Pharmaceutical Chemistry Journal (v.51, #9)

Effects of Testosterone on the Functional Activity of P-Glycoprotein by A. V. Shchul’kin; E. N. Yakusheva; I. V. Chernykh; A. A. Nikiforov; N. P. Popova (743-747).
The effects of testosterone undecanoate on the functional activity of P-glycoprotein (ABCB1 protein) were studied in male Chinchilla rabbits. Testosterone was given as single intramuscular doses of 12 or 24 mg/kg. The functional activity of P-glycoprotein was determined in terms of the pharmacokinetics of its marker substrate - fexofenadine - on days 7, 14, and 21 after hormone administration. Administration of testosterone at a dose of 12 mg/kg (n = 7) increased the C max of fexofenadine on days 7 and 14 and AUC 0-t on day 14 and decreased total clearance on day 14. Use of testosterone at a dose of 24 mg/kg (n = 7) led to increases in the C max of fexofenadine on day 7 and AUC 0-t on days 7, 14, and 21 and decreased total clearance on days 7 and 14. These changes in the pharmacokinetics of fexofenadine provide evidence of decreases in the functional activity of Pgp on the background of testosterone administration. Correlational relationships were found between measures of the pharmacokinetics of fexofenadine and serum testosterone levels.
Keywords: Pgp; ABCB1 protein; fexofenadine; functional activity; testosterone

The purpose of this study was to investigate the effects of cilostazol on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined following oral and intravenous administration of nifedipine (1.5 and 6.0 mg ・ kg-1) in rats. Cilostazol inhibited CYP3A4 enzyme activity at a 50% inhibitory concentration (IC50) of 4.1 μM. The areas under the plasma concentration–time curve (AUC 0-∞) and the peak concentration (C max) of nifedipine were significantly increased, respectively, in the presence of cilostazol compared to that in the control. The total body clearance (CL/F) was significantly decreased by cilostazol. Consequently, the absolute bioavailability (AB) of nifedipine with cilostazol was significantly higher than that in the control. The metabolite to parent AUC ratio (MR) in the presence of cilostazol was significantly decreased compared to that in the control. The AUC 0-∞ of intravenous nifedipine was significantly increased with cilostazol compared to that in the control. The increased bioavailability of nifedipine in rats can be mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver by cilostazol. In addition, the reduction of CL/F of nifedipine by cilostazol may also be a factor.
Keywords: nifedipine; cilostazol; CYP3A4; pharmacokinetics; bioavailability; rats

Synthesis and Cytotoxic Activity of Arylsubstituted Tetrazolocyclanopyrimidines by N. O. Vasil’kova; M. A. Ivonin; G. L. Burygin; A. Yu. Prilepskii; A. P. Kriven’ko (756-759).
A series of arylsubstituted tetrazolocyclanodihydropyrimidines was prepared and their cytotoxic actions on SPEV-2 cells were studied. The activity of these substances was found to depend on the nature and position of the substitution groups in the benzene ring and the size of the alicycle. The most active compounds were o-chloro(methyl)phenyltetrazolohexahydroquinazolines.
Keywords: tetrazoloquinazolines; tetrazolocyclanopyrimidines; isomers; NMR spectra; cytotoxicity; SPEV-2 cells

Synthesis and Antitumor Activity of 2-N-,3-S-Substituted 5-(4-Benzyloxyphenyl)-1,2,4-Triazoles by M. A. Kaldrikyan; R. G. Melik-Ohanjanyan; F. H. Arsenyan (760-763).
Cyclization of substituted thiosemicarbazides in alkaline medium was used to synthesize the corresponding 3-thio-4-benzyl(cyclohexyl, allyl)-5-(4-benzyloxyphenyl)-1,2,4-triazoles. These compounds were 3-S-alkylated with ethylene chlorohydrin, chloroacetamide, 3-bromo-4-methoxybenzyl chloride, and chloroacetic, 2-bromopropionic, and 2-bromocaproic acids. Aminomethylation and oxymethylation reactions were studied. 2-N-Aminomethylene and 2-N-oxymethylenetriazoline-3-thiones were prepared. The antitumor activity of the compounds synthesized here were studied.
Keywords: hydrazide; isothiocyanate; thiosemicarbazide; S-alkylation; N-aminomethylation; N-oxymethylation; triazolinethione-3

