Pharmaceutical Chemistry Journal (v.51, #4)

Synthesis, Immunomodulating and Antitumor Activities of Copolymers of Dialkylaminoethyl Methacrylates and Vinylsaccharides by O. V. Nazarova; L. S. Potapenkova; A. N. Stukov; Yu. I. Zolotova; O. N. Zhuravskaya; T. N. Nekrasova; E. F. Panarin (245-249).
Water-soluble random copolymers of N,N-(dimethylamino)ethyl methacrylate or N,N-(diethylamino)ethyl methacrylate with vinylsaccharides (N-methacryloyl aminoglucose, 3-O-methacryloyl glucose, 1-O-methacryloyl sorbose) were synthesized. The copolymers differed in composition, structure of the carbohydrate fragment, and type of carbohydrate–main-polymer-chain bonds. The immunomodulating activity and antitumor properties of the synthesized copolymers were established. Copolymers containing sorbose residues possessed the most pronounced immunodepressant properties.
Keywords: dialkylaminoethyl methacrylates; vinylsaccharides; immunomodulating activity; antitumor activity

Polymeric Complexes of Ofloxacin and Their Activity Against Tuberculosis Mycobacteria by M. V. Solovskii; M. S. Borisenko; E. N. Vlasova; E. B. Tarabukina; N. V. Zakharova; T. A. Prazdnikova (250-253).
The available oral forms of the antituberculosis drug ofloxacin do not ensure its long-term supply to the blood system. New polymeric complexes of ofloxacin based on copolymers of N-vinylpyrrolidone and 2-aminoethyl methacrylate hydrochloride with molecular masses of 25,000 – 87,000 were obtained with the purpose of creating effective prolonged release forms of ofloxacin. The polymeric complexes contained 25 – 35% ofloxacin, exhibited high activity against Mycobacterium tuberculosis H37Rv, and ensured gradual release of ofloxacin (45 – 57% in 50 h) in pH 2.0 buffer at 37°C.
Keywords: ofloxacin; prolonged release; copolymer of N-vinylpyrrolidone and 2-aminoethyl methacrylate hydrochloride; polymeric complexes; antituberculosis activity

Some Physicochemical Properties and Antifungal Activity of Cetylpyridinium Peroxodisulfate by A. K. Dovlatyan; P. A. Kazaryan; R. S. Arutyunyan (254-257).
Some physicochemical properties of cetylpyridinium peroxydisulfate (CPPS), the reaction product of potassium persulfate and cetylpyridinium bromide, were studied using calorimetry and IR spectroscopy. Its antibacterial and antifungal activities were studied. It was found that CPPS possessed weak antibacterial activity against the test cultures but high antifungal activity against Candida albicans.
Keywords: potassium persulfate; cetylpyridinium bromide; cetylpyridinium peroxydisulfate; biological activity

Synthesis of New 7-bromo-5-(2’-chlorophenyl)-3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine Derivatives and Their Influence on Appetite in Rats by T. L. Karaseva; E. B. Likhota; Ya. R. Krivenko; S. A. Semibrat’ev; V. I. Pavlovskii (258-261).
A series of new 7-bromo-5-(2′-chlorophenyl)-3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine derivatives (II-VIII) were synthesized. The series of synthesized compounds included those that had a substantial effect on appetite in rats, exhibiting both orexigenic and anorexigenic effects at low doses (2.07 – 2.21 μM). Compound VI had anorexigenic activity comparable with that of the hormone leptin, which reduces the appetite and food intake. Co-administration of leptin and III, which exhibited a pronounced orexigenic effect, reduced appetite by 73%.
Keywords: synthesis; 1,2-dihydro-1,4-benzodiazepin-2-one; appetite; leptin

