Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity

Abstract

Nineteen new quinazolin-4(3H)-one derivatives 3a–g and 6a–l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI₅₀ = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59–9.55 µM). Compound 6d potently inhibited EGFR with IC₅₀ = 0.069 ± 0.004 µM in comparison to erlotinib with IC₅₀ value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.

Keywords:

• Quinazolin-4(3H)-one
• antiproliferative activity
• molecular modelling
• EGFR inhibition
• cell cycle analysis

Acknowledgements

The authors are thankful to the associates of the National Institutes of Health, USA for performing the anticancer screening. The authors are grateful to Dr. Esam Rashwan, Head of the confirmatory diagnostic unit VACSERA-EGYPT, for carrying out EGFR, caspase-3, cell cycle analysis and apoptosis assays.

Disclosure statement

The authors declare that they do not have conflict of interest. The authors are only responsible for the content and writing of this manuscript.