Anthracene-based inhibitors of dengue virus NS2B- XXXX protease.

@entity778 @entity984 @entity7643 @entity779 @entity204
@entity778 ( @entity778 ) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (CDC, 2010), Australia (Hanna et al., 2009), Taiwan (Kuan et al., 2010) and France (La Ruche et al., 2010). @entity778 infection can cause significant disease, including @entity779 , @entity7643 , @entity7643 , and @entity204 . There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B- @entity984 protease complex provides a strategic target for antiviral drug development since @entity984 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the @entity778 protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (Tomlinson et al., 2009a). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four "second series" analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between    2- and 60-fold, resulting in selective low micromolar dengue protease inhibitors.
