Synthesis, Biological Evaluation, and Computational Studies of Pyridine-Thiazolyl Hydrazones as Anticancer Candidates Targeting EGFR Kinase

Abstract— Objective: Synthesis, characterization, biological evaluation, and in silico studies of new 2-amino pyridine-thiazolyl hydrazones (5a–5h) as novel anticancer agents targeting the EGFR kinase protein. Methods: All designed compounds were synthesized via a one-pot multicomponent reaction. The synthesized compounds were evaluated for their anticancer activity against selected cancer cell lines in vitro, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and EGFR enzymatic assay. A computational study was conducted to explore the properties of the targeted compounds, which included drug similarity, molecular docking, and ADMET profiling. Results and Discussion: Among all, compounds (5d), (5g), and (5h) showed the most potent anticancer activity with IC₅₀ values of 9.02, 10.02, and 8.09 μM against A549, MCF-7, and DU145, respectively. Additionally, in vitro EGFR enzymatic activity provided insight into the anticancer mechanisms of the majority of the active molecules. Compound (5d) exhibited in vitro enzymatic inhibitory activity with an IC₅₀ value of 5.11 μM, compared to the standard osimertinib (IC₅₀ = 1.35 μM). The molecular docking study was performed against mutant EGFR (T790M/C797S) (PDB ID: 5D41) and wild-type EGFR (PDB ID: 4I23) to gain information about the interactions of the synthesized molecules with the binding pockets. The molecular docking, ADMET, and drug-likeness properties of all synthesized derivatives were computationally determined as EGFR inhibitors. Conclusions: Compounds (5d), (5g), and (5h) demonstrated significant efficacy against prostate, lung, and breast cancer cell lines. This research suggests that 2-amino pyridine-thiazolyl hydrazone molecules have the potential to be developed into effective anticancer agents in the future.