One-Pot Synthesis of Isatin-Pyrazole Hybrids as VEGFR-2 Inhibitors and Molecular Docking Studies

Herein, we described the synthesis of isatin-pyrazole hybrids (6 a-o) using Acyl-Sonogashira coupling reaction and evaluated for their in vitro cytotoxicity against three human cancer cell lines such as A549, PC3 and MCF-7 by using MTT assay and 5-fluorouracil as the reference drug. Some of the compounds 6 a, 6 j and 6 n were found to be more active than the standard 5-fluorouracil against three human cancer cell lines. The in vitro VEGFR-2 tyrosine kinase inhibitory activity reveals that 6 j has exhibited double inhibitory potency with IC50 value of 16.28 +/- 1.21 nM compared to reference drug sorafenib and 6 a and 6 n were also shown more inhibition capacity than the standard. Molecular docking studies of the compounds 6 a, 6 j and 6 n towards human VEGFR2 kinase shown that they have good binding interactions with the target protein with binding energies ranging from -10.30 kcal/mol to -10.80 kcal/mol. Finally, the in silico pharmacokinetic profile (ADMET) of potent compounds 6 a, 6 j and 6 n were also studied, where all of them have followed Lipinski rule, Ghose rule, Veber rule, Egan rule and Muegge rule without any deviation and the compounds 6 a and 6 j have shown lead likeness in medicinal chemistry point of view.