A novel series of 1, 2, 3-thiadiazole thioacetanilide (TTA) derivatives have been designed, synthesized and evaluated for its anti-HIV activities in MT-4 cells. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Among them, 2-[4-(2, 4-dichlorophenyl)-1, 2, 3-thiadiazol-5-ylthio]-N-(2-nitrophenyl) acetamide 7d2 was identified as the most promising compound (EC50= 0.059±0.02 μM, CC50> 283.25 ...