Phthalazine Derivatives as VEGFR-2 Inhibitors: Docking, ADMET, Synthesis, Design, Anticancer Evaluations, and Apoptosis Inducers

New phthalazine-derived inhibitors for VEGFR-2 were synthesized for Anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR-2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative 3f was the greatest effective compound against HepG2 and MCF-7 Cancer cell lines with IC₅₀ = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives 3b, 3e, 3f, 3g, 6a, and 6b were estimated for their VEGFR-2 inhibitory effects. Derivative 3f was the greatest effective compound which inhibited VEGFR-2 at IC₅₀ = 0.0557 ± 0.002 µM. The activities of 3f were assessed against MCF-7 Cancer cells for Apoptosis induction, cell cycle distribution, and growth inhibition. Compound 3f induced early Apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound 3f induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the Other hand, compound 3f improved the level of the pro-apoptotic protein; Bax by approximately fivefolds. Moreover, compound 3f noticeably decreased the levels of the anti-apoptotic proteins Bcl-2 by nearly fourfolds in comparison to the control. In addition, derivative 3f remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives 3f, 3g, and 6b revealed good in silico considered ADMET profile in comparing to sorafenib.

VEGFR‐2 inhibitors; anticancer agents; molecular docking; phthalazines.