Synthesis, biological evaluation, and computational studies of thiazolyl hydrazone derivatives as triple mutant allosteric EGFR inhibitors

Herein, new thiazole-2-yl-based hydrazone derivatives were synthesized and assessed for in vitro anticancer activity against wild type A549, MCF7, DU145, and mutant H1975 cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all, 4-(4-Chlorophenyl)-2-(2-((4-methylthiazol-5-yl)methylene)hydrazineyl)thiazole (4b) elicited prominent anticancer activity against wild-type epidermal growth factor receptor (WT-EGFR) MCF7 cancer cell line with an IC₅₀ value of 9.57 ± 1.80 μM, whereas 4-Methyl-5-((2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazineylidene)methyl)thiazole (4c) showed appreciable activity with an IC₅₀ value of 11 ± 0.7 μM against the mutated EGFR H1975 lung cancer cells. Doxorubicin and Osimertinib were used as the standard drugs for comparison of activity. Compound (4b) significantly increased early apoptosis (30.2%) and late apoptosis (7.6%) at a 5 μM concentration in comparison with the control (early apoptosis 2.5%, late apoptosis 1.2%). The molecular docking study was performed against mutant EGFR (T790M/C797S) (PDB: 5D41) enzyme to gain information about interactions of synthesized molecules with binding pockets. Moreover, ADME study and molecular dynamic simulation studies were accomplished to gain insight into drug-likeness and conformational stability, respectively. The findings demonstrate a promising alignment between the observed anticancer effects and computational analyses.