Pharmaceutical Chemistry Journal (v.50, #11)

N-Phenylacetylglycyl-L-Proline Ethyl Ester Converts into Cyclo-L-Prolylglycine Showing a Similar Spectrum of Neuropsychotropic Activity by T. A. Gudasheva; K. N. Kolyasnikova; E. A. Kuznetsova; S. A. Litvinova; N. N. Zolotov; T. A. Voronina; R. U. Ostrovskaya; S. B. Seredenin (705-710).
Previously designed cyclo-L-prolylglycine (CPG), a peptide prototype of piracetam, was discovered as an endogenous compound in rat brain and exhibited nootropic and anxiolytic properties. N-Phenylacetylglycyl-L-proline ethyl ester (GZK-111) was synthesized in the present work. It was established that GZK-111 converted to CPG and possessed nootropic, anxiolytic, and antihypoxic activities typical of CPG at doses of 0.1 – 1.5 mg/kg (i.p.). The effects of both GZK-111 and CPG were stereoselective with only the L-enantiomers being active. GZK-111 could be considered as a prodrug that enhanced cognitive functioning with an anxiolytic component.
Keywords: cycloprolylglycine; substituted glyproline; nootropic activity; anxiolytic activity; antihypoxic activity; stereospecific pharmacological effect; prodrug

Conjugation of Succinate to Chitosan Increases the Cochlear Cytoprotective Effect by A. A. Panevin; A. A. Golyshev; Yu. A. Skorik; S. G. Zhuravskii; D. L. Sonin (711-714).
N-Succinylchitosan (SC) with degree of substitution 0.86 was prepared by reacting chitosan with succinic anhydride. The otoprotective potential of a single i.v. injection of a solution (0.3%) of the sodium salt of SC in 60 rats (males, Wistar, 220 – 250 g) was studied. A solution of meglumine sodium succinate (MSS) at an equivalent concentration was used as a reference. The drugs were administered 2 h or 5 min prior to induction of acute injury of the auditory analyzer by acoustic stimulation (AS). The condition of hearing was estimated by studying optoacoustic emission (OAE) at the frequency of distortion product 1 h, 24 h, and 7 d after the AS. SC showed a more pronounced protective effect with early preventive administration (p < 0.02; ANOVA with Bonferroni correction). Conversely, MSS exhibited its protective properties only with immediate administration. A comparison of the two drug administration modes showed that the OAE amplitude was depressed more after MSS administration than after SC injection (p < 0.05; Tukey’s test). It was concluded that conjugation to chitosan prolonged the elimination half-life of succinate and improved its access to cochlear back-barrier tissues.
Keywords: otoprotection; targeted drug delivery; elimination half-life increase; permeability of blood—cochlear barrier; N-succinylchitosan; meglumine sodium succinate

The spread of bacterial strains with multiple drug resistance to various classes of antibiotics is a key problem of modern medicine. The ability of bacteria to form biofilms is an important factor of their drug resistance. Therefore, new antimicrobial compounds that act efficaciously against pathogenic bacteria regardless of their metabolic activity, physiological properties, and localization must be discovered. Cationic antimicrobial peptides (AMP) are especially interesting among such compounds. The goal of the present work was to study the anti-biofilm activity of arenicin-1 and its therapeutically valuable analog V8R prepared previously by us as compared with several known β-hairpin AMP of animal origin. A number of β-hairpin AMP at micromolar concentrations suppressed completely not only planktonic growth but also biofilm formation by Pseudomonas aeruginosa PAO1 and also killed bacteria within the biofilms and caused their degradation.
Keywords: antimicrobial peptides; β-hairpin; arenicin; biofilms; Pseudomonas aeruginosa

Synthesis and Antimicrobial Activity of 3-Aryland 3-Arylmethyl-Cyclopenta[c]Pyrazoles and -Cyclopenta[d ]Isoxazoles by A. A. Pantyukhin; A. G. Mikhailovskii; T. F. Odegova; N. N. Pershina (721-723).
Acylation of 1-piperidinocyclopentene by aromatic and arylacetic acid chlorides synthesized the corresponding 1,3-diketones that were reacted with hydrazine hydrate to give 3-aryl- and 3-arylmethylcyclopenta[c]pyrazoles and with hydroxylamine to give the corresponding cyclopenta[d]isoxazoles. The diketones and heterocyclic compounds prepared from them exhibited weak inhibitory activity against Staphylococcus aureus and Escherichia coli. The starting diketone containing a p-NO2 group was the most active compound with a minimum inhibitory concentration of 125 μg/mL.
Keywords: 1-piperidinocyclopentene; aromatic and arylacetic acid chlorides; 1,3-diketones; 3-aryl- and 3-arylmethyl-cyclopenta[c]pyrazoles and -cyclopenta[d]isoxazoles