A database of some S,N,N,N′-tetrasubstituted isothiourea derivatives possessing neuroprotective properties was successfully clustered in order to study the quantitative structure – activity relationship. Clustering by k-means was carried out in the factor space of topological descriptors. The identified clusters were combined according to analyses of intra- and intercluster distances. The initial number of clusters in the k-means clustering was determined from the number of iterations for which a solution was obtained. The homogeneity of the database and the identified clusters was estimated by using a coefficient of molecular diversity. A plot of the database compounds as points in factor space led to a conclusion about the successful applicability of the proposed clustering approach.
Keywords: clustering; topological descriptors; isothiourea derivatives

Biochemical Evaluation of Copper Compounds Derived from O- and N-/O- Donor Ligands by Muhammad Nadeem Akhtar; Muhammad Shahid; Masaaki Sadakiyo; Muhammad Ikram; Sadia Rehman; Irshad Ahmed (272-276).
The title should read: BIOLOGICAL EVALUATION OF COPPER COMPLEXES DERIVED FROM O- AND N-, O-DONOR LIGANDSCompounds [CuII 2(benz)4(Hbenz)2] (1) and [CuII(ppa)2(H2O)2] n (2), where benz = benzoate and ppa = 3-pyridinepropionic acid, were synthesized and studied for their 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and the inhibition of enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), lipoxygenase (LOX), urease, chymotrypsin and α-glucosidase. The synthesized compounds were also studied by hemolytic method for their cytotoxicity and found to be low-toxicity substances. For AChE inhibition, compound 2 showed IC50 = 31.22 ± 0.45 μM, as compared to compound 1with IC50 = 36.52 ± 0.44 μM. Both compounds showed comparably low activity against BChE and were also active against urease, but compound 1 exhibited selective anti-urease activity. The anti-α-glucosidase activity of both compounds was comparable with that of standard drug used.
Keywords: copper complexes; benzoate; 3-pyridinepropionic acid; antioxidant activity; α-enzyme inhibition; hemolytic activity

HPLC-UV Method for Determing Flavonoids in Hawthorn Flowers and Leaves by V. A. Sagaradze; E. Yu. Babaeva; E. I. Kalenikova (277-280).
An HPLC technique with UV spectrophotometric detection was developed for qualitative and quantitative determination of vitexin, rutin, hyperoside, and quercetin in Crataegus sanguinea hawthorn herbs (flowers and leaves). The separation used a Luna C18(2) column (4.6 × 150 mm, 5 μm) and a stepwise gradient. Calibration curves for the four flavonoids exhibited good linearity (r 2 > 0.995) in the studied ranges. The analytical recoveries over one day/week were 95.9-104.3%/95.6 – 102.9% for vitexin; 94.0 – 102.2%/93.5 – 101.5% for rutin; 98.0 – 102.2%/97.5 – 102.9% for hyperoside; and 96.0 – 109.8%/97.2 – 111.0% for quercetin. The intra- and interday coefficients of variation (RSD, %) were <3%. The relative error (ε, %) of a single determination at confidence level 95% was <3% for rutin, hyperoside, and vitexin and <4% for quercetin.
Keywords: Crataegus sanguinea ; HPLC-UV; flavonoids; rutin; hyperoside; vitexin; quercetin

Determination of Arbutin in Vaccinium vitis-idaea L. Leaves by V. A. Kurkin; T. K. Ryazanova; I. A. Platonov; L. V. Pavlova (281-284).
A reversed-phase HPLC method for quantitative determination of arbutin in leaves of cowberry (Vaccinium vitis-idaea L.) was developed. The optimal conditions for extracting arbutin from the plant raw material were found.
Keywords: cowberry; Vaccinium vitis-idaea L.; arbutin; HPLC analysis; spectrophotometry; iodometry; standardization

