Pharmaceutical Chemistry Journal (v.48, #8)

Modern analytical methods used to study the pharmacokinetics of quercetin and other flavonols, i.e., biologically active compounds that exhibit various therapeutic properties, were reviewed. The preparation of biological fluids and tissues for analysis, chromatography conditions, and mass spectrometric detection for various flavonols as the aglycons and glycosides and their metabolites were discussed. Quantitative analyses of flavonol concentrations in biological samples and their mass spectrometric identification in in vitro and in vivo studies during tests with pure compounds and multi-constituent plant extracts were presented as typical examples.
Keywords: quercetin; flavonols; flavonoids; flavonoid pharmacokinetics; bioanalytical methods; liquid chromatography-mass spectrometry (LC-MS/MS)

Effect of Melatoninergic Drugs on the Specific Activity of Glutathione Redox-Cycle Enzymes in Experimental Hyperthyroidism by T. N. Popova; A. A. Agarkov; M. V. Gorbenko; S. S. Popov; K. K. Shul’gin; A. V. Semenikhina (499-504).
The effect of melatoninergic drugs [melaxen and agomelatine (Valdoxan)] on the activity of glutathione antioxidant system enzymes and NADPH suppliers was investigated for experimental hyperthyroidism in rats. The administration of these protectors at the pathology was accompanied by a change of the specific activity of glutathione reductase (EC, glutathione peroxidase (GP, EC, glutathione transferase (GT, EC, NADP-isocitrate dehydrogenase (NADP-IDH, EC, and glucose-6-phosphate dehydrogenase (G6PDH, EC in rat liver, heart, and blood serum toward the control values. Apparently, this effect was related to a decreased load on the glutathione antioxidant system due to effective interaction of melatonin with free radicals upon correction of its level by melaxen and agomelatine.
Keywords: melatonin; melaxen; Valdoxan; glutathione antioxidant system; NADPH; experimental hyperthyroidism; rats; enzymes

Synthesis and Biological Activity of New 1,3-Benzothiazole Derivatives by N. A. Pulina; F. V. Sobin; T. A. Yushkova; T. F. Odegova; A. I. Krasnova (505-508).
2-Benzothiazolylamides of 4-aryl-2-hydroxy-4-oxo-2-butenoic and 4-aryl-3-bromo-2,4-dioxobutanoic acids in addition to complexes with manganese, cobalt, and copper were synthesized. Their hypoglycemic and antimicrobial activity was studied. Compounds with low toxicity and activity comparable to or exceeding that of reference drugs were discovered.
Keywords: 2-benzothiazolylamides of 4-aryl-2-hydroxy-4-oxo-2-butenoic and 4-aryl-3-bromo-2,4-dioxobutanoic acids; complexes; hypoglycemic and antimicrobial activity

Synthesis and Physicochemical and Biological Properties of 8-Amino-Substituted 7-(2-Aryl-2-Oxoethyl)Xanthines by N. I. Romanenko; M. V. Nazarenko; V. I. Kornienko; B. A. Samura; O. A. Pakhomova (509-512).
Asimple laboratory method for preparing 8-amino-substituted 7-(2-aryl-2-oxoethyl)xanthines by reacting the corresponding 8-bromo derivatives with primary and secondary amines in ethoxyethanol was developed. The structures of the synthesized compounds were confirmed by PMR spectroscopy. The analgesic and anti-inflammatory activities of the synthesized compounds were studied in laboratory animal tests. It was established that the majority of the tested compounds possessed moderate or strong analgesic and anti-inflammatory activities. Several compounds exhibited activity stronger than or comparable to that of metamizole sodium (analgin) and diclofenac. 7-(2-Oxo-2-phenylethyl)-8-(4-methylpiperidinyl-1)theophylline (XIV) and 7-(2-oxo-2-phenylethyl)-8-(4-ethylpiperazinyl-1)-3-methylxanthine (XVII) could be introduced as analgesic and anti-inflammatory agents after detailed pharmacological testing.
Keywords: xanthine; synthesis; analgesic activity; anti-inflammatory activity

