Design and synthesis of [1,2,4]triazolo[3,4-b]thiadiazine-1,2,4-oxadiazoles as EGFR tyrosine kinase inhibitors.

A novel series of heterocyclic compounds was developed, synthesized, and assessed for their in vitro anticancer efficacy and EGFR inhibitory activities. The cytotoxicity of the synthesized compounds was evaluated against A-549 and NCI-H460 lung cancer cell lines, as well as normal HEK-293 cells, using erlotinib and doxorubicin as reference standards. Multiple compounds had considerable anticancer efficacy, with 8f and 8g identified as the most effective possibilities, with IC₅₀ values ranging from 2.53 to 6.51 μM, surpassing erlotinib. These compounds exhibited significant EGFR inhibition, with 8f (IC₅₀ = 0.26 μM) and 8g (IC₅₀ = 0.36 μM) surpassing the standard drug. Molecular docking analyses of the EGFR kinase domain demonstrated advantageous binding affinities and significant interactions with the hinge region residue MET769, corroborated by many hydrogen bonds and substantial π-interactions. A strong association between docking scores and biological activity was noted, validating EGFR as a potential molecular target. The findings designate 8f and 8g as prospective lead compounds for further development as EGFR-targeted anticancer therapies.