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Eur J Med Chem. 2016 Jul 28;123:397-406. doi: 10.1016/j.ejmech.2016.07.064. [Epub ahead of print]
Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors.
Das A1, Adak AK1, Ponnapalli K1, Lin CH1, Hsu KC2, Yang JM3, Hsu TA4, Lin CC5.
Author information
Abstract
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.
Copyright ? 2016 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Influenza; Neuraminidase inhibitors; Triazole; Zanamivir
PMID: 27487569 DOI: 10.1016/j.ejmech.2016.07.064
[PubMed - as supplied by publisher]
Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors.
Das A1, Adak AK1, Ponnapalli K1, Lin CH1, Hsu KC2, Yang JM3, Hsu TA4, Lin CC5.
Author information
Abstract
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.
Copyright ? 2016 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Influenza; Neuraminidase inhibitors; Triazole; Zanamivir
PMID: 27487569 DOI: 10.1016/j.ejmech.2016.07.064
[PubMed - as supplied by publisher]