Computational insights into fenbendazole encapsulation by Cucurbit[n]urils (n = 7, 8): Implications for drug delivery and nanocarrier design through integrated structural, electronic, thermodynamic, and spectroscopic investigations.

Fenbendazole (fenben), a benzimidazole anthelmintic with emerging anticancer potential, faces significant challenges in clinical applications due to its poor aqueous solubility and potential toxicity at high doses. To address these limitations, this study explores the encapsulation of fenben within cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) using computational methods to evaluate host-guest interactions, stability, and electronic properties. Density functional theory (DFT) calculations at the APFD/6-31+G(d) level revealed that CB[7] forms more stable complexes with fenben than CB[8], with interaction energies (ΔEinter) reaching between -30 and -38 kcal mol-1 in the gas phase and between -27 and -37 kcal mol-1 in aqueous media. Non-covalent interaction (NCI) and electrostatic potential (ESP) analyses highlighted the role of hydrogen bonding and van der Waals forces in stabilizing these complexes. Notably, the encapsulation significantly altered fenben's conformational rigidity, as evidenced by dihedral angle distortions. Thermodynamic parameters confirmed the favorability of complexation, with Gibbs free energy (ΔG) values as low as -15.11 kcal mol-1 for CB[7]. These computational predictions are further supported by experimental 1H NMR and UV-vis spectroscopy, which confirm the formation of a stable inclusion complex between fenben and CB[7] in aqueous solution. These findings underscore CB[7]'s superior potential as a drug delivery vehicle for fenben, offering enhanced solubility and reduced toxicity, while providing molecular-level insights into the design of supramolecular drug delivery systems.