氟康唑衍生物的设计合成及体外抗真菌活性研究

为了寻找活性更好的抗真菌化合物,基于已有的计算机辅助药物设计结果,保留氟康唑母体结构必需药效团,设计、合成了22个含对甲酚和胸腺嘧啶的氟康唑新衍生物.目标化合物的结构经1H NMR、元素分析和ESI-MS确证,初步体外抗真菌活性试验结果表明,化合物5l对7种真菌都表现出了较好的抗真菌活性(烟曲霉菌除外),化合物5a～5e,5g,5h,7a和7b对不同真菌表现出了一定的抗真菌活性.炔丙基取代氨基侧链结构的引入有利于提高该类目标化合物体外抗真菌活性,值得进一步深入研究.     

Properties and limits of some essential oils: chemical characterisation,antimicrobial activity,interaction with antibiotics and cytotoxicity

Because of the emergence of multi-drug resistance bacteria and fungi, alternatives to conventional antimicrobial therapy are needed. This study aims to evaluate in vitro the antimicrobial activity of: Mirtus communis, Coriandrum sativum, Pelargonium capitatum, Cuminum cyminum, Ocimum basilicum, Citrus aurantium amara, Cymbopogon. winterianus, Cymbopogon martini, Salvia sclarea, Melaleuca alternifolia and Mentha suaveolens essential oils on bacteria and fungi, in relation to their chemical composition. The potential interaction of M. alternifolia (TTO), C. sativum (CDO) and M. suaveolens (EOMS) essential oils when used in combination with gentamicin and fluconazole has been evaluated. The results obtained showed a synergic effect on some bacteria and fungi, with FICI values ≤5. The cytotoxicity of TTO, CDO and EOMS was investigated towards HeLa cells. Only EOMS did not result cytotoxic at the active concentrations on micro-organisms. Further studies are necessary to obtain optimal ratios and dosing regimens for higher therapeutic efficacy and to decrease toxicological profiles.     

Total Aseptization of Boar Semen,to Increase the Biosecurity of Reproduction in Swine

The aim of the study was to establish the complete microbiological profile of boar semen (Sus scrofa domesticus) and to choose the most effective antiseptic measures in order to control and optimize AI reproduction in pig farms. One hundred and one semen samples were collected and analyzed from several pig farms. The microbiological profile of ejaculates was determined by evaluating the degree of contamination of fresh semen and after dilution with specific extenders. The bacterial and fungal load of fresh boar semen recorded an average value of 82.41/0.149 × 10³ CFU/mL, while after diluting the ejaculates the contamination value was 0.354/0.140 × 10³ CFU/mL. Twenty-four germs (15 bacterial and 9 fungal species) were isolated, the most common being Candida parapsilosis/sake (92%) and Escherichia coli (81.2%). Modification of the sperm collection protocol (HPBC) reduced contamination in raw sperm by 49.85% in bacteria (significant (p < 0.00001) and by 9.67% in fungi (non-significant (p < 0.111491). The load in bacteria and filamentous fungi can be controllable, but not in levuras fungi. Some fluconazole-added extenders (12.5 mg%), ensure fungal aseptization, and even an increase in sperm progressivity (8.39%) for at least a 12 h shelf life after dilution. Validation of sperm aseptization was done by maintaining sow fecundity unchanged after AI (insignificant p > 0.05).     

Synthesis and polypyrrole-loading study of antifungal medicine fluconazole functionalized Keggin polyoxotungstates

To rich the coordination polymer and polyoxometalate (POM) chemistry, two new hybrid compounds based on Keggin POMs with antifungal medicine fluconazole (Hfkz = [1-(2,4-difluorophenyl)-1,1-bis [(1H-1,2,4-triazol-1-yl)-methyl]methanol]), [Ag₄(Hfkz)₂][PW₁₂O₄₀] (AgFkzPW₁₂) and [Ag₄(Hfkz)₂][SiW₁₂O₄₀] (AgFkzSiW₁₂), have been successfully synthesized and structurally characterized. Moreover, to improve the photogenerated electron-hole pair separation properties, the surface of hybrid compounds was loaded by polypyrrole (PPy) through a chemical oxidation polymerization process in situ fabricating hybrid nanocomposites AgFkzPW₁₂@PPy and AgFkzSiW₁₂@PPy. As a result, the Hfkz molecules were successfully grafted onto the surface of the Keggin polyoxoanions, and their nanocomposites exhibit better photocatalytic activity than the respective matrix compounds under the irradiation of visible light.     

