Pharmaceutical Chemistry Journal (v.50, #8)

Novel Pyrrolo[1,2-a]Pyrazines (TSPO Ligands) with Anxiolytic Activity Dependent on Neurosteroid Biosynthesis by M. A. Yarkova; G. V. Mokrov; T. A. Gudasheva; S. B. Seredenin (501-504).
A series of novel pyrrolo[1,2-a]pyrazines that were ligands of 18 kDa translocator protein (TSPO) were synthesized at Zakusov SIP. The compounds N-benzyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-1) and N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-3) were found to possess high TSPO affinity and pronounced anxiolytic activity. The anxiolytic effects of GML-1 and GML-3 in elevated plus-maze tests were completely blocked by the neurosteroidogenic-enzyme inhibitors trilostane and finasteride.
Keywords: 18 kDa translocator protein; anxiolytic activity; pyrrolo[1,2-a]pyrazines; neurosteroids

Effects of Melaxen and Valdoxan on Free-Radical Oxidation in Rat Heart with Experimental Hyperthyroidism by T. N. Popova; A. A. Agarkov; M. V. Gorbenko; S. S. Popov; K. K. Shul’gin (505-508).
The rate of free-radical oxidation in rat heart with experimental hyperthyroidism (EH) was estimated after Melaxen and Valdoxan administration. It was found that the content of protein carbonyl groups increased if the pathology developed in cardiomyocytes. This indicated that they were oxidized. Increased concentrations of primary lipid peroxidation products (diene conjugates), inhibition of aconitate hydratase activity, and accumulation of citrate were noted. Injection of Melaxen and Valdoxan to rats with EH normalized these parameters. The melatonin-correcting capability of the used drugs and the antioxidant activity of melatonin probably facilitated normalization of free-radical homeostasis in rat cardiomyocytes with the pathology.
Keywords: protein oxidation; diene conjugates; Melaxen; Valdoxan; hyperthyroidism; rats

Activities of Tetramethylene-Bis-Onium Reversible Cholinesterase Inhibitors as Influenced by the Nature of the Onium Atom by N. E. Basova; B. N. Kormilitsyn; A. Yu. Perchenok; E. V. Rozengart; V. S. Saakov; A. A. Suvorov (509-512).
Inorganic tetramethylene bis-onium compounds were studied as reversible inhibitors of various cholinesterases (ChE), i.e., human erythrocyte acetyl-ChE, horse blood serum butyryl-ChE, grass frog Rana temporaria brain ChE, and Pacific squid Todarodes pacificus and commander squid Berryteuthis magister visual ganglia ChE from various habitats in the northwest Pacific Ocean, in order to study the influence of the nature of the onium atom on their anti-ChE activities. bis-Phosphonium inhibitors turned out to be significantly more potent effectors than bis-ammonium compounds, which may actually have been due to the significant increases of size and hydrophobicity of the onium groups. The bis-ammonium organosilicon compound and its monoammonium analog turned out to be equally active as reversible ChE inhibitors in mammals. The bis-phenyliodonium derivative was studied for the first 7time, was characterized by significantly increased hydrophobicity due to introduction of F atoms into the tetramethylene spacer in the onium chain, and exhibited marked anti-ChE activity with respect to mammalian ChE.
Keywords: cholinesterases; reversible inhibitors; bis-ammonium compounds

Synthesis of and HIV-1 Integrase Inhibition by 2-[7-(Fluorobenzyloxy)-4-Oxo-4hchromen-3-Yl]-1-Hydroxyimidazoles by P. A. Nikitina; I. I. Tkach; E. S. Knyazhanskaya; M. B. Gottikh; V. P. Perevalov (513-518).
A series of six new 2-[7-(fluorobenzyloxy)-4-oxo-4H-chromen-3-yl]-1-hydroxyimidazoles were synthesized and characterized as potential HIV-1 integrase inhibitors. Prototropic tautomerism of the obtained 1-hydroxyimidazoles was discussed. Their ability to inhibit integrase catalytic activity in 3′-terminal processing and chain transfer reactions was studied. It was shown that these compounds did not exhibit noticeable inhibition.
Keywords: 1-hydroxyimidazoles; prototropic tautomerism; HIV-1; integrase; inhibitors

