Aim:
Aim: Design, synthesis and cytotoxic evaluation of new series of isatin-niflumic acid derivatives as vascular endothelial growth factor receptor tyrosine kinase inhibitors.

Material and methods:
Materials and Methods: A molecular docking study was performed to assess the binding affinities of the synthesized compounds against the kinase domains of the vascular endothelial growth factor receptor 2. The compounds were synthesized through the esterification process of Niflumic acid, followed by treating the obtained ethyl ester compound with hydrazine monohydrate to form the Niflumic acid hydrazide compound. This compound was further reacted with six Isatin derivatives utilizing the ketone-amine condensation reaction to form the final six new compounds.

Results:
Results: The synthesized compounds (I-VI) showed optimum binding affinity (S. score) values ranging from -9.1782 to -9.5120 Kcal/mol and precise binding mode (RMSD) values ranging from 1.0608 to 1.8914 with the active kinase site of the vascular endothelial growth factor receptor 2 (PDB code: 4AG8). At the same time, the cytotoxicity results showed an optimum inhibitory effect (20.87 μM to 78.48 μM) against the A549 (non-small cell lung cancer) and a safer effect (175.49 μM to 280.27 μM) against the MRC-5 (normal lung tissue cells). In contrast to the reference drug (Sunitinib).

Conclusions:
Conclusion: The new synthesized compounds (I-VI) are potent vascular endothelial growth factor receptor 2 tyrosine kinase inhibitors, inhibiting cell proliferation, angiogenesis and exhibiting promising anticancer agents.