Pharmaceutical Chemistry Journal (v.51, #12)

3-Methyl-7-(1,1-dioxothietan-3-yl)-8-cyclohexylamino-1-ethyl-1H-purine-2,6(3H,7H)-dione was synthesized via the reaction of 8-bromo-3-methyl-7-(1,1-dioxothietan-3-yl)-1-ethyl-1H-purine-2,6(3H,7H)-dione and cyclohexylamine and exhibited antidepressant activity that was most pronounced at a dose of 1.6 mg/kg.
Keywords: xanthines; thietanes; synthesis; antidepressant activity

Hemostasis Parameters and Toxic Effects of 3-Substituted and Condensed Chromen-2-Ones (Coumarins) by D. N. Ibragimova; O. V. Fedotova; A. G. Ozerova; O. V. Koftin; V. B. Borodulin; V. A. Samokhvalov (1053-1056).
Due to an error in preparing the XML file of this paper, all numerical data in Table 1 were omitted. The corrected table appears below:Biochemical investigations of 3-substituted chromen-2-ones (coumarins) and those condensed with biologically active azaheterocycles assessed their toxic effects and influence on the blood-coagulation system. The studied group of compounds behaved in the initial time period like the well-known anticoagulant warfarin and exhibited insignificant toxic effects.
Keywords: chromen-2-ones; Mannich bases; chromenopyrimidobenzimidazolones; chromenopyrazolopyrimidinones; hemostasis

A synthetic method for 7,10-dimethyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclopentane]- 4(6H)-one from ethyl 4′-amino-5′,8′-dimethyl-1′-H-spiro[cyclopentane-1,2′-naphthalene]-3′-carboxylate was developed. Reaction of the spirobenzo[h]quinazoline with various alkyl(benzyl) halides synthesized a novel series of spirobenzo[h]quinazolines containing methyl substituents on the benzene ring. The antidepressant, anticonvulsant, and antibacterial activities of the synthesized spirobenzo[h]quinazolines were investigated.
Keywords: benzo[h]quinazoline; dihydronaphthalene; benzoxazine; anti-monoamine oxidase; anticonvulsant activity

Anti-Candida Activity of 4-Morpholino-5-Nitro- and 4,5-Dinitro-Imidazole Derivatives by Dorota Olender; Lucjusz Zaprutko; Anna Mertas; Ewelina Szliszka; Dariusz Wyrozumski; Wojciech Król (1063-1067).
The activities of some 4-morpholino-5-nitro- and 4,5-dinitro-imidazole derivatives with respect to several Candida species were evaluated. It is established that 4,5-dinitroimidazole derivatives constitute an important group of compounds possessing antifungal activity against Candida species. Some analogs showed moderate antifungal ability in vitro, especially in relation well-known antifungals such as flucytosine (5FC). The best results of antifungal action were obtained for 1-(3-bromo-2-hydroxypropyl)-2-methyl-4,5-dinitroimidazole (3c), 1-(3-bromo-2-oxopropyl)-2-methyl-4,5-dinitroimidazole (4c) and 2-methyl-1-phenacyl-4,5-dinitroimidazole (2b). The latter compound proved to be effective against Candida sake S-1 (in contrast to inactive 5FC).
Keywords: antifungal activity; Candida species; nitroimidazoles; flucytosine

Benzimidazole Ring System as a Privileged Template for Anticancer Agents by Afshan Kanwal; Furqan Ahmad Saddique; Sana Aslam; Matloob Ahmad; Ameer Fawad Zahoor; Noor-ul-Amin Mohsin (1068-1077).
Cancer still remains a continued threat for human race in the 21st century. It is the major cause of human casualties globally and is thus, a hot topic of research in medicinal laboratories. Scientists are striving to find selective anticancer agents having low toxicity for normal human cells. Heterocyclic ring systems play key role as templates/pharmacophores for various drugs, and benzimidazole ring is especially important for its anticancer derivatives. In this review article, we have focused on the structural features of anticancer derivatives based on benzimidazole ring system. It highlights various benzimidazole-based anticancer compounds which have been developed in recent years.
Keywords: benzimidazole derivatives; heterocyclic compounds; biological significance; anticancer activity

Coumarinyl Thiosemicarbazides as Antimicrobial Agents by M. Molnar; M. Tomić; V. Pavić (1078-1081).
Two series of coumarinyl thiosemicarbazides were synthesized: one, using the coumarin core substituted in position 7 and another, using same core substituted in position 4. All these compounds were obtained in reactions of the corresponding hydrazide and various isothiocyanates. The structures of all products were confirmed by the 1H and 13C NMR and mass spectrometry techniques. The antimicrobial properties of compounds were tested on four bacterial strains: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. 2-(2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acetyl)-N-(2,4,6-trichlorophenyl)hydrazine-1-carbothioamide was found to be the most potent agent against B. subtilis.
Keywords: thiosemicarbazide; coumarin; antibacterial activity

