Design and synthesis of 1-methyl-2-oxoindolin-3-ylidene-thiazolidine-2,4-dione-pyrazole hybrids as VEGFR-2 targeting anti-proliferative agents

A new series of 1-methyl-2-oxoindolin-3-ylidene-thiazolidine-2,4-dione-pyrazoles (8a-8o) having characteristics of VEGFR-2 inhibitors were synthesized using Knoevenagel condensation and aqueous phase tandem one-pot acyl-Sonogashira-cyclocondensation as key approaches. The anti-proliferative efficacy of compounds (8a-8o) were assessed against HepG2, Caco-2 and MDA-MB231 cancer cell lines. Compound 8d displayed higher activity (IC50 = 2.4-7.5 mu M) against all cancer cells tested than the Doxorubicin (HepG2; IC50 = 2.9-9.2 mu M). As well, compound 8l has shown superior activity against Caco-2 (IC50 = 7.9 mu M) and MDA-MB231 (IC50 = 7.6 mu M) cells than the positive control. Besides, compared with the Doxorubicin, compounds 8e and 8m displayed greater activity against Caco-2 and MDA-MB231 cells with IC50 values of 7.3 and 6.8 mu M respectively. The in vitro VEGFR-2 studies of most anti-proliferative compounds revealed that compound 8d (IC50 = 51.3 nM) showed higher activity than the Sorafenib (IC50 = 53.8 nM), while, compounds 8e, 8l and 8 m demonstrated promising activity in comparison to Sorafenib with IC50 values ranging from 56.1 to 75.8 nM. Finally, molecular docking studies on VEGFR-2 (PDB ID 3VHE) showed that compounds 8d, 8e, 8l and 8 m have shown greater binding energies than the sorafenib which were ranging from -10.68 kcal/mol to -12.93 kcal/mol.