Pharmaceutical Chemistry Journal (v.45, #12)

Synthesis and antitumor activity of new furyl-2-substituted 1,3,4-thiadiazoles and 1,2,4-triazoles by T. R. Ovsepyan; S. V. Grboyan; F. G. Arsenyan; R. G. Melik-Ogandzhanyan (705-708).
A series of new furyl-2-substituted derivatives of 1,3,4-thiadiazole and 1,2,4-triaozle have been synthesized. The S-alkylation and aminomethylation of the latter leading to their 3-mercapto- and 2-aminomethylene-substituted derivatives have been studied. Results of antitumor activity testing of the synthesized compounds are presented and discussed.
Keywords: hydrazide; thiosemicarbazide; cyclization; alkylation; antitumor activity

Synthesis and antiviral activity of fluorine-containing 4-arylaminoquinazolines by G. N. Lipunova; E. V. Nosova; A. A. Laeva; V. N. Charushin (709-711).
2-Methylthio-4-phenylamino-6,7,8-trifluoro-3H-quinazolin-4-one was synthesized by means of intramolecular cyclizations of S-methyl-N-(tetrafluorobenzoyl)isothiourea followed by a reaction with POCl3 and nucleophilic substitution at the 4-position. The reactions of the synthesized compound with amines proceed, depending on their nature, via substitution of either the F(7) atom or the SMe fragment in the 2-position. The antiviral activity of the obtained 6,7,8-trifluoro-2-ethylthioquinazolin-4-ones was investigated using monkeypox virus, smallpox vaccine, and ectromelia virus. It is shown that fluorinated quinazoline derivatives have good prospects in the search for new active substances.
Keywords: 2-methylthio-4-phenylamino-6,7,8-trifluoro-3H-quinazolin-4-one; 6,7,8-trifluoro-2-ethylthioquinazolin-4-ones; synthesis; antiviral activity

Synthesis and biological activity of n-acyl-4-phenyl-1,2-epoxy-2,3,3a,4,5,9b-hexahydro-1h-cyclopenta[c]quinolines by G. F. Krainova; L. V. Anikina; Yu. B. Vikharev; V. A. Glushkov (712-716).
Oxidation of substituted N-acyl-4-phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines led to the corresponding 1,2-epoxides and 1,2-diols. The synthesized 1,2-epoxides were characterized with respect to acute toxicity, cytotoxicity, analgesic activity, and influence on locomotion and exploration in an open-field test.
Keywords: Quinoline; Povarov reaction; epoxides; neurotropic activity

Synthesis, toxicity, and mouse biodistribution of 9-thiocyano-7,8-dicarba-nido-undecaborate during neutron-capture therapy by V. A. Yadrovskaya; S. N. Koryakin; S. E. Ul’yanenko; E. V. Isaeva; E. E. Beketov; D. A. Rudakov; V. L. Shirokii; V. I. Potkin (717-720).
Potassium 7,8-dicarba-nido-undecaborate was thiocyanated by nondiaphragm electrolysis. The salt Me4N+[9-SCN-7,8-C2B9H11] was isolated and converted into the trimethylammonium salt using ion-exchange. Methods for the synthesis of water-soluble sodium 7,8-dicarba-nido-undecaborate and its biphasic iodination (for 131I introduction) were developed. Thus, the synthesis and analysis of the radioactive iodine-labeled sodium salt of 11-(131I)-9-thiocyanato-7,8-dicarba-nido-undecaborate were proposed and carried out. The toxicity of the synthesized compound was evaluated. It was established that 100 and 75 mg/kg doses are 100% lethal for test animals while no significant disorders were observed at doses of 35 and 20 mg/kg. The biodistribution of the compound in organs and tissues was studied in mice with melanoma B-16. The maximum accumulation of labeled compound in tumor, skin, muscle, liver, kidneys, and spleen was observed 3 – 6 h after administration. A comparison of drug accumulation in tumor and normal tissues showed that the preparation does not possess pronounced tumor-targeting properties.
Keywords: boron-containing compounds; electrolysis; thiocyanation; toxicity; radioactive label; 131I; biodistribution; B-16 melanoma; neutron-capture therapy

Synthesis and antibacterial activity of n-(6-x-7-methyl-5-oxo-5 h-1,3,4-thiadiazolo[3,2-a]-pyrimidin-2-yl)diazo-18-crown-6 by Z. G. Sangov; Z. J. Ashurova; Z. D. Khalikova; M. A. Kukaniev; T. M. Salimov; J. N. Dzhamshedov (721-722).
The synthesis of N-(6-X-7-methyl-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)diazo-18-crown-6 is described. The antibacterial activity and acute toxicity of the obtained compound were investigated.
Keywords: 2-bromo-7-methyl-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine; N-(7-methyl-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)-18-crown-6; N-(6-X-7-methyl-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)-18-crown-6, S. aureus, E. coli, Klebsiella

