Pharmaceutical Chemistry Journal (v.51, #1)

Angiotensin AT1 Receptors and Their Ligands (Review) by A. A. Spasov; D. S. Yakovlev; A. A. Brigadirova (1-8).
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.
Keywords: AT1 receptor; AT1 antagonists; angiotensin; sartans; arterial hypertension; renin-angiotensin system; vasoconstriction

2-Thiomorpholino-5-Aryl-6H-1,3,4-Thiadiazine Hydrobromides and Their Ability to Inhibit Nonenzymatic Protein Glycosylation by L. P. Sidorova; T. A. Tseitler; V. V. Emel’yanov; E. A. Savateeva; N. E. Maksimova; N. N. Mochul’skaya; V. A. Chereshnev; O. N. Chupakhin (9-12).
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.
Keywords: 1,3,4-thiadiazine; cyclocondensation; α-halogenacetophenones; 4-morpholine thiosemicarbazides; nonenzymatic protein glycosylation

Synthesis and Antiviral Properties of Ethyl(3-ethyladamant-1-yl)carbamate by Yu. N. Klimochkin; I. K. Moiseev; M. V. Leonova; S. N. Nikolaeva; E. I. Boreko (13-17).
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.
Keywords: adamantine; ethylcarbamate; virus infections; antiviral activity

Synthesis and Analgesic Activity of 1-substituted 3-methyl-6-methoxy-7(n-butoxy)-3,4-dihydroisoquinolines by O. V. Surikova; A. S. Yusov; R. R. Makhmudov; A. G. Mikhailovskii (18-21).
Cyclocondensation of O-butylated eugenol with various nitriles was used to synthesize 1-substituted derivatives of 3-methyl-6-methoxy-7-(n-butoxy)-3,4-dihydroisoquinoline. Hydrochlorides of the study compounds were tested for analgesic activity using the “hot plate” test. The experiments showed that the study compounds had analgesic effects greater than those of metamizole sodium and similar to those of ibuprofen.
Keywords: 1-substituted 3-methyl-6-methoxy-7-(n-butoxy)-3,4-dihydroisoquinolines; hydrochlorides; analgesic activity; metamizole sodium; ibuprofen

Synthesis, Antihelminthic and Insecticidal Activity of 2-[3-Methyl-6-Methoxy-7-(n-Propoxy)-3,4-Dihydroisoquinolin-1]Ethanoic Acid Amides by O. V. Surikova; A. G. Mikhailovskii; B. Ya. Syropyatov; A. S. Yusov; Yu. D. Khudyakova (22-25).
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.
Keywords: cyclocondensation of O-n-propylated eugenol with cyanoacetamides; 2-[3-methyl-6-methoxy-7-(n-propoxy)-3,4-dihydroisoquinolin-1]ethanoic acid amide hydrochlorides; antihelminthic activity greater than that of Pyrantel; insecticidal activity comparable with that of diazinon and pirimiphos

A synthesis of 4-amino-5-(2-thienyl)-1,2,4-triazol(4H)-3-ylthioacetanilides was developed, and these were chemically modified to produce 2-[5-(2′-thienyl-4-(1H-1-pyrrolyl)-4H-1,2,4-triazol-3-ylthio]acetanilidfes. The structures of the synthetic compounds were confirmed by 1H NMR spectroscopy. Predictions of pharmacological activity showed that the compounds synthesized here were likely to act on the CNS. The antitumor activity of the study compounds was assessed.
Keywords: 1,2,4-triazole derivatives; thioacetanilides; synthesis; antitumor activity

Synthesis and Various Biological Properties of 3-(4-Benzylpiperizino)-1-(4-Ethoxyphenyl)-1-Alkyl(Aryl)-2-Phenylpropan-1-OL Dihydrochlorides by G. A. Gevorgyan; N. K. Gasparyan; O. A. Papoyan; A. E. Tumadzhyan; A. A. Tatevosyan; G. A. Panosyan (30-34).
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.
Keywords: aminomethylation; benzylpiperazinopropanone; benzylpiperazinoalkanols; Grignard reagents; anti-inflammatory; analgesic; antipyretic; and peripheral n-cholinolytic activity

