Design, Synthesis, Molecular Docking, and Biological Evaluation of Isatin-Based Fused Heterocycles As Epidermal Growth Factor Receptor Inhibitors.

A series of isatin-based fused heterocycles were designed, synthesized, and evaluated for anticancer activity against four cancer cell lines: MCF-7, MDA-MB-231, A549, and HL-60. Among them, Q₃ and T₄ were found to be potent anticancer agents. Furthermore, two compounds Q₃ and T₄ were selected for epidermal growth factor receptor (EGFR) inhibitory activity. Two compounds Q₃ and T₄ were found to be most potent EGFR inhibitors with IC₅₀ of 0.22 ± 0.10 and 0.19 ± 0.07 μM. The EGFR inhibitory activity of standard drug erlotinib was 0.08 ± 0.02 μM. Structural Activity Relationship studies showed that electronegative atoms were necessary for EGFR inhibitory potential. Finally, molecular docking studies were carried out to check the binding pattern of synthesized derivatives with the adenosine triphosphate (ATP) binding site of EGFR and results revealed that compounds Q₃ (-9.2 kcal/mol) and T₄ (-8.9 kcal/mol) exhibited better binding affinity than reference drug erlotinib (-7.3 kcal/mol).