Pharmaceutical Chemistry Journal (v.46, #11)

Biological Activity of Organogermanium Compounds (A Review) by L. G. Menchikov; M. A. Ignatenko (635-638).
Data on the main biologically active organogermanium compounds that were synthesized in the past 5 – 10 years were reviewed. The dietary trace element germanium is necessary to ensure normal functioning of the body. Therefore, practically all water-soluble stable organogermanium compounds exhibit biological activity and attract the attention of researchers.
Keywords: germanium compounds; biological activity

5-Ht6 Receptor Antagonists. V. Structure – Activity Relationship of (4-Phenylsulfonyloxazol-5-yl)amines by A. V. Ivachtchenko; E. S. Golovina; M. G. Kadieva; O. D. Mitkin; I. M. Okun (639-646).
Both novel and previously reported (4-phenylsulfonyloxazol-5-yl)amine derivatives containing a substituted sulfonyl group were studied in order to discover highly active 5-HT6 receptor antagonists. A new pharmacophore model of 5-HT6 receptor antagonists was proposed based on the structure—5-HT6 antagonist activity relationship. It was established that the activity of the synthesized compounds depended strongly on the nature of the amine located vicinal to the sulfonyl. The most active ligands were methyl-(4-phenylsulfonyloxazol-5-yl)amines. Replacing the methyl by a bulkier alkyl radical and conversion to tertiary amines was accompanied by a dramatic reduction of their activity for 5-HT6 receptors.
Keywords: (4-phenylsulfonyloxazol-5-yl)amines; sulfonyl group; activity, serotonin receptors; antagonists; structure—activity; pharmacophore model; conformations; stabilization

Synthesis and pharmacological activity of amides of 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazolyln-acetic acids by V. A. Anisimova; A. A. Spasov; V. A. Kosolapov; I. E. Tolpygin; E. V. Tibir’kova; O. A. Salaznikova; V. A. Kuznetsova; N. A. Gurova; K. V. Lenskaya; D. S. Yakovlev; D. V. Mal’tsev; N. A. Kolobrodova; T. M. Mitina; O. Yu. Grechko (647-652).
A series of amides of 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazolyl-N-acetic acids were synthesized. Their pharmacological activity was studied. It was established that the synthesized substances possessed antiaggregant properties and antiarrhythmic activity. Some of these amides exhibited antioxidant and hypoglycemic effects in addition to antagonist activity with respect to serotonin 5-HT2 and purine P2Y1 receptors.
Keywords: synthesis; acetamides; 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2a]benzimidazoles; antiaggregant properties; antiarrhythmic activity; P2Y1- and 5-HT2-antagonist activity; hypoglycemic properties; antioxidant action

Synthesis and biological properties of copolymers based on N,N-diallyl-N,N-dimethylammonium chloride by A. I. Vorob’eva; G. R. Sultanova; A. K. Bulgakov; V. I. Zainchkovskii; S. V. Kolesov (653-655).
Copolymers of N,N-diallyl-N,N-dimethylammonium chloride with sulfur dioxide, maleic acid, and vinylacetate were synthesized by radical polymerization. Their biological properties were studied. It was established that the obtained copolymers belonged to class IV low-toxicity substances and exhibited pronounced antimicrobial activity with respect to some bacterial and fungal species.
Keywords: N,N-diallyl-N,N-dimethylammonium chloride; sulfur dioxide; maleic acid; vinylacetate; copolymers; antimicrobial activity

Analysis of reasons for the impossibility of creating Copaxone generics by G. Ya. Shvarts; G. V. Ramenskaya (656-660).
The characteristics of Copaxone (glatiramer acetate, GA), an immunomodulating drug for the treatment of the serious autoimmune CNS disease multiple sclerosis, were presented. GA is the acetate of a mixture of synthetic polypeptides of various lengths composed of the natural amino acids L-glutamine, L-alanine, L-tyrosine, and L-lysine in stable molecular ratios that are prepared in definite and strictly controlled laboratory and manufacturing conditions. The polymerization reaction is carried out by addition of separate monomers and not whole peptide chains. The average length of the heterogeneous peptides in GA varies from 20 to 200 amino acids. The amino-acid sequence of the GA polypeptides is controlled to a large extent by the polymerization reaction conditions. The average molecular weight of the GA polypeptides varies in the range 5000 – 9000 Da. The majority of GA polypeptides have a molecular-weight distribution of approximately 2,500 – 20,000 Da. An analysis of the materials regarding features of the chemical structure, pharmacological and toxicological properties of GA and its analogs (glatiramoids) indicated that creating GA generics is at present practically impossible.
Keywords: Copaxone; glatiramer acetate; multiple sclerosis; immunomodulator; generic

A new series of 1,3,4-thiadiazole derivatives containing oxadiazole (3a – 3e), thiadiazole (4a – 4e), and triazole (5a – 5e) moieties have been prepared using 2-(5-phenyl-1,3,4-thiadiazol-2-ylamino)acetic acid (2) as intermediate. The structures of newly synthesized compounds are confirmed by 1H NMR, 13C NMR, and FT-IR spectroscopy, LC/MS mass spectrometry, and elemental analysis data. Furthermore, all the newly synthesized compounds were also tested for their in vitro antibacterial activity against selected human pathogens viz. Escherichia coli, Salmonella typhimurium, Legionella monocytogenes, Klebsiella pneumonia, Salmonella typhi, Staphylococcus aureus and Bacillus subtilis and antifungal activity against Candida albicans, Streptococcus pyogenes and Fusarium solani strains. The preliminary results revealed that certain compounds exhibited promising antimicrobial activities against the test microorganisms. Nine of the total of 15 compounds exhibited excellent antibacterial activity and antifungal activity.
Keywords: 1,3,4-Thiadiazoles; synthesis; antibacterial activity; antifungal activity; minimum inhibitory concentration

