Pharmaceutical Chemistry Journal (v.45, #6)

The main trends in the pharmacology and medicinal chemistry of triple reuptake inhibitors of monoamine transporters (serotonin, norepinephrine, dopamine) are reviewed. The inhibitors are grouped on the basis of common structural fragments that favor the given pharmacological activity. The most probable fields of application, including antidepressants with broader efficacy and quicker onset of action, for treating obesity, and with analgesic effects, are considered.
Keywords: triple reuptake inhibitors; monoamine transporters; antidepressants; serotonin; norepinephrine; dopamine

Effect of nitroxyalkyl derivatives of fullerenylproline on the activity of CA3+-ATPase of sarcoplasmic reticulum by L. V. Tat’yanenko; O. V. Dobrokhotova; R. A. Kotel’nikova; D. A. Poletayeva; D. V. Mishchenko; I. Yu. Pikhteleva; G. N. Bogdanov; V. S. Romanova; A. I. Kotel’nikov (329-332).
The effect of nitroxyalkyl derivatives of fullerenylproline methyl ester on the enzymatic activity of Ca2+-ATPase of sarcoplasmic reticulum (SR) has been studied. It is shown that hybrid derivatives of C60 fullerene are capable of inhibiting the activity of Ca2+-ATPase of SR. The mononitrate inhibits the hydrolytic activity of the enzyme with K i = 1.92 × 10−6 M; active Ca2+ transport, with K i = 3.79 × 10−6 M. The dinitrate inhibits ATP hydrolysis with K i = 2.38 × 10−8 M; Ca2+ transport, with K i  = 3.08 × 10−8 M. Fullerenylproline methyl ester does not affect the enzymatic activity of Ca2+-ATPase. Based on these data it is possible to predict the possible fields of application for hybrid fullerene derivatives as potential drugs.
Keywords: Ca2+-Mg2+-ATPase of sarcoplasmic reticulum; phosphodiesterase of cyclic guanosine monophosphate; fullerenylproline nitrates

Investigation of pharmacokinetic characteristics of the 99mTc- and 188Re-labeled monopotassium salt of 1-hydroxyethylidenediphosphonic acid (KHEDP) in rats showed that the level of accumulated activity at 5 min and 1 and 3 h after i.v. injection of 188Re-KHEDP is higher in most organs and tissues than that after injection of 99mTc-KHEDP. In the subsequent period (6 and 24 h), the specific activities in the majority of soft organs and tissues equalized due to greater elimination of 188Re-KHEDP. The dynamics of labeled drug accumulation in bone tissues is characterized by a gradual increase in the activity concentration followed by its slow decrease. The maximum accumulation of 99mTc-KHEDP in bone was achieved within 3 – 6 h whereas the activity of 188Re-KHEDP was at a maximum 1 h after injection. The activity gradually decreases after reaching the maximum value. The rate of 99mTc-KHEDP elimination from bone is slower than that for 188Re-KHEDP. The ratios of the specific activity in organs and tissues upon i.v. injection of 99mTc-KHEDP and 188Re-KHEDP are illustrated more clearly by the coefficients of differential accumulation (CDA) of activity in bone (bone of femur, rib, skull, and spine) relative to soft organs and tissues. The dynamics of the change in these values is characterized by a gradual increase over 24 h after injection. The growth is more pronounced for 188Re-KHEDP than for 99mTc-KHEDP. These data show that the elimination of activity from bone upon injection of 188Re-KHEDP is faster than that for 99mTc-KHEDP. A comparative analysis of the CDA values allows the dynamics of drug accumulation and elimination rates from soft organs and tissues to be evaluated in comparison to bone. Using the CDA values, it is also possible to determine the optimum conditions for carrying out scintigraphy studies of the skeleton using a gamma camera. The results from the study of the pharmacokinetic characteristics of 99mTc-KHEDP and 188Re-KHEDP in rats showed that these complexes have similar structures and substantially different biological properties, as indicated by the substantial differences in their in vivo behavior upon i.v. injection.
Keywords: Tc- and 188Re-labeled radiopharmaceuticals; monopotassium salt of 1-hydroxyethylidenediphosphonic acid (KHEDP); pharmacokinetics

Experimental safety evaluation of the porphyrin metabolism corrector arhem by I. V. Smirnov; L. T. Minina; I. V. Kuznetsov; T. N. Gusarova; A. V. Osokina; V. V. Nosova; V. V. Gladun; V. N. Bovenko; I. A. Gal’yanova (341-343).
Preclinical study of the safety of arhem (heme arginate), a new drug intended for the treatment of porphyrin metabolism disorders, has been performed. Arhem proved to be a nontoxic preparation with a large therapeutic margin (high ratio of the toxic dose to effective dose). Even during long-term administration at high doses, arhem does not affect most systems and organs, except for the liver and red blood, where the changes caused by high doses of the drug are a consequence of its medical efficacy.
Keywords: porphyria; heme arginate; preclinical study

Synthesis of new derivatives of inositolcontaining phospholipid dimer analogs as potential inhibitors of virus adsorption by E. O. Baranova; T. Ph. L. Dang; S. V. Eremin; D. S. Esipov; N. S. Shastina; V. I. Shvets (344-350).
The majority of known agents against human immunodeficiency virus (HIV) are targeted at the virus enzymes protease and integrase but do not prevent HIV entry into host cells. Therefore, it is critical to seek small polyanionic molecules as potential inhibitors of virus adsorption. Inositol-containing phospholipids, which are naturally occurring biologically active compounds that are involved in cell regulation, may be promising lead compounds for antiviral drug design. In the present study, dimer analogs of inositol-containing phospholipids were synthesized using the H-phosphonate method. Carboxymethyl and sulfate derivatives based on them were obtained and proposed as potential virus adsorption inhibitors.
Keywords: inositol-containing phospholipids; phosphorylation; polyanions; virus adsorption inhibitors

Synthesis, antibacterial, and antifungal activities of 8-quinolinealdehyde chalcogensemicarbazones and their copper(II) complexes by M. D. Revenko; V. I. Prisacari; A. V. Dizdari; E. F. Stratulat; I. D. Corja; L. M. Proca (351-354).
The antibacterial and antifungal activities of a series of 8-quinolinealdehyde chalcogensemicarbazones have been studied. Only the selenium analog shows activity against Gram-positive bacteria. 8-Quinolinealdehyde thiