New 4-amino-3-chloro benzoate ester derivatives as EGFR inhibitors: synthesis, in silico and biological analyses.

Aim: The main goal of this study was to synthesize new derivatives of 4-amino-3-chloro benzoate ester, including 1,3,4-oxadiazole derivatives (N3a-d), benzohydrazone derivatives (N4a-c), and hydrazine-1-carbothioamide derivatives (N5a-d) that target epidermal growth factor receptor (EGFR) tyrosine kinase.

Materials & methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR, and the anti-proliferative properties were tested in vitro.

Results: In silico analysis showed that the hydrazine-1-carbothioamide derivatives (N5a-d) had the best matching pattern with EGFR pharmacophoric queries compared to erlotinib, exhibited a favorable safety profile, and showed the best stability among the tested compounds. Compound N5a induced cytotoxicity in the three cancer cell lines tested (A549, HepG2, and HCT-116), by targeting EGFR and activating caspase 3 and caspase 8, therefore, inducing the extrinsic apoptotic pathway.

Conclusion: The results of this study show that compound N5a is a promising cytotoxic compound that inhibits the tyrosine kinase activity of EGFR.