Novel 5,6-dichlorobenzimidazole derivatives as dual BRAF(WT) and BRAF(V600E) inhibitors: design, synthesis, anti-cancer activity and molecular dynamics simulations.

A new series of 1-substiuted-5,6-dichloro-2-(4-methoxyphenyl)-1H-benzo[d]imidazoles 10a-p was designed and synthesized to target both BRAF(WT) and BRAF(V600E). The design strategy ensures that these derivatives would effectively occupy the ATP binding pocket of BRAF(WT/V600E) kinase domains and extend over the gate area interacting through hydrogen bonding with the surrounding key amino acids Glu500 and Asp593 and to finally occupy the allosteric hydrophobic back pocket. Some synthesized derivatives demonstrated impressive potency against BRAF(WT) with % inhibition approaching 91% at a concentration of 10 µM. The most potent candidate 10h demonstrated IC(50) values of 1.72 and 2.76 µM on BRAF(WT) and BRAF(V600E), respectively. At the same time, the synthesized benzimidazoles 10a-p were examined for their growth inhibitory activity on NCI-60 cancer cell lines. Again, compound 10h revealed a potent GI(50) across a range of cancer cell lines. Moreover, it arrested cell cycle progression in HT29 colon cancer cell line at G2/M phase and induced apoptosis in the same cell line. Molecular dynamics simulations supported the validity of the design assumption, simultaneously, ADME prediction study displayed that the designed benzimidazoles exhibit promising physiochemical and drug-likeness properties as anticancer agents.