Benzyl‐Functionalised Imidazolium Ionic Liquids as Lead Candidates Against Human Breast Cancer: An Integrated In Vitro and In Silico Screening Approach

ABSTRACT 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, CH 3 , F, Cl, Br, NO 2 , 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, CH 3 , F, Cl, and Br exhibited similar growth inhibition strength against MCF‐7 (IC 50 ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC 50 = 15.41 µM). However, the presence of NO 2 (IC 50 = 8.10 µM) and CN (IC 50 = 17.52 µM) significantly reduced their growth inhibition potentials (two‐ to four‐fold) in NIH 3T3 (IC 50 > 40 µM). The NO 2 ‐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 = NO 2 ) 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.