Identification of Thieno[3,2‐b]Pyrrole Derivatives as Novel Small Molecule Inhibitors of Neurotropic Alphaviruses
Open Access
- 1 April 2009
- journal article
- Published by Oxford University Press (OUP) in The Journal of Infectious Diseases
- Vol. 199 (7), 950-957
- https://doi.org/10.1086/597275
Abstract
Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses cause serious and potentially fatal central nervous system infections in humans and are high-priority potential bioterrorism agents. There are currently no widely available vaccines or licensed therapies for these virulent pathogens. To identify potential novel antiviral drugs, we developed a cell-based assay with a western equine encephalitis virus replicon that expresses a luciferase reporter gene and screened a small molecule diversity library of 51,028 compounds. We identified and validated a thieno[3,2-b]pyrrole compound with a half maximal inhibitory concentration of 20, and potent activity against live virus in cultured neuronal cells. Furthermore, a structure-activity relationship analysis with 20 related compounds identified several with enhanced activity profiles, including 6 with submicromolar half maximal inhibitory concentrations. In conclusion, we have identified a novel class of promising inhibitors with potent activity against virulent neurotropic alphavirusesKeywords
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