Design and Antimicrobial Evaluation of 1-Methylimidazole Derivatives as New Antifungal and Antibacterial Agents by Maryam Iman; Asghar Davood; Bert Klein Gebbink; Parisa Azerang; Mona Alibolandi; Soroush Sardari (513-519).
Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). In this research, a group of 1-methylimidazole derivatives were synthesized for evaluation as antibacterial and antifungal agents. Antimicrobial evaluation revealed that some of these compounds exhibited significant antimicrobial activities against tested pathogenic fungi and bacteria, wherein compounds 3 and 8 were most potent. To find the action mechanism, all of these compounds were subjected to docking studies using the AutoDock 4.2 program. The results show that all of the azoles (2 – 5, 7, and 8) interacted with 14α-DM, wherein azole – heme coordination, hydrogen binding, and -cation interactions were involved in the drug – receptor interaction. These studies offer some useful references in order to understand the action mechanism; moreover, performing the molecular design or modification of this series as a lead compound can assist in identifying new and potent antimicrobial agents.
Keywords: antibacterial; antifungal; azole; docking; imidazole

An improved synthetic process has been developed for preparation of 4-[(3'-chloro-4'-fluorophenyl)amino]-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline(gefitinib) (X) from economically available starting material, 3-hydroxy-4-methoxybenzaldehyde (isovaniline) (I) through a sequence of simple reactions with readily available reagents. The additional advantages of this convenient synthetic approach are non-tedious work-up, high yield, and high purity without employing laborious and time-intensive column chromatography techniques.
Keywords: gefitinib; anticancer agent; high-yield synthesis; economic approach

Rhizomes and roots of Rhodiola rosea L. (Crassulaceae) are popular and in demand. The plant has long been used in folk and traditional medicine and in official practice. However, the variety of drugs derived from the rhizomes and roots of R. rosea is very restricted despite the rather diverse phytochemical composition. Optimization of the production technology for medicinal preparations based on substances from this plant and their analytical methods are currently critical issues.
Keywords: Rhodiola rosea ; rhizomes and roots; adaptogen; salidroside; rosavin; rosiridin; extract

Cytotoxic Triterpene from Barringtonia asiatica by Consolacion Y. Ragasa; Dinah L. Espineli; Chien-Chang Shen (529-533).
Triterpenes isolated from the dichloromethane extract of Barringtonia asiatica, namely, a mixture of betulinic acid (1) and 22-O-tigloylcamelliagenin A (2) in a 1 : 2 ratio and a mixture of 3β-olean-18-en-3-yl palmitate (7), 3β-urs-12-en-3-yl palmitate (8) and 3β-olean-12-en-3-yl palmitate (9) in a 4 : 1 : 2 ratio (isolated from the bark), as well as germanicol caffeoyl ester (3), germanicol trans-coumaroyl ester (4), germanicol cis-coumaroyl ester (5) and germanicol (6) (from the leaves), and a phenolic compound, verimol K (10) from the flowers, were assessed for cytotoxicity against a human cancer cell line, colon carcinoma (HCT 116), using the MTT assay. The mixture of 1 and 2 exhibited IC50 =8.0 μg · mL–1 against this cell line, while 6 exhibited an IC50 value of 29.6 μg · mL–1. The other compounds tested (35, 710) were inactive against the HCT 116 cell line. The mixture of 1 and 2 and compound 6 were further tested for cytotoxicity against the non-small cell lung adenocarcinoma (A549) cell line. The mixture of 1 and 2 and compound 6 exhibited IC50 values of 6.0 and 35.6 μg · mL–1, respectively. The cytotoxicity for the mixture of 1 and 2 may be attributed to betulinic acid (1), a known cytotoxic compound.
Keywords: Barringtonia asiatica ; Lecythidaceae; betulinic acid; germanicol; MTT; cytotoxic activity

New Synthesis of Diethyl-5-[(N,N-Diethylglycyl)Amino]-2-Hydroxy-4,6-Dimethylisophthalate by N. A. Komar; D. G. Slashchinin; G. A. Suboch; M. S. Tovbis (534-536).
A new convenient synthesis of diethyl-5-[(N,N-diethylglycyl)amino]-2-hydroxy-4,6-dimethylisophthalate with anti-arrhythmic properties was developed.
Keywords: synthesis; diethyl-5-[(N,N-diethylglycyl)amino]-2-hydroxy-4,6-dimethylisophthalate

Mixed-valence oxides of ruthenium (RuO x ) and iridium (IrO x ) and a composite based on them (IrO x —RuO x ) exhibited catalytic activity for allopurinol oxidation when electrodeposited on the surfaces of unmodified glassy-carbon electrodes and those modified with functionalized single-walled carbon nanotubes (SWCNT). The greatest catalytic effect was observed on the electrode modified with composite IrO x —RuO x —SWCNT. A flow-injection method for amperometric detection of allopurinol at the modified electrode was developed. The analytical signal was linearly dependent on allopurinol concentration in the range 1 × 10– 6 – 5 ×10−3 M.
Keywords: chemically modified electrodes; mixed-valence Ru and Ir oxides; electrochemical oxidation of allopurinol; flow-injection analysis

