Exploration of the VEGFR-2 inhibition activity of phthalazine derivatives: design, synthesis, cytotoxicity, ADMET,...

Novel phthalazine derivatives were designed, synthesized and evaluated against Hep G2 and MCF-7 as VEGFR-2 inhibitors. In particular, compounds 2g and 4a were found to be the most potent derivatives among all the tested compounds against MCF-7 and Hep G2 cancer cell lines with IC₅₀ values of 0.15 and 0.12 and 0.18 and 0.09 μM respectively. Moreover, compounds 3a, 3c, 5a and 5b displayed excellent anticancer activities against MCF-7 and Hep G2 cancer cell lines. The highly active derivatives 2g, 3a, 3c, 4a, 5a and 5b were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activities with IC₅₀ values ranging from 0.148 to 0.892 μM. Among them, compounds 2g and 4a were found to be the most potent derivatives that inhibited VEGFR-2 with IC₅₀ values of 0.148 and 0.196 μM respectively. Compounds 3a, 3c, 5a and 5b exhibited good activity with IC₅₀ values of 0.375, 0.892, 0.548 and 0.331 μM respectively. Sorafenib was used as a reference drug in this study. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with those obtained from molecular modeling studies. Moreover, MD simulation results indicated the stability of ligand-target interaction. Furthermore, our derivatives 2g and 4a showed a good in silico calculated ADMET profile.