Formation Of Equimolar Complex Research Articles

Density functional theory study of equimolar complexation of urea or thiourea with 2-alcoxybenzamide

The equimolar complexation behavior of urea or thiourea with 2-alcoxybenzamides has been studied by theoretical calculations. Structural models for the calculation were constructed from the X-ray crystallographic structures of 2-methoxybenzamide (MB) crystal and 2-ethoxybenzamide (EB)-thiourea, MB-thiourea, and MB-urea equimolar cocrystals. Structural optimization for EB—urea equimolar cocrystal was performed by the density functional theory (DFT) method (B3LYP/6-31G** level) and the complexation energy was determined using the DFT with higher order basis set (6–31+G**). Energetic stabilization by the equimolar complexation was observed in the three equimolar complexes. The reason why the amide group of MB is out-of-plane in unprocessed MB crystals is well explained by the calculations. It was suggested that intermolecular hydrogen bonding increases in the out-of-plane structure of MB and that subsequently leads to stabilization in the crystal. The amide group of MB or EB was inplane by the complex formation with urea or thiourea. Finally, we predict the possibility of EB-urea equimolar complex formation in terms of the complexation energy.

Comparative analysis of binary and ternary cyclodextrin complexes with econazole nitrate in solution and in solid state

The aim of this work was to investigate in-depth interactions of econazole nitrate (ECN), a very poorly water-soluble antifungal agent, with different β-cyclodextrin (βCD) derivatives, and to evaluate the potential synergistic effect of suitable third compounds (l-amino acids, citric acid, hydrophilic polymers). Phase-solubility studies showed the formation of equimolar complexes with all tested CDs, and indicated sulfobutyl-βCD (SBEβCD) as the best complexing and solubilizing agent for ECN, followed by hydroxypropyl-βCD (HPβCD). 1D and 2D 1H NMR studies demonstrated the actual formation of inclusion complexes of 1:1mol:mol stoichiometry, and gave insight about different inclusion modes of ECN molecule into the CD cavity, simultaneously existing in solution. Among the different tested ternary systems, only those with citric acid (CA) enabled a significant increase in complexing and solubilizing ability towards the drug with respect to the binary ones, indicating a synergistic effect between SBEβCD and CA and the formation of highly soluble ternary complexes, which was further supported by NMR studies. Solid equimolar binary and ternary systems of ECN, CDs and CA were prepared by co-grinding in high energy vibrational micro-mills and characterized by differential scanning calorimetry, X-ray powder diffractometry and in vitro dissolution studies. In the case of binary systems, total sample amorphization, indicative of strong solid state interactions and possible inclusion complex formation, was obtained only for co-ground products with HPβCD and SBEβCD, but they both presented a dissolution profile typical of a supersaturated system, with a limited improvement of drug dissolution efficiency (8.3 and 22.13 times, respectively). On the contrary, the ternary ECN/SBEβCD/CA co-ground product presented superior dissolution properties, increasing the ECN dissolution efficiency of 66.62 times, clearly having the best potential for further development of a novel ECN delivery system for efficient delivery of the drug to the oral cavity, thus improving the therapy of oral candidosis.

Thermodynamic study of inclusion complexes of zaleplon with natural and modified cyclodextrins

The thermodynamics and stoichiometry of zaleplon (ZAL) complexation with different cyclodextrin derivatives [β-CD, hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated-β-cyclodextrin (RAMEB), sulphobutylether-β-cyclodextrin (SBE-β-CD)] in aqueous solution was studied by spectrofluorimetry and 1H NMR spectroscopy in order to obtain a more general understanding of the driving forces behind the inclusion phenomena. Job’s plot derived from the NMR spectral data and statistical analysis of spectrofluorimetric titration data confirmed the formation of equimolar complexes in all systems tested, excluding the possibility of higher order complex formation. Furthermore, thermodynamic parameters obtained by both techniques gave similar and negative values of ΔG° for all complexes, indicating spontaneous inclusion of drug into CDs. From a thermodynamic point of view, two types of inclusions were determined. One is enthalpy driven ZAL complexation with β-CD, HP-β-CD and RAMEB, while the other is entropy driven complexation observed in the case of SBE-β-CD. The mechanisms behind each type of inclusion were discussed in detail.