Synthesis and Antimicrobial Properties of Ammonium Salts Containing a Substituted Butyn-2-yl Group by M. O. Manukyan; K. S. Barsegyan; A. Kh. Gyulnazaryan; R. V. Paronikyan; G. M. Stepanyan; N. S. Minasyan; A. V. Babakhanyan (764-768).
Interaction of 1-dimethylamino-4-diethylaminobutyn-2, 1-dimethylamino-4-piperidinobutyn-2, and 1-dimethylamino-4-morpholinobutyn-2 with the corresponding alkyl esters of monobromo(chloro)acetic acid was used to synthesize novel monoammonium salts. Studies of the antimicrobial activity of the resulting compounds showed that salts containing hydrophobic alkoxycarbonylmethyl radicals had marked antibacterial activity against Gram-positive and Gram-negative microorganisms.
Keywords: diamines; ammonium salts; antimicrobial activity; Gram-positive and Gram-negative microorganisms

Tuberculostatic Activity of 2-Amino-6-Chloropurine Derivatives by V. P. Krasnov; A. Yu. Vigorov; D. A. Gruzdev; G. L. Levit; M. A. Kravchenko; S. N. Skornyakov; O. B. Bekker; D. A. Maslov; V. N. Danilenko; V. N. Charushin (769-772).
Studies of the antimycobacterial activity of 2-amino-6-chloropurine and its N-acyl derivatives against laboratory (Mycobacterium tuberculosis H37Rv, M. avium, M. terrae) and clinical Mycobacterium tuberculosis strains (MDR-TB) identified compounds with high tuberculostatic activity (MIC from 0.35 – 1.5 μg/ml). The cytotoxic activities of the compounds with antimycobacterial activity against human embryo fibroblasts were studied in the MTT test, which showed that the study compounds were essentially nontoxic (IC50 > 50 μM). Further chemical modification may yield compounds with potential for creating drugs for the treatment of tuberculosis. With the aim of identifying the possible mechanism of the tuberculostatic activity, the ability of the study compounds to inhibit mycobacterial serine-threonine protein kinases (STPK) was assessed. The tuberculostatic activity of 2-amino-6-chloropurine derivatives was not linked with their inhibition of STPK.
Keywords: purines; tuberculostatic activity; protein kinases

Preparation and Activity of a Complex of Oligohexamethyleneguanine with P-Aminosalicylic Acid Derivatives by S. A. Kedik; D. O. Shatalov; P. M. Isaikina; A. D. Askretkov; I. P. Sedishev; A. V. Panov; A. S. Evseeva (773-776).
Approaches to creating complexes based on branched oligohexamethyleneguanidine hydrochloride are addressed. Novel combinations of bactericidal agents were obtained, methods for the synthesis of a series of p-aminosalicylic acid derivatives were selected, the solubilities of their complexes with oligohexamethyleneguanidine were determined, and the bactericidal activities of the resulting complexes against Mycobacterium smegmatis were assessed. The minimum inhibitory concentrations of all complexes were in the range 0.1 – 1 μg/ml of culture medium. Thus, these complexes may be useful for creating a bactericidal formulation with powerful and long-lasting biocidal action, highly reproducible properties, and low toxicity.
Keywords: oligohexamethyleneguanidine; p-aminosalicylic acid; bactericidal formulations

Seasonal Oscillations in Statistical Mean Measures of Blood Composition and Blood Cell Morphology in Healthy White Rats by A. S. Pushkin; E. D. Drugova; S. A. Kamshilin; N. V. Obraztsov; O. V. Polekhina; S. I. Dvoretskaya; A. I. Churyumova (777-782).
The aim of the present work was to identify seasonal oscillations in the composition and morphology of the blood in intact rats. Morphometric measures of blood were determined in 36 clinically healthy adult male rats in different seasons (spring, summer, and autumn) using the Mekos programmable system. Seasonal oscillations within established reference ranges were found and these need to be considered when performing preclinical studies of medicines in relation to their efficacy and safety.
Keywords: blood cell morphology; rats; seasonal oscillations