Synthesis and antibacterial activity of 4-(2-r-vinyl) derivatives of functionally substituted 2,5-dihydrofurans by A. A. Avetisyan; L. V. Karapetyan; R. V. Paronikyan; G. M. Stepanyan (723-724).
Aseries of 4-(2-R-vinyl) derivatives of 2,5-dihydrofurans have been synthesized and their antibacterial activity has been investigated. The experimental results showed that the synthesized compounds possess significant antibacterial activity with respect to both Gram-positive and Gram-negative bacterial species.
Keywords: 4-(2-R-vinyl) derivatives; functionalized 2,5-dihydrofurans; synthesis; antibacterial activity

The synthesis of sydnone sulfonamides bearing thiazole, benzothiazole and pyrimidine heterocycles is described. The newly synthesized compounds were characterized by IR, NMR and elemental analysis and evaluated for their antibacterial activity against some important Gram-positive and Gram-negative bacterial strains. Most of these compounds showed good to moderate activity against tested microbes.
Keywords: Sydnone; thiazole; benzothiazole; pyrimidine; sulfonamide; antimicrobial activity

Antioxidant activity of synthetic analogs and pure active principles of rhodiola rosea and raspberry ketone by N. M. Storozhok; N. V. Gureeva; R. A. Khalitov; A. S. Storozhok; A. P. Krysin (732-735).
The antioxidant action of natural tyrosol derivatives, raspberry ketone, and their synthetic analogs was studied in comparison with α-tocopherol and butylhydroxytoluene. It is shown that hydroxylation of tyrosol increases the antioxidant activity 1.5 times. The introduction of one o-tert-butyl substituent increases the inhibiting action by a factor of 3.5; of two o-tert-butyl substituents, by greater than 4.0 times. The maximum inhibiting effect was observed for tert-butylhydroxytyrosol, the structural modification of which included simultaneously both hydroxylation and alkylation. The antioxidant activity of the studied substances was lower than that of α-tocopherol and butylhydroxytoluene. It was established that the induction periods of the studied antioxidants (AOs) in addition to many natural inhibitors (α-tocopherol, carotenoids, flavonoids) as functions of the concentrations of the studied AOs exhibit peaks. Thus, directed structural modifications of natural compounds yielded new effective oxidation inhibitors, the application of which will probably avoid undesired effects related to overdoses of the existing drugs.
Keywords: Antioxidants; tyrosol; analogs; α-tocopherol; structure modification

Developing analytical techniques for GB-115 determination in solid dosage form (tablets) by V. S. Klumova; L. N. Grushevskaya; N. I. Avdyunina; B. M. Pyatin; L. M. Gaevaya; M. S. Sergeeva; M. E. Dudenkova; K. V. Alekseev; E. V. Blynskaya; N. V. Tikhonova; K. G. Turchinskaya (736-740).
The principal pharmacopoeial quality parameters of GB-115 tablets were studied. Methods for determining the authenticity, impurities, dose homogeneity, and quantitative determination using UV spectrophotometry and HPLC were elaborated. Conditions for the pharmacopoeial dissolution test were worked out.
Keywords: GB-115; tablets; pharmaceutical analysis; UV spectrophotometry; high-performance liquid chromatography (HPLC)

Influence of processing factors on the quality of the liposomal form of the new photosensitizer tiosens by E. V. Sanarova; A. P. Polozkova; I. G. Meerovich; A. V. Lantsova; E. V. Ignat’eva; O. L. Orlova; N. A. Oborotova (741-745).
The optimum composition of a stable lyophilized liposomal formulation of tiosens is established and includes lecithin, cholesterol, and PEG-2000-DSPE in a molar ratio of 1:0.22:0.002 and sucrose solution as a cryoprotector in a 1:9 lecithin:cryoprotector weight ratio. The effects of sonication, homogenization, and filtration on the quality of the liposomal preparation were studied. The results of preliminary studies lead to a conclusion about the satisfactory storage stability of the liposome form of tiosens.
Keywords: liposomes; tiosens; homogenization; filtration; cryoprotector

Optimization of the composition and production technology of cifelin stealth liposomes by E. A. Kotova; A. P. Polozkova; T. V. Denisova; I. I. Krasnyuk; N. A. Oborotova (746-749).
Cifelin is a hydrophobic anticancer drug. It is recommended to use this drug in high doses in order to achieve a therapeutic effect. Unfortunately, this treatment leads to a number of side effects. Inclusion of the drug in stealth liposomes reduces the toxicity and ensures a long circulation of cifelin in the bloodstream. In this study, the optimum molar ratio of components (165:8:1) was found for liposomal membranes composed of phosphatidylcholine, cholesterol, and PEG-2000-DSPE, respectively. The possibilities of using liposome technology based on extrusion and sonication were compared. For cifelin liposomes with vesicle size about 150 ± 10 nm, an entrapment efficiency of 98.3 % was estimated after sterilizing filtration of the dispersion. The liposome composition was confirmed by thin-layer chromatography with a mobile phase consisting of butanol:glacial acetic acid:water (12:3:5).
Keywords: cifelin; stealth liposomes; extrusion; hydrophobic substance; molar ratio; entrapment efficiency; thin-layer chromatography

