob. Agents Chemother. 2001,
45, 2723–2732.
31. Roberts, N.A., Govorkova, E.A. e activity of neuraminidase
inhibitor oseltamivir against all subtypes of influenza viruses. In:
Mitrasinovic, P.M., Ed., Global View of the Fight against Influenza.
New York: Nova Science Publishers Inc., 2009, pp. 93–118.
© 2011 Informa UK, Ltd.