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Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors.
Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2016 Nov 10; Vol. 123, pp. 397-406. Date of Electronic Publication: 2016 Jul 28. - Publication Year :
- 2016
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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.<br /> (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antiviral Agents chemical synthesis
Antiviral Agents chemistry
Antiviral Agents metabolism
Antiviral Agents pharmacology
Binding, Competitive
Catalytic Domain
Chemistry Techniques, Synthetic
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Enzyme Inhibitors metabolism
Enzyme Inhibitors pharmacology
Influenza A Virus, H1N1 Subtype drug effects
Influenza A Virus, H1N1 Subtype enzymology
Influenza A Virus, H3N2 Subtype drug effects
Influenza A Virus, H3N2 Subtype enzymology
Molecular Docking Simulation
Molecular Dynamics Simulation
Neuraminidase metabolism
Zanamivir chemistry
Zanamivir metabolism
Drug Design
Neuraminidase antagonists & inhibitors
Triazoles chemistry
Zanamivir chemical synthesis
Zanamivir pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 123
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27487569
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.07.064