Design, synthesis and molecular docking simulation of oxindole-based derivatives with dual VEGFR-2 and cholinesterase inhibitory activities

Abstract

Oxindole-based compounds are deemed to be an interesting scaffold with significant VEGFR-2 and cholinesterase inhibitory properties. Regarding the studies that displayed the adverse effect of cancer chemotherapy on cognitive function which can be long-lasting and negatively affect the quality of life, a series of dispiropyrrolodinyl-oxindoles 4‒27 have been designed and synthesized through a classical 1,3-dipolar cycloaddition reaction. Derivatives 9‒12, 18 and 21 were the best among the tested series that disclosed auspicious mutual inhibitory properties against breast cancer and VEGFR-2 kinase. Whereas compound 12 displayed superior activity than that of the reference drug, tamoxifen. PI-flow cytometry of compound 12 supported the cessation of the cell cycle at the G1/S phase and can be considered as an apoptotic inducer via activation of caspase-3. Moreover, the new chemical entities 17, 18, 21 and 22 exhibited dual-targeted cholinesterase inhibitory properties against AChE and BChE. comparable with donepezil. The possible applicability of the mutual most potent candidates 9‒13, 17, 18, 21 and 22 were supported by the promising safety profiles on normal (non-cancer, VERO) cells. Analogs 18 and 21 exhibited dual VEGFR-2 and cholinesterase inhibitory properties, which can be used as lead compounds for the discovery of prominent dual anti-breast cancer agents and cholinesterase inhibitors. Molecular docking studies of the most promising derivatives within the active sites of VEGFR-2, AChE and BChE enzymes were carried out to confirm the improvement of the binding features through the substituent variation at p-3 and p-4′ of dispiropyrrolodinyl-oxindole as well as the chain length of an alkyl group at indolyl N-1.