1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation

• Three series of 1-piperazinyl-4-phenylphthalazines 16a-k, 18a-e & 21a-g were synthesized.
• The prepared phthalazines were evaluated for their inhibitory activity against VEGFR-2.
• 16k and 21d inhibited VEGFR-2 with IC50 = 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively.
• Anticancer activity of seventeen selected compounds was screened by the NCI USA.
• Compound 16k exhibited potent broad spectrum anti-proliferative activity in NCI assay.

In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.

Three novel series of phthalazine derivatives based on the1-piperazinyl-4-phenylphthalazine scaffold were designed and synthesized as potential VEGFR-2 inhibitors and antitumor agents.Figure optionsDownload as PowerPoint slide