Pharmaceutical Chemistry Journal (v.51, #7)

Modification of the Antitumor Action of Cytostatic Drugs Using a Copolymer of N-Vinylpyrrolidone and 2-Methyl-5-Vinylpyridine by A. V. Panov; Yu. V. Kochkina; E. I. Yartsev; D. V. Eremin; T. A. Yakovleva; S. A. Kedik (523-527).
Simultaneous administration of a copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine and cytostatic agents to mice with a variety of implanted tumors was found to increase treatment efficacy, promoting increases in survival time. This effect is of interest for further studies of the possible use of copolymer as an immunomodulator in chemotherapy.
Keywords: N-vinylpyrrolidone; 2-methyl-5-vinylpyridine; copolymer; cytostatic; antitumor effect; immunomodulator

Determination of Cohort Size for Studies of Bioequivalence Using Computer Modeling by V. S. Arnautov; D. V. Reikhart; A. S. Borisov (528-532).
The randomized crossover (2 × 2) protocol is a standard design for studies of bioequivalence, reducing intraindividual variability. Determination of cohort size for studies of bioequivalence is an important element in planning studies and must be evidence-based. The aim of the present work was to produce and validate an algorithm for determining the required cohort size for studies of bioequivalence using computer simulation. The proposed algorithm is based on a procedure for assessing the power of the statistical test for known numbers of observations, variance, and preset values of acceptable first-order error levels.
Keywords: bioequivalence; pharmacokinetics; cohort size; simulation

Synthesis and Antidiabetic Activity of Thiazolo[2,3-f]Purine Derivatives and Their Analogs by A. A. Spasov; F. A. Khaliullin; D. A. Babkov; G. A. Timirkhanova; V. A. Kuznetsova; L. V. Naumenko; D. R. Muleeva; O. Yu. Maika; T. Yu. Prokhorova; E. A. Sturova (533-539).
Thiazolo[2, 3-f]purine derivatives and their analogs – dihydrothiazolo[2, 3-f]purine, 7-(thietan-3-yl)purine, and 8-(2-hydroxypropylthio)purine derivatives – were synthesized. The compounds synthesized here had no effects on protein glycation reactions using glucose; they gave weak inhibition of glycogen phosphorylase; they had no hemorheological activity. Substances with hypotensive activity greater than that of Dibazol were found. A number of substances had hypoglycemic effects greater than those of chlorpropamide and Adebit. Two compounds inhibited dipeptidylpeptidase-4, but were less active than reference agent vildagliptin.
Keywords: thietanes; purine; antidiabetic activity

Starting with the (R) and (S) enantiomers of 2-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)ethanol, prepared previously by partial acylation of the corresponding racemic alcohol in the presence of the most easily available lipase, from the yeast Candida cylindracea, a four-stage syntheses was developed for both enantiomers of {2-[6-hydroxy-2,5,7,8-tetramethylchroman-2-yl]ethyl}trimethylammonium p-toluenesulfonate (MDL-73404), which are chiral analogs of α-tocopherol. Comparative biomedical testing of samples of MDL-73404 salts with different enantiomer compositions in relation to their effects on the generation of reactive oxygen species by peritoneal macrophages from white rats in systems containing luminol or lucigenin demonstrated different levels of inhibition of spontaneous and 12-O-myristyl-13-O-acetylphorbol-activated macrophage chemiluminescence.
Keywords: 2-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)ethanol; yeast Candida cylindracea lipase; enantiomeric acetylation; {2-[6-hydroxy-2,5,7,8-tetramethylchroman-2-yl]ethyl}trimethylammonium p-toluenesulfonate (MDL-73404); (R) and (S) enantiomers; antioxidant activity; spontaneous and 12-O-myristyl-13-O-acetylphorbol-activated chemiluminescence

Synthesis and Antiarrhythmic Activity of 1-Benzyl-3,3-Dialkyl-3,4-Dihydroisoquinoline Chlorides by A. G. Mikhailovskii; O. V. Gashkova; I. P. Rudakova; D. A. Peretyagin (546-549).
Cyclocondensation of dialkylbenzylcarbinols with benzylcyanides was used to synthesize 1-benzyl-3,3-dialkyl-3,4-dihydroisoquinolines. The hydrochlorides of the compounds synthesized here were tested for antiarrhythmic activity in a calcium chloride model. The maximum antiarrhythmic index (AI) was found with isoquinolines with cycloalkanone fragments such as cyclopentanone and cyclohexanone in position 3, which had AI values of 15.5 and 16.3, three times the corresponding value for lidocaine.
Keywords: cyclocondensation; dialkylbenzylcarbinones; benzylcyanides; 1-benzyl-3,3-dialkyl-3,4-dihydroisoquinoline chlorides; antiarrhythmic actions; calcium chloride model; lidocaine

