Pharmaceutical Chemistry Journal (v.48, #11)

Prospects of Using Brain-Derived Neurotrophic Factor for the Treatment of Optic-Nerve Neuropathy (A Review) by I. V. Khalin; N. Z. Musina; R. N. Alyautdin; B. K. Romanov; N. D. Bunatyan (699-702).
The literature on the use of brain-derived neurotrophic factor (BDNF) as a promising agent capable of preventing the loss of retinal ganglion cells was reviewed. Mechanisms of BDNF action and the possible pathways for delivering this protein to the retina were considered.
Keywords: BDNF; retinal ganglion cells; stem cells; nanoparticles

IR spectroscopy showed that unithiol disulfide derivatives accelerated the reaction between acetaldehyde and dopamine, the product of which was a tetrahydroisoquinoline. Conversely, unithiol itself inhibited this reaction. This led to the conclusion that unithiol injection was inappropriate for prevention and treatment of alcoholism because injected unithiol was rapidly converted into its disulfide derivatives.
Keywords: acetaldehyde; dopamine; vicinal dithiols; unithiol (DMPS); unithiol disulfide derivatives; tetrahydroisoquinolines

Synthesis and Pharmaco-Toxicological Characteristics of 3-Substituted 4-Hydroxy-6-Phenyl-3,4-Dihydro-2H-1,3-Oxazines by S. S. Zykova; T. F. Odegova; S. V. Boichuk; A. R. Galembikova (706-710).
Reactions between 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-dione and various arylidenearylamines formed 3-substituted 4-hydroxy-6-phenyl-3,4-dihydro-2H-1,3-oxazines. The synthesized compounds were examined in vitro for antioxidant properties, cytotoxic activity, and acute toxicity. The highest antioxidant activity was observed for (2Z)-3-hydroxy-3-[(4-hydroxy-2-(4-methylphenyl)-3, 6-diphenyl-3, 4-dihydro-2H-1,3-oxazin-4-yl]-1-phenylprop-2-en-1-one (IIb) and (2Z)-3-hydroxy-[4-hydroxy-3-(4-methoxyphenyl)-2-(4-methylphenyl)-6-phenyl-3,4-dihydro-2H-1,3-oxazin-4-yl]-1-phenylprop-2-en-1-one (IIc). The synthesized compounds did not exhibit cytotoxic properties in vitro.
Keywords: 3-substituted 4-hydroxy-6-phenyl-3,4-dihydro-2H-1,3-oxazines; antioxidant activity; antiradical activity; DPPH; cytostatic activity; MTT test

3-Substituted [3,4-dihydroisoquinolin-1(2H)-ylidene]acetonitriles were synthesized via replacement of Cl by a cyano group in the corresponding 1-chloromethylisoquinolines. The hydrochlorides of the synthesized compounds exhibited weak antimicrobial and antifungal activities. The maximum activity against Staphylococcus aureus, Escherichia coli, and Candida albicans was observed for the compound with a 3-spiro-cyclopentyl radical, the MIC of which was 250 μg/mL.
Keywords: replacement of Cl; 3-substituted [3,4-dihydroisoquinolin-1(2H)-ylidene]acetonitriles; 3-substituted 1-cyanomethyl-3,4-dihydroisoquinolinium hydrochlorides; antimicrobial and antifungal activities

Efficiency of Combining Free and Polymer-Immobilized Prospidin with Doxorubicin for Treatment of Zajdel Ascites Hepatoma in Rats by N. A. Pyataev; K. G. Gurevich; A. V. Zaborovskii; A. V. Kokorev; O. V. Minaeva; N. N. Zyrnyaeva; A. A. Kladiev; P. P. Bychkovskii; M. Yu. Revtovich (714-717).
The antitumor activity and side effects of the drug combinations prospidin + doxorubicin and prospidin hydrogel + doxorubicin were studied in rats with transplanted Zajdel ascites hepatoma. Test animals were divided into one control group and five test groups depending on the therapy protocol. Control animals were not treated. Test groups received (i) an aqueous solution of prospidin; (ii) prospidin hydrogel; (iii) doxorubicin; (iv) prospidin + doxorubicin; and (v) prospidin hydrogel + doxorubicin. The maximum tolerated doses (MTDs) of the drugs were used in monotherapy; half the MTD, in combination chemotherapy. The antitumor activity was evaluated in terms of lethality, lethality from tumor progression, total cure rate, average life expectancy, and prolonged life expectancy. Side and toxic effects were evaluated using data on the blood cell composition and biochemical parameters. It was established that the antitumor activity of combined aqueous prospidin and doxorubicin did not exceed the activity of doxorubicin monotherapy. Side effects of this combination had the same character as those of doxorubicin and were represented by leuko- and thrombocytopenia and nephropathy. The antitumor effect of combined prospidin hydrogel + doxorubicin with respect to lethality was significantly more pronounced than the effect of each individual component. This combination had a statistically significantly lower toxicity than that of the most toxic component.
Keywords: Zajdel ascites hepatoma; prospidin; doxorubicin; antitumor activity; combined chemotherapy

