Design, synthesis, antiproliferative evaluation, and molecular docking study of new quinoxaline derivatives as apoptotic inducers and EGFR inhibitors

A new series of quinoxaline derivatives synthesized and pharmacologically evaluated against (HepG-2, HCT-116, and MCF-7) cell lines. Seven compounds were found to possess the highest activities against the examined cell lines with IC50 values ranging from (7.57 to 28.44 mu M). To further analyze its apoptotic potential in MCF-7 cells, the most active 3a, 3b, 6, 7b, 7c, 7d , and 7f members have been selected. Interestingly, it found that the Bcl-2 level decreased by 1.95-3.99 folds, and the BAX level increased by 7.2-10.6 folds relative to the control. They also increased the active Caspase-3 level by 5.77-10.69 folds compared to untreated cells. WI38 cells were treated with these compounds to estimate the cytotoxicity level of those compounds in non-tumorigenic cells, and they displayed higher IC50 values (142.21-335.03 mu M), suggesting may less toxic effect on the normal ones. Further studies on the mechanism of the most promising compounds 3a, 6, 7b and 7d , revealed that it increases apoptotic cells and induced cell cycle arrest at pre-G1 and G2/M phases. Besides, both wild EGFR(WT) and mutant EGFRL858R-TK inhibitory activity for these derivatives showed that these derivatives had IC50 values ranging from 0.075-1.547 mu M versus wild EGFR(WT) and 63.70-87.34 nM versus the mutant type. Erlotinib was used as a standard reference with IC50 values of 0.0656 mu M and 59.56 nM versus both types. Finally, the molecular docking study of most potent quinoxaline derivatives exhibited a good binding inside the active site of EGFR (1M17), with binding energy ranged between (-15.86 to-16.97) compared to Erlotinib (-17.84) kcal/mol. Also, by applying Lipinski's parameters, it was found that these derivatives showed no violations and indicated promiscuity to formulate orally. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

A new series of quinoxaline derivatives showed high activity against liver cancer, colon cancer, and breast cancer cells, affecting apoptosis and cell cycle. These compounds also increased active Caspase-3 levels compared to untreated cells. They displayed low cytotoxicity in non-tumorigenic cells, suggesting minimal impact on normal cells.