Design, synthesis, and biological investigations of new pyrazole derivatives as VEGFR2/CDK-2 inhibitors targeting liver cancer.

New Series of N-Manniche bases 3,4 (a-c) and 5,6 (a-b) were synthesized through the reaction of benzaldehyde and amine with 3-methyl-4-(aryldiazenyl)-1H-pyrazol-5-ol derivatives 2(a-c), they were fully characterized by FT-IR, (H, C) NMR data in addition to their mass spectra. The Structural Activity Relationship of the target compounds were examined for their cytotoxicity. Some newly synthesized compounds showed promising antiproliferation properties when tested against HepG2 cancer cells. Compounds 4a, 5a, and 6b showed potent cytotoxicity against HepG2 with IC values of 4.4, 3.46 and 2.52 µM compared to Sorafenib (IC = 2.051 µM) and Roscovitine (IC = 4.18 µM). Furthermore, they were safe against the THLE2 cells with higher IC values. Compound 6b exhibited promising dual VEGFR2/CDK-2 inhibition activities; it had an IC value of 0.2 μM with VEGFR2 inhibition of 93.2%, and it had an IC value of 0.458 μM with CDK-2 inhibition of 88.7%. In comparison to the untreated control group (0.95%), compounds 5a (38.32%) and 6b (42.9%) considerably increased the cell population in total apoptosis. In addition, compounds 5a and 6b arrested the cell population at G0-G1 and S phases, respectively. Molecular docking experiments confirmed the virtual binding mechanism of the most active drugs, which were found to have good binding affinities with both receptor active sites.