Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Hend Kothayer; Samar Rezq; Ahmed S Abdelkhalek; Damian G Romero; Samar S Elbaramawi

doi:10.1080/14756366.2023.2199166

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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2199166. doi: 10.1080/14756366.2023.2199166.

Authors

Hend Kothayer¹, Samar Rezq^{2

3

4

5

6}, Ahmed S Abdelkhalek¹, Damian G Romero^{3

4

5

6}, Samar S Elbaramawi¹

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
³ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS, USA.
⁴ Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, USA.
⁵ Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
⁶ Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.

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.

Keywords: Triple EGFR/COX-2/15-LOX inhibitors; anticancer; in vitro anti-inflammatory; phenyl urea; quinazoline.

MeSH terms

Anti-Inflammatory Agents / pharmacology
Celecoxib
Cyclooxygenase 2 / genetics
Cyclooxygenase 2 / metabolism
Diclofenac / therapeutic use
ErbB Receptors* / metabolism
Humans
Lung Neoplasms* / drug therapy
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors / pharmacology
Quinazolinones / pharmacology
Structure-Activity Relationship
Tumor Necrosis Factor-alpha
Urea / pharmacology

Substances

ErbB Receptors
Cyclooxygenase 2
Quinazolinones
Celecoxib
Diclofenac
Tumor Necrosis Factor-alpha
Protein Kinase Inhibitors
Anti-Inflammatory Agents
Urea
EGFR protein, human

Grants and 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.