A new series of thiazolopyrane 5a–d, 11–13 and thiazolopyranopyrimidine 6–10, 7b, 8b, and 14 derivatives bearing a sulfonamide moiety were designed and synthesized. The molecular design was performed using molecular operating environment software to predict the binding mode of the proposed compounds on hCAII. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human liver cancer cell line in which hCAII is overexpressed. Compounds 8b and 14 showed higher activities compared with doxorubicin as a positive control. The radiosensitizing ability of the promising compounds 3, 7a, 8b, 12, and 14 was studied which showed an increase in the cell killing effect of c-radiation after combination with them.