Triple targeting of mutant EGFR, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation.

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives () that triple target the double mutant EGFR, COX-2, and 15-LOX. Compounds (, , , , and ) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFR over wild-type EGFR. Except for and , all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds and reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, and had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.