Host-Guest Interactions of Cucurbit[7]uril with Nabumetone and Naproxen: Spectroscopic, Calorimetric, and DFT Studies in Aqueous Solution

Abstract

The complexation of nabumetone (NAB) and naproxen (NAP) with cucurbit[7]uril (CB7) was investigated in aqueous solution by isothermal titration microcalorimetry, mass spectrometry, NMR spectroscopy, and computation methods. High-resolution mass spectrometry was used for the determination of the binding stoichiometry and the gas-phase stability of the drug-CB7 complex. The doubly charged NH₄⁺ or Na⁺ adducts of the 1:1 complex were observed in the mass spectra. The dissociation of complexes was monitored at different collision energies, (1-16) eV, leading to the neutral loss of NH₃ and the drug, with charge retention observed on CB7. By performing ITC experiments, all the thermodynamic parameters were determined for the NAB-CB7 complex in water at 25 °C. The corresponding values amounted to the following: logK = 4.66 ± 0.01; Δ_rG° = -26.7 ± 0.1 kJ/mol; Δ_rH° = -20.2 ± 0.7 kJ/mol; TΔ_rS° = 6.4 ± 0.8 kJ/mol, i.e., the formation of the inclusion complex is enthalpy driven and has a favorable entropy. The inclusion phenomena were further confirmed by NMR spectroscopy (¹H, ROESY, and DOSY), suggesting the encapsulation of the naphthalene ring of both drugs inside the CB7 cavity. The results of the DFT calculations and the IGMH analysis were in accordance with the experimental ones, suggesting that van der Waals interactions play a major role in drug-CB7 complexation.

Keywords: DFT; HR-MS; IGMH; ITC; NMR; cucurbit[7]uril; inclusion complex; nabumetone; naproxen.

Figure 1

Molecular structure of nabumetone (NAB), its active metabolite (6-MNA), naproxen (NAP), and cucurbit[7]uril.

Figure 2

ESI + HRMS spectrum of nabumetone and CB7 solution in molar ratio 1:1. c (NAB) = 2.15 × 10⁻⁵ M (a); enhanced view of ion signals between m/z 712 and 720 (b).

Figure 3

MS/MS spectrum of [CB7 + NAB + 2NH₄]²⁺ ion (m/z 713.2606) at 5 eV; inset showing enlarged spectral region between m/z 580 and 715.

Figure 4

ESI + HRMS spectrum of naproxen and cucurbituril7 solution in molar ratio 1:1. c(NAP) = 2.15 × 10⁻⁵ M (a); enhanced view of ion signals between m/z 713 and 722 (b).

Figure 5

The relative intensities of complex molecular ions [CB7 + NAP + 2NH₄]²⁺ (■) and [CB7 + NAB + 2NH₄]²⁺ (●) as a function of the collision energy (CE). Error bars represent the standard deviation for the quadriplicate analyses.

Figure 6

¹H NMR spectra of (a) CB7; (b) NAB-CB7 1:1 complex; and (c) NAB in D₂O at 25 °C.

Figure 7

A part of the ROESY spectrum, showing the intermolecular interactions of NAB with CB7 in a 1:1 complex in D₂O at 25 °C.

Figure 8

A part of the DOSY spectum of the NAB-CB7 1:1 complex in D₂O at 25 °C.

Figure 9

¹H NMR spectra of (a) CB7; (b) NAP-CB7 1:1 complex; and (c) NAP in pure D₂O at 25 °C.

Figure 10

(a) Microcalorimetric titration of NAB (c₀ = 48.9 × 10⁻⁶ mol L⁻¹) with CB7 (c₀ = 3.81 × 10⁻³ mol L⁻¹) in water at 298 K. (b) Dependence of normalized successive enthalpy changes on CB7/NAB molar ratio. ■ means experimental; ― means calculated.

Figure 11

The structure (left) and the IGMH analysis (right) of the NAB-CB7 1:1 host–guest complex. In the IGMH analysis, the isosurfaces of the δg^inter = 0.002 a.u. are colored with sign(λ₂)ρ in the range of −0.05 (blue), 0.00 (green), and 0.05 (red), revealing weak attractive interactions, van der Waals interactions, and repulsive interactions, respectively.

Figure 12

The structure (left) and the IGMH analysis (right) of the NAP(acid)–CB7 1:1 host–guest complex. In the IGMH analysis, the isosurfaces of the δg^inter = 0.002 a.u. are colored with sign(λ₂)ρ in the range of −0.05 (blue), 0.00 (green), and 0.05 (red), revealing weak attractive interactions, van der Waals interactions, and repulsive interactions, respectively.

Figure 13

The structure (left) and the IGMH analysis (right) of the NAP(anion)–CB7 1:1 host–guest complex. In the IGMH analysis, the isosurfaces of the δg^inter = 0.002 a.u. are colored with sign(λ₂)ρ in the range of −0.05 (blue), 0.00 (green), and 0.05 (red), revealing weak attractive interactions, van der Waals interactions, and repulsive interactions, respectively.