Host–guest system of etodolac in native and modified β-cyclodextrins: preparation and physicochemical characterization

Etodolac, being a practically insoluble candidate, exhibits certain toxic effects and a limited bioavailability. Upon chronic use, it causes gastro-intestinal injury and increases the risk of ulcer complications. The approach of this study was to improve the physicochemical properties of the drug utilizing complexation phenomenon with β-, methyl-β- and hydroxypropyl-β-cyclodextrins, which may enhance the aqueous solubility and dissolution rate of etodolac, in an effort to increase oral bioavailability. In certain instances, this approach can be used to increase drug solubility, improve organoleptic properties and maximize the gastrointestinal tolerance by reducing drug irritation after oral administration. Differential UV measurements as well as continuous variation plots revealed the formation of equimolar complex with hydroxypropyl-β-cyclodextrin and 1:2 complexes with β-cyclodextrin and its methyl derivative. Differential scanning calorimetry (DSC), X-ray and FT-IR measurements were applied to prove inclusion complex formation and characterize the complexes. These results lend support to the idea that solubilization of etodolac is mainly related to inclusion complex formation and to a lesser extent to cyclodextrin aggregates. Understanding the factors that influence the performance of etodolac, will allow us to state that molecular encapsulation of the drug and other modifications with appropriate hydroxylation or methylation of parent β-cyclodextrin is able to overcome its problems and facilitate safe and efficient delivery of the drug.

Structure of palladium(II) complexes with nitrilotrimethylenephosphonic acid in aqueous solutions according to 31P and 1H NMR data

The complex formation in the K2PdCl4-nitrilotrimethylenephosphonic acid (NTMP) system with a metal to ligand molar ratio of 1: 1 and 1: 2 was studied by 31P and 1H NMR spectroscopy. The formation of equimolar complexes with NTMP coordinated in the bidentate ([N,O]) and tridentate ([N,O,O]) fashions depending on the reactant and chloride ion concentrations and solution pH was observed.

Palladium(II) complexes with 1-hydroxyethylidene-1,1-diphosphonic acid

Complex formation in a K2PdCl4-HEDP system (HEDP is 1-hydroxyethylidene-1,1-diphosphonic acid) at the metal-to-ligand ratios 1 : 1 and 1 : 2 is studied by 31P and 1H NMR spectroscopy. The formation of equimolar complexes, in which HEDP is coordinated to palladium(II) in a bidentate mode through two oxygen atoms of the phosphonic groups, is found in these systems. The structure and charge characteristics of conformers of the complexes are simulated by the quantum-chemical methods.

Equimolar Complex Formation of Urea or Thiourea with 2-alkoxy-benzamides: Structural Factors Required for the Equimolar Complex Formation

Equimolar complex formation of either urea or thiourea with 2-ethoxy-benzamide (2-EB) and 2-methoxy-benzamide (2-MB) was investigated. Complex formation of urea and 2-MB was observed both by co-grinding method and by coprecipitation method. Molecular arrangement of the complex was determined by single crystal X-ray diffraction method as an equimolar complex. The crystal structure of the urea-2-MB complex, especially hydrogen bond networks, was quite different from that of thiourea-2-MB complex. In urea-2-MB equimolar complex, not only intermolecular hydrogen bond between urea and 2-MB but also hydrogen bond network between urea molecules played important roles to form the complex. When urea was co-ground with 2-EB, equimolar complex formation was not observed. Conformational change of guest molecules by the complexation was investigated in terms of intramolecular hydrogen bond length and the dihedral angles. Reduction of intramolecular hydrogen bond length of 2-MB and the conformational change to the flatter structure affected the equimolar complex formation.

Grinding-induced equimolar complex formation between thiourea and ethenzamide.

