A chemoselective coupling reaction between an arylsulfonyl fluoride and an aryl silyl ether is known as the sulfur(VI) fluoride exchange (SuFEx) reaction. This “sulfate click reaction” is extremely efficient and provides the desired products in essentially quantitative yields.
Our laboratory recently reported the discovery of biaryl sulfate core-based HCV NS5A inhibitors, which exhibit two-digit picomolar EC50 values against HCV genotype 1b and 2a. Herein, we demonstrate the utilization of the SuFEx chemistry to modify the structures of sulfate-core part of the NS5A inhibitors for further optimization of antiviral activities against HCV. The products obtained through the SuFEx click reactions were obtained in high yields. Among the compounds prepared through the SuFEx chemistry, products with potent NS5A inhibitors had two-digit picomolar EC50 values against GT-1b and single digit nanomolar activities against GT-2a strain of HCV. In addition, the biotinylated probe targeting NS5A protein and nonsymmetrical inhibitors containing an imidazole and amide linkers at the opposite sides of the core sulfate structures were also synthesized through the use of the same synthetic methodology.
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