Antimicrobial Activity of 1,2,5-Trimethylpiperidin-4-Ol Derivatives by M. A. Dyusebaeva; N. S. Elibaeva; S. N. Kalugin (550-552).
The antimicrobial activity of 1,2,5-trimethylpiperidin-4-ols (I – IV) against 20 test microorganisms was studied. 1,2,5-Trimethyl-4-(1′,2′-dihydroxyethyl)piperidin-4-ol benzoate hydrochloride (III) had the widest spectrum of antimicrobial activity (active against 16 test microorganisms) and is suitable for further testing of antimicrobial activity.
Keywords: piperidine; 1,2,5-trimethylpiperdin-4-ols; antimicrobial activity

Continuing the search for novel biologically active substances among the 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides series, we report here the synthesis of a series of {[(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)carbonyl]amino} benzoic acids asd their derivatives at the carboxyl group. Pharmacological testing showed that compounds with a free carboxyl group are of interest as potential diuretics, while carbamide derivatives have potential as analgesics. Esterification of the carboxyl group with lower alkyl alcohols was less effective.
Keywords: aminobenzoic acids; anilides; 4-hydroxy-2,1-benzothiazines; synthesis; analgesic acid; diuretic actions

With the aim of obtaining potential anti-inflammatory compounds, 2-{[5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}-1-(phenyl)ethanone and a series of its derivatives were synthesized, purified by flash chromatography, and characterised by spectral and elemental analysis. All the new synthesized compounds were evaluated for their anti-inflammatory activity using carrageenan-induced paw edema test on Wistar albino rats. The results suggest that 1-(4-fluorophenyl)-2-{[5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethanone 7l exhibit remarkable activity when compared with indomethacin even in the absence of carboxyl group in its structure, which reduces the possibility of gastric irritation.
Keywords: 5-(2-chlorophenyl)-4H-[1,2,4]triazole-3-thiol; 2-bromo-1-(substituted phenyl)ethanone; anti-inflammatory activity

A series of 2-pyrazoline derivatives (PS-1 to PS-16) were synthesized by reacting different aromatic/heteroaromatic aldehydes and ketones, in a two-step reaction through Claisen – Schmidt condensation, followed by cyclization of the resulting chalcones with hydrazine hydrate in the presence of a base using conventional and microwave approaches. The synthesized derivatives were characterized by various physicochemical methods including IR, 1H-NMR, 13C-NMR, and mass spectroscopic data and elemental analysis. The antidepressant and anti-anxiety activities were evaluated using suitable animal models. Compounds PS-3, and PS-14 showed noticeable antidepressant activity, by reducing the duration of immobility in both tests, while compounds PS-9 and PS-12 were found to possess good anxiolytic activity (by increasing the number of arm entries and open arm exploratory time) at the tested doses (50 and 100 mg/kg b.w.) in comparison to standard drugs imipramine and diazepam, respectively. In order to elucidate binding interactions of the synthesized derivatives to the MAO-A target protein, molecular docking was employed which demonstrated the key interactions with amino acid residues Phe208, Asn181, and Tyr407 at the binding site. Further, the ADME properties of the synthesized derivatives were predicted and found to fall within the stated limits.
Keywords: 3, 5-Disubstituted-4,5-dihydro-(1H)-pyrazoles; antidepressant; anti-anxiety: MAO inhibitors; microwave synthesis; molecular docking

Synthesis and Antinociception Activities of New Substituted Aminobenzothiazole Analogs of Lidocaine by Abbas Ahmadi; Mohsen Khalili; Javad Hasanabadi; Mahnaz Rezavil; Babak Nahri-Niknafs (576-581).
Local anesthetics are the most widely used drugs in practical medicine which provide the loss of sensation in a specific body part without loss of consciousness or impairment of central control of vital functions. Lidocaine (I) is the most common local anesthetic drug which has been widely used in all cases because of its excellent diffusing and penetrating properties as well as rapid onset of surgical analgesia. In this study, new aminobenzothiazole analogs (with many useful biological and pharmacological properties) were synthesized by changing the amine moiety of I. The acute and chronic pain properties of new compounds (II – VI) were studied using the tail immersion and formalin tests on mice and the results were compared to control and lidocaine groups. According to the obtained results, aminobenzothiazole derivatives are better candidates than diethylamine group for replacement in the amine moiety of I. In addition, derivatives with electron-withdrawing groups on this amine (V and VI) could decrease pain better than compounds (II and III) with electron-donating groups (especially in position 6 of this amine, II and V) which may be concern to more blockades of specific sodium channels by these compounds.
Keywords: lidocaine; local anesthetics; aminobenzothiazole; acute pain; chronic pain; tail immersion test; formalin test