New ligand 3-amino-6,8-dibromo-2-methylquinazolin-4(3H)-one (L) has been synthesized in good yield by the reaction of methyl 3,5-dibromoanthranilate with acetic anhydride, followed by the replacement of oxygen with nitrogen of hydrazine. When the ligand reacts with Co(II), Zn(II), and Cu(II), new complexes are formed. The chemical structures of all prepared compounds were characterized by IR, elemental analysis, 1H NMR, 13C NMR, GC-MS, and UV/visible spectra; in addition, metal to ligand molar ratios M : L were determined. The free ligand and obtained metal complexes were tested in vitro against a number of microorganisms, including Gram positive bacteria (Staphylococcus aureus, Bacillus species and Enterococcus feacalis), Gram negative bacteria (Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa), and fungi (Candida albicans) in order to assess antimicrobial properties. All complexes showed considerable activity against all test bacteria.
Keywords: metal complexes; 3-amino-6,8-dibromo-2-methylquinazolin-4(3H)-one; 3,5-dibromomethylanthranilate

Synthesis, Characterization, and In Vitro Antimicrobial and Antifungal Activity of Novel Acridines by Muharrem Kaya; Yılmaz Yıldırır; Gökçen Y. Çelik (722-726).
Novel acridines (4a – 4l) were synthesized by reaction of tetraketones (3a, 3b) and aromatic amines. The structures of compounds were characterized by FT-IR, 1H NMR, mass spectroscopy, and elemental analysis. Furthermore, all the synthesized compounds were tested in vitro for their antimicrobial and antifungal activity. The results were compared with conventional reference antibiotics. Many of the acridine compounds considerably reacted against Esherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis, and Staphylococcus aureus. Particularly, compound 4k showed more pronounced activity than reference antibiotics against Salmonella enteritidis. All the compounds showed moderate activities against Candida albicans and Candida glabrata.
Keywords: acridine; cyclizations; antimicrobial activity; atifungal activity; antibiotic

Water-distilled essential oil from the leaves of Artemisia diffusa Krasch. ex Poljakov, collected from north east of Iran, was investigated for phytochemical constituents and anticancer, cytotoxic, mutagenic and antimutagenic activities. Camphor (28.30%), 1,8-cineole (21.03%) and β-thujone (14.20%) were the major components in this oil. The largest part of the leaf oil of A. diffusa was formed by oxygenated monoterpenes (75.58%). Cytotoxicity was measured using a modified MTT assay against Hela and lymphocyte cells. The IC50 shows that cytotoxicity of the oil with respect to human tumor cell line (IC50 = 16.34 μg/mL) is much higher than that for healthy human cells (IC50 = 4594.92 μg/mL). These results indicate low adverse side effects of the oil. The mutagenic and antimutagenic activities of the A. diffusa oil were evaluated by the Ames Salmonella/microsome assay, using the Salmonella typhimurium tester strains TA98 and TA100, with and without the presence of metabolic activation of rat liver (S9). The excellent anti-mutagenic effect was seen in 1.16 mg/plate against both strains of S. typhimurium TA100 and TA98, without the presence of S9 fraction.
Keywords: Artemisia diffusa ; camphor; cytotoxicity; MTT assay; Ames Salmonella/microsome test; anti-mutagenic agent

Solubility of Diclofenac Acid Form from Solid Dispersions by I. I. Krasnyuk Jr.; L. V. Ovsyannikova; O. I. Nikulina; A. V. Belyatskaya; I. I. Krasnyuk; Yu. Ya. Kharitonov; V. V. Grikh; L. A. Korol’; Yu. A. Obidchenko; A. N. Vorob’ev (733-737).
The influence of solid dispersions (SD) on diclofenac solubility was determined by studying diclofenac (acid form) and its SD with polyethyleneglycol-1500 (PEG) and polyvinylpyrrolidone-10000 (PVP). SD formation increased the solubility and dissolution rate of the non-steroidal anti-inflammatory drug (NSAID). Diclofenac solubility from the SD with PVP increased by 2.5 times; from the SD with PEG (solvent evaporation method), by 8 times compared with diclofenac drug substance. A combination of physicochemical methods showed that the improved release of diclofenac from the SD occurred because of reduced crystallinity, formation of drug solid solutions in the polymer matrix, and formation of a colloidal drug solution.
Keywords: solid dispersions; solubility; NSAID; diclofenac; polyethyleneglycol-1500; polyvinylpyrrolidone-10000; crystallinity; bioavailability

The literature on metal complexes with ethylenediaminedicarboxylic acids and their derivatives as promising pharmacological and diagnostic agents was reviewed. Complexes of platinum-group metals are promising anticancer agents. Bactericidal and fungicidal properties were found for several Pt(IV) and Pd(II) complexes. Complexes of Zn(II) and VO(IV) with ethylenediamine-N,N'-dicarboxylic acids were viewed as hypoglycemic (insulin-mimetic) agents. Complexes of radionuclides (99mTc, 111In, 67Ga) were described as diagnostic radiopharmaceuticals.
Keywords: ethylenediaminedicarboxylic acid; metal complexes; zinc; vanadium; platinum; ruthenium; insulin-mimetic; antitumor agents; radiopharmaceuticals