Differential Approach to Analysis of Tannin-Containing Herbal Raw Materials and Medicines by A. M. Kalinin; N. P. Antonova; T. N. Bokovikova; S. S. Prokhvatilova; E. P. Shefer (1082-1084).
A differential quantitative determination method for tannins in herbal raw materials and medicines is described. The main feature of the method is the ability to vary the analysis conditions (reference standards, analytical wavelength, sample weight) considering the structural class of the extracted tannins.
Keywords: tannins; quantitative determination; standardization

Hydrophobic Constituents Extracted from Chaga by Ethylacetate by G. I. Kyyamova; V. R. Khabibrakhmanova; M. A. Sysoeva (1085-1087).
Chaga can be extracted with EtOAc to afford ~0.88% extracted substances, of which ~58% are lipophilic compounds with the remainder being phenolic compounds. Tetracyclic triterpenes, sterols and their esters, sesquiterpenes (azulenes), bicyclic monoterpenes (iridoids), phenolcarboxylic acids, simple phenols, and flavonoids were identified in the extract. Stilbene-type compounds, a phenanthrene derivative, and 9(11)-dihydroergosteryl benzoate were observed in chaga for the first time.
Keywords: chaga; EtOAc; sterols; tetracyclic triterpenes; azulenes; iridoids; flavonoids

This study was aimed to evaluate in vitro total content of polyphenols and flavonoids and in vivo antioxidant effect of the hydroalcoholic extract of Carduus acanthoides L. as compared to that of Vaccinium myrtillus L. The total content of polyphenols and flavonoids was evaluated by a spectrophotometric method. The chemical composition of plant extracts was determined using thin-layer chromatography, HPLC, and GC-MS techniques. Tests for the antioxidant activity were performed using streptozotocin-diabetic adult Swiss albino mice distributed in four groups, including three control groups – mice with normal pancreatic function (group I), diabetic mice (group II), and diabetic mice treated with V. myrtillus extract recognized for its antioxidant effect (group IV) – and the test group of diabetic mice treated with C. acanthoides extract at 150 mg/kg b.w. (group III). At the end of experiments, the animals were sacrificed and the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase were tested, the level of lipid peroxides was determined, and a histological analysis of the pancreas was performed. Both plant extracts contain polyphenols and flavonoids in significant amounts due to which they have antioxidant properties. The antioxidant enzymes exhibited higher activities in mice treated with C. acanthoides extract, but the level of lipid peroxides was significantly lower in mice treated with V. myrtillus extract.
Keywords: antioxidant effect; diabetes; streptozotocin; vegetal extract

Compatibility of Ramipril and Lercanidipine Drug Substances in a Single Solid Dosage Form by A. A. Shadrin; E. V. Flisyuk; E. N. Kirillova (1096-1101).
The chemical properties of ramipril and lercanidipine drug substances were studied to select the conditions necessary for technology development of solid dosage forms. Mixtures containing two or three ingredients were formulated to study the chemical compatibility of the substances and their compatibility with the excipients and were placed into storage. Analyses of these mixtures showed that the substances could be compatible in a single dosage form. Samples of intermediates (mixtures, granulates, tableting masses, tablet cores) and finished products (film-coated tablets) were manufactured, placed into storage, and analyzed to find the optimum processing factors. It was proven that the tableting process and the coexistence of ramipril and lercanidipine in any kinds of intermediates had significant effects on the ingrowth of impurities. The need to use bilayer tablet technology was justified.
Keywords: combined drugs; compatibility; stability; bilayer tablets

Development and Validation of a Method for Determination of a New Effective Inhibitor of Influenza Virus H1N1 in Blood Plasma by A. S. Sokolova; O. I. Yarovaya; A. A. Nefedov; N. F. Salakhutdinov (1102-1105).
A new GC-MS method for determining an antiviral agent (camphecin) in blood plasma was developed. Sample preparation consisted of precipitating proteins using MeOH. The method was validated for selectivity, calibration curve, accuracy, precision, limit of quantitation, carryover, and stability. The analytical range was 0.1 – 2 μg/mL. The method could be used for pharmacokinetic studies.
Keywords: camphecin; plasma; validation; GC-MS

Development of a Procedure for Identification of Biperiden Hydrochloride with Specificity for Triperiden Hydrochloride by N. E. Kuz’mina; S. V. Moiseev; V. I. Krylov; A. A. Kutin; V. A. Yashkir; V. A. Merkulov (1106-1110).
Biperiden hydrochloride, (1RS)-1-[(1RS, 2SR, 4RS)-bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)prop an-1-ol hydrochloride, is one of the most efficacious cholinolytics. It is used to treat Parkinson’s disease and various types of muscular spasms and to ameliorate uncoordinated muscular movements that can accompany the use of several tranquilizers [1, 2]. Biperiden appears in the vital and essential drug list that was approved by an order of the RF Government [3].
Keywords: biperiden hydrochloride; triperiden hydrochloride; identity; specificity; mass spectrometry; IR spectrometry; NMR spectroscopy

