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

ABSTRACT: BACKGROUND:Fluconazole (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. RESULTS:Inclusion complex of fluconazole with beta-cyclodextrins (beta-CD) were investigated by applying NMR and molecular modelling methods. The 1:1 stoichiometry of FLZ:beta-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:beta-CD complexation. The shielding of cavity protons of beta-CD and deshielding of aromatic protons of FLZ in various 1H-NMR experiments show complexation between beta-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 beta-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 beta-CD from the wider end. CONCLUSION:Various NMR spectroscopic studies of FLZ in the presence of beta-CD in D2O at room temperature confirmed the formation of a 1:1 (FLZ:beta-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 beta-CD suggest some chiral differentiation of guest by beta-CD.

SUBMITTER: Upadhyay SK

PROVIDER: S-EPMC2739844 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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

Upadhyay Santosh Kumar SK Upadhyay Santosh Kumar SK Kumar Gyanendra G

Chemistry Central journal 20090810

<h4>Background</h4>Fluconazole (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 impor ...[more]

PMID: 19664263

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Project description:BACKGROUND:Flunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state. RESULTS:The structural assignments of FLN and ?-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, ?-CD and their mixtures confirmed the formation of ?-CD-FLN inclusion complex in solution. 1H NMR titration data for ?-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a = 157 M-1 and change in Gibbs free energy of ?G?=?- 12.65 kJ mol-1. The binding constant of the ?-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the ?-CD cavity. The possible geometrical structures of the ?-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the ?-CD truncated cone. CONCLUSION:NMR spectroscopic studies of FLN, ?-CD and FLN:?-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into ?-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of ?-CD. The splitting of aromatic signals of FLN in the presence of ?-CD suggests chiral differentiation of the guest FLN by ?-CD.

Dataset Information

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

Publications

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

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