Discovery of 3,3a,4,5-tetrahydro-2H-benzo[g]indazole containing quinoxaline derivatives as novel EGFR/HER-2 dual inhibitors

Abstract

In the present study, twenty-five pyrazole–quinoxaline derivatives (4a–4y) were designed and synthesized, and their biological activity as potential EGFR or HER-2 kinase inhibitors was evaluated. Among them, compound 4l displayed better antiproliferative activity against A549 and MCF-7 cell lines than Eroltinib. Further kinase inhibitory activity assay results indicated that compound 4l demonstrated the most potent enzyme inhibitory activity. Docking simulations were then performed to position compounds 4l and 4x into the active binding site of EGFR to determine the probable binding model. 3D-QSAR models were built to aid in the effective design of the presently studied and future EGFR inhibitors. These discoveries suggested that the title compounds are potential EGFR/HER-2 dual inhibitors and compound 4l may be a promising lead compound for the development of novel antitumor agents, potentially via inhibiting EGFR/HER-2.