A series of methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates were synthesized using the reaction of methyl 2,4-dioxobutanoates with arylidenemalononitriles in EtOAc in the presence of catalytic amounts of morpholine or piperidine. The structures of the compounds were elucidated using IR, PMR, 13C NMR, and mass spectral data. The antimicrobial, analgesic, and antipyretic activities of the synthesized compounds and their influence on antibody response were studied.
Keywords: methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates; arylidenemalononitrile; 2,4-dioxobutanoic acids; biological activity; antibody response

Synthesis and Antiproliferative Activity of New Acylcatechins by A. O. Pozdeev; E. N. Rasadkina; A. A. Burym; V. V. Knyazev; M. P. Koroteev; A. I. Matyushin; A. M. Koroteev; A. V. Semeikin; N. L. Shimanovskii (523-525).
New peracyl derivatives of the natural flavonoid (±)-catechin were synthesized. It was shown that carboxylic-acid acyl residues enhanced to various degrees the cytotoxicity of peracyl catechins against HeLa cell line. The structures of the synthesized compounds were confirmed by PMR and 13C NMR spectroscopy and elemental analysis. The catechins were compared with previously studied analogous dihydroquercetin derivatives.
Keywords: cytotoxicity; acylation; catechin; PMR; 13C NMR

Synthesis and Fungi/Bactericidal Activities of 4-(4-Dimethylaminophenyl)Pyridine Derivatives by D. A. Lomov; M. G. Abramyants; N. V. Astashkina; N. I. Korotkikh; V. I. Lubenets; V. P. Novikov; E. Z. Komarovskaya-Porokhnyavets; N. N. Smolyar (526-529).
A series of 4-(4-dimethylaminophenyl)pyridine derivatives were synthesized and tested for antimicrobial activity. 4-(4-Dimethylaminophenyl)-1-phenacylpyridinium bromide and 4-(4-dimethylaminophenyl)-1-dimethylcarbamoylpyridinium chloride were highly active against M. luteum and C. tenuis test cultures.
Keywords: 4-(4-dimethylaminophenyl)pyridine; synthesis; quaternary salts; fungi/bactericidal activity

N-Aryl(hetaryl)methylidene-4-[9-(thio)xanthenyl]anilines, N-arylmethylidene-{4-(5H-chromeno[2,3-b]pyridin-5-yl)phenyl}amines, and N-aryl(hetaryl)methyl-4-[9-(thio)xanthenyl]anilines were synthesized via the reaction of imines and amines with xanthydrol, thioxanthydrol, and 1-azaxanthydrol and exhibited antibacterial activity with respect to S. aureus No. 906 and E. coli No. 1257. Six museum and five hospital microorganism strains and three compounds that exhibited earlier high biological activity against three cultures (S. aureus No. 906, E. coli No. 1257, and C. albicans No. 24433) were tested in an expanded study.
Keywords: dibenzopyran-9-ol (xanthydrol); dibenzothiopyran-9-ol (thioxanthydrol); 5-hydroxybenzopyrano[2,3-b]pyridine (1-azaxanthydrol); imines; amines; antibacterial activity

2-Thiocyanato-(2-methyl)-3-[4-(3-)-thiocyanatophenyl]propionamides exhibited rather high antimicrobial activity with respect to staphylococci, E. coli, yeast-like fungi, and pseudomonas that was practically absent in bis-thiocyanatoamides of benzidine and its derivatives.
Keywords: bis-diazonium salts; thiocyanatoarylation; mono- and bis-thiocyanatoamides; antimicrobial properties; synthesis

Development of Manufacturing Technology for Prolonged-Release Oral Amben Preparation by G. O. Nifontova; S. P. Krechetov; E. V. Korostylev; A. R. Akhmetzyanova; I. I. Krasnyuk (537-542).
Results from technology development for manufacturing an amben prolonged-release preparation based on a Kollidon SR hydrophobic polymer matrix were presented. It was shown that dry and wet granulation could improve the processing properties of mixtures for preparing tablets and provide the required amben release kinetics.
Keywords: hydrophobic polymer matrix; amben; prolonged release; granulation

