Benzyl-Functionalised Imidazolium Ionic Liquids as Lead Candidates Against Human Breast Cancer: An Integrated In...

The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selectivity and efficacy. In this study, a new series of benzyl functionalised imidazolium ILs with varying para substituents (R = H, CH₃, F, Cl, Br, NO₂, CN) is reported. Their cytotoxicity against human neuroblastoma (SHSY-5Y), estrogen-positive breast cancer cells (MCF-7), neuroblastoma (SHSY-5Y), lung carcinoma (A549), liver cancer cells (HepG2), colorectal adenocarcinoma (HT-29), and mouse embryonic fibroblasts (NIH 3T3) was evaluated. The ILs were cytotoxic against all tested cell lines but were generally more selective toward MCF-7. ILs bearing H, CH₃, F, Cl, and Br exhibited similar growth inhibition strength against MCF-7 (IC₅₀ ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC₅₀ = 15.41 µM). However, the presence of NO₂ (IC₅₀ = 8.10 µM) and CN (IC₅₀ = 17.52 µM) significantly reduced their growth inhibition potentials (two- to four-fold) in NIH 3T3 (IC₅₀ > 40 µM). The NO₂-containing IL had a broad safety window against MCF-7 (selectivity index > 4). All the ILs have high drug-likeness (complied with all criteria stated in Lipinski's rule of five and Veber's rule). The most selective IL against MCF-7 (R = NO₂) induced caspase-dependent but reactive oxygen species independent pro-apoptosis in MCF-7 cells. Substituent modifications in the benzyl group regulated cytotoxicity and selectivity, thus reinforcing ILs as a valuable platform for the development of a new class of effective anticancer lead compounds.