Abstract
This study investigates the formation and characteristics of inclusion complexes between β-cyclodextrin and two compounds: N-aminomorpholine hydrazone and its phthalimidine derivative. Structural features of the encapsulated forms of these new N-aminomorpholine derivatives were characterized using 1H and 13C NMR spectroscopy, as well as two-dimensional 1H─1H (COSY) and 1H─13C (HMBC, HSQC) NMR experiments. Using molecular modeling methods, the influence of structural factors and the principle of geometric complementarity on the complexation processes between the host and guest molecules were assessed. A conformational study of the guest molecules was carried out using the semiempirical GFN2-xTB method in combination with the GOAT algorithm. Employing density functional theory (DFT), the inclusion complexes were optimized at the ωB97X-D/6-311G(d,p) level, including aqueous solvation effects as described by the CPCM model. The thermodynamic parameters of complex formation were estimated. NMR analysis confirmed 1:1 stoichiometry and showed significant chemical shift perturbations for cavity protons, while DFT calculations revealed spontaneous complexation (ΔG°298 = −2.54 to −3.45 kcal/mol) driven by exothermic enthalpies and hydrophobic/van der Waals interactions, with an enantioselective preference for the R-phthalimidine enantiomer. These findings demonstrate β-CD's potential to enhance the solubility, stability, and bioavailability of these promising antiviral and antibacterial agents for pharmaceutical applications.