Pharmaceutical Chemistry Journal (v.45, #2)

New group of class III antiarrhythmic drugs: piperid-4-ylethane derivatives by R. G. Glushkov; S. D. Yuzhakov; A. I. L’vov; G. P. Zhikhareva; N. K. Davydova; O. S. Sizova; V. V. Asnina; E. N. Salin (65-74).
A series of new piperid-4-ylethane derivatives possessing antiarrhythmic activity has been synthesized and studied. The most active compound, 1-(4-fluorophenyl)-1-(4-nitrobenzoylamino)-2-(N-ethylpiperid-4-yl)ethane (niferidyl) hydrochloride, was selected for clinical trials as a potential class III antiarrhythmic drug.
Keywords: piperid-4-ylethane derivatives; synthesis; class III antiarrhythmic activity; 1-(4-fluorophenyl)-1-(4-nitrobenzoylamino)-2-(N-ethylpiperid-4-yl)ethane hydrochloride; pharmacological study

An improved method for the synthesis of fluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepines is proposed. For this, 3-hydroxyimines were obtained via nitrosation of 1,3-diketones and 3-oxoesters by tert-butylnitrite in diethylether under acid catalysis conditions and were reacted without isolation and further purification with ortho-phenylenediamine. It was found that polyfluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepin-2-ones and 2-hydroxy-3-hydroxyimino-2-trifluoromethyl-4-phenyl-1H-1,5-benzodiazepine possess high tuberculostatic activity comparable with that of isoniazide. Tests for acute toxicity of the trifluoromethylated heterocycles showed that they are less toxic than isoniazide.
Keywords: fluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepines; synthesis; tuberculostatic activity

Synthesis and psychotropic activity of 5-cyclohexyl-5-methyl-2-sulfanyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-4-one by N. P. Grigoryan; L. A. Tarzyan; A. I. Markosyan; R. G. Paronikyan; R. S. Sukasyan (79-83).
Ethyl 2-cyano-3-cyclohexyl-3-methyl-4-phenylbutanoate was synthesized from ethyl (2Z)-2-cyano-3cyclohexylbut-2-enoate using a Grignard reagent. It was shown that the reaction occurred exclusively at the ethylene bond. Because this cyanoester contained two asymmetric centers, PMR spectra showed two diastereoisomeric forms. These were cyclized in the presence of conc. H2SO4 into ethyl 4-amino-2-cyclohexyl-2-methyl-1,2-dihydronaphthalenecarboxylate, which was used to synthesize benzo[h]quinazolines, alkyl-substituted benzo[h]quinazolines, triazole, and tetrazole.
Keywords: benzo[h]quinazolines; dihydronaphthalene; asymmetric center; diastereoisomeric forms; tetrazole; triazole; psychotropic activity

Synthesis and experimental study of a dextran-ferrite-based magnetically driven nanopreparation as an MRI contrast agent for tumor-feeding vessels by N. A. Brusentsov; Yu. A. Pirogov; A. A. Uchevatkin; V. A. Polyanskii; T. N. Brusentsova; A. V. Ivanov (84-87).
Dextran-ferrite (DF) nanoparticles were synthesized and the related DF sol was successfully tested in vivo as a negative contrast agent for enhancing early magnetic resonance imaging (MRI) detection of tumor, capsule, and tumor-feeding vessels. Intravenous injection of DF in combination with Magnevist and subsequent T2,T 2 * -weighted 3D scanning gave enhanced MRI images that defined the arrangement and functional state of surface and other vessels feeding capsule and tumor in C57Bl/6j mice with a mammary adenocarcinoma (Ac755) model.
Keywords: dextran-ferrite; negative contrast nanopreparations; tumor-feeding vessels

