Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5-12) and the 6-aryl-thiomethyl analogues 25-27 has been described. Deblocking of 5-12 and 25-27 afforded the free acyclic C-nucleosides 13-20, and 28-30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.