Synthesis of Coumarin Appended 1,3-Oxazines as Potent Antimicrobial and Antioxidant Agents by Renuka Nagamallu; Pavithra Gurunanjappa; Ajay Kumar Kariyappa (582-589).
A convenient protocol for the synthesis of coumarin appended 1,3-benzoxazine derivatives (4a – 4g) is described. Cyclisation of hydrazones (3a – 3g) using triphosgene in dichloromethane gave the corresponding 1,3-oxazines in a relatively good yield. The proposed structures of newly synthesized compounds were confirmed by spectral methods and elemental analysis. Oxazine derivatives 4a – 4g were evaluated for their in vitro antimicrobial activity against various bacteria and fungi. Compounds 4b and 4d inhibited growth of test microbes thus proving significant antimicrobial activity. In addition, in vitro antioxidant activity of the synthesized compounds was evaluated and compared to that of standards, showing DPPH, NO, and OH radical scavenging properties. Compounds 4b and 4f exhibited higher antioxidant activity than a standard drug.
Keywords: antioxidant; antimicrobial; coumarin; hydrazones; oxazine; triphosgene

Preparation of Nuflein - an Alkaloid from the Yellow Waterlily Nuphar Lutea - and its Cytotoxic Action on Cultures of Normal and Tumorous Human Cells by T. A. Fedotcheva; O. P. Sheichenko; V. V. Anufrieva; V. I. Sheichenko; N. I. Fedotcheva; N. L. Shimanovskii (590-595).
The alkaloid from the yellow waterlily nuflein, whose preparation is described here, has cytotoxic activity against HeLa cervical cancer tumor cells. Suppression of the viability of normal fibroblasts requires nuflein concentrations 67 times greater than suppression of the viability of the same number of HeLa tumor cells. Cytotoxic activity is mediated by induction of the mitochondrial apoptosis pathway, as nuflein induces opening of mitochondrial pores and release of cytochrome c, which activates caspases. Nuflein also inhibits cellular energy generation due to uncoupling of oxidative phosphorylation in mitochondria and inhibition of mitochondrial respiration. The cytotoxic action of nuflein has been suggested to result from the properties of the sulfur atom in the thioether bond in the pharmacophore molecule. Utilization of the chemical properties of nuflein, allowing its steric structure to be “tuned,” may lead to the creation of a whole series of probes with different activities directed at modifying or inhibiting biologically important thiols. The greater selectivity of the antiproliferative activity of nuflein in relation to tumor cells as compared with the known antitumor substance cisplatin points to a specific antitumor nature for the activity of nuflein.
Keywords: alkaloid; nuflein; yellow waterlily; mitochondrial pore; HeLa; fibroblasts

Effects of Extracts of Agrimonia Asiatica and Geranium Collinum on Lipid Peroxidation and the Blood Antioxidant Enzyme Activity in Rats with Alloxan Diabetes by O. A. Sapko; A. K. Tursunova; A. O. Abaildaev; O. V. Chebonenko; A. V. Krasnoshtanov; A. Sh. Utarbaeva (596-601).
The effects of 70% ethanolic extracts of the above-ground parts of Agrimonia asiatica Juz. (D1) and the roots of Geranium collinum Steph. (D2) on lipid peroxidation (LPO) and the plasma and erythrocyte levels of activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP), and glutathione reductase (GR) were studied in rats with alloxan-induced diabetes. Significant decreases in erythrocyte membrane LPO (by 51-80%) were seen with D1 and D2. Extract D1 induced plasma SOD activity (by factors of 1.6 – 2.6) and erythrocyte CAT (by factors of 1.6-2.3). D2 induced SOD activity (by factors of 1.5 – 1.8), CAT activity (by factors of 1.9 – 2.7), and GR activity (by factors of 1.4 – 1.9) in erythrocytes. Both substrates, D1 and D2, showed statistically significant suppression of plasma GR activity (by 7 – 18%) and countered an alloxan-induced increase in erythrocyte GP activity (by 20 – 60%).
Keywords: Agrimonia asiatica ; Geranium collinum ; 70% ethanolic extracts; alloxan diabetes; lipid peroxidation; antioxidant enzymes

This study demonstrated the antioxidant activity of aqueous and aqueous-ethanolic (40%, 70%, 95%) extracts of the above-ground parts of the dropwort (Filipendula vulgaris Moench) in relation to the process of electroreduction of oxygen. Antioxidant properties were more marked in the more lipophilic dropwort extract. The lipophilic fraction of the aqueous extract (extracted with ethyl acetate) had marked antioxidant activity, and its efficacy was greater than those of dihydroquercetin and ascorbic acid, and this resulted from the more complete extraction of total biologically active compounds of phenolic (simple phenols, flavonoids, hydroxycoumarins, phenolcarboxylic acids) and triterpene (acids, saponins) nature, as well as amino acids.
Keywords: Filipendula vulgaris Moench; phenolic and triterpene compounds; cathodic voltammetry