Simultaneous Determination of Metoprolol and Bisoprolol in Human Serum by HPLC-MS/MS for Clinical Drug Monitoring by T. A. Rodina; E. S. Mel’nikov; A. I. Dmitriev; S. A. Belkov; A. V. Sokolov; V. V. Arkhipov; A. B. Prokof’ev (1111-1118).
A method for simultaneous determination of metoprolol and bisoprolol in human blood serum by HPLC-MS/MS was developed and validated. The analytical ranges of the method were 5 – 250 ng/mL and 1 – 250 ng/mL for metoprolol and bisoprolol, respectively. The suitability of the developed for therapeutic drug monitoring during treatment for arterial hypertension and other cardiovascular diseases was demonstrated. In particular, the proposed method could identify patients at high risk for developing adverse effects and help to monitor a switch between metoprolol and bisoprolol while changing the pharmacotherapy regime.
Keywords: metoprolol; bisoprolol; HPLC-MS/MS; arterial hypertension; therapeutic drug monitoring

Determination of Bacterial Endotoxins in Drugs: False-Negative Results by O. V. Shapovalova; N. P. Neugodova; G. A. Sapozhnikova; L. V. Simutenko; A. A. Agashirinova (1119-1122).
One of the possible causes of false-negatives in bacterial endotoxin determinations, endotoxin aggregation and adsorption, was examined in a model experiment (positive control). A solution for eliminating the interfering actor using kinetic methods and a dispersing solvent was proposed based with the drug caspofungin as an example.
Keywords: bacterial endotoxins; interfering factors; inhibition; false-negative results; metal-containing polyanionic dispersing solvent

Flupirtine Determination in Human Blood Plasma by HPLC with Mass-Spectrometric Detection and its Application to Pharmacokinetic Studies by L. M. Krasnykh; T. A. Rodina; E. S. Mel’nikov; G. F. Vasilenko; V. V. Smirnov; A. V. Sokolov; V. V. Arkhipov (1123-1128).
A validated method for quantitative determination of flupirtine in human blood plasma using liquid chromatography combined with tandem mass spectrometry (HPLC-MS/MS) was proposed. Biological samples were prepared by precipitating proteins using MeOH. The chromatographic separation used a Zorbax Eclipse Plus C18 column with gradient elution. A Shimadzu 8040 triple quadrupole mass spectrometer in multiple-reaction-monitoring mode (+MRM) with chemical ionization at atmospheric pressure (APCI) was used to determine the molecular ion of flupirtine with m/z 305.2. Acalibration curve for flupirtine was linear (R = 0.994) in the concentration range 25 – 2,500 ng/mL with a lower detection limit of 25 ng/mL. Validation of the method indicated that it was highly sensitive, specific, accurate, and precise and that the analyte was stable. The method was successfully applied to comparative pharmacokinetic studies of drugs containing flupirtine.
Keywords: flupirtine; HPLC-MS/MS; multiple-reaction-monitoring mode; pharmacokinetics

HPLC-MS/MS Method for Determining Dabigatran in Human Blood Serum by T. A. Rodina; E. S. Mel’nikov; A. A. Aksenov; S. A. Belkov; A. V. Sokolov; A. B. Prokof’ev; G. V. Ramenskaya (1129-1137).
An HPLC-MS/MS method for determining dabigatran in human blood serum was developed. Samples were prepared by precipitation of proteins using MeOH followed by centrifugation and dilution with deionized H2O. The developed method had a simple sample-preparation procedure, short analysis time, and wide analytical range (from 1 to 1,000 ng/mL). This method was suitable for routine bioanalytical studies, in particular, therapeutic drug monitoring.
Keywords: novel oral anticoagulants (NOACs); dabigatran; dabigatran etexilate; HPLC-MS/MS; therapeutic drug monitoring

Novel Free-Radical Scavengers Based on Ferrofluid/Polyaniline Nanocomposites by Forough Nasuhi Pur; Nasser Arsalani; Kazem Dindar Safa (1138-1142).
We investigated the antioxidant activity of novel ferrofluid/polyaniline nanocomposites with various mass ratios synthesized via in situ chemical oxidative polymerization of aniline without stirring in the presence of stabilized Fe3O4 nanoparticles and citric acid as a surfactant. The structural, morphological, thermal, magnetic, and electrical properties of the nanocomposites were characterized by IR and UV spectroscopy, XRD, SEM, TEM, TGA, VSM, and four-point-probe methods. The antioxidant potency was determined by modified 2,2-diphenyl-1-picrylhydrazyl (DPPH) method using an in vitro system. The DPPH free-radical scavenging tests of nanocomposites showed that their antioxidant properties depended on the amount of polyaniline in the composition. Results of the comparison of DPPH scavenging capacity of nanofiber polyaniline and granular ferrofluid/polyaniline nanocomposite show that the antioxidant activity is related to the morphology of polyaniline.
Keywords: free-radical scavenging; ferrofluid; polyaniline; nanocomposites

Correction to: Hemostasis Parameters and Toxic Effects of 3-Substituted and Condensed Chromen-2-Ones (Coumarins) by D. N. Ibragimova; O. V. Fedotova; A. G. Ozerova; O. V. Koftin; V. B. Borodulin; V. A. Samokhvalov (1143-1143).
Due to an error in preparing the XML file of this paper, all numerical data in Table 1 were omitted. The corrected table appears below: