Design, synthesis, and biological study of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia

Abstract

Purpose

In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.

Methods

A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.

Results

The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC₅₀ value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC₅₀ values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results.

Conclusion

This study provides insights for developing hypoxia-activated kinase inhibitors.

Keywords:

• EGFR inhibitor
• hypoxia
• tumor
• 4-anilinoquinazoline
• 2-nitroimidazole

Acknowledgments

The authors are grateful for the support of the National Natural Science Foundation of China (81703417), the Major Science and Technology Project of Henan Province (161100310100), and Henan Medical Science and Technology Research Project (2018020039). Dr Weiyan Cheng is grateful for the support of the Young Scholar Fund from The First Affiliated Hospital of Zhengzhou University.

Disclosure

The authors report no conflicts of interest in this work.