NMR and molecular modelling studies on the interaction of fluconazole with β-cyclodextrin (original) (raw)
Related papers
NMR and molecular modelling studies on the interaction of fluconazole with beta-cyclodextrin.
"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."
Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2012
The inclusion complex between the anti-helminthic drug thiabendazole (TBZ) and the b-cyclodextrin (bCD) was characterized in solution using fluorescence and 1 H-Nuclear Magnetic Resonance spectroscopy and studied theoretically by semi empirical PM3 and density functional theory (DFT) quantum mechanical calculations. Thermodynamic stability associated with the formation of the TBZ:bCD inclusion complex in aqueous solution was determined treating the drug's fluorescence enhancement in the presence of cyclodextrin by a non-linear model, which indicated a moderate host-guest affinity at equilibrium (K 150 ± 31 at 25°C). Its supramolecular structure in solution was studied through the 1D-ROESY NMR experiment, which produced evidence that the guest molecular encapsulation occurs preferably via the drug's benzimidazole group. Theoretical study employing molecular optimization with the semi empirical PM3 method provided two energetic-equivalent complex structures that are in accordance with the NMR experimental evidences. Single point energy calculations with DFT at the B3LYP/6-31G (d,p) level suggest the most stable structure of the inclusion complex and further comprehension on the interactions and conformational strains involved in its formation.
Journal of inclusion phenomena and macrocyclic chemistry, 2018
Spectroscopic investigation supported by molecular modeling methods has been used to describe the inclusion complex of β-cyclodextrin (β-CD) with 1-Methyl-1-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl) piperidinium chloride (1MPTMPC) in solution and in solid state. The formation of inclusion complex between the β-CD and the 1MPTMPC has been investigated both in solution and in the solid state. Solution-state complexation between the 1MPTMPC and β-CD was established using 1 H NMR spectroscopy and isothermal titration calorimetry (ITC). From the 1 H NMR spectroscopic studies, 1:1 complex stoichiometry was deduced with an association constant (K) of 925 M −1. Using an independent binding model, the ITC technique provides a K value of the same order with the one determined by NMR and the thermodynamic parameters ΔH, ΔS and ΔG which reveals driving forces involved during complex formation. The formation of the solid inclusion compound was confirmed by X-ray powder diffraction and differential scanning calorimetry. The most probable conformation of the inclusion complex obtained through a molecular docking investigation corroborates well to ROESY experiment.
The Journal of Physical Chemistry C, 2015
Characterization of the structure and dynamics for the solid inclusion complexes (ICs) between β-cyclodextrin (β-CD; host) and sodium perfluorooctanoate (SPFO; guest) was carried out using 1 H/ 19 F/ 13 C NMR spectroscopy. The 1:1 and 2:1 β-CD/SPFO solid complexes were prepared by a modified dissolution method. Evidence for the formation of β-CD/SPFO ICs was provided by 13 C DP (direct polarization) and CP (cross-polarization) solid-state NMR spectroscopy with magic angle spinning (MAS) at 20 kHz. The complexation-induced shifts (CIS) of 1 H/ 19 F/ 13 C nuclei between solution and the solid state for β-CD/SPFO complexes and the closely related complexes of β-CD/PFOA (perfluorooctanoic acid) were compared. The counterion effect for SPFO and PFOA was observed according to their variable structure and binding as inclusion compounds with β-CD. The effect of sodium versus hydronium counterions on the structure and dynamics of inclusion complexes for these systems was supported by DSC, TGA, FT-IR, and powder X-ray diffraction (PXRD). Simulations of the CF 3 19 F NMR with MAS at 25 kHz and selected dipolar coupling strengths were utilized in conjunction with deconvolution analyses of the experimental CF 3 lineshapes to probe the dynamic properties of SPFO and its complexes with β-CD. The dynamics of the guest are influenced by the host/guest binding geometry and the stoichiometry of the complex, where free rotation of the CF 3 group as well as rotations of the C−F bonds occur. 19 F DP/MAS NMR results and spin−lattice (T 1) and spin−spin (T 2) relaxation times in the laboratory frame at variable temperatures in the solid phase indicate that the dynamics of SPFO in β-CD/SPFO complexes are unique compared to those of PFOA in β-CD/PFOA complexes, due to the role of counterion effects of the guest.
The Journal of Physical Chemistry B, 2013
The structural characterization of solid-and solution-state inclusion complexes (ICs) of β-cyclodextrin (β-CD; host) with perfluorobutyric acid (PFBA; guest) is presented in this study. Complexes in the solid state were prepared at various host/guest mole ratios (i.e., 1:1 and 2:1) using a modified dissolution method. Thermal analyses and multinuclear 13 C NMR methods employing direct polarization (DP) and cross-polarization (CP) techniques with magic angle spinning (MAS) and high-power 1 H/ 19 F decoupling were used to characterize the solid-state host−guest complexes. Unequivocal evidence of the formation of β-CD/PFBA inclusion compounds was provided using 19 F → 13 C CP/MAS NMR results. Powder X-ray diffraction reveals that PFBA forms a "cage-type" structure with β-CD, in which the guest adopts gauche and near-linear conformations in the 1:1 and 2:1 complexes, respectively, according to Fourier transform infrared spectroscopy results. Interpretation of the NMR splitting patterns of PFBA spectrum in solution reveals that PFBA undergoes fast rotation of the CF 3 group on a 3-fold axis, while the remainder of the chain experiences a significant C−C bond rotation; hence, it is not locked in a particular rotamer configuration. The distribution of the rotational and axial motions in the β-CD/PFBA complexes in the solid state as revealed by NMR relaxation dynamic studies is a function of the host/guest mole ratios and is determined by the binding geometry of the guest.
Journal of Pharmaceutical and Biomedical Analysis, 2006
Praziquantel (PZQ) is a broadly effective anthelminthic drug available for human and veterinary use, being the drug of choice for the treatment of all forms of schistosomiasis. Nevertheless, large doses are required in order to achieve adequate concentrations at the target site due to the poor solubility of PZQ and its significant first pass metabolism. To improve it, avoiding efficiency loss, we have designed a controlled-release system, in which PZQ was encapsulated in -cyclodextrin (-CD). The inclusion complexes between PZQ/-CD were studied at two different stoichiometries 1:1 and 1:2, through experimental and theoretical analysis. Molecular modeling calculations were used to foresee the better stoichiometry of the complex formed as well as the possible orientations of PZQ inside the -CD cavity. The complexes prepared were analyzed through 1 H two-dimensional nuclear magnetic resonance ( 1 H 2D-NMR) experiments, which provide (evidences) for the 1:1 complexation of PZQ/-CD. 1 H 2D-NMR also revealed details of PZQ/-CD molecular interaction, in which the isoquinoline ring of praziquantel is located inside the -CD cavity. Finally, phase-solubility diagrams revealed a five-fold increase in praziquantel water solubility upon addition of increasing -CD concentrations up to 16 mM, corresponding to the solubility of -CD itself. The solubilization profile is consistent with 1:1 stoichiometry of the PZQ/-CD complex while the solubilization effect will certainly increase the pharmacological activity of praziquantel.
Journal of Pharmaceutical and Biomedical Analysis, 2006
Praziquantel (PZQ) is a broadly effective anthelminthic drug available for human and veterinary use, being the drug of choice for the treatment of all forms of schistosomiasis. Nevertheless, large doses are required in order to achieve adequate concentrations at the target site due to the poor solubility of PZQ and its significant first pass metabolism. To improve it, avoiding efficiency loss, we have designed a controlled-release system, in which PZQ was encapsulated in -cyclodextrin (-CD). The inclusion complexes between PZQ/-CD were studied at two different stoichiometries 1:1 and 1:2, through experimental and theoretical analysis. Molecular modeling calculations were used to foresee the better stoichiometry of the complex formed as well as the possible orientations of PZQ inside the -CD cavity. The complexes prepared were analyzed through 1 H two-dimensional nuclear magnetic resonance ( 1 H 2D-NMR) experiments, which provide (evidences) for the 1:1 complexation of PZQ/-CD. 1 H 2D-NMR also revealed details of PZQ/-CD molecular interaction, in which the isoquinoline ring of praziquantel is located inside the -CD cavity. Finally, phase-solubility diagrams revealed a five-fold increase in praziquantel water solubility upon addition of increasing -CD concentrations up to 16 mM, corresponding to the solubility of -CD itself. The solubilization profile is consistent with 1:1 stoichiometry of the PZQ/-CD complex while the solubilization effect will certainly increase the pharmacological activity of praziquantel.
Praziquantel (PZQ) is a broadly effective anthelminthic drug available for human and veterinary use, being the drug of choice for the treatment of all forms of schistosomiasis. Nevertheless, large doses are required in order to achieve adequate concentrations at the target site due to the poor solubility of PZQ and its significant first pass metabolism. To improve it, avoiding efficiency loss, we have designed a controlled-release system, in which PZQ was encapsulated in -cyclodextrin ( -CD). The inclusion complexes between PZQ/ -CD were studied at two different stoichiometries 1:1 and 1:2, through experimental and theoretical analysis. Molecular modeling calculations were used to foresee the better stoichiometry of the complex formed as well as the possible orientations of PZQ inside the -CD cavity. The complexes prepared were analyzed through 1H two-dimensional nuclear magnetic resonance (1H 2D-NMR) experiments, which provide (evidences) for the 1:1 complexation of PZQ/ -CD. 1H 2D-NMR also revealed details of PZQ/ -CD molecular interaction, in which the isoquinoline ring of praziquantel is located inside the -CD cavity. Finally, phase-solubility diagrams revealed a five-fold increase in praziquantel water solubility upon addition of increasing -CD concentrations up to 16 mM, corresponding to the solubility of -CD itself. The solubilization profile is consistent with 1:1 stoichiometry of the PZQ/ -CD complex while the solubilization effect will certainly increase the pharmacological activity of praziquantel.
Complexation of fluvastatin sodium with β-cyclodextrin: NMR spectroscopic study in solution
2006
1 H NMR spectroscopic study of fluvastatin sodium (FLU), b-Cyclodextrin (b-CD) and their mixtures confirmed the formation of FLU/b-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (K s) was calculated to be 340 M)1. Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the b-CD cavity and there is chiral differentiation by the b-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the b-CD cavity was also established and structure of the complex has been proposed.