Enhancing the stability and solubility of esculetin by cucurbit[n]uril (n = 6-8) encapsulation: A computational study...

Esculetin (Eu) is a naturally occurring secondary metabolite with ethnopharmacological significance and is widely used as an anti-inflammatory, antimicrobial, and anticancer drug, but it has poor aqueous solubility. To address this limitation, this study explores encapsulating Eu within cucurbit[n]urils (n = 6-8) using density functional theory (DFT) methods and evaluates the resulting structure, stability, and electronic properties. DFT calculations at the Domain-based Local Pair Natural Orbital Coupled-Cluster with Singles, Doubles, and perturbative Triples, DLPNO-CCSD(T)/def2-SVP//M06-2X-D3/6-31G(d) method revealed that CB[6] forms a more stable complex with Eu than CB[7] and CB[8]. Thermodynamic parameters confirm the formation of the inclusion complexes, with a larger Gibbs free energy and enthalpy change for the Eu complex with CB[6] than for the other studied inclusion complexes. Frontier orbitals and their energy gaps show that the complexes share similar features with Eu. Noncovalent interaction analysis (NCI) and Independent Gradient Model (IGM) analyses showed hydrogen bonding between the phenolic group of Eu and CB[n], with a cooperative effect of van der Waals interactions predominantly in the Eu@CB[6] complex. Quantum Theory of Atoms in Molecules (QTAIM), Dispersion Interaction Density (DID), and Local Energy Decomposition (LED) analyses show that hydrogen bonding between Eu and the carbonyl portal of CBs plays a major role in stabilization, with a significant attractive electrostatic contribution, followed by dispersion and exchange terms. LED analysis shows that Eu@CB[6] has the highest preparation energy, followed by the dispersion interaction, while the DID analysis shows a continuous dispersion density around the carbonyl portal. Born-Oppenheimer molecular dynamics show that Eu remains inside the cavity throughout the simulation for CB[6] and CB[8], whereas in CB[7] the guest gets expelled from the cavity. Overall, the findings show that the Eu molecule can be encapsulated inside CB[6], and the complex shows higher polarity and improved solubility in polar solvents, with higher kinetic and chemical stability.