HPLC‐DAD for the determination of three different classes of antifungals: method characterization,statistical approach,and application to a permeation study

This study describes and characterizes methods for high‐performance liquid chromatography diode array detection (HPLC‐DAD) analysis of formulations containing molecules with antifungal activity of three different classes: terbinafine and butenafine (allylamines), miconazole and fluconazole (azoles), and geraniol, neral and geranial (monoterpenes). All methods used the same chromatographic column (RP₁₈), enabling the analysis to be performed in a single batch. The specificity was extensively discussed through the establishment of purity peak methods. The analytical parameters (linearity, precision and accuracy) were calculated and discussed in detail using specific statistical approaches. All substances showed satisfactory results for chromatographic and analytical parameters. Limits of 1.3% to mean repeatability and 2.0% for intermediate precision are suggested as acceptance criteria in validation of methods by HPLC‐DAD, in situations where there is no extensive pretreatment of the samples. The methods proved to be robust and significant factors were discussed regarding their influence on chromatographic parameters (retention time, resolution, tailing factor and column efficiency). Finally, the application of the developed methods was demonstrated by the results of a permeation study of the antifungal agents through bovine hoof membranes. Copyright © 2014 John Wiley & Sons, Ltd.     

Hydrogen ADPs with Cu Kα data? Invariom and Hirshfeld atom modelling of fluconazole

For the structure of fluconazole [systematic name: 2‐(2,4‐difluorophenyl)‐1,3‐bis(1H‐1,2,4‐triazol‐1‐yl)propan‐2‐ol] monohydrate, C₁₃H₁₂F₂N₆O·H₂O, a case study on different model refinements is reported, based on single‐crystal X‐ray diffraction data measured at 100 K with Cu Kα radiation to a resolution of sin θ/λ of 0.6 Å⁻¹. The structure, anisotropic displacement parameters (ADPs) and figures of merit from the independent atom model are compared to `invariom' and `Hirshfeld atom' refinements. Changing from a spherical to an aspherical atom model lowers the figures of merit and improves both the accuracy and the precision of the geometrical parameters. Differences between results from the two aspherical‐atom refinements are small. However, a refinement of ADPs for H atoms is only possible with the Hirshfeld atom density model. It gives meaningful results even at a resolution of 0.6 Å⁻¹, but requires good low‐order data.     

Two Crystal Forms of a Hydrated 2:1 β-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures,Dehydration Profiles,and Conditions for Their Individual Isolation

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ.     

Validated HPLC method for the determination of fluconazole in human plasma

A high-performance liquid chromatographic assay with UV detection was developed for the determination of fluconazole in human plasma. The method utilized solid-phase extraction for sample clean-up. The separation was performed on a C18 column by isocratic elution with a mobile phase of 10 mM acetate buffer at pH 5.0 and methanol and UV detection at 210 nm. Validation was performed according to the current recommendations of the USFDA bioanalytical method validation guidance. The method proved to be specific, accurate, precise and linear between 200 and 10,000 ng/mL with correlation coefficients greater than 0.999. The coefficient of variation was within 11% and relative deviation was less than 10%.     

Dinuclear Nickel（Ⅱ） Complex with a Rare Ni（μ2-O）3Ni Core： Crystal Structure and Magnetic Studies

The first triple μ2-O-bridged dinuclear Ni(II) complex, [Ni2(Flu)3](ClO4)·(H2O) (1, HFlu = 2-(2′,4′-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol), has been synthesized and structurally and magnetically characterized. Complex 1 crystallizes in monoclinic, space group P21/n with a = 12.7143(3), b = 21.3392(6), c = 17.6497(5), β = 106.142(2)o, V = 4599.8(2)3, Z = 4, μ(MoKα) = 0.975 mm-1, Dc = 1.662 g/cm3, GOF = 0.83, the final R (I > 2σ(I)) = 0.0503 and wR (all data) = 0.1288. In 1, three Flu anions encapsulate two nickel(II) ions bridged by three deprotonated μ2-O groups. The central alkoxo and terminal triazolyl group chelate one nickel(II) in a six-membered boat configuration. Variable temperature magnetic susceptibilities show an intramolecular anti-ferromagnetic interaction between the Ni(II) ions with J = -26.7(3) cm-1.     

Thermal analysis in evaluation of the radiochemical stability of some fungicidal drugs

Four azole derivatives showing antimycotic activity (Miconazole, Ketoconazole, Clotrimazole, Fluconazole) in solid phase were exposed to beta irradiation at the dose of 20-200 kGy and then alterations in the physicochemical properties of the above derivatives were studied using the methods: scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. It was found that the compounds irradiated with sterilising doses (20-50 kGy) showed no significant alterations in their physicochemical properties, while application of doses >50 kGy resulted in small changes in the X-ray diffraction patterns and in the course of DSC curves, including a decrease in the melting points and enthalpy of the process. For Miconazole and Fluconazole, a linear and relatively strong correlation was found (from r =0.9782 to r =0.9003) between the size of the dose of irradiation and the decrease in the melting point and enthalpy value. This revised version was published online in July 2006 with corrections to the Cover Date.