Comparison of the Antitumor Efficacy of Bismuth and Gadolinium as Dose-Enhancing Agents in Formulations for Photon Capture Therapy by A. A. Lipengol’ts; A. A. Cherepanov; V. N. Kulakov; E. Yu. Grigor’eva; I. B. Merkulova; I. N. Sheino (783-786).
The efficacy of photon capture therapy (PCT) is to a significant extent determined by the properties of the formulation containing the element efficiently absorbing external X-irradiation and operating as a dose-enhancing agent (DEA). We report here a comparison of the efficacies of bismuth and gadolinium as DEA in PCT technologies with X-irradiation at 110 kV for the treatment of superficial tumors. Bismuth and gadolinium are comparable in that they are available as the same chemical form – a complex with diethylenetriaminepentaacetic acid, for which the physicochemical properties are similar for both elements. Studies were performed on mice with transplanted B16F10 melanoma as a tumor model. Both DEAwere given by the intratumor route at the same dose of 5 mg of DEAper animal. Irradiation was with an x-ray apparatus with a tension of 110 kV using a dose of 20 Gy. The results showed significantly greater antitumor efficacy for PCT with both gadolinium and bismuth than with short-focus radiotherapy. In terms of the log dead cells (lgN), there was an increase in lgN from 0.78 for short-focus irradiation to 2.5 for PCT using gadolinium or bismuth, with identical dose exposure. There were no significant differences in the antitumor efficacies of PCT with bismuth and gadolinium for x-ray irradiation at 110 kV.
Keywords: radiotherapy; photon capture therapy; gadolinium; bismuth; x-ray irradiation; dose-enhancing agent

In the search for new anticonvulsants, the (arylalkyl)azole framework has been considered as a valuable scaffold. Accordingly, a series of trans-3-imidazolylflavanones (1 – 15) and their flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones (16 – 19) containing an (arylalkyl)azole substructure were evaluated for their anticonvulsant activities by using pentylenetetrazole (PTZ) and maximal electroshock (MES)induced seizure tests. Also, the effect of substituent on the pendant phenyl ring and the impact of structural flexibility were investigated. The obtained results revealed that 2-(azol-1-yl)ethanone derivatives 16 – 18 exhibited 50 – 100% protection against MES-induced seizures at a dose of 100 mg/kg. Particularly, compound 16 was found to be significantly active at doses of 10 and 30 mg/kg (25 and 75% protection, respectively). This compound showed full protection at a dose of 100 mg/kg. The structure – activity relationship study revealed that the dichloro substituent in the secondary phenyl ring can improve the anticonvulsant activity. Furthermore, disconnection of the C2 – C3 bond of flavanone in trans-3-imidazolylflavanones results in flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones with improved anticonvulsant activity. Docking study of representative compound 16 with possible targets involved in convulsions demonstrated that the GABAA receptors can be considered as the main target for anticonvulsant activity of compound 16.
Keywords: anticonvulsant activity; (arylalkyl)azoles; 1H-imidazole; 1,2,4-triazole; flavanone; structure – activity relationship

Synthesis, Spectral Characterization, In Vitro Antibacterial Evaluation and POM Analyses of Palladium(II) Thiocyanate Complexes of Thioamides by Shafqat Nadeem; Muhammad Sirajuddin; Saeed Ahmad; Sadaf Yaqub; Muhammad Irshad Ali; Syed Ahmed Tirmizi; Saqib Ali; Abdul Hameed (793-799).
Palladium(II) thiocyanate complexes of general formula, [PdL4](SCN)2, where L = thiourea (Tu), N-methylthiourea (Metu), N,N-dimethylthiourea (Dmtu), tetramethylthiourea (Tmtu), imidazolidine-2-thione (Imt) and thionicotinamide (Tna) were prepared by the reaction of K2[PdCl4] with thioamides followed by the addition of Potassium thiocyanate in 1:2:2 molar ratio. The complexes were characterized by elemental analysis, and spectroscopic techniques (IR, 1H and 13C NMR), and were screened for antibacterial activities against four strains of bacteria {Staphylococcus aureus (ATCC 25923), Bacillus subtilis (DSM 3256), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 10197)}. Some of the compounds exhibited signifiacnt antibacterial activity even higher than the standards showing the potential for their use as potent antibacterial agents. POM analyses reveal that the compounds are slightly toxic. Moreover, they have 8 ~ 12 % drug score, which is an important parameter for a compound possessing the drug properties.
Keywords: palladium(II) complexes; thiocyanate; thioamide; antibacterial activity; POM analysis