Antitumor Activity of a Polymer Composite of Etoposide and Biodegradable Poly(Lactide-Co-Glycolide) by G. A. Posypanova; L. B. Gorshkova; A. V. Rodina; Yu. P. Semochkina; V. G. Perevozchikova; E. Yu. Moskaleva; M. G. Ratushnyak; E. A. Vorontsov; S. L. Kuznetsov; I. A. Tubasheva; A. I. Murav’eva; S. E. Severin (543-547).
A method for preparing an antitumor polymer form of etoposide (PFE) as submicron particles based on poly(lactide-co-glycolide) with a 50:50 ratio of monomers (PLGA 50/50) was described. It was shown that the PFE possessed high cytotoxicity against various types of human tumor cells. The activity of the PFE against multiple drug resistant K562ADR cell line was greater than that of free etoposide. A grafted solid P388 murine lymphatic leukemia model showed that the PFE exhibited high in vivo antitumor activity that was prolonged compared with that of free etoposide.
Keywords: etoposide; poly(lactide-co-glycolide); antitumor activity

Casette Dosing for Optimization of Toxico(pharmaco)kinetic Investigations by E. I. Savel’eva; P. N. Sorokoumov; O. I. Orlova; N. L. Koryagina (548-552).
The need to screen the kinetic characteristics of pharmaceuticals in early development stages is justified. The advantages and limitations of cassette dosing in pharmacokinetic investigations are discussed. The dose and the presence or absence of pharmaceutical interactions are shown to be the critical factors affecting the reliability of pharmacokinetic parameters assessed by the cassette method. The hypothesis that toxicokinetic cassette screening of compounds capable of interacting is appropriate for describing the slow elimination phase was verified by comparing lewisite excretion parameters after injection into laboratory animals of lewisite and a mustard-gas—lewisite mixture.
Keywords: cassette dosing; pharmacokinetics; toxicokinetics; pharmaceutical interactions

Vinpocetine Release From a Microencapsulated Form by Yu. A. Polkovnikova; A. I. Slivkin (553-555).
Microencapsulated vinpocetine was produced by liquid—liquid dispersion using a mixture of beeswax and cocoa oil in a 3:2 ratio as the carrier. The dispersion media were purified H2O and sodium carboxymethylcellulose (Na-CMC) solution (2%). Drug release from the microcapsules was studied in vitro as a function of microcapsule size, shell material, and dispersion medium. The best characteristics were observed for microcapsules with a hydrophobic coating containing beeswax and cocoa oil in a 3:2 ratio of size 0.5 – 1 mm that were produced in Na-CMC solution (2%).
Keywords: vinpocetine; microencapsulation; biopharmaceutical investigation

Potentiometric Sensor for Povidone-Iodine Determination by Zh. Kormosh; T. Savchuk (556-557).
Adiiodobromide sensor with a plasticized polyvinylchloride membrane was developed. The sensor contained an ionic associate of diiodobromide and rhodamine B and had a linear response for I2Br- concentrations of 10–6 – 10–1 M with an electrode function slope characteristic of singly charged ions. The sensor was used as an indicator electrode for potentiometric determination of povidone-iodine in pharmaceuticals.
Keywords: diiodobromide sensor; potentiometry; povidone-iodine determination

Biological Evaluation of Terrestrial and Marine Plant Originated Labdane Diterpenes (A Review) by Mahesh Pal; Tripti Mishra; Anil Kumar; Shri Krishana Tewari (558-567).
Recent progress on studies of labdane diterpenoids is compiled. Seventy seven biologically active labdane diterpenes isolated from various higher plants, mosses, liverworts, algae, etc. are reported. The absolute configurations of compounds 1 – 77 were established using extensive spectroscopic techniques. The wide range of biological activities possessed by these diterpenoids suggests that thorough evaluation of some structure-activity relationships is overdue. In this review, data on the natural sources, isolation, structure and biological activities of labdane diterpenoids isolated from various plants are summarized.
Keywords: labdane diterpene, antimicrobial activity; algicidal activity; cytotoxic activity; anti-inflammatory activity

Traditional Chinese medicinal plant Paeonia veitchii Lynch. has a complicated chemical composition. For profound study of the medicinal value of Paeonia genus, systematic chromatographic investigations were carried out on n-butyl alcohol fractions of the ethanol extract for the separation of monoterpene glycoside compounds. Six compounds were isolated from the extract, which were identified on the basis of spectral analysis and physicochemical evidence. They are paeoniflorin (1), 4-O-methyloxypaeoniflorin (2), 4-O-methylpaeoniflorin (3), 4-O-ethylpaeoniflorin (4), paeonidanin (5), and 9-ethyl-neo-paeoniaflorin A (6). Compounds 2, 3, and 5 were isolated from this plant for the first time.
Keywords: Paeonia veitchii Lynch; monoterpene glycosides; isolation