We prepared and characterized a grinding-induced equimolar complex of thiourea with ethenzamide. When thiourea and ethenzamide were co-ground at a molar ratio of 3 : 1, new powder X-ray diffraction (PXRD) peaks were observed in addition to PXRD peaks of thiourea crystals. The optimum stoichiometry of the new structure was confirmed as 1 : 1 mol/mol. Effect of grinding time on the thiourea-ethenzamide equimolar complex formation was investigated by using PXRD, differential scanning calorimetry and Fourier transform infrared spectroscopy. The equimolar crystal structure was confirmed by X-ray diffraction measurements of the single crystal which was recrystallized from ethanol. It was found that the intermolecular hydrogen bond formations between thiourea and ethenzamide molecules contributed to the equimolar complex formation. The complex formation was not observed in the cases where benzamide, salicylamide or 3-ethoxybenzamide was co-ground with thiourea. 2-Alcoxyl benzamide structures should be required for the grinding-induced equimolar complex formation with thiourea.

Specificity of interactions of galectin-3 with Chrp, a cysteine- and histidine-rich cytoplasmic protein

Earlier work described the cloning of a gene from murine 3T3 cells encoding a cytoplasmic protein Chrp containing a cysteine- and histidine-rich motif characteristic of Zn-finger proteins. The interaction of Chrp with murine galectin-3 first became evident in a yeast two-hybrid screen, but it was also observed in co-precipitation experiments from 3T3 cell lysates. Here, the formation of equimolar complexes by murine Chrp and hamster galectin-3 is shown. Moreover, we found that Chrp binds to the carbohydrate-recognition domain (CRD) of hamster galectin-3 and not to the N-terminal domain carrying the proline- and glycine-rich repeats characteristic of galectin-3 and absent in other galectins. However, galectin-1 does not bind to Chrp, although its CRD is homologous to the galectin-3 CRD. Finally, we report that galectin-3, in a complex with Chrp, binds to laminin in surface plasmon resonance experiments with similar kinetics and affinity as it does in the free state. The formation of higher-order complexes containing these proteins and additional binding partners may be relevant to cytoplasmic functions involving galectin-3.

Toxic effects of linear alkylbenzene sulfonate, quaternary alkylammonium chloride and their complexes onDunaliellasp. andChlorella pyrenoidos

AbstractThe toxic effects of linear alkylbenzene sulfonate (LAS), quaternary alkylammonium chlorides (cationic surfactants[CS]), and their complexes (LAS‐CS) were examined inDunaliellasp. by proton nuclear magnetic resonance spectroscopic analysis of glycerol and inChlorella pyrenoidosaby growth inhibition. The glycerol content decreased quantitatively with increased concentrations of LAS, CS, and LAS‐CS complexes. The 24‐h median effective concentration (EC50] values of LAS and CS in free form were 0.38 to 18 mg/L and the toxic effects were in the order alkyltrimethylammonium chloride (TM) > alkyldimethylbenzylam‐monium chloride (BM) > LAS > dialkyldimethylammonium chloride (DM). The 24‐h EC50 values of LAS‐CS complexes at molar ratios of 1:1 and 2:1 were 1.3 to 13 and 5.6 to 9.6 mg/L as LAS‐equivalent concentration, respectively. The order of toxic effects was LAS‐TM > LAS = LAS‐BM > 2LAS‐BM > 2LAS‐DM > 2LAS‐TM > LAS‐DM. The toxic effect of LAS was enhanced by equimolar complex formation with TM. The 96‐h EC50 values of LAS and CS on the inhibition of growth inC. pyrenoidosawere 0.28 to 29 mg/L for the compounds in free form and their toxic effects were in the order TM > BM ≫ DM > LAS. The 96‐h EC50 values of LAS‐CS complexes at molar ratios of 1:1 and 2:1 were 1.4 to 59 and 11 to 86 mg/L, respectively, and the order of toxic effects was LAS‐BM > LAS‐TM > 2LAS‐BM > 2LAS‐TM > LAS > LAS‐DM > 2LAS‐DM. The toxic effects of LAS were also enhanced by the formation of complexes with TM or BM at molar ratio of 1:1 and 2:1. Thus, not only LAS but also its CS complexes might exert toxic effects on organisms in the environment.