A novel ecdysteroid-containing pharmaceutical substance – Lychnis chalcedonica extract – was developed. The phytoecdysteroid composition of the ethanolic extract was determined. Courses of intragastric administration of Lychnis chalcedonica extract (150 mg/kg) were accompanied by anabolic effects in both trained and untrained animals. The actoprotector properties of the Lychnis chalcedonica extract and improvements in carbohydrate metabolism on exhaustive physical exertion were seen only in trained animals. Lychnis chalcedonica extract is a pharmaceutical substance with potential for use as the basis for developing formulations with actoprotector activity.
Keywords: Lychnis chalcedonica extract; ecdysteroids; actoprotector activity

A method of extracting mangiferin from dried powdered leaves from mango trees using the solvent mixture isopropanol and water (60:40 v/v) was used. The yields of technical product and purified mangiferin recrystallized from a mixture of isopropanol and water (50:50 v/v) were 1.46% (purity 88.6%) and 0.8% (purity 98.2%). The chemical structure of mangiferin was confirmed by UV-VIS and IR spectrophotometry, electrospray mass spectrometry, and 1H and 13C NMR spectroscopy. Technical product and mangiferin were tested for biological activity in terms of blockade of α-glucosidase, as compared with acarbose. Mangiferin provided significantly greater blockade of α-glucosidase than acarbose, with IC50 values of 11.18 and 5.82 μg/ml for technical product and mangiferin respectively and 199.47 μg/ml for acarbose. These results are important preliminary investigations for further investigation of mangiferin and the development of therapeutic formulations of this highly active hypoglycemic substance.
Keywords: diabetes mellitus; mangiferin; Mangifera indica L.; α-glucosidase; spectrophotometry

The present article reports on the biogenic synthesis of silver nanoparticles using Ficuspalmata leaf extract. A color change in the reaction mixture of AgNO3 and leaf extract was the first sign of silver nanoparticles synthesis, further confirmed by UV-VIS spectroscopy. The obtained nanoparticles were characterized by x-ray diffTaction (XRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). XRD revealed crystalline nature of nanoparticles. SEM showed that the synthesized particles were predominantly spherical with an average particle size of 28 – 33 nm. FTIR revealed that organic compounds like flavonoids, alkaloids, and saponins were present in leaf extract and mainly involved in the reduction of Ag+1 to Ag0. Antibacterial assays showed that synthesized silver nanoparticles had the power to inhibit the growth of both Gram-positive and Gram-negative bacterial strains. The results indicate that F. palmata leaf extract can be used for the synthesis of silver nanoparticles producing antibacterial effect.
Keywords: silver nanoparticles; Ficus palmata ; extract; antibacterial efficacy; SEM; XRD; FTIR

A controlled, randomized study using an experimental model of contrast (iopromide)-induced nephropathy (CIN) in normal mongrel rats showed that the combination of treatment by hydration with the nicotinamide adenine dinucleotide (NAD)-containing formulation Nadcin®, with cytoprotective and antiischemic actions, decreased the plasma creatinine and urea nitrogen levels 72 h after induction of CIN. Aclose correlational relationship (r = 0.78, p < 0.001) was found between the blood endothelin-1 (ET-1) level and O2 generation, while there was no relationship between hydrogen peroxide production and the ET-1 level (r = 0.13, p > 0.05) or between the ET-1 level and catalase activity (r = 0.41, p > 0.05). In contrast to monotherapy with hydration, inclusion of Nadcin normalized blood ET-1 and the blood ET-1/creatinine ratio, the blood and renal NAD/NADH and NADP/NADPH redox potentials, and had more marked actions on reversing the overproduction of free radicals and on the antioxidant defense system in the blood and renal tissue. It is suggested that ET-1, the ET-1/creatinine ratio, and the plasma redox potential can be used as early markers for increases in the risk of developing stable impairment of renal function on use of x-ray contract agents.
Keywords: contrast-induced nephropathy; iopromide; NAD-containing compounds; endothelin; antioxidant defense system; redox potential; creatinine

