Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors

Abstract

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5–19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5–19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC₅₀ ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC₅₀ 0.009 and 0.021 µM for EGFR and HER2, respectively.

Graphical Abstract

Keywords:

• Benzo[g]quinazolin
• benzenesulfonamide
• EGFR
• HER2

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The authors are thankful to the Deanship of the Scientific Research and Research Centre, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.