Sofosbuvir Thio-analogues: Synthesis and Antiviral Evaluation of the First Novel Pyridine- and Pyrimidine-Based Thioglycoside Phosphoramidates

[Image: see text] The synthesis and antiviral screening of the first reported series of pyridine- and pyrimidine-based thioglycoside phosphoramidates are herein reported. They were prepared through two synthetic steps: The first step is via coupling of mercapto-derivatized heterocyclic bases with the appropriate α-bromo per-acetylated sugars. The second one is the hydrolysis of the acetate esters under basic conditions that were consequently conjugated with the phosphoramidating reagent to afford the desired thioglycoside protides. Eight compounds were evaluated for their antiviral activities against different viral cell lines, namely, adenovirus 7, HAV (hepatitis A) HM175, Coxsackievirus B4, and HSV-1 (herpes simplex virus type 1), in addition to the antiviral bioassay against ED-43/SG-Feo (VYG) replicon of HCV (hepatitis C virus) genotype 4a. Both compounds 5b and 11 showed notable antiviral activity against Coxsackie virus B4, reflected from the CC(50) values of 17 and 20 μg/100 μL and IC(50) values of 4.5 and 6.0 μg/100 μL, respectively. Same two compounds elicited remarkable activities toward herpes simplex virus type 1, represented by CC(50) values of 17 and 16 μg/100 μL and IC(50) values of 6.3 and 6.6 μg/100 μL, respectively. Combination of 11 with acyclovir elicited a notable synergistic activity in comparison with acyclovir alone, as inferred from herpes simplex polymerase enzyme inhibitory assay values of 2.64 and 4.78 μg/100 mL, respectively. Only compound 11 elicited a remarkable activity against HCV. Potential promising activities of compound 11 have been shown with respect to CC(50), IC(50), and enzyme assay inhibitory activities.