Synthesis and Antitumor Properties of New 1,2,4-Triazoles and 1,3,4-Thiadiazoles by T. R. Ovsepyan; F. G. Arsenyan; L. E. Nersesyan; I. S. Danielyan; A. G. Agaronyan; R. G. Melik-Ogandzhanyan (724-727).
New S-substituted derivatives were synthesized via alkylation of mercapto-substituted 1,2,4-triazoles and 1,3,4-thiadiazoles by various aliphatic and aromatic halides. Aminomethylation of 5-thio-1,2,4-triazoles formed the corresponding Mannich bases. The antitumor properties of the synthesized compounds against sarcoma 37 and EAC grafted tumor models and their influence on DNA methylation were studied
Keywords: triazole; thiadiazole; alkylation; aminomethylation; experimental tumors; tumor DNA

Lipids and Lipophilic Constituents of Comfrey (Symphytum Officinale L.) Seeds by S. G. Yunusova; S. S. Lyashenko; N. I. Fedorov; M. S. Yunusov; O. N. Denisenko (728-731).
The compositions of lipids and lipophilic constituents from seeds of Symphytum officinale L. (Boraginaceae Juss., comfrey) were studied. Neutral and polar lipids were identified and quantified. The fatty-acid composition was determined. It was found that the greatest amounts of polyunsaturated fatty acids (PUFA) were concentrated in total NL (57.6%, including 16% γ-linolenic acid) and triacylglycerides (56.5%). A fraction with 99% PUFA, including 72% γ-linolenic acid, was obtained as clathrates with urea. Lipophilic constituents, i.e., sterols, were identified.
Keywords: Symphytum officinale L; Boraginaceae Juss; lipids; fatty acids

Production Technology for Katatsin Antihypoxic Drug Substance from Roots of Polygonum Coriarium Grig by B. T. Sagdullaev; R. Kh. Shakhidoyatov; M. A. Mamatkhanova; Sh. M. Turaboev; N. S. Beknazarova; S. F. Aripova; Sh. Sh. Sagdullaev (732-735).
A production technology using vortex extraction, baromembrane methods, and spray drying was developed for obtaining increased yields of katatsin drug substance from roots of Polygonum coriarium Grig.
Keywords: production technology; drug substance; katatsin; roots of Polygonum coriarium Grig; vortex extraction; baromembrane methods; spray drying

The aim of this study was to investigate the chemical constituents, chelating ability, tyrosinase inhibition, antimicrobial, antioxidant, cytotoxic, and radical scavenging activities of the essential oil of Artemisia aucheri Boiss., an endemic Asteraceae herb growing wild in Iran. Water-distilled essential oil of A. aucheri was analyzed by GC and GC/MS. The antibacterial activity of the oil was evaluated by determination of inhibition zones, minimum inhibitory concentration, minimum bactericidal concentration, and decimal reduction time. Phenolic content of the oil was determined using the Folin – Ciocalteu assay. Antioxidant properties of the oil of A. aucheri were determined by three methods: the ferric reducing antioxidant power, bleaching of DPPH, and a-carotene–linoleic acid assay. Cytotoxicity was measured using a modified MTT assay. Radical scavenging activities, chelating ability, and tyrosinase inhibitory effect were determined by spectrophotometric techniques. Camphor (25.15%), 1,8-cineole (18.26%), and verbenone (16.63%) were the major components in this oil. Bactericidal kinetics of the oil indicates that C. albicans is the most vulnerable strain (MIC = 0.04 mg/mL). Total phenolic content of the oil was found to be 133.87 ± 6.50 ig GAE/mg. The A. aucheri oil exhibited a dose-dependent scavenging of DPPH, nitric oxide, and superoxide anion radicals with IC50 values of 15.75 mg/mL, 21.73 μg and 44.31 μg, respectively. Ferrous-ion chelating activity of the oil (IC50 = 452.35 μg) was lower than that of EDTA. IC50 values for HeLa and lymphocyte cells were found to be 7.11 and 6322.85 μg/mL, respectively. The results suggest application of A. aucheri oil as a natural antioxidant and anticancer agent.
Keywords: Artemisia aucheri ; antimicrobial activity; DPPH bleaching; cytotoxicity; chelating ability; tyrosinase inhibition; HeLa cell line

