Experimental pK _a Determination and Computational Profiling of Benzimidazole Derivatives as Potential Anticancer Lead Compounds

ABSTRACT

Benzimidazole derivatives represent a privileged scaffold in medicinal chemistry and are continuously evaluated for their promising anticancer potential. Determining the ionization constants (pK _a ) of these drug candidates is critical for defining the properties of ADME. In the presented study, the liquid chromatographic behavior of acidic/basic nitrogen in the structure of synthetic compounds containing some benzimidazolium salts (SA‐92, SA‐93, SA‐112, and SA‐118) was determined in hydroorganic mixtures containing acetonitrile (ACN) and water at 37°C. The anticancer potential of the synthesized compounds was evaluated in the liver cancer cell line (HepG2) for 72 h. The findings revealed that two compounds (SA‐92 and SA‐93) exhibited inhibitory effects on cell proliferation in the cell line studied. The mechanism of action for the compounds' activity was explored through molecular docking and molecular dynamics (MD) simulations. The docking study revealed that compounds SA‐92 and SA‐93 could bind to EGFR. Together with this, the binding ability of the relatively active compounds was comparable to that of the complex ligand inside the crystal structure used. The MD simulation demonstrated that the protein‐compound SA‐92 complex was relatively stable and stayed inside the receptor's binding area. The in silico pharmacokinetic study revealed that the synthesized compounds have drug‐like characteristics.