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

Gálvez, José A. (Universidad de Zaragoza) ; Clavería-Gimeno, Rafael ; Galano-Frutos, Juan J. (Universidad de Zaragoza) ; Sancho, Javier (Universidad de Zaragoza) ; Velázquez-Campoy, Adrian (Universidad de Zaragoza) ; Abian, Olga (Universidad de Zaragoza) ; Díaz-de-Villegas, María D.

Resumen: GSK3082 e a hepatitis C virus RNA polymerase inhibitor e 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.

Idioma: Inglés

DOI: 10.1016/j.ejmech.2019.03.019

Año: 2019

Publicado en: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 171 (2019), 401-419
ISSN: 0223-5234

Factor impacto JCR: 5.572 (2019)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 5 / 61 = 0.082 (2019) - Q1 - T1

Factor impacto SCIMAGO: 1.144 - Drug Discovery (Q1) - Pharmacology (Q1) - Organic Chemistry (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CPII13-0017
Financiación: info:eu-repo/grantAgreement/ES/MEC/FPU13-3870
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)