Chemical compositions and the relative yield of petroleum ether extract of Canarium album have been investigated by gas chromatography/mass spectrometry (GC/MS). Thirty components, representing 95.05% of petroleum ether extract, were identified. Among these, ethyl linoleate (27.94%), linoleic acid (22.14%), n-hexadecanoic acid (18.74%), and ethyl palmitate (8.63%) are the main constituents, and 12 components are first time reported for C. album. The antioxidant capacity of petroleum ether extract was determined by DPPH· and ABTS+· assay. The results revealed that petroleum ether extract of C. album exhibited good antioxidant activity in both systems. It is the first report on the antioxidant activity of petroleum ether extract of C. album.
Keywords: Canarium album ; petroleum ether extract; chemical composition; antioxidant activity

Dehydration of 9a-Hydroxyandrost-4-ene-3,17-Dione in Organic Solvents by T. S. Savinova; A. V. Kazantsev; Luu D. Huy; N. V. Lukashev (612-615).
An effective method of dehydrating 9_-hydroxyandrost-4-ene-3,17-dione by mineral acids in organic solvents, producing essentially quantitative formation of androsta-4,9(11)-diene-3,17-dione is proposed. Quantitative isomerization of the side product androsta-4,8(9)-diene-3,17-dione to target product was shown to be pssible.
Keywords: 9α-hydroxyandrost-4-ene-3,17-dione; dehydration; androsta-4,9(11)-diene-3,17-dione; androsta-4,8(9)-diene-3,17-dione; isomerisation

Efficacy of an Intravenous Form of Rifapentine in a Model of Experimental Tuberculosis in Mice by K. P. Ostrovskii; N. S. Osipova; L. V. Vanchugova; E. V. Shipulo; V. D. Potapov; É. R. Pereverzeva; I. D. Treshchalin; O. O. Maksimenko; S. É. Gel’perina (616-621).
Solubilization of rifapentine with human serum albumin (HSA) was used to produce a water-miscible form consisting of a colloidal suspension of particles of size 538 ± 9 nm. Dilution of the suspension more than 20-fold led to dissociation of the aggregates formed during solubilization procedure, producing a transparent solution. This was associated with a reduction in particle size to 10 – 20 nm, corresponding to the particle size in HSA solution at the same concentration. A fluorescence method showed that suspensions contained both free rifapentine and its complex with HSA. Studies of the activity against the pathogen of tuberculosis, Mycobacterium tuberculosis H37Rv, in a model of acute infection in Balb/c mice showed that the water-miscible form of rifapentine given intravenously had high activity against mycobacteria, comparable with the activity of rifapentine substance, decreasing mycobacterial loadings in the parenchymatous organs from 106 – 107 to 102 – 103 cfu/organ. Thus, use of HSA as solubilizer yielded an intravenous form of rifapentine retaining the activity of the antibiotic against Mycobacterium tuberculosis.
Keywords: human serum albumin; rifamycins; rifapentine; tuberculosis

Optimization of the Conditions for Assay of Glutamic Acid by Thin Layer Chromatography by O. V. Trineeva; A. I. Slivkin; E. F. Safonova (622-626).
We report here the selection and evidential basis of optimum conditions for the chromatography of glutamic acid in a thin layer of sorbent. The conditions for identifying and assaying this amino acid by high-performance thin layer chromatography on a personal computer using specialist software were optimized. The method was used to estimate glutamic acid contents in complexes of free amino acids in extracts from medicinal herb material (using sea buckthorne fruits and nettle leaves as examples).
Keywords: glutamic acid, high-performance thin layer chromatography; sea buckthorne fruits; nettle leaves

Ce3+ Doped Clindamycin Nanoparticles Loaded in Gelatin Media: Study of Photoluminescence Properties and Antibacterial Effect by Sanaz Kazemzade Anari; Shahriar Ghammamy; Hossein Ghasemzadeh; Mohammad Reza Khanlary (627-633).
In this work, Ce3+doped clindamycin nanoparticles (Ce3+/CLA-NP) loaded in gelatin media were prepared by sol-gel technique and characterized by x-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and photoluminescence (PL) spectra. The PL spectra of Ce3+/CLA-NP show two UV bands, at 325 and 355 nm, which are not detected from undoped CLA-NP. The morphology of the nanocomposite and the size of nanoparticles were estimated by scanning electron microscopy (SEM). The average particle size in Ce3+/CLA-NP was about 50 – 120 nm. The drug release profile was determined by UV–Vis spectroscopy. Finally, in vitro antibacterial properties of Ce3+/CLA-NP were evaluated against Staphylococcus aureus.
Keywords: doped nanoparticles; Ce3+ ; drug delivery; gelatin; clindamycin; antibacterial effect; photoluminescence