Novel benzimidazole-1, 3, 4-thiadiazole derivatives as casein kinase-2 inhibitors: synthesis, in vitro and in silico investigations.

A new set of benzimidazole-thiadiazole derivatives has been designed and synthesized using 2-(chloromethyl)-1H-benzo[d]imidazole (1). Compounds 4a-m were achieved by amide bond formation using acid chlorides and pyridine in 1, 2-dichloroethane. The newly synthesized compounds were characterized and subjected to cytotoxicity studies against HeLa cells. Compounds 4c, 4 d, and 4e exhibited good inhibitory activity with IC₅₀ values of 15, 25, and 25 µM, respectively. Molecular docking studies were performed to elucidate the binding interactions of compounds 4c and 4e with human Casein kinase-2 (CK2). Compound 4c exhibited maximum cytotoxicity against HeLa cells with the lowest binding energy values of -8.61 kcal/mol towards CK2. Compound 4c underwent molecular dynamics (MD) simulations to assess their stability and interactions within the active site. Density functional theory (DFT) calculations also provided insights into the synthesised compounds' electronic structure, reactivity, and charge distribution.