The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole-containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM–31 nM) range. Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region.
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
Das, A., Adak, A. K., Ponnapalli, K., Lin, C. H., Hsu, K. C., Yang, J. M., Hsu, T. A., & Lin, C. C. (2016). Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors. European Journal of Medicinal Chemistry, 123, 397-406. https://doi.org/10.1016/j.ejmech.2016.07.064