Abstract
BackgroundFluconazole (FLZ) is a synthetic, bistriazole antifungal agent, effective in treating superficial and systemic infections caused by Candida species. Major challenges in formulating this drug for clinical applications include solubility enhancement and improving stability in biological systems. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocyles, and can easily encapsulate fluconazole inside their hydrophobic cavity. NMR spectroscopy has been recognized as an important tool for the interaction study of cyclodextrin and pharmaceutical compounds in solution state.ResultsInclusion complex of fluconazole with β-cyclodextrins (β-CD) were investigated by applying NMR and molecular modelling methods. The 1:1 stoichiometry of FLZ:β-CD complex was determined by continuous variation (Job's plot) method and the overall association constant was determined by using Scott's method. The association constant was determined to be 68.7 M-1 which is consistent with efficient FLZ:β-CD complexation. The shielding of cavity protons of β-CD and deshielding of aromatic protons of FLZ in various 1H-NMR experiments show complexation between β-CD and FLZ. Based on spectral data obtained from 2D ROESY, a reasonable geometry for the complex could be proposed implicating the insertion of the m-difluorophenyl ring of FLZ into the wide end of the torus cavity of β-CD. Molecular modelling studies were conducted to further interpret the NMR data. Indeed the best docked complex in terms of binding free energy supports the model proposed from NMR experiments and the m-difluorophenyl ring of FLZ is observed to enter into the torus cavity of β-CD from the wider end.ConclusionVarious NMR spectroscopic studies of FLZ in the presence of β-CD in D2O at room temperature confirmed the formation of a 1:1 (FLZ:β-CD) inclusion complex in which m-difluorophenyl ring acts as guest. The induced shift changes as well as splitting of most of the signals of FLZ in the presence of β-CD suggest some chiral differentiation of guest by β-CD.
Highlights
Fluconazole (FLZ) is a synthetic, bistriazole antifungal agent, effective in treating superficial and systemic infections caused by Candida species
Complexation of pharmaceutical compounds with cyclodextrins (CDs), to form a host-guest complex in solution as well as solid states, results in altered physicochemical properties of the guest, like solubility, stability, dispersibility, volatility, masking of undesirable properties and so on, which are desirable for their use as pharmaceuticals [4]
NMR spectroscopy has been recognized as an important tool for the structural elucidation of organic compounds, in solution state in view of its application in drug discovery
Summary
Inclusion complex of fluconazole with β-cyclodextrins (β-CD) were investigated by applying NMR and molecular modelling methods. The association constant was determined to be 68.7 M-1 which is consistent with efficient FLZ:β-CD complexation. The shielding of cavity protons of β-CD and deshielding of aromatic protons of FLZ in various 1H-NMR experiments show complexation between β-CD and FLZ. Based on spectral data obtained from 2D ROESY, a reasonable geometry for the complex could be proposed implicating the insertion of the m-difluorophenyl ring of FLZ into the wide end of the torus cavity of β-CD. The best docked complex in terms of binding free energy supports the model proposed from NMR experiments and the m-difluorophenyl ring of FLZ is observed to enter into the torus cavity of β-CD from the wider end
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