Title of article :
Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase
Author/Authors :
Sun-Hee Kim، نويسنده , , Martin T. Tran، نويسنده , , Frank Ruebsam، نويسنده , , Alan X. Xiang، نويسنده , , Benjamin Ayida، نويسنده , , Helen McGuire، نويسنده , , David Ellis، نويسنده , , Julie Blazel، نويسنده , , Chinh V. Tran، نويسنده , , Douglas E. Murphy، نويسنده , , Stephen E. Webber، نويسنده , , Yuefen Zhou، نويسنده , , Amit M. Shah، نويسنده , , Mei Tsan، نويسنده , , Richard E. Showalter، نويسنده , , Rupal Patel، نويسنده , , Alberto Gobbi، نويسنده , , Laurie A. LeBrun، نويسنده , , Darian M. Bartkowski، نويسنده , , Thomas G. Nolan، نويسنده , , et al.، نويسنده ,
Abstract :
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC50 values. The most potent compound exhibited IC50 less than 10 nM against the genotype 1b HCV polymerase and EC50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Keywords :
1-dioxoisothiazole , 1-dioxide , Hepatitis C virus (HCV) , DMPK properties , NS5B inhibitors , 1 , X-ray co-crystal structures