A series of 4-(2-chloro-4-fluorophenyl)-5-(4-substituted phenylsulfanyl)-thiazole-2-ylamines/acetamides (3a – 5b) and 5-(4-substituted benzenesulfonyl)-4-(2-chloro-4-fluorophenyl)-thiazole-2-ylamines/acetamides (6a – 8b) derivatives have been synthesized. The title compounds (3a – 5b) were obtained by the nucleophilic substitution of bromo derivatives (2a – 2b) with various substituted thiophenols. Structures of all the newly synthesized compounds were established by analytical and spectral data. The synthesized compounds have been screened for their antimicrobial activity against Gram-negative (Escherichia coli) and Gram-positive (methicillin resistant Staphylococcus aureus) bacteria and Aspergillus niger and Candida albicans fungi.
Keywords: Thiazole; sulfides; sulfones; antimicrobial activity

Chemical composition of Allium schoenoprasum leaves and inhibitory effect of their extract on tumor growth in mice by T. I. Shirshova; I. V. Beshlei; V. P. Deryagina; N. I. Ryzhova; N. V. Matistov (672-675).
A comprehensive chemical study of the cultivated plant Allium schoenoprasum L. from the collection of the Botanical Garden of the Institute of Biology (Komi Scientific Center, UB, RAS) showed that its leaves contained a wide range of biologically active substances and trace elements involved in the antioxidant and anticarcinogenic protection system of humans. An experiment for the evaluation of the antitumor potential of these substances showed that the aqueous and aqueous-alcohol extracts of onion leaves tended to inhibit the growth of subcutaneously grafted Ehrlich carcinoma in male BDF mice at the stage of intense tumor development.
Keywords: A. schoenoprasum L.; extract; anticarcinogenic effect

Alternative synthesis of lenalidomide by A. N. Balaev; K. A. Okhmanovich; V. E. Fedorov (676-678).
A three-step alternative synthesis of lenalidomide was developed. The proposed route produced the desired product in 59.8% yield and 99.6% purity.
Keywords: lenalidomide; preparation

Application of Gas Chromatography/Mass Spectrometry to Therapeutic Monitoring of Valproic Acid by D. A. Abaimov; A. K. Sariev; I. A. Tyurin; D. I. Prokhorov; T. Yu. Noskova; V. V. Shvedkov; R. D. Seifulla (679-683).
A new method for quantitative determination of the anticonvulsant valproic acid that was based on gas chromatography with mass spectrometric detection of three characteristic ionized fragments with m/z = 73, 102, and 115 was developed. The proposed technique was used to solve tasks of therapeutic anticonvulsant drug monitoring and applied to the determination of individual pharmacokinetic characteristics of valproic acid in patients at the Research Center of Neurology of the Russian Academy of Medical Sciences.
Keywords: therapeutic drug monitoring; valproic acid; gas chromatography; mass spectrometry; epilepsy

The possibility of using mobile phases with ion-pairing reagents for HPLC determination of benzethonium chloride in eye drops was studied. The most suitable mobile phases among those studied were acetonitrile:aqueous tetrabutylammonium hydrophosphate (5 mM) (65:35) and acetonitrile:aqueous tetrabutylammonium hydrophosphate (2.5 mM) and sodium heptanesulfonate (2.5 mM) (65:35). The most efficient chromatography columns for the benzethonium peak were Zorbax SB C8 (150 × 4.6 mm, 3.5 μm) and Diaspher-110-Phenyl (150 × 4.6 mm, 5 μm).
Keywords: HPLC; ion-pairing reagents; benzethonium chloride

Qualitative and quantitative compositions of fluids for electronic cigarettes by A. B. Uryupin; A. S. Peregudov; K. A. Kochetkov; L. N. Bulatnikova; S. S. Kiselev; Yu. S. Nekrasov (687-692).
The composition of fluids used in “electronic cigarettes” was studied without preliminary preparation procedures using one- and two-dimensional homo- and heteronuclear 1H and 13C NMR spectroscopy in addition to electrospray ionization mass spectrometry (ESI-MS). It was shown that the main components of the mixtures were non-tobacco products.
Keywords: fluids for electronic cigarettes; chemical analysis; nuclear magnetic resonance; mass spectrometry

Registration, insurance, and medical application of biotechnological drugs in Russia by L. E. Ziganshina; R. R. Niyazov; A. U. Ziganshin (693-697).
Existing approaches to the registration, insurance, and application of biotechnological drugs in Russia were analyzed using monoclonal antibody drugs and those produced using recombinant DNAtechnology as examples. Pharmacoeconomic aspects of using these drugs in the RF were described and compared with WHO recommendations for their use.
Keywords: biotechnological drugs; drug provision; pharmacoeconomics