Synthesis, characterization, and anticancer potential of novel NHC ligands and their selenium complexes: a combined in vitro and in silico investigation

Abstract

We report herein the efficient synthesis of new benzimidazolium salts (A1–A6) and their corresponding selenium-NHC complexes (B1–B6), along with the evaluation of their cytotoxicity profiles against two cancer cell lines (HCT116 and SH-SY5Y) and one normal cell line (BEAS-2B). The findings revealed that the benzimidazolium salts (A1–A6) exhibited significantly higher cytotoxicity toward all tested cell lines compared to their selenium derivatives (B1–B6). Among them, compounds A3, A4, and A5 showed the most potent cytotoxic effects, with IC₅₀ values ranging from 3.09 to 26.12 µM, approximately ten times lower than that of cisplatin. However, these compounds also exhibited relatively low IC₅₀ values in normal BEAS-2B cells, although still higher than those observed in the cancer cell lines, indicating a preferential cytotoxicity toward cancer cells. Structure–activity relationship analysis revealed that the benzimidazolium core acts as the pharmacophore of these compounds, while substitution on the aromatic ring—particularly with bulky groups—enhances cytotoxicity. Conversely, incorporation of the selenium atom was found to markedly reduce or even eliminate cytotoxicity up to concentrations of 800 µM. Further in silico studies were conducted to gain a deeper understanding of the molecular structures and chemical reactivity of these compounds. In addition, molecular docking studies against PARP-1 and tubulin highlighted the strong inhibitory potential of the most active compounds (A3, A4, and A5) toward both targets, suggesting their potential involvement in the observed cytotoxic effects. Overall, these investigations propose benzimidazolium salts A3, A4, and A5 as promising anticancer agents and highlight the selenium derivatives as non-toxic selenium-based NHC complexes. Further studies should be undertaken to optimize the biological activity of these compounds and to enhance their selectivity toward cancer cells.