A Comparative Dissolution Kinetics Test for Omeprazole-Containing Medicines, Reproducing Secretory and Motor-Evacuatory Impairments the Stomach of Patients with Acid-Dependent Diseases by G. F. Vasilenko; L. M. Krasnykh; S. Yu. Serebrova; A. B. Prokof’ev; G. V. Ramenskaya; E. A. Smolyarchuk; D. O. Kurguzova; A. O. Barkov (824-828).
A comparative dissolution kinetics test was used to study the release (dissolution kinetics) of an original and 10 generic formulations of omeprazole from different manufacturers in a medium simulating the moderately acidic conditions in the stomach typical of the state of medication-induced suppression of acidity; tests were also performed in a model of pathological duodenogastric reflux. HPLC was used to measure omeprazole concentrations in aliquots collected at 4, 10, 15, 20, 30, 45, and 60 min in solution with pH 7.0 ± 0.05 after 2 h of exposure at pH 1.2 ± 0.05 or 4.0 ± 0.05. The duration of action of pathological duodenogastric reflux on the therapeutic formulations of omeprazole was 4 min. Not all the study formulations could be completely recognized as equivalents to the original formulation in the in vitro test conditions.
Keywords: omeprazole; comparative dissolution kinetics test; in vitro equivalence; therapeutic equivalence; interchangeability

Validation of a Method of Measuring Mean Molecular Weight of Dextrans by Diffusion-Ordered Spectroscopy by S. V. Moiseev; N. E. Kuz’mina; V. I. Krylov; V. A. Yashkir; V. A. Merkulov (829-832).
Amethod for measuring the mean molecular weight of dextrans by diffusion-ordered NMR spectroscopy was developed and validated. This method allows measurements of dextran self-diffusion coefficients to determine their mean molecular weight. The linearity, correctness, similarity, intralaboratory precision, and specificity of the method were evaluated. “Added/found” ratios for different dextrans were used to determine the standard deviations, coefficients of variation, significance intervals, systematic errors, Fisher’s F test, and Student’s t test for measurements of mean molecular weight. These statistical characteristics satisfied the criteria for validation parameters in the Russian and foreign normative documentation.
Keywords: diffusion-ordered NMR spectrometry; peak molecular weight of polymers; coefficient of self-diffusion; dextrans; validation of analytical method; linearity; correctness; similarity; precision

Evaluation of Anti-Hyperglycemic Effect of Synthetic Schiff Base Vanadium(IV) Complexes by F. A. El-Saied; T. A. Salem; S. A. Aly; M. M. E. Shakdofa (833-842).
A chain of new vanadium(IV) complexes of Schiff bases, derived from acetohydrazide (HL1-3) or 4-aminoantipyrine (HL4-7) have been prepared and physicochemically distinguished using different tools including analytical, spectral, and magnetic techniques. The spectral and analytical data showed that ligands HL1-3 acted as neutral bidentate ligands, chelated through hydrazono carbonyl and azomethine groups, whereas HL4 acted as neutral tetradentate ligand coordinated via pyrazolone carbonyl, NH group, hydrazono carbonyl, and azo (N=N) groups forming binuclear complexes. The HL5 and HL6 behave as neutral bidentate ligands coordinating through pyrazolone carbonyl and NH groups; in case of ligand HL6, in addition to the mentioned mode, C=N and CN groups participated to bind a second VO(II) ion form binuclear complexes. HL7 behaves as a monobasic bidentate ligand bonded via deprotonated OH and azomethine groups. All complexes adopt square pyramidal geometry around vanadium ion. Results revealed that the oral management of vanadium complexes significantly reduced the blood glucose level in rats suffered from diabetes. The correction of altered biochemical parameters via treatment with vanadium complexes points the improved glucose balance.
Keywords: vanadium complexes; anti-diabetic activity; antipyrine; acetohydrazide