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 (<b>4a</b>–<b>4r</b>) and thiophene-chalcone ureas (<b>5a</b>–<b>5p</b>). 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 <b>4e</b>, <b>4f</b>, and <b>4g</b> (pyrrole series) showed strong cytotoxicity against A549 and HT-29, while <b>5b</b>, <b>5c</b>, and <b>5d</b> (thiophene series) were effective on 769P. Compound <b>5c</b> 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 <b>4r</b>, <b>5c</b>, and <b>5d</b> 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.