Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies

Abstract

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.

Benzimidazole derivatives as a new scaffold of anticancer agents: Synthesis, optical properties, crystal structure and DFT calculations

“…Benzimidazoles are well known nitrogen-containing bioactive compounds. They showed a variety of activities including anti-diabetic [ 1 ], antimicrobial [ 2 ], antifungal [ 3 ], antiviral [ 4 ], anti-cancer activity [ [5] , [6] , [7] ] (including anti breast cancer [ 8 ]) and anthelminthic [ 9 ]. Recent studies in medicinal chemistry have demonstrated them as potential drug motifs for the pharmaceutical industry [ 10 ].…”