NMR and molecular modelling studies on the interaction of fluconazole with β-cyclodextrin

Inclusion 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.Various 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.Fluconazole (FLZ), diflucan, chemically known as α-(2,4)-difluorophenyl)-α-(1H-1,2, 4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol (figure 1), used to treat variety of fungal pathogens that cause systemic mycoses. It is an orally active bistriazole antifungal agent, well absorbed and has been found to be safe and effective in treating superficial and systemic infections with Candida species and maintenance therapy for cryptococcal meningitis, particularly in patients with AIDS [1]. It is also effective in preventing invasive Candida infections in patients