Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases

• Verfasst von: Nitsche, Christoph [VerfasserIn]
• Verfasst von: Steuer, Christian [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases
• Verf.angabe: Christoph Nitsche, Christian Steuer, Christian D. Klein
• E-Jahr: 2011
• Jahr: 25 October 2011
• Umfang: 10 S.
• Fussnoten: Gesehen am 28.09.2022
• Titel Quelle: Enthalten in: Bioorganic & medicinal chemistry
• Ort Quelle: Amsterdam [u.a.] : Elsevier, 1993
• Jahr Quelle: 2011
• Band/Heft Quelle: 19(2011), 24, Seite 7318-7337
• ISSN Quelle: 1464-3391
• DOI: doi:10.1016/j.bmc.2011.10.061
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Aldol condensation
• Sach-SW: Dengue virus
• Sach-SW: Flavivirin
• Sach-SW: Nitrile
• Sach-SW: NS2B-NS3 protease
• Sach-SW: West Nile virus
• K10plus-PPN: 1817717561

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 Ki-value of 35.7μM at the Dengue and 44.6μM 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.