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.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nitsche
authors.forename: Christian
authors.initials: C
authors.lastname: Steuer
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014901:West Nile Fever / Q000188:drug therapy; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000178:Acrylamides; D000998:Antiviral Agents; D011480:Protease Inhibitors; D010447:Peptide Hydrolases