Discovery and evaluation of novel pyrrole/thiophene chalcone urea EGFR inhibitors via biological and docking studies

This study aimed to synthesize novel chalcone-urea derivatives and evaluate their anticancer potential through antiproliferative, apoptotic, and epidermal growth factor receptor (EGFR) inhibitory activities, supported by molecular modeling.
Thirty-three chalcone-urea derivatives were synthesized in two series: pyrrole-chalcone ureas (4a–4r) and thiophene-chalcone ureas (5a–5p). Compounds were characterized using1 H NMR, 13 C NMR, and mass spectrometry. Their antiproliferative effects were assessed against renal adenocarcinoma (769P), lung carcinoma (A549), colorectal adenocarcinoma (HT-29), and healthy kidney (HEK-293) cell lines. Selected compounds were further evaluated for EGFR inhibition, apoptotic activity, and cell cycle arrest. Molecular docking was performed to predict binding interactions with wild-type human EGFR.
Compounds 4e, 4f, and 4g (pyrrole series) showed strong cytotoxicity against A549 and HT-29, while 5b, 5c, and 5d (thiophene series) were effective on 769P. Compound 5c exhibited the highest EGFR inhibition (IC₅₀ = 1 nM), potent apoptotic induction, and cell cycle arrest at the S phase in A549 cells. Docking studies confirmed favorable binding of 4r, 5c, and 5d within the EGFR active site.
Several chalcone-urea derivatives demonstrated potent anticancer properties, with compound 5c emerging as a promising EGFR inhibitor with strong cytotoxic and pro-apoptotic effects.