Rational Design of Triazole Hydrazide Derivatives With Imidazo[2,1-b]thiazole Scaffolds as Targeted EGFR Inhibitors...

A novel series of triazole hydrazide derivatives 8a-o was rationally designed, synthesized, and systematically evaluated for their anticancer potential. Cytotoxicity screening against A549 lung adenocarcinoma cells identified compounds 8a-d as the most potent, exhibiting IC₅₀ values of 3.15-4.93 µM, which are comparable to doxorubicin (IC₅₀ = 2.77 µM). Mechanistic studies revealed that lead compound 8a induced apoptosis through upregulation of Bax and caspase-3 and downregulation of Bcl-2. Additionally, 8a significantly inhibited A549 cell migration (34.46% wound closure vs. 61.61% in controls) and reduced clonogenic survival (surviving fraction = 0.5725). Importantly, 8a displayed low cytotoxicity toward normal lung fibroblasts (WI-38, IC₅₀ = 47.21 µM). Enzyme inhibition assays demonstrated potent EGFR kinase inhibition by 8a and 8 d (IC₅₀ = 74.85 and 75.87 nM, respectively), comparable to erlotinib (IC₅₀ = 34.89 nM). Moreover, in silico ADMET profiling predicted favorable drug-likeness and oral bioavailability, while molecular docking supported the stable binding of 8a within the EGFR active site. These findings identify compound 8a as a promising therapeutic lead for the development of targeted EGFR inhibitors in non-small cell lung cancer (NSCLC) therapy.