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

Abstract This study focuses on the design and synthesis of 3‐substituted‐2‐oxindole derivatives aimed at developing dual‐active molecules with anti‐cancer and anti‐inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug‐likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI 50 value 3.00E −05 against MDA‐MB‐231, 4 b has shown GI 50 value 2E −05 against MDA‐MB‐231, 4 c has shown GI 50 value 6E −05 against VERO, 4 d has shown GI 50 value 8E −05 each against both the MDA‐MB‐231 and MCF‐7 and 4 e has shown GI 50 values 2E −05 and 5E −05 each against both the MCF‐7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (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 4 d , 4 e , 3 b , 3 i , and 3 e 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 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.