Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases.
Authors: Nitsche C,Steuer C,Klein CD,
Address: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
Journal: Bioorg Med Chem.
Publication: 2011 Dec 15;19(24):7318-37. doi: 10.1016/j.bmc.2011.10.061. Epub 2011 Oct 25.
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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