Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a] indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRAF(V600E) inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV(600E). Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC50 = 80 +/- 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRAF(V600E) (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI(50) = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRAF(V600E) active sites to clarify their binding modes.

Automated summary

This study developed dual-targeting EGFR and BRAF(V600E) inhibitors with potential therapeutic activity against cancer, as well as good antioxidant activity. These compounds may serve as potential drug candidates for treating cancer.