Hybrid Isatin and Imatinib Analogues as Potential Antineoplastic Agents

ABSTRACT Cancer is a multifactorial disease often linked to genetic mutations that disrupt protein tyrosine kinases (PTKs) and signaling pathways such as PI3K/Akt/mTOR, driving malignancies such as chronic myeloid leukemia (CML), prostate carcinoma, glioblastoma, and gastrointestinal stromal tumors (GISTs). Tyrosine kinase inhibitors (TKIs), including imatinib and sunitinib, have revolutionized cancer therapy by selectively targeting kinases such as Bcr‐Abl1 (CML) and KIT/PDGFRα (GIST), offering substantial clinical benefits. Motivated by their success, 15 hybrid derivatives ( 4a–e , 5a–e , 6a–e ) based on the isatin–phenylaminopyrimidine pyridine (PAPP) scaffold were designed, synthesized, and evaluated in cell lines with dysregulated tyrosine kinase activity. Among them, compounds 6b and 6e showed promising cytotoxicity against the K562 cell line (Bcr‐Abl1), with CC₅₀ values of 8.7 and 12.2 μM, though they also affected WSS‐1 cells, suggesting limited tumor selectivity. Compound 4c displayed strong cytotoxic activity against several solid tumor cell lines, including DU145 (3.9 μM), MCF7 (3.5 μM), HT29 (7.7 μM), NCI‐H1299 (19.5 μM), and T98G (9.0 μM). Importantly, all tested compounds showed low erythrocytic toxicity (CC₅₀ > 30 μM).