Design, synthesis, anti-cancer, anti-inflammatory and in silico studies of 3-substituted-2-oxindole derivatives.

This study focuses on the design and multistep synthesis of diverse structural and functional 3-substituted-2-oxindole derivatives aimed at being dual-active molecules with anti-cancer and anti-inflammatory properties. In vitro evaluations confirmed the dual activity of these derivatives. 4a exhibited GI50 value 3.00E-05 against MDA-MB-231; 4b has shown GI50 value 2E-05 against MDA-MB-231; 4c has shown GI50 value 6E-05 against VERO; and 4d has shown GI50 value 8E-05 each against both MDA-MB-231 and MCF-7. 4e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3c (71.19%), 3e (66.84%), and 3g (63.04%) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4d, 4e, 3b, 3i, and 3e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The quantum mechanics-based independent gradient model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4d and 4e compared to Sunitinib, suggesting stronger and diverse attractive forces.