Synthesis, Characterization, and Biological Evaluation of Novel Isatin‐Bearing Amino Acid Derivatives: Cytotoxic Activity and Prospective Applications in Medicinal Chemistry

ABSTRACT A new series of isatin‐based derivatives incorporating amino acid residues was synthesized and structurally characterized using IR, 1 H, and 13 C NMR spectroscopies. The designed compounds were developed with the aim of enhancing anticancer activity through the incorporation of biologically active scaffolds, such as isatin and natural amino acids. The synthesized compounds were evaluated for their in vitro cytotoxic activity against three human cancer cell lines: MCF‐7 (breast adenocarcinoma), HEPG‐2 (hepatocellular carcinoma), and A‐549 (lung carcinoma). Among the tested derivatives, compound 14 ; (S‐(((2R)‐2‐(2‐(2,3‐dioxo‐2,3,3a,7a‐tetrahydro‐1H‐indol‐1‐yl) acetamido)‐3‐methoxy‐3‐oxopropyl) thio)‐L‐cysteine) demonstrated the most potent anticancer activity, with significantly lower IC 50 values compared to the reference drug doxorubicin. To further elucidate its mechanism of action, molecular docking studies were performed at the active site of human topoisomerase IIβ complexed with DNA and etoposide, revealing strong and specific binding interactions that suggest its potential role in stabilizing the DNA cleavage complex. These findings underscore the potential of isatin–amino acid hybrids as promising lead compounds for the development of novel anticancer agents.