Conversion of sugars into furans in acidic solution was used to quantify the carbohydrate contents in plant medicines using juice from fresh greater burdock (Arctium lappa L.) leaves as an example. Hexoses (fructose, glucose) and inulin degraded in acidic solution to form 5-hydroxymethylfurfurol (HMF) and other compounds. Fructose and sucrose could be quantified by spectrophotometry and HPLC and could also be determined spectrophotometrically after UV degradation by using the formation by acid hydrolysis of HMF and its derivatives with chromophores at 283 – 285 nm. It was found experimentally that furan derivatives (HMF) with absorption maximum at 283 nm, which was taken as the analytical wavelength, were formed via acid degradation of the juice and a solution of fructose. The carbohydrate contents in the test samples varied from 1.05 to 1.36%. The relative error of the mean of the result from the proposed method was 7.5%.
Keywords: sugar; Arctium lappa L.; acid hydrolysis; furans

Comparative Assessment of the Prebiotic Activity of Some Pectin Polysaccharides by Zh. I. Islamova; D. K. Ogai; O. I. Abramenko; A. L. Lim; B. B. Abduazimov; M. Kh. Malikova; R. K. Rakhmanberdyeva; Z. A. Khushbaktova; V. N. Syrov (288-291).
The isolation of pectinic polysaccharides from the aerial part of Ferula kuhistanica growing wild in Uzbekistan, Malus sieversii rosemary variety apples cultivated under local conditions (apple pomace after juice production was used), and tangerine peels (Citrus reticulata, tangerine variety) is reported. Their prebiotic activities for several probiotic cultures of Bifidobacterium longum 17x and Propionibacterium avidum 1 in addition to monocultures of Lactobacillus delbrueckii subsp. bulgaricus 906 and Lactobacillus rhamnosus 925ak were determined. According to the results, pectinic polysaccharide from F. kuhistanica was most promising in this respect.
Keywords: pectinic polysaccharides; Ferula kuhistanica ; apple pomace; tangerine peels; prebiotic activity

The biologically active melanin fraction was isolated from the mushroom chaga and investigated. Terpenic and phenolic compounds were found in it by using mass spectrometry. The total contents of lipids, phenols, and carbohydrates were determined. It was found that the isolated fraction possessed antioxidant, fungicidal, fungistatic, and prebiotic activity for several microorganism groups.
Keywords: chaga; melanin; terpenes; phenolic compounds; GC-MS; fungicidal activity; fungistatic activity; prebiotic properties

In vitro Cytotoxic and Genotoxic Evaluation of Morinda tinctoria Roxb. Leaf Extracts by Kolli Deepti; Karteek Rao Amperayani; Nagendra Sastry Yarla; Uma Devi Parimi (295-300).
The in vitro cytotoxic and genotoxic evaluation of hexane, chloroform, ethyl acetate, and methanol extracts of Morinda tinctoria leaves was carried out by MTT assay and chromosomal aberration (CA), sister chromatid exchange (SCE), cell proliferation kinetics (CPK), and mitotic index (MI) tests. Five cancer cell lines [SW480 (colon adenocarcinoma); MCF-7 (breast cancer); K562 (chronic myeloid leukemia); NCIH-23 (lung cancer); SKMEL-28 (skin melanoma)] were chosen for the MTT assay. The genotoxic evaluation was carried out on human lymphocyte cell cultures at various concentrations (5, 10, 15, 20 and 25 mg/mL). The results obtained showed (i) concentration-dependent percentage inhibition with the IC50 values of different solvent extracts for cell lines studied ranging from 3.99 to 20.84 mg/mL, (ii) decrease in MI and very slight modification in the CPK values, and (iii) statistical increase in the percentage of cells with CA and the frequency of SCE for cultures exposed to various crude extracts. This is the first report on cytotoxic and genotoxic effects of M. tinctoria leaves extracts. The results suggest that the plant extracts exhibit cytotoxic and possible genotoxic effects with increasing concentration.
Keywords: MTT assay; cytotoxicity; genotoxicity; Morinda tinctoria leaves; extract; mitotic index; sister chromatid exchange