Quantitative hplc estimation of flavonoids in showy tick trefoil (Desmodium canadense) herbs by G. Puodziuniene; V. Kairyte; V. Janulis; A. Razukas; Z. Barsteigiene; O. Ragazinskiene (88-90).
Quantitative and qualitative analyses of flavonoids in showy tick trefoil (Desmodium canadense L., Fabaceae) herbs during various vegetative phases were performed using HPLC techniques at the Department of Medicinal Herbs of the Kaunas Botanical Garden (Vytautas Magnus University). A total of 15 flavonoids of aglycone and glycoside nature was determined including apigenin, apigenin-7-O-glycoside, luteolin, rutin, 2-vicenin, vitexin, isovitexin, vitexin rhamnoside, orientin, homoorientin, quercitrin, quercetin, hyperoside, astragalin, and kaempferol. The maximum amount of identified flavonoids was observed during the flowering phase and was 2.45% in the second vegetative year and 1.28% in the sixth vegetative year, i.e., it decreased constantly during the plant perennial vegetation process. Of these, orientin and homoorientin varied from 45.9 to 38.9% of the total flavonoids; 2-vicenin, from 16.3 to 12.8; vitexin, from 12.7 to 8.6; isovitexin, from 13.0 to 7.7; rutin, from 11.6 to 6.9. The optimum collection time of showy tick trefoil herbs as plant raw material was the flowering and budding phases of herbs regrowing after mowing. The recommended optimal exploitation time of a plantation is up to six years.
Keywords: showy tick trefoil (Desmodium canadense); herb; flavonoids; vegetative phases

Composition and antiradical activity of lilac extracts by A. A. Fedoseeva; O. S. Lebedkova; L. V. Kanibolotskaya; A. N. Shendrik; V. V. Dudzinskaya; L. N. Tkachenko; N. V. Shineva (91-92).
The composition and antioxidant properties of aqueous and EtOH extracts of the flowers and bark of various lilac species (Syringa vulgaris L., varieties Jeanne d’Arc and Lavoisier; S. josikaea Jacq. fil.; S. microphylla superba, and S. amurensis Rupr.) were investigated. It is found that the antiradical activity does not depend on the variety and species of lilac. Thus, any of the studied species can be used as pharmacological raw material. It is established that the antiradical properties of lilac extracts are determined to a considerable extent by compounds of nonphenolic nature.
Keywords: lilac; extracts; DPPH; antiradical activity

Various aspects of investigating microorganisms present in drugs are considered. Sources of contamination in nonsterile drugs are indicated. Problems related to changes in the organoleptic properties and therapeutic quality of contaminated drugs and the hazard of microorganisms for human health are analyzed. Data on the qualitative and quantitative composition of contaminant microflora isolated from various drugs are presented. Effective methods of contaminant isolation are described. Modern culture media and methods for the identification of bacteria and fungi during the microbiological quality control of drugs are presented.
Keywords: drugs; microorganism contamination; microbiological quality control

Synthesis of substituted dipeptide GB-115 as a potential selective anxiolytic by E. P. Kir’yanova; E. A. Kuznetsova; S. V. Nikitin; L. A. Zhmurenko; T. A. Gudasheva (103-106).
A new potential selective anxiolytic GB-115 [N-(6-phenylhexanoyl)glycyl-L-tryptophan amide] has been prepared. The optimum method for GB-115 synthesis consists of five steps: (1) phenylhexanoylchloride synthesis using thionyl chloride; (2) glycine acylation with the resulting chloride under alkaline conditions at 0°C; (3) L-tryptophan esterification using thionyl chloride at room temperature; (4) N-(6-phenylhexanoyl)glycyl-L-tryptophan ethyl ester synthesis by the mixed anhydride method in dimethylformamide using isobutylchloroformate; (5) ammonolysis of the resulting dipeptide ester with gaseous ammonia in methanol. The activated ester and carbodiimide methods were also studied in addition to the mixed anhydride method with various solvents and different ways of product extraction.
Keywords: CCK-4; peptides; dipeptide; anxiolytic activity

One way of establishing the interchangeability of generic drugs is based on an in vitro study of the dissolution kinetics (biowaiver). The most common approaches for assessing the ability to use the biowaiver procedure instead of the traditional bioequivalence evaluation for generics are reviewed.
Keywords: generic drugs; biopharmaceutics classification system (BCS); biowaiver; dissolution kinetics.

