Novel series of diazepam bearing sulfonamide moieties 5 and 7 were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC = 8.98 ± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5 exhibited higher activity than sorafenib, (IC = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell lines respectively. Compounds 5, 5, 5, 5, 5 and 7 are respectively, 5.77, 8.58, 9.54, 5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most sensitive cells) than in VERO normal cells. All the synthesized compounds 5 and 7 were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5 was found to be the most potent derivative that inhibited VEGFR-2 at IC value of 0.10 ± 0.01 µM, which is equipotent to sorafenib IC value (0.10 ± 0.02 µM). Compound 5 exhibited excellent activity with IC value of 0.12 ± 0.01 µM which nearly equipotent to that of sorafenib. Compounds 5, 5 and 5 exhibited very good activity with the same IC value of 0.14 ± 0.02 µM. Also, compounds 7 and 7 possessed good VEGFR-2 inhibition with IC values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the half activity of that of sorafenib. The data obtained from docking studies were highly correlated with that obtained from the biological screening.