Axoglatiran® FS: Generic of Copaxone® Preparation Based on Glatiramer Acetate by Yu. V. Skornyakov; A. A. Deryabin; O. V. Skornyakova (301-306).
General information about the synthesis and properties of glatiramer acetate (GA) drug substance and the principles and methods for verifying the pharmaceutical identity of GA drug substance and Copaxone® and generic Axoglatiran® FS (INN) that are based on it was presented. Registration certificate No. LP-003572 dated Apr. 18, 2016, was issued by the RF for the first domestic GA-based generic drug Axoglatiran® FS.
Keywords: glatiramer acetate; multiple sclerosis; generic; Copaxone® ; Axoglatiran® FS

Lyophilization as a Method for Stabilizing Pharmaceuticals by L. L. Nikolaeva; I. D. Gulyakin; O. L. Orlova; A. P. Polozkova; N. A. Oborotova; E. V. Sanarova; A. V. Lantsova; V. V. Khlamov; N. D. Bunyatyan (307-311).
Lyophilization (freeze drying) is among the most effective methods used to stabilize drugs and increase their shelf life. It is influenced by many factors, the most important of which are the properties of the parent drug substance and the excipients and the freezing and drying conditions. This review considers in detail the excipients used in lyophilized dosage forms and gives examples of sublimation regimes used for the lyophilization of some antitumor drugs.
Keywords: freeze drying; excipients; lyophilizate structure; drying regime; liposomes

Analysis of Problems Hindering Implementation of Modern Drug Technologies: Searching for Possible Solutions by I. A. Narkevich; Z. M. Golant; A. A. Semin; N. S. Kartashova; A. A. Teslev (312-317).
Problems hindering the implementation of modern technologies into pharmaceutical substance manufacturing are analyzed and classified according to the degree of negative impact. Proposals for their solution were developed considering the opportunities and constraints of implementing and scaling technologies presently in the pilot stage of development. A forecast of the emergence of new technologies at both the pilot and commercial development stages was presented.
Keywords: drug manufacturing technology; pharmaceutical substance; commercial production; medicinal products; local production; research and development; implementation; synthesis; clusters

Ultrasonic-microwave assisted extraction (UMAE) was employed to extract total flavonoids (TF) from Scutellaria baicalensis roots. Single-factor experiments to evaluate effects of the process parameters (solvent-to-material ratio, ethanol concentration, extraction time, ultrasonic power, microwave power, and extraction temperature) on the TF yield were performed, and the response surface methodology (RSM) was used to optimize the extraction parameters. The optimum conditions to obtain the maximum TF yield were as follows: solvent-to-material ratio, 24; ethanol concentration, 52%; extraction time, 15.0 min; extraction temperature, 62.0°C; ultrasonic power and microwave power, 300 W each. The TF yield under these conditions reached 8.71 ± 0.26%. The analysis of variance and validation test indicated that the proposed method is useful and reliable.
Keywords: total flavonoids; ultrasonic-microwave assisted extraction; Scutellaria baicalensis ; response surface methodology

A sensor array composed of individual cylindrical cavities in a sheet of Plexiglas®, which served as tiny reaction compartments, has been developed previously by Abbaspour, et al. [39–41] based on holes created in the matrix sheet by laser beam. The cells containing sample solutions were scanned with a usual flatbed scanner, and then the obtained color image of each cell was analyzed with software written in Visual Basic (VB 6) media in red, green and blue (RGB) values. In this work, this simple, fast and inexpensive method has been used for determining free salicylic acid in aspirin tablets and urine in ferric nitrate solution. The results showed that Fe(III) forms a colored 1 : 1 complex with salicylic acid and the system response is linear in a concentration range of 2 – 280 μg/L of salicylic acid with a detection limit of 0.84 μg/L for pH in the range of 2.2 – 2.4. The scanner was used instead of a spectrophotometer and a series of interferences was examined.
Keywords: salicylic acid; aspirin; urine