Design and Synthesis of Indole‐Linked Hybrids as Selective Anticancer Agents: In Vitro Cytotoxicity, Molecular Docking, and ADME Studies

ABSTRACT A series of indole‐based hybrid derivatives (MP2‐1 to MP2‐8) were synthesized in high yields (85%–93%) through a two‐step synthetic approach involving N‐alkylation and subsequent Schiff base condensation. The in vitro anticancer activity of the compounds was evaluated against MCF‐7 (breast carcinoma), HEP‐G2 (hepatocellular carcinoma), and HEK293 (normal kidney epithelial) cell lines. Among the series, MP2‐5 and MP2‐4 exhibited the most potent antiproliferative effects, with IC 50 values of 102.28 µg/mL and 104.93 µg/mL, respectively, against MCF‐7 cells, while MP2‐2 showed the moderate activity against HEP‐G2 cells (IC 50 = 91.37 µg/mL), all outperforming the standard drug cisplatin. Molecular docking studies against EGFR wild‐type and mutant variants (T790M and T790M/C797S) supported the SAR findings, highlighting key interactions such as hydrogen bonding and π–π stacking with active site residues. Notably, MP2‐2 and MP2‐5 showed strong binding affinities with resistant EGFR mutants, suggesting potential as kinase inhibitors. Drug‐likeness and ADME properties were predicted using QikProp, with most compounds showing good oral absorption, membrane permeability, and favourable physicochemical profiles. These results establish MP2‐2, MP2‐4, and MP2‐5 as promising lead candidates for further development as targeted anticancer agents.