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 BRAFV600E 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 BRAFV600E.
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
BRAFV600E (IC50 =55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell pro
liferation (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
BRAFV600E active sites to clarify their binding modes.