New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling,Synthesis, and Experimental Confirmation

In the modern world, complications caused by disorders in the blood coagulation system are found in almost all areas of medicine. Thus, the development of new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis is an urgent task. The blood coagulation factor XIIa is one of the most promising therapeutic targets for the development of anticoagulants based on its inhibitors. The initial stage of drug development is directly related to computational methods of searching for a lead compound. In this study, docking followed by quantum chemical calculations was used to search for noncovalent low-molecular-weight factor XIIa inhibitors in a focused library of druglike compounds. As a result of the study, four low-molecular-weight compounds were experimentally confirmed as factor XIIa inhibitors. Selectivity testing revealed that two of the identified factor XIIa inhibitors were selective over the coagulation factors Xa and XIa.     

New 1,3,4-Thiadiazole Derivatives with Anticancer Activity

We designed and synthesized the 1,3,4-thiadiazole derivatives differing in the structure of the substituents in C2 and C5 positions. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and normal cell line (fibroblasts). The results showed that in both breast cancer cell lines, the strongest anti-proliferative activity was exerted by 2-(2-trifluorometylophenylamino)-5-(3-methoxyphenyl)-1,3,4-thiadiazole. The IC₅₀ values of this compound against MCF-7 and MDA-MB-231 breast cancer cells were 49.6 µM and 53.4 µM, respectively. Importantly, all new compounds had weaker cytotoxic activity on normal cell line than on breast cancer cell lines. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds. The most likely mechanism of action for the new compounds is connected with the activities of Caspase 3 and Caspase 8 and activation of BAX proteins.     

Strongly Basic Anion Exchange Resin Based on a Cross-Linked Polyacrylate for Simultaneous C.I. Acid Green 16, Zn(II), Cu(II), Ni(II) and Phenol Removal

The adsorption ability of Lewatit S5528 (S5528) resin for C.I. Acid Green 16 (AG16), heavy metals (Zn(II), Cu(II) and Ni(II)) and phenol removal from single-component aqueous solutions is presented in this study to assess its suitability for wastewater treatment. Kinetic and equilibrium studies were carried out in order to determine adsorption capacities, taking into account phase contact time, adsorbates’ initial concentration, and auxiliary presence (NaCl, Na₂SO₄, anionic (SDS) and non-ionic (Triton X100) surfactants). The pseudo-second-order kinetic model described experimental data better than pseudo-first-order or intraparticle diffusion models. The adsorption of AG16 (538 mg/g), phenol (14.5 mg/g) and Cu(II) (5.8 mg/g) followed the Langmuir isotherm equation, while the uptake of Zn(II) (0.179 mg^1−1/nL^1/n/g) and Ni(II) (0.048 mg^1−1/nL^1/n/g) was better described by the Freundlich model. The auxiliary’s presence significantly reduced AG16 removal efficiency, whereas in the case of heavy metals the changes were negligible. The column studies proved the good adsorption ability of Lewatit S5528 towards AG16 and Zn(II). The desorption was the most effective for AG16 (>90% of dye was eluted using 1 mol/L HCl + 50% v/v MeOH and 1 mol/L NaCl + 50% v/v MeOH solutions).     

Reaction Products of β-Aminopropioamidoximes Nitrobenzenesulfochlorination: Linear and Rearranged to Spiropyrazolinium Salts with Antidiabetic Activity

