Novel N-substituted isatin-ampyrone Schiff bases as a new class of antiproliferative agents: Design, synthesis, molecular modeling and in vitro cytotoxic activity

Thirteen novel isatin-ampyrone Schiff bases derivatives were synthesized in only two steps of 70%-90% overall yields. In vitro cytotoxic activity of these new Schiff bases against three human tumor cell lines (MCF-7, A549, and SCOV3) as well as normal breast cell line (MCF-10A) were evaluated by MTT assay. Structure-activity relationship of the tested compounds revealed that chlorine group at C-5 position of the isatin ring significantly increased the cytotoxic activity. This study generally led to introduce a highly active molecule (M-12) with IC50 values of 5.12, 25.5, and 12.9 mu M, on MCF-7, A549, and SCOV3, respectively. Furthermore, molecular docking studies of the synthesized compounds were also done to investigate their binding modes towards VEGFR-2 and JNK3-MAP kinase as the main targets for isatin-containing anticancer agents. Binding free energy values of the compounds showed positive correlation with their cytotoxic activities. To confirm the docking results, molecular docking simulations of potent compound (M-12) against VEGFR-2 and JNK3 MAP kinase were also performed. According to the cytotoxic results and in silico ADMET predictions together, M-12 can be considered as a potent candidate for the future anticancer studies.