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Stereoselective synthesis and biological evaluation as inhibitors of hepatitis C virus RNA polymerase of GSK3082 analogues with structural diversity at the 5-position

AuthorsGálvez, José A. ; Claveria-Gimeno, Rafael; Galano-Frutos, Juan J.; Sancho, Javier ; Velazquez-Campoy, Adrian; Abian, Olga ; Díaz de Villegas, María D.
KeywordsHepatitis C virus (HCV)
HCV replication inhibitors
Structure-activity relationshiphs
Issue Date2019
CitationEuropean Journal of Medicinal Chemistry 171: 401-419 (2019)
AbstractGSK3082 – a hepatitis C virus RNA polymerase inhibitor – and a series of analogues with structural diversity at the 5-position were prepared from a 2,2,4,5-tetrasubstituted pyrrolidine obtained with a well-defined stereochemistry from the 1,3-dipolar cycloaddition of the chiral imino ester derived from leucine tert-butyl ester and (R)-2,3-O-isopropylideneglyceraldehyde with methyl acrylate. The chiral 2,2-dimethyl-1,3-dioxolane moiety provided by the glyceraldehyde served as a synthetic equivalent for different substituents and functional groups and these transformations usually required mild reaction conditions and simple work-up procedures. The inhibitory activity of the resulting GSK3082 analogues was studied in vitro in a cell-based assay of the subgenomic HCV RNA replication system. Some of the analogues showed good inhibitory activity with IC50 values in the nanomolar concentration range.
Publisher version (URL)https://doi.org/10.1016/j.ejmech.2019.03.019
Appears in Collections:(IQFR) Artículos
(ISQCH) Artículos
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