Nitrobenzenesulfochlorination of β-aminopropioamidoximes leads to a set of products depending on the structure of the initial interacting substances and reaction conditions. Amidoximes, functionalized at the terminal C atom with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine and phenylpiperazine), as a result of the spontaneous intramolecular heterocyclization of the intermediate reaction product of an S_N2 substitution of a hydrogen atom in the oxime group of the amidoxime fragment by a nitrobenzenesulfonyl group, produce spiropyrazolinium ortho- or para-nitrobenzenesulfonates. An exception is ortho-nitrobenzenesulfochlorination of β-(thiomorpholin-1-yl)propioamidoxime, which is regioselective at room temperature, producing two spiropyrazolinium salts (ortho-nitrobezenesulfonate and chloride), and regiospecific at the boiling point of the solvent, when only chloride is formed. The para-Nitrobezenesulfochlorination of β-(benzimidazol-1-yl)propioamidoxime, due to the reduced nucleophilicity of the aromatic β-amine nitrogen atom, is regiospecific at both temperatures, and produces the O-para-nitrobenzenesulfochlorination product. The antidiabetic screening of the new nitrobezenesulfochlorination amidoximes found promising samples with in vitro α-glucosidase activity higher than the reference drug acarbose. ¹H-NMR spectroscopy and X-ray analysis revealed the slow inversion of six-membered heterocycles, and experimentally confirmed the presence of an unfavorable stereoisomer with an axial N–N bond in the pyrazolinium heterocycle.     

Molecular Characteristics and Antioxidant Activity of Spruce (Picea abies) Hemicelluloses Isolated by Catalytic Oxidative Delignification

Spruce (Picea abies) wood hemicelluloses have been obtained by the noncatalytic and catalytic oxidative delignification in the acetic acid-water-hydrogen peroxide medium in a processing time of 3–4 h and temperatures of 90–100 °C. In the catalytic process, the H₂SO₄, MnSO₄, TiO₂, and (NH₄)₆Mo₇O₂₄ catalysts have been used. A polysaccharide yield of up to 11.7 wt% has been found. The hemicellulose composition and structure have been studied by a complex of physicochemical methods, including gas and gel permeation chromatography, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. The galactose:mannose:glucose:arabinose:xylose monomeric units in a ratio of 5:3:2:1:1 have been identified in the hemicelluloses by gas chromatography. Using gel permeation chromatography, the weight average molar mass M_w of hemicelluloses has been found to attain 47,654 g/mol in noncatalytic delignification and up to 42,793 g/mol in catalytic delignification. Based on the same technique, a method for determining the α and k parameters of the Mark–Kuhn–Houwink equation for hemicelluloses has been developed; it has been established that these parameters change between 0.33–1.01 and 1.57–472.17, respectively, depending on the catalyst concentration and process temperature and time. Moreover, the FTIR spectra of the hemicellulose samples contain all the bands characteristic of heteropolysaccharides, specifically, 1069 cm⁻¹ (C–O–C and C–O–H), 1738 cm⁻¹ (ester C=O), 1375 cm⁻¹ (–C–CH₃), 1243 cm⁻¹ (–C–O–), etc. It has been determined by the thermogravimetric analysis that the hemicelluloses isolated from spruce wood are resistant to heating to temperatures of up to ~100 °C and, upon further heating, start destructing at an increasing rate. The antioxidant activity of the hemicelluloses has been examined using the compounds simulating the 2,2-diphenyl-2-picrylhydrazyl free radicals.     

Complexing properties of methyl and phenyl glycine derivatives in their compounds with H+, Ni(II), Cu(II), and Zn(II)

The influence of the solvent and the substituents on the complexing properties of methyl and phenyl glycine derivatives is discussed. On the basis of a computer analysis of potentiometric titration results, the composition and the stability constants of the complexes ofN-methylglycine,N,N-dimethylglycine,N-phenylglycine and phenylglycine with H⁺ and with Ni(II), Cu(II), Zn(II) were determined. The ligand-metal coordination mode as well as the zwitterion level in percent in ligand/proton systems were determined by spectral analyses and equilibria studies.