A Ranged Series of Drug Molecule Fragments Defining Their Neuroavailability by P. G. Polishchuk; A. P. Kosinskaya; V. B. Larionov; L. N. Ognichenko; V. E. Kuz’min; N. Ya. Golovenko (35-38).
Computer modelling methods based on “structure-property” relationships (QSPR) allows rational planning of both experimental studies and the effective generation of structures with the ability to cross the blood-brain barrier (BBB). The aim of this work was to create a “structure-property” model based on the simplex presentation of molecules for non-experimental assessment of their ability to cross the BBB and to carry out structural interpretation of the model, taking account of the mutual influences of atoms in the molecule. The simplex method for representing molecular structures was used to evaluate the contributions of different molecular fragments and functional groups to the level of neuroavailability of compounds diffusing across the BBB. The presence of strongly polar and ionogenic groups (carboxyl, carbonyl, phenol hydroxyl) was found to have adverse effects on the ability of substances to penetrate into the brain. The presence of halogen atoms and aromatic fragments had positive influences on transfer of substances through the BBB. The QSPR model constructed here was characterized by satisfactory predictive accuracy as assessed using the RandomForest internal model validation procedure (R2 = 0.54; RMSE = 0.47).
Keywords: blood-brain barrier; diffusion; simplex; QSPR

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.
Keywords: pyrogallol; thiopyrimidine; cyanopyridones; antitumor activity; toxicity

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.
Keywords: dihydroquercetin; stereoisomers; enantiomers; chirality; larch wood; extraction

In this work, total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP) of roots, leaves and inflorescences of Artemisia fragrans Willd. and Artemisia vulgaris L. have been investigated. The results indicate that the TPC, TFC and FRAP in leaves and inflorescences are higher than in roots and there is significant positive correlation (P < 0.05, r 2 = 0.761) between TPC and FRAP. According to our results it seems that inflorescences and leaves of Artemisia plants possess significant antioxidant activity and there is significant difference (P < 0.05) between the two species.
Keywords: Artemisia fragrans Willd.; Artemisia vulgaris L., phenolic content, ferric reducing antioxidant power; antioxidant activity

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.
Keywords: 2-amino-2-thiazolines; heterocyclic tricarbonylmethane derivatives; esters; thiazolo[3,2-a]pyrimidines

Development of a Microencapsulated Medicinal Form of Vinpocetine for Administration by Inhalation by Yu. A. Penkina; O. P. Pavlovskaya; G. V. Avramenko (60-64).
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.
Keywords: microcapsules; vinpocetine; polylactide; microcirculation

An algorithm developed for selecting the method for preparing liposomal forms of biologically active substances (BAS) was used to prepare nanoencapsulated forms of a series of pyrazolesulfonylchlorides and piperazinecarboxylates.
Keywords: liposomes; encapsulation; biologically active compounds; algorithm

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.
Keywords: qualitative microbiological methods; validation parameters; microbial test strains; drugs

LC Method Development and Validation for the Determination of Ropivacaine Hydrochloride in Bulk Drug and Pharmaceutical Formulations by Sridevi Chigurupati; Raju Nemela Appala; Kesavanarayanan Krishnan Selvarajan; Chu How Khaw; Chun Foo Teoh; Livyashry Batumanathan; Jahidul Islam Mohammad (71-80).
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.
Keywords: Ropivacaine hydrochloride; liquid chromatography; method development; validation; stability testing

A new biodegradable magnetic polymeric nano-carrier based on magnetite nanoparticles encapsulated by poly(vinylpyrrolidone(-block-poly(ethylene glycol)-block-poly(methacrylic acid) (PVP-PEG-PMAA) matrix has been developed for targeted and controlled delivery of lovastatin. The carrier was characterized by TEM, SEM, XRD, VSM, TGA, DSC and FT-IR techniques and its carboxylic acid content was determined by acid-base titration. The carrier has a mean particle diameter of 22 nm with a narrow size distribution and is superparamagnetic with a saturation magnetization of 27.3 emu g-1 at room temperature. The nano-carrier also possesses pH-responsive properties due to the polymeric layer covering the nanoparticle surface, which adopts conformational changes in the polymer and improves its loading and delivery efficiency. The loading efficiency and pH-controlled release properties of the carrier were examined using a hydrophobic model drug lovastatin. Typically, a loading efficiency of about 94% and a sustained release of 12 h were achieved under simulated human body conditions (37°C; pH 1.2, 5.5 and 7.2). The results indicate that the PVP-PEG-PMAA covalently-coated magnetic nanoparticle is a stable carrier with good loading capacity and controlled-release properties.
Keywords: nano-carrier; drug delivery; magnetic nanoparticles, pH-responsive polymer; lovastatin