The Effects of Solvent Polarity on Hypoglycemic and Hypolipidemic Activities of Vaccinium Arctostaphylos L. Unripe Fruits by Abbas Ahmadi; Mohsen Khalili; Fatemeh Mashaee; Babak Nahri-Niknafs (746-752).
New lifestyle is the main reason of diseases related to high blood glucose and lipid levels. Treatment by chemical drugs is common way for the remedy of these illnesses, which is replaced by application of medicinal plants. Vaccinum arctostaphylos fruits have been used extensively as traditional medicines for treatment of diabetic and lipidemic symptoms. These fruits have additional health benefits as they are rich in phytochemicals such as flavonoids and polyphenols, which have been reported to possess many pharmacological activities. In this research, the effect of solvent polarity on bioactive extract yield from unripe fruits of this plant was evaluated by GC-MS analysis. Then, antidiabetic and antilipidemic properties of different extracts were investigated in rats with streptozotocin-induced diabetes and compared to glibenclamide as reference chemical drug for diabetes. The results indicate that all extracts (particulaly, carbon tetrachloride extract) produce significant decrease in blood glucose and lipid levels, which can be related to the high content of fatty acids, sterols, phenolics, and unsaturated alcohols in these extracts.
Keywords: Vaccinum arctostaphylos ; unripe fruits; solvent polarity; blood glucose and lipid levels, streptozotocin-induced diabetes; rats

Physicochemical Properties, Toxicity, and Specific Activity of a Follitropin Alpha Biosimilar by I. I. Vorob’ev; O. V. Proskurina; Yu. A. Khodak; A. I. Gosudarev; A. S. Semikhin; D. V. Byrikhina; M. S. Krasil’shchikova; B. S. Mel’nik; M. V. Serebryakova; M. A. Polzikov (753-760).
Comparative analysis of the primary structure of recombinant human follicle-stimulating hormone (r-hFSH) in samples of follitropin alpha biosimilar (FAB) preparation and the reference drug Gonal-F showed they were identical while spectral analysis of their secondary and tertiary structures indicated they were bioequivalent. Analytical results for N-glycans and sialic acids revealed that the main glycan structures were similar and the distributions of the main forms of sialic acids in the compared samples differed insignificantly. Results of in vitro and in vivo biological activity testing confirmed that FAB and Gonal-F were equivalent with respect to WHO standards. Comparative testing of the acute and subacute toxicity did not reveal significant differences between the two drugs and also confirmed they were identical. Thus, the investigation proved that FAB and the reference drug were equivalent with respect to the main physicochemical, pharmacodynamic, and toxicological characteristics.
Keywords: recombinant human follicle-stimulating hormone (r-hFSH); preclinical investigation; Gonal-F

Technology Development for the Synthesis of S-Amlodipine Nicotinate Drug Substance by G. A. Kim; Zh. M. Kozlova; S. O. Pchelintsev; R. T. Savel’yanova; N. M. Berezina; I. I. Krasnyuk (761-763).
Technology for the synthesis of S-amlodipine nicotinate drug substance was developed based on an acceptable method of effective separation of the amlodipine optical isomers. A literature review suggested that the most promising methods employed 2-propanol (pure or with small additions of cosolvents) as the main solvent. However, experiments showed that the optimum solvent was DMSO. The proposed synthesis of S-amlodipine nicotinate drug substance was confirmed to be stable and reproducible. Standardization methods were developed.
Keywords: S-amlodipine nicotinate; amlodipine optical isomers; nicotinic acid

Elixir Dosage Form in Pharmaceutical Practice by E. I. Sakanyan; M. N. Lyakina; A. S. Alekseeva; L. I. Shishova; T. B. Shemeryankina (764-767).
The elixir dosage form according to Russian and foreign pharmacopoeias was analyzed. A list of currently registered Russian and foreign drugs in this dosage form was given. The quality parameters by which drugs in the elixir dosage form must be standardized were listed based on an analysis and generalization of information provided in regulatory documentation of Russian and foreign drug manufacturers.
Keywords: elixir; balm; pharmacopoeial monographs; regulatory documentation

New Synthetic Methods for Pyrazolesulfonyl Chlorides as Drug Precursors by V. A. Stepanov; A. Yu. Matyukhin; K. N. Akkuzin (768-769).
Sulfonyl chlorides were synthesized from pyrazoles via sulfonation by chlorosulfonic acid. The optimum conditions for synthesizing pyrazolesulfonyl chlorides in preparative yields were determined.
Keywords: sulfonyl chloride; chlorosulfonic acid

Biopharmaceutical Analysis of Coenzyme Q10 (Ubidecarenone) by E. I. Kalenikova; M. G. Tokareva; E. A. Gorodetskaya; A. A. Galeeva; E. M. Kibizova; O. S. Medvedev (770-773).
The literature on the most frequently used methods for quantitative determination of coenzyme Q10 in biological materials was reviewed. HPLC in combination with electrochemical detection had the advantage among spectrophotometric, electrochemical, and chromatographic methods owing to high selectivity and sensitivity and the availability of modern detectors.
Keywords: ubidecarenone; coenzyme Q10 ; ubiquinone; ubiquinol; spectrophotometric method; electrochemical method; HPLC