Production and Quantitative Determination of Thymofer Drug Substance by B. M. Kholnazarov; N. D. Bunyatyan; A. N. Shakhmatov; G. M. Bobiev (744-746).
Immunomodulating thymofer drug substance was prepared as an aqueous solution (0.0148%) of the Fe(II) coordination complex with isoleucine-tryptophan. The drug substance was produced by mechanical mixing of equimolar amounts of powdered dipeptide and iron(II) sulfate. The physicochemical parameters of the preparations obtained from the resulting drug substance and that prepared by mixing aqueous solutions of the dipeptide and iron salt did not differ. Quality control methods for thymofer drug substance were developed for the main parameters. Use of the developed preparation could avoid the steps of preparing the dipeptide and iron-salt solutions and mixing them to produce the finished dosage form.
Keywords: immunomodulating preparation; coordination compounds; dipeptide; development; standardization; thymofer

Voltammetric Determination of Acyclovir in Drugs Using an Electrode Modified by Ruthenium Hexachloroplatinate or Hexacyanocobaltate Film by L. G. Shaidarova; A. V. Gedmina; E. R. Zhaldak; I. A. Chelnokova; H. K. Budnikov (747-752).
A voltammetric method for determining acyclovir using a chemically modified electrode with catalytic properties was developed. The catalytic properties for acyclovir oxidation of glassy-carbon electrodes modified by inorganic films of Ru(III) hexachloroplatinate or hexacyanocobaltate were compared. The catalytic effect was manifested as a decreased potential and multiply increased oxidation current at the proposed film electrodes. The greatest catalytic effect was observed using an electrode with a film of Ru(III) hexachloroplatinate. The catalytic current depended linearly on the analyte concentration in the range from 0.5 μM to 5 mM. The proposed method was used to determine acyclovir in drugs.
Keywords: acyclovir; voltammetric determination; modified electrode; ruthenium hexachloroplatinate and hexacyanocobaltate; inorganic films

Sorption-Catalytic Determination of Rutin, Lysine, and Collagen in Pharmaceuticals and Cosmetics by O. Yu. Vetrova; K. A. Kokorina; Zh. B. Bazhaeva; Yu. V. Mel’nik; Yu. Yu. Petrova (753-758).
The effects of ionic surfactants and ionic liquids on the TLC separation of rutin and lysine in model mixtures were studied. Procedures combining TLC, including that modified by sodium dodecylsulfate solutions, with subsequent sorption-catalytic determination of rutin, lysine, and collagen directly on the plates were developed, were highly sensitive and selective, and required only simple and readily available equipment. The procedures were used to determine rutin, lysine, and collagen in pharmaceuticals and cosmetics.
Keywords: TLC; sorption-catalytic determination; rutin; lysine; collagen

Chemical Stability of Pharmacy-Compounded Cefazolin Sodium Eye Drops by A. Kh. Valiev; A. A. Zdoryk; V. A. Georgiyants (759-761).
The stability of pharmacy-compounded cefazolin sodium eye drops was studied experimentally using three series of model solutions that were divided into two groups depending on the storage conditions at (5 ± 3)°C and (25 ± 2)°C in the dark. The influence of stress factors such as lighting and temperature (40 ± 2)°C on the model solutions was studied. The cefazolin sodium content during the stability study was determined by HPLC. The organoleptic characteristics (color, aroma, transparency) were also evaluated. The test results established that pharmacy-compounded cefazolin sodium eye drops were stable for 14 d when stored in a refrigerator (5 ± 3)°C.
Keywords: cefazolin sodium; pharmacy-compounded drugs; HPLC; stability

Quantitative Determination of a New Adenine Derivative Possessing Antiviral Activity by L. A. Smirnova; E. A. Suchkov; A. F. Ryabukha; K. A. Kuznetsov; A. A. Ozerov (762-764).
Aquantitative HPLC method was developed for pharmacokinetic analysis of adenine derivative VMA-99-82. The method was highly sensitive and selective and could be used in bioassays. The sample preparation method was optimized and had practically no effect on the average measurement error of the quantitative chromatographic method.
Keywords: HPLC; adenine derivatives; quantitative determination

The complexation reactions between Fe3+, Cu2+ and Pd2+ ions with tetracycline HCl (TC) in water or DMF were studied by the spectrophotometric methods at [(15, 25, 35 and 45 ± 0.1) °C]. The complexation process was optimized in terms of pH, temperature and time. The stoichiometry of the complexes (metal ion/ligand) were found to be 1:2 [for Pd(II)-TC and Fe(III)-TC] and 1:1 [for Cu(II)-TC]. The formation constants of the resulting complexes were determined from computer fitting absorbance-mole ratio data and emphasized by the KINFIT program. The values of the thermodynamic parameters for complexation reactions were obtained from the temperature dependence of the stability constants. Tetracycline could be determined by measuring the absorbance of each complex at its specific λmax.
Keywords: Tetracycline; Metal ions; Complexation; Thermodynamic; KINFIT