Development and standardization of dermalic ointment by T. G. Yarnykh; O. A. Garkavtseva; V. N. Chushenko (750-753).
The optimum composition and technology of Dermalic ointment consisting of the dense extract of licorice root and essential oils of chamomile and tea tree intended for the treatment of atopic dermatitis have been theoretically and experimentally validated. The results of biological tests were used to determine the optimum concentrations of active ingredients in the ointment. A water/oil emulsion base has been developed based on technological, physicochemical, and biopharmaceutical investigations. Methods for qualitative and quantitative determination of active ingredients in the preparation have been developed according to the State Pharmacopoeiaof Ukraine. The stability of the ointment during storage has been studied.
Keywords: atopic dermatitis; emulsion base; dense extract of licorice root; essential oils; technology; standardization

Determining Niferidil in Blood Serum Using Reversed-Phase High-Performance Liquid Chromatography by S. M. Filimonova; N. S. Bogomolova; V. V. Chistyakov (754-756).
A reversed-phase high-performance liquid chromatography (RP-HPLC) technique is described that can be used for the determination of niferidil in rat blood serum. The RP-HPLC procedure is carried out on a Silasorb SF C8 column (150 × 4 mm, 5 μm) eluted with a MeOH:H2 O (45:55) mobile phase (adjusted to pH 2.5 with orthophosphoric acid and then to pH 3.5 with propylamine) at a flow rate of 1 mL/min with UV detection at 265 nm. The procedure is as follows: mix rat blood serum (1 mL), NaHCO3 solution (100 μL), and CHCl3 (3 mL) in a 10-mL glass centrifuge tube. Shake for 2 min and centrifuge at 3,000 rpm for 10 min. Transfer the CHCl3 phase into another tube and evaporate to dryness under a stream of nitrogen. Reconstitute the residue in mobile phase (100 μL) and inject an aliquot (20 μL) into the chromatographic column. The average recovery of niferidil is 70%. The detection limit is 0.01 μg/mL. The method was linear from 0.02 to 0.5 μg/mL with a correlation coefficient of 0.968. The coefficient of variation was less than 12% within a day (n = 5). The proposed method was successfully used to determine some pharmacokinetic parameters after intravenous injection of niferidil in rats.
Keywords: antiarrhymthic drug; niferidil; RP-HPLC; blood serum; quantitative analysis

Spectrophotometric determination of mesalazine in urine for assessing the acetylation phenotype in vivo in humans by S. Yu. Garmonov; Z. C. Nguyen; I. F. Mingazetdinov; L. M. Yusupova; N. S. Shitova; R. N. Ismailova; V. F. Sopin (757-760).
The conditions for spectrophotometric determination of mesalazine in urine using 7-chloro-4,6-dinitrobenzofuroxane as an analytical reagent have been established. The optimum analytical results are achieved at a wavelength of 500 nm for a solution with pH 6 – 8. The detection limit for mesalazine is 0.31 μg/mL. The possibility of using the proposed method for assessing mesalazine acetylation in metabolic processes by individual human phenotypes has been shown.
Keywords: 5-aminosalicylic acid; urine; spectrophotometry; metabolism; acetylation phenotype

HPLC Determination of foreign impurities in tropoxin parent substance and tablets by M. E. Dudenkova; L. N. Grushevskaya; M. S. Sergeeva; N. I. Avdyunina; B. M. Pyatin; K. V. Alekseev; E. V. Blynskaya; E. Yu. Karbusheva (761-765).
A high-performance liquid chromatography (HPLC) technique has been developed for determining foreign impurities in tropoxin parent substance and tablets. Reliable separation of tropoxin and impurities was achieved in gradient elution mode on a liquid chromatograph equipped with a spectrophotometric detector and a stainless steel column (250 × 4.6 mm) packed with C18 (5 μm) sorbent. The detection limits for tropoxin and identified impurities were determined. It was found that the area under the impurity peak was a linear function of the tropoxin concentration in stock solutions in the range from 0.02% to 2%. The results were repeatedly reproduced in model mixtures, parent substance samples, and different batches of tropoxin tablets.
Keywords: Tropoxin; parent substance; tablets; foreign impurities; HPLC; linear gradient

Stability-indicative HPLC determination of donepezil hydrochloride in tablet dosage form by B. K. Singh; R. K. Srivastava; S. Senthil Kumar; P. K. Dutta (766-770).
Asimple, selective, precise and stability-indicative high-performance liquid chromatography (HPLC) method of analysis of donepezil hydrochloride in tablet dosage form has been developed and validated. The drug undergoes degradation under acidic, basic, peroxide, photochemical and thermal conditions. The method has been statistically validated for linearity, accuracy, precision, limit of detection, limit of quantitation, solution stability, and selectivity according to ICH recommendations. Due to its simplicity and accuracy, the method can be used for routine drug quality control.
Keywords: Donepezil hydrochloride; HPLC; tablets; dosage form; validation

Chemistry, Years, Life … by M. M. Rasulov (771-772).