Sorption properties of the new natural enterosorbent Klimont by A. N. Zhuchkov; A. S. Berlyand; A. S. Alikhanyan; N. A. Plesskaya (110-113).
It is established that the new enterosorbent Klimont absorbs effectively toxic organic substances (phenol, aniline, benzene, urea) in addition to heavy-metal cations even if the concentrations of these toxicants are many times over their maximum permitted concentrations in water. The sorption capacity of Klimont is comparable with that of other zeolites used for the purification of potable water.
Keywords: Klimont; sorption; sorption equilibrium; toxic organic and inorganic substances; Langmuir and Freundlich equations

New interpolyelectrolyte complexes (IPECs) between oppositely charged types of Eudragit EPO and Eudragit L100 were synthesized at pH 6.0, 6.5, and 7.0 with a view to their application in oral controlled drug delivery systems. Differences among the obtained IPECs were evaluated by FTIR spectroscopy and elemental analy- sis. The results confirm that the polycomplexes are stabilized by intermacromolecular ionic bonds and have compositions Z = 1.02, 1.49, and 2, respectively. Monitoring of microenvironmental changes in the polycomplex matrices during swelling in model gastrointestinal fluids indicates that all IPECs can be considered as potential pH-sensitive carriers due to structural and compositional transformations. The established properties of the synthesized IPECs suggest that they have high potential to be used as pH-dependent oral drug delivery systems.
Keywords: polycomplex matrix; Eudragit EPO; Eudragit L100; structural and compositional transforma- tions; monitoring

A new class of N-basic side chains was obtained from 2,3-dihydro-2H-3-oxobenzo[d]isothiazole and aliphatic or aromatic aldehydes. Secondary amines (morpholine, N-methylpiperazine and ethyl isonipecotate) afforded tertiary N-basic side chains (46), while dibasic secondary amines (such as piperazine) gave bis-tertiary N-basic side chains (2). On the other hand, the use of mono- or dibasic primary amines namely; aniline, anisidine, phenyl hydrazine, o-hydroxy benzoic acid hydrazide, hydrazine hydrate, and ethylenediamine (instead of secondary amines) afforded secondary N-basic side chain as mono component or as bis component 7a-c, 9a-c, 11 and 12a-c. In addition, secondary Mannich base was synthesized via Michael addition to the corresponding aldimine. The new compounds were investigated for antioxidant and antimicrobial activities. Compounds 2, 7c and 12a exhibited significant antimicrobial activity, whereas compounds 7a, 7b, 9b, 9c and 11 exhibited high antioxidant activity as compared to ascorbic acid, These compounds showed the best protective effect against DNA damage induced by bleomycin.
Keywords: Saccharin; Mannich base; antimicrobial activity; antioxidant activity

A new, simple and accurate high-performance thin-layer chromatography (HPTLC) method has been developed for the separation and simultaneous analysis of B1, B2, B6 and B12 vitamins. Standard and sample solutions of vitamins were applied onto precoated aluminum-backed silica gel G 60 F254 HPTLC plate. The plates were developed with about thirty different solvent systems, and the ethanol – chloroform – acetonitrile – toluene – ammonia – water (7 : 4 : 4.5 : 0.5 : 1 : 1, v/v) mixture was chosen as the optimum mobile phase. UV detection was performed densitometrically at 254 nm. The retention factors of B1, B2, B6 and B12 vitamins were 0.36, 0.60, 0.85 and 0.46, respectively. The linearity range for indicated compounds was 10 – 2500 ng per spot and the correlation coefficients were R 2 = 0.97 – 0.98. The limits of quantification (LOQ) were 141.72, 42.41, 100.31 and 11.50 ng and the limits of detection (LOD) were 42.52, 12.72, 30.09 and 3.45 ng for B1, B2, B6 and B12 vitamins, respectively. Analyses of standard solutions showed good precision and repeatability.
Keywords: High-performance thin-layer chromatography; separation; vitamin B group; determination; quantitative analysis