Rationale, in silico docking, ADMET profile, design, synthesis and cytotoxicity evaluations of phthalazine derivatives as VEGFR-2 inhibitors and apoptosis inducers

Abstract

New phthalazine derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors were synthesized joined to different spacers including pyrazole, α,β-unsaturated ketonic fragment, pyrimidinone and/or pyrimidinthione. A docking study was carried out to explore the suggested binding orientations of the novel derivatives inside the active site of VEGFR-2. The obtained biological data were extremely interrelated to that of the docking study. In particular, compounds 4b and 3e showed the highest activities against Michigan Cancer Foundation-7 (MCF-7) and Hepatocellular carcinoma G2 (HepG2) with half maximal inhibitory concentration (IC₅₀) = 0.06, 0.06 μM and 0.08, 0.19 μM respectively. Our derivatives 3a–e, 4a,b and 5a,b were evaluated for their cytotoxicity against normal VERO cells. Our compounds exhibited low toxicity concerning normal VERO cells with IC₅₀ = 3.00–4.75 μM. In addition, our final derivatives 3a–e, 4a, 4b, 5a and 5b were investigated for their VEGFR-2 inhibitory activities. Derivative 4b exhibited the highest VEGFR-2 inhibitory activities at an IC₅₀ value of 0.09 ± 0.02 μM. Derivatives 3e, 4a and 5b demonstrated good activities with IC₅₀ values = 0.12 ± 0.02, 0.15 ± 0.03 and 0.13 ± 0.03 μM respectively. Furthermore, the activities of 4b were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution and growth inhibition. Compound 4b caused cell growth arrest in growth 2-mitosis (G2-M) phase; accumulation of cells at that phase became 6.92% after being 13.2 in control cells. Moreover, our derivatives 3e, 4b and 5b revealed a good in silico considered absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile in comparison to sorafenib.