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

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 Gl/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. (C) 2022 Elsevier B.V. All rights reserved.