Quinazolinone-diarylpyrazole hybrids as dual EGFR/COX-2 inhibitors: antiproliferative, mechanistic, and in silico studies.

Abnormal epidermal growth factor receptor (EGFR) signaling and cyclooxygenase-2 (COX-2) mediated inflammatory pathways contribute to tumor progression and survival, supporting their simultaneous pharmacological targeting. Herein, a series of quinazolinone-diarylpyrazole hybrids 7a-l was designed, synthesized, and evaluated as dual EGFR/COX-2 inhibitors. Compound 7f exhibited the most balanced inhibitory profile against the two targets, exhibiting EGFR and COX-2 IC50 values of 0.24 ± 0.03 and 0.08 ± 0.01 µM, respectively, together with a COX-2 selectivity index of 197.88. Compound 7j displayed the highest EGFR inhibitory activity within the series (IC50 = 0.15 ± 0.02 µM). The hybrids showed marked antiproliferative activity against A431, A549, and HCA-7 cancer cells, with 7f exhibiting IC50 values of 1.18 ± 0.14, 1.42 ± 0.17, and 0.86 ± 0.17 µM, respectively, and a cellular selectivity index of 14.08 toward MRC-5 cells. Cellular studies further demonstrated that 7f inhibited cellular EGFR phosphorylation (IC50 = 0.77 ± 0.11 µM) and suppressed PGE-2 release by 89.9% at 1 µM. Moreover, 7f increased Bax expression, reduced Bcl-2 levels, and enhanced caspase-3 and caspase-9 levels, supporting induction of apoptosis. Molecular docking analyses supported favorable accommodation of 7f within the binding sites of wild-type EGFR and COX-2, consistent with its experimentally observed dual inhibitory activity. Collectively, these findings identify 7f as a promising lead displaying concurrent EGFR and COX-2 inhibitory activity together with pronounced antiproliferative effects.