Triple targeting of mutant EGFR^L858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Abstract

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFR^L858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) 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^L858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j 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.

Graphical Abstract

Keywords:

• Triple EGFR/COX-2/15-LOX inhibitors
• quinazoline
• phenyl urea
• in vitro anti-inflammatory
• anticancer

Acknowledgements

We thank the developmental Therapeutics Program at the Division of cancer treatment and diagnosis of the National Cancer Institute of Health for the screening using the NCI60 cancer cell line panel. We are also thankful to the Faculty of Pharmacy at Zagazig University for the purchase of MOE license version 2019 (Chemical Computing Group, Montreal, CA, USA).

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

The biological work was supported by the National Institutes of Health, National Institute of General Medical Sciences grant P20GM121334 (S.R. and D.G.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.