A series of novel substituted isatin ribonucleosides 3b-3f were synthesized in good yields by a TMSOTf catalysed coupling reaction between the silylated nitrogenated base (1b-1f) and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (2). Isatin nucleoside 3a previously reported was also prepared using this method giving high yield. From the compounds tested, ribonucleoside 3f proved to be the most active one when assayed for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibition of virus yield. All the isatin derivatives tested did not inhibit HIV-1 Reverse Transcriptase (RT) activity.