Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity

Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment. The aniline derivatives 6a-d and the allylidene compounds 10a-f were the most active on the panel of fourteen cell lines and against VEGFR-2 and EGFR kinases. [Display omitted] •Five series of 1-substitutedphthalazine derivatives were synthesized.•Cytotoxicity was performed against fourteen cancer cell lines.•VEGFR-2 and EGFR kinase inhibition was investigated.•Compounds were active in the nanomolar level.•The most active compounds were 6a-d and 10a-f.