Benzimidazole-based derivatives as apoptotic antiproliferative agents: Design, synthesis, docking, and mechanistic studies
A new class of benzimidazole-based derivatives (4a–j, 5, and 6) with potential dual
inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were
submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized
compounds 4a–j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single
concentration of 10 μM. Some compounds tested demonstrated remarkable antiproliferative activity
against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against
60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia
subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer
assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential
targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant
antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced
apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2
protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act
as dual EGFR/BRAFV600E inhibitors
