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

Abstract

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.

Keywords: Antiproliferative; BRAF(V600E); EGFR; Indole; Melanoma cell.