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Komplexbildung der Methyl- und Phenylglycin-Derivate in ihren Verbindungen mit dem Proton und Ni(II), Cu(II) und Zn(II)

Zusammenfassung Der Einfluß des Lösungsmittels und der Substituenten auf die komplexbildenden Eigenschaften der Methyl- und Phenylglycin-Derivate wird diskutiert. Anhand einer Computer-Analyse von potentiometrischen Daten wurden die Zusammensetzung und die Beständigkeitskonstanten der Komplexe vonN-Methylglycin,N,N-Dimethylglycin,N-Phenylglycin und Phenylglycin mit H⁺, Ni(II), Cu(II) und Zn(II) festgestellt. Mittels spektroskopischer Methoden und Gleichgewichtstudien wurde der Koordinationstyp des Liganden mit dem Metall festgestellt sowie der Prozentanteil des Zwitterions im Ligand/Proton-System.

     

Reactions of theortho-metallated rhodium(I) complex of the formula Rh[P(OC6H4)(OPh)2][P(OPh)3]3 with HX molecules

Summary Theortho-metallated complex [RhP₃Pt] [P=P(OPh)₃, P=P(OC₆H₄)(OPh)₂] was obtained in the reaction of [RhP₄]ClO₄ with KOH. It reacts easily with proton donors HX (X=ClO₄, F, Cl, SCN, or acetylacetonate) to produce complexes [RhP₃X] when X is a strong donor. If X is a weaker donor (X=ClO₄ or F), pentacoordinate compounds of the type [PhP₄X] are formed. [RhP₃P] reacts with acetylacetone (Hacac) to produce [Rh(acac)P₂].     

Operational comparison of various thermodynamic treatments of organic substance adsorption at the electrode/solution interface

Three isotherms are considered: Frumkin's Bennes' and Mohilner's. The relationship between the interaction parameters in the first two and the adsorbate activity coefficient in the last is discussed. The significance of various standard states for the definition of ΔG° _ads is analysed. The operational derivation of ΔG°_ads in the three cases and the relationship between the resulting three quantities are illustrated. The isotherms have been used to describe the adsorption of 1,4-dioxane on a polarized Hg electrode. The analysis has been carried out both at constant potential and constant charge. The picture emerging in each of the three cases is discussed in the light of the results obtained in the other two. It is concluded that the three approaches give the same qualitative information about the interfacial behaviour of dioxane, especially as far as the effect of the electric field and the particle-particle lateral interaction are concerned. The usefulness of the Frumkin isotherm for analysing promptly experimental adsorption data is thus maintained. Limitations of the present approach are discussed.     

α-Hydroxyalkylation of heteroaromatic bases by alcohols and hydroxylamine-O-sulphonic acid

The homolytic decomposition of hydroxylamine-O-sulphonic acid in alcoholic solvents was investigated in the presence or absence of protonated heteroaromatic bases and Fe(II) salt. The addition of the α-hydroxyalkyl radicals to the base and their oxidation by Fe(III) salt to the corresponding alkyl cyanide were competitive processes. A redox chain process involving the amino radical cation, NH₃^t., is suggested and the factors affecting the yields of the homolytic substitution are discussed.     

o-quinone methides 2. Stereoselectivity in cycloaddition reactions of o-quinone methides with vinyl ethers

Cycloaddition reactions between vinyl ethers 3 and $\text{o}$-quinone methides 2, thermally generated from 2-hydroxybenzyl alcohols 1, have been studied. The structure and conformational preferences of the 4-substituted 2-ethoxy-(2,3)-dihydro-2$\text{H}$-benzopyrans 4–9 obtained, which show new interesting features, are discussed together with competitive kinetic data. The cycloaddition process is concerted and involves $\text{o}$-quinone methides in the $\text{E}$-configuration. The OEt-$\text{endo}$ transition state seems to be preferred with ethyl vinyl ether and $\text{Z}$-1-propenyl ethyl ether, whereas with $\text{E}$-1-propenyl ethyl ether the stereoselectivity of the cycloaddition process depends on substituents on the methylene group of the starting alcohol 1. These results are discussed in terms of $\text{endo}$ and $\text{exo}$ preference of the propenyl ether methyl group.