Benzimidazole-based hybrids as inhibitors of EGFR/VEGFR-2 and their combinations with other enzymes: design, synthesis, and activity

In this review we aimed to summarize the accomplished advances in the field of benzimidazole hybrids-based EGFR/VEGFR inhibitors creation during the last few years. In the fight against cancer, special attention is paid to the treatment using enzyme inhibitors. EGFR, VEGF and VEGFR proteins are expressed on numerous non-endothelial cells including tumor cells. Benzimidazole molecule is known as a nitrogen-containing building block, recognized for its pharmacological applications. Due to its electron-rich architecture and favorable combination of hydrogen bond donor/acceptor atoms benzimidazole scaffolds are able to bind to a great number of therapeutic targets. Depending on the substituents position the discussed benzimidazoles are divided into six groups. The focus of our study was their synthesis and the enzyme inhibitory activity. It was found that many of the discussed benzimidazole hybrids have demonstrated outstanding EGFR resp. VEGFR-2 inhibition effects with IC₅₀ in the range 0.048-0.109 μM, and 0.107 μM to 6.7 nM, respectively, underlined their anti-angiogenic properties. Some of the studied compounds manifested dual inhibitory efficacy - EGFR-VEGFR-2, EGFR-HER, EGFR-BRAF. The molecular docking studies gave useful insight into the binding modes of the compounds within the active site of the enzymes and structural basis for further design. Characteristically of the binding to the active site of VEGFR is that in the ATP-binding and the allosteric hydrophobic back pocket, while to EGFR, the binding occurs through hydrophobic interactions with amino acid residues in both the C-terminal and the α-Helix transmembrane domains. The results achieved by the researchers can serve as a basis for generation of new safer or more selective benzimidazole hybrids without effect on normal cells.