Creating Chitosan-Based Prolonged-Release Film Coatings by E. I. Kulish; A. S. Shurshina; L. G. Kuzina; S. V. Kolesov; V. P. Zakharov (543-545).
The interaction of chitosan with cephalosporin (cefazolin and cefotaxime) and aminoglycoside (amikacin and gentamicin) antibiotics was investigated. It was established that the medicinal preparation could be distributed in the polymer matrix in two ways during formation of the film coating. Apart of it was bound rather strongly to the polymer chain, e.g., via complexation. Another part of it was concentrated in the polymer free space (in polymer pores). Astudy of antibiotic release from chitosan film coatings showed that the release rate from the film was determined on one hand by the amount of antibiotic complexed to chitosan and, on the other, to the condition of the polymer matrix. These films could be suitable for treatment of surgical wounds, burns, and slow-healing wounds of various etiology.
Keywords: medicinal films; chitosan; antibiotics

It was established that chromatographic columns with nitrile sorbents (Nova-Pak CN HP and Zorbax Eclipse XDB-CN) could be applied to the analysis of Pt(II) coordination compounds. The compounds could be analyzed by both reversed-phase chromatography (MeCN:H2O mobile phase, 3:97) and normal-phase chromatography (MeCN:H2O mobile phase, 96:4). The analytes were better resolved for normal-phase chromatography. Chromatography columns with various phenyl sorbents and a pentafluorophenyl sorbent (Discovery HS F5) could be used to analyze Pt(II) coordination compounds only by reversed-phase chromatography (MeCN:H2O mobile phase, 5:95). The properties of the nitrile and phenyl columns differed substantially for analysis of Pt(II) coordination compounds using mobile phases with >90% MeCN. Sorption of the Pt compounds to the nitrile columns at high MeCN contents was due to specific coordination interactions between the Pt atom and sorbent nitriles. In contrast to this, phenyl groups possessed practically no such ability.
Keywords: HPLC; oxaliplatin; carboplatin

Properties of Emulsions Obtained Using Triethanolammonium Salts of Alkylitaconates and -Maleates by Kh. R. Tukhtaev; S. N. Aminov; Kh. K. Abdullaeva (550-552).
Data on the use of triethanolammonium salts of alkylmaleates and -itaconates to prepare castor-oil emulsions were presented. It was shown that the thermal and mechanical stability, dispersion, and other technical properties of the emulsions were related to the molecular structures of the surfactants and the colloidal chemical features of the emulsifiers. It was found that introducing drugs into the system had an insignificant effect on the dispersion of the resulting emulsions.
Keywords: emulsion; surfactants; triethanolammonium salts of alkylmaleates and -itaconates; dispersion; colloidal chemical and technical properties

A new spectrophotometric method for quantitative determination of taurine in dosage forms was developed and validated. The method was based on measurement of aqueous taurine solution absorption at 470 nm. The proposed method satisfied requirements of the Ukrainian Pharmacopeia for drug quantitative analytical methods and could be recommended for use in laboratories of the State Inspection for Quality Control of Medicines and quality-control departments of pharmaceutical enterprises.
Keywords: taurine; quantitative determination method; quality control of medicines

A simple kinetic and thermodynamic study of spectrophotometric method for the quantitative analysis of adrenaline (AD) in pure and pharmaceutical dosage forms has been performed. The method is based on the formation of a sensitive green complex between ferrous ion (resulting from the redox reaction between AD and ferric chloride) and nitroso-R-salt reagent (NRS). The increase in absorbance of the colored complex is followed spectrophotometrically at 712 nm as a function of time. The initial rate and fixed time techniques were adopted for constructing the calibration curves. The linearity ranges were found to be 0.5 – 10 and 0.1 – 8 μg·mL–1 for the initial rate and fixed time methods, respectively. Thermodynamic parameters, including the free energy change, enthalpy of formation, and entropy were determined for the reaction product. The method was applied successfully for the estimation of AD in commercial dosage forms with results in a good agreement with those obtained by the official method.
Keywords: drug kinetics; adrenaline; quantitative determination; spectrophotometry