Cancer remains a leading cause of mortality, underscoring the need for novel agents to improve therapeutic outcomes and overcome drug resistance. Guided by the known antitumor potential of thiazolidinones, a series of arylidene-thiazolidinone derivatives was synthesized via a one-pot cyclocondensation of pyrazolyl-thiosemicarbazone, with chloroacetic acid and aromatic aldehydes. In vitro antiproliferative screening against HCT-116 (colon) and A549 (lung) cancer cell lines identified compounds 3c (2,4-dihydroxybenzylidene) and 3a (4-dimethylaminobenzylidene) as the most potent, with stronger activity than the reference drugs doxorubicin and roscovitine, and reduced toxicity toward normal fibroblast (WI-38) cell line. Selectivity index analysis confirmed preferential activity toward cancer cells, suggesting a favorable safety profile. In silico target prediction indicated kinases as probable targets, and docking to EGFR protein (PDB ID: 3W32) revealed that thiazolidinone 3a showed the best binding affinity (with appropriate RMSD and good ligand efficiency), forming key π‑hydrogen interactions common with those of the co-crystallized ligand, suggestive of possible EGFR inhibitory activity. ADME predictions further showed favorable gastrointestinal absorption, lipophilicity, oral bioavailability, and drug-likeness for thiazolidinones 3a, 3b, and 3 f. Collectively, these findings highlight these derivatives as promising scaffolds for further development of antiproliferative therapies.
