Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAF^V600E 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 BRAF^V600E. 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 (GI₅₀ = 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.