Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases

Christoph Nitsche; Christian Steuer; Christian D. Klein

doi:10.1016/j.bmc.2011.10.061

Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases

Christoph Nitsche, Christian Steuer, Christian D. Klein^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

98 Citations (Scopus)

Abstract

The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K _i-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.

Original language	English
Pages (from-to)	7318-7337
Number of pages	20
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2011.10.061
Publication status	Published - 15 Dec 2011
Externally published	Yes

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title = "Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases",

abstract = "The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K i-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.",

keywords = "Aldol condensation, Dengue virus, Flavivirin, Nitrile, NS2B-NS3 protease, West Nile virus",

author = "Christoph Nitsche and Christian Steuer and Klein, {Christian D.}",

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AU - Nitsche, Christoph

AU - Steuer, Christian

AU - Klein, Christian D.

PY - 2011/12/15

Y1 - 2011/12/15

N2 - The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K i-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.

AB - The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K i-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.

KW - Aldol condensation

KW - Dengue virus

KW - Flavivirin

KW - Nitrile

KW - NS2B-NS3 protease

KW - West Nile virus

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JF - Bioorganic and Medicinal Chemistry

IS - 24

ER -

Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases

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