Vol 51, No 1 (2017)

This review addresses on the most intensely studied biological targets in the body – type 1 angiotensin receptors. Particular attention is focused on receptor structure and its interaction with various intracellular signal molecules. Data on long-known and newly created ligands able to influence AT₁ receptors are presented. The individual structural fragments of AT₁ antagonist molecules with functional significance for this type of activity are described. The review includes a brief analysis of the potentials for the clinical use of AT₁ antagonists in a number of pathological states additional to the registered indications, including arterial hypertension, chronic heart failure, and nephropathy in type 2 diabetes mellitus. These results from the discovery of additional aspects of the mechanism of action of antagonists and their ability to produce effects such as neuroprotective and anti-inflammatory actions, as well as various organ-protective properties.

Cyclocondensation of α-halogenacetophenones with an original 4-morpholine thiosemicarbazide was used to synthesize a group of new Captions: of the 1,3,4-thiadiazine group, containing a thiomorpholine fragment at position 2 of the thiadiazine ring. Two members of this group of compounds were found to produce effective inhibition of nonenzymatic protein glycosylation in an in vitro model system. These test results allow compounds containing phenyl and fluorophenyl fragments IIIa and IIIb to be recommended for further study in in vivo experiments.

The new adamantine derivative ethyl(3-ethyladamant-1-yl)carbamate was found to have high antiviral activity against herpes simplex virus and vaccinia viruses, as well as adenovirus (EC₅₀ = 0.62, 5.15, and 48.5 μg/ml respectively). Activity against the herpesvirus was demonstrated in experiments in various cell cultures using different virus strains, including a variant resistant to acycloguanosine (ACG). Simultaneous application of ethyl(3-ethyladamant-1-yl)carbamate and ACG increased the inhibition of herpesvirus reproduction in cell cultures and decreased the mortality of laboratory animals with experimental herpesvirus neuroinfection as compared with the use of each substance alone. 3-Ethyladamant-1-yl)carbamate was a low-toxicity compound, did not inhibit DNAsynthesis in uninfected cell cultures, and its acute intragastric LD₅₀ for white mice was 1831.8 mg/kg.

Cyclocondensation of O-n-propylated eugenol with cyanoacetamides was used to synthesize 2-[3-methyl-6-methoxy-7-(n-propoxy)-3,4-dihydroisoquinolin-1]ethanoic acid amides. The hydrochlorides of these compounds were tested for antihelminthic and insecticidal activity. The most active compounds were amides containing a cyclic amine fragment (pyrrolidine, piperidine, morpholine), which had greater activity than Pyrantel. Compounds without substituents at the amide nitrogen and the N-ethylamide had insecticidal activity at the levels of diazinon and pirimiphos.

Aminomethylation of 1-(4-ethoxyphenyl)-2-phenylethanone yielded 3-(4-benzylpiperazin-1-yl)-1-(4-ethoxyphenyl)-2-phenylpropan-1-one. Reduction of this compound with lithium aluminum hydride produced 3-(4-benzylpiperazin-1-yl)-1-(4-ethoxyphenyl)-2-phenylpropan-1-one, and interaction of this with Grignard reagents produced 3-(4-benzylpiperazinyl)-1-(4-ethoxyphenyl)-1-alkyl(aryl)-2-phenylpropan-1-ones. Some of the dihydrochlorides of the resulting compounds were found to have anti-inflammatory, analgesic, and peripheral n-cholinolytic activity.

Our previously reported compound, 3-(2-hydroxy-3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1), was allowed to react with acetophenone, ethyl cyanoacetate and/or malononitrile to give the corresponding compounds 2a, 2b and 2c, respectively. Treatment of compounds 2b and 2c with thiourea afforded thiopyrimidine derivatives 3a and 3b, respectively. The coupling of 3a and 3b with 2′,3′,4′,6′-tetra-O-acetyl-_-D-glucopyranosyl bromide (4) afforded compounds 5a and 5b, respectively. Reaction of compound 2c with acetophenone yielded pyridone derivative 6, which was fused in pyridine hydrochloride to give demethylated product 7. The coupling of compound 6 with some cyclic and acyclic halosugars afforded various N-glycoside derivatives (8, 9, 11, 13, and 14). New compounds were tested for their antitumor activity on MCF-7 human breast adenocarcinoma cell line and HepG2 liver carcinoma cell line. Almost all tested compounds exhibited antitumor activity, especially 4-(3-(2-hydroxy-3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carbonitrile (6) which displayed the most potent inhibitory activity with IC₅₀ = 2.97 and 2.67 g/mL against MCF-7 and HepG2 cell lines, respectively. Compound 6 was tested for its acute toxicity (lethal dose) and found to have very low toxicity based on LD₅₀ values (no label > 600 < 2000 mg/kg) as recommended by the Organization for Economic Co-operation and Development.

A method for the microencapsulation of vinpocetine by solvent evaporation in polylactide (PLA) shells with different molecular weights using a mixture of polyvinyl alcohol (PVA) and dioctylsulfosuccinate sodium (Aerosol OT, AOT) at a mass ratio of 1:1 as stabilizer was developed. Microencapsulation efficiency was found to increase when PLA with higher molecular weight was used, though the process was essentially independent of the quantity used. Microcapsule dispersity was evaluated. The best samples were obtained using PLA with a molecular weight of 30,500 Da and a vinpocetine:PLA mass ratio of 1:10.

Asimple liquid chromatography method has been developed for the assay of ropivacaine hydrochloride in raw material and final products. The chromatographic separation employs gradient elution using C₈ column, mobile phase consisting of solvent [A] (monobasic phosphate buffer adjusted to pH 2.5) and solvent [B] (acetonitrile) delivered at a flow rate of 1.0 mL/min. The analytes were detected at 220 nm and peak purity was examined using a photodiode array detector. The proposed method was validated to demonstrate its selectivity, accuracy, precision, robustness, and linearity within a given range. The limits of detection and quantitation were 0.1 and 0.5 g/mL, respectively. The specificity of the method was investigated under various stress conditions, including hydrolysis, heat, oxidation, and photolysis. Stress testing showed degradants, which were well separated from the parent compound proving the stability and indicating capacity of the method.

The optimum parameters for the process of extraction of the dihydroquercetin (DHQ) isomer with the greatest antioxidant activity were identified. Use of ethyl acetate as extractant in this process was found to have clear advantages over other industrial solvents. An optimum method of extracting DHQ from larch wood with a large enantiomer excess was proposed. The method was developed and the quantitative content of the (+)-2R,3R isomer of DHQ extracted from wood of Larix sibirica Ledeb. was assayed.

An effective method was developed for the preparation and x-ray diffraction analysis of the spatial structure of 7-hydroxy-5-oxo-2,3-dihydro-5H-[1, 3]thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester, which is of interest as a starting material for the synthesis of new, potentially biologically active derivatives of thiazolo[3,2-a]pyrimidine hydrogenated in the thiazole part of the molecule.

We present here the results of validation of qualitative microbiological methods, particularly a modified method for determining the microbiological purity of medicines. The parameters required for validating qualitative microbiological methods and criteria for evaluating them were identified. Experimental data from validation studies demonstrate the value of using improved methods for determining microbiological purity using smaller sample sizes, and confirm that this is possible.