The inhibition of human factor Xa by plasminogen activator inhibitor type 1 in the presence of calcium ion, and its enhancement by heparin and vitronectin

Plasminogen activator inhibitor type 1 (PAI-1), a member of serine proteinase inhibitor superfamily, is known to inhibit thrombin in the presence of either heparin or vitronectin. We analyzed possible inhibitory activity of PAI-1 on human factor Xa. PAI-1 inhibited factor Xa in the presence of calcium ion (Ca 2+), whereas no inhibition was observed in the absence of Ca 2+. Half maximal enhancement by Ca 2+ was obtained at 0.8 mM. An equimolar complex formation between factor Xa and PAI-1 in the presence of Ca 2+ was observed by SDS polyacrylamide gel electrophoresis. Both unfractionated heparin and vitronectin enhanced the inhibition only in the presence of Ca 2+. Apparent second-order rate constant ( k i) for the inhibition of factor Xa by PAI-1 at 5 mM Ca 2+ was 1.6 × 104 M −1 s −1, and was enhanced 3-fold by 2 u/ml of heparin (4.6 × 104 M −1 s −1[ and 10-fold by 100 nM vitronectin (1.6 × 105 M −1 s −1, respectively. The interaction between Ca 2+-bound factor Xa and PAI-1 could be important from the view of PAI-1 neutralization and enhancement of fibrinolysis.

Conformation ability test of human, rabbit and bovine plasminogens and their specific interaction with streptokinase

Human, rabbit and bovine plasminogens, having different sensitivity to streptokinase-activating action, differ, according to spectrophotometric titration, tryptophan fluorescence and circular dichroism spectroscopy, in the state of tyrosine and tryptophan residues, and in secondary and tertiary structures. Human plasminogen-streptokinase equimolar complex formation (according to gel chromatography) is accompanied by a differential ultraviolet spectrum. Difference spectroscopy is a convenient and adequate means of studying the formation of the said complexes. Streptokinase-human plasminogen complex formation is not hindered by partial substitution of water (20%) with ethanol or dimethylsulphoxide or by addition of 0.001 M sodium dodecylsulphate. The complex is not formed in 6 M urea, in solution, at pH less than 2.0 or approximately 12.0-13.0, or with bovine plasminogen. Circular dichroism and tryptophan fluorescence spectral pattern changes during streptokinase-plasminogen complex formation enable us to conclude that streptokinase secondary and tertiary structures undergo certain rearrangements in the framework of the complex, while tryptophan-containing sites of the molecule are not drastically changed. The data obtained enable us to presuppose formation of streptokinase-rabbit plasminogen complexes which differ from human plasminogen complexes with streptokinase.

Isolation and characterization of thrombomodulin from bovine lung

Bovine thrombomodulin was isolated from the lung by Triton X extraction, affinity chromatography on diisopropyl phosphate-thrombin-agarose, and gel filtration on Ultrogel AcA-44. The final preparation was purified 6000-fold from the membrane extract with a yield of 21%. It showed apparent M r of 78 000 and 105 000, before and after reduction, respectively, on polyacrylamide gel electrophoresis in SDS. The activity of the thrombomodulin was stable under the conditions of 1% SDS, 8 M urea, pH 2 and 10, and heat treatment at 60°C for 30 min, but was unstable against treatment with 2-mercaptoethanol. Activation of protein C by thrombin in the presence of the thrombomodulin depended on Ca 2+, and an equimolar complex formation between thrombin and thrombomodulin was required for the maximum rate activation. The rate of protein C activation by thrombin was increased 900-fold by thrombomodulin. Thrombomodulin inhibited the thrombin-induced fibrinogen clotting and platelet activation. However, it did not affect the inhibition of thrombin by antithrombin III with or without heparin, a protein C inhibitor or several synthetic inhibitors. These properties of bovine thrombomodulin were similar to those of rabbit thrombomodulin reported earlier.