Deciphering the role of flutamide, fluorouracil, and furomollugin based ionic liquids in potent anticancer agents: Quantum chemical, medicinal, molecular docking and MD simulation studies

• Thermodynamic study reveals the spontaneous formation of IL pairs. • AIM and IGMH reveals the H-Bonding and non-covalent interactions. • The metabolic pathway supports the pharmacokinetic profile of a drug. • Molecular docking for structure activity of ligands and proteins for anticancer therapy. Ionic liquids (ILs) have emerged as a versatile candidate in medicinal chemistry, electrochemistry catalysis, and biotechnology. In this work, we explored the electronic interionic interactions, stability, and reactivity of FDA approved drug-based cations flutamide ([FT1] + , [FT2] + ) , fluorouracil ([FU1] + ) , and furomollugin ([FM1] + , [FM2] + ) , paired with amino acid [NH] − , nitrate [NO 3 ] − , and triflate [CF 3 ] − anions, in gas and solvent phases (benzene and water). Frontiers molecular orbitals (FMOs) showed that [FT1] + [NH] – exhibits the smaller E gap on both gas and solvent phase from 5.24 to 4.39 eV, suggesting high reactivity and increasing solubility. Notably, the IL pair [FT1] + [NH] – possessed substantial interaction energies in the gas phase (−426.64 kcal/mol), in benzene (−390.24 kcal/mol), and in water (−369.69 kcal/mol), highlighting its potential to disrupt cancer cell growth and exhibit strong anticancer efficacy. The stability of [FT1] + [NH] – was further corroborated by significant Gibbs free energy and enthalpy values (−545.30 and −560.36 kcal/mol). Bioinformatics studies reveal that our studied ILs possess superior drug-likeness along with supportive medicinal chemistry parameters. Such as, toxicity evaluation based on the TOX21 pathway confirmed the non-toxic attributes of these ILs, bolstering their potential as antitumor drugs. The metabolic prediction for [FM1] + was consistent with its expected behavior in the biological system with its likelihood ranging from 89 % to 83 %. Additionally, in silico docking investigations against the protein (PDB ID: 1B38) showed that all designed ligands [FT1] + , [FT2] + , [FU1] + , [FM1] + , and [FM2] + display binding affinities values of −7.82, −6.30, −6.09, −5.86, and −7.72 kcal/mol superior to both the reference and reported drug fluorouracil. Molecular dynamics (MD) simulation reinforced the docking results by utilizing root mean square deviation (RMSD) values of [FT1] + varies from 0.147387 to 0.539310 Å and [FM2] + lies between 0.138098 Å and 0.583763 Å and root means square fluctuation (RMSF) values for [FT1] + was 0.069428–0.298235Å and [FM2] + 0.070097–0.364413Å provides insight into stability and the time-dependent atomic deviations. In addition, Ramachandran plots indicate that >90 % of residues occupy the favored regions supporting the protein structure stability. Thus, these analyses confirm that the newly identified ILs exhibit superior binding affinities and acceptable bioinformatics profiles, making them attractive candidates for the development of anticancer drugs.