Synthesis, EGFR-TK inhibition and anticancer activity of new quinoxaline derivatives

Abstract

Ethyl 4-substituted-3-oxo-quinoxaline-2-carboxylates 3–5 were obtained via alkylation of ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (1). Compound 1 was heterocyclized using hydrazines, ethylenediamine, and ethanolamine to give pyrazoloquinoxalines 6, 7, diazepinoquinoxaline 8, and oxazepinoquinoxaline 10. The quinoxaline-2-carboxamides 9, 11, 12 were prepared via condensation of compound 1 with different amines. Compound 1 was thiated using Lawesson’s reagent affording quinoxaline-3-thione 13, in fair yield. In addition, the reaction of 4-methyl-3-oxoquinoxaline 3 with some binucleophiles led to a series of new oxoquinoxaline derivatives 14–18. The molecular structure of compounds 1, 3, and 9 was confirmed by X-ray crystallography.

The anti-proliferative activity showed that among all the tested compounds, compounds 3, (IC₅₀ 2.51 ± 3.0, 4.22 ± 1.6 and 2.27 ± 1.9 µM), 11 (IC₅₀ 1.32 ± 2.61, 1.41 ± 1.23 and 1.18 ± 1.91 µM) and 17 (IC₅₀ 1.72 ± 1.32, 1.85 ± 0.94 and 1.92 ± 4.83 µM) showed noteworthy anti-proliferative effects against the three cancer cell lines, HCT116, HePG2 and MCF7, respectively, compared to the reference drugs doxorubicin (IC₅₀ 1.41 ± 0.58, 0.90 ± 0.62 and 1.01 ± 3.02 µM) and erlotinib (IC₅₀ 1.63 ± 0.81, 1.57 ± 0.62 and 1.49 ± 0.54 µM). Compounds 3 (0.899 nM), 11 (0.508 nM) and 17 (0.807) showed strong EGFR inhibitory activity compared to Erlotinib (0.439 nM) and these results are in agreement with the docking study. These results suggest that compounds could probably be promising anticancer agents with EGFR inhibitory activity.

Graphical Abstract

Keywords:

• Anti-proliferative activity
• heterocyclization
• molecular docking
• nucleophilic reactions
• quinoxaline derivatives
• X-ray crystallography

Acknowledgements

We are thankful to Sohag University and Faculty of Science in Egypt for the support of this work.