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.

Automated summary

Thirteen novel Schiff base derivatives were synthesized and their cytotoxic activities against tumor cells and normal cells were evaluated. One of the compounds, M-12, showed high activity and was found to bind to VEGFR-2 and JNK3-MAP kinase. Based on the in vitro experiments and in silico predictions, M-12 could be a promising candidate for future anticancer studies.