Design, synthesis, and antiproliferative activity of new 1,2,3-triazole/quinazoline-4-one hybrids as dual EGFR/BRAF V600E inhibitors

A novel series of 1,2,3-triazole/quinazoline-4-one hybrids (8a–t) were designed and synthesized as dualtargeted antiproliferative agents. Compounds 8a–t were evaluated for their antiproliferative efficacy against a panel of four cancer cell lines. The results indicated that most of the evaluated compounds exhibited strong antiproliferative activity, with 8f, 8g, 8h, 8j, and 8l demonstrating the highest potency. These five compounds were investigated as EGFR and BRAFV600E inhibitors. The in vitro tests showed that compounds 8g, 8h, and 8j are strong antiproliferative agents that might work as dual EGFR/
BRAFV600E inhibitors. Compounds 8g and 8h were further examined as activators of caspases 3, 8, and Bax and down-regulators of the anti-apoptotic protein Bcl2. The results indicated that the studied compounds had considerable apoptotic antiproliferative action. The investigation of the cell cycle and apoptosis revealed that compound 8g induces cell cycle arrest during the G1 phase transition. Molecular docking experiments are thoroughly examined to validate the binding interactions of the most active hybrids with the active sites of EGFR and BRAFV600E. ... mehrThe data indicated that the examined compounds
can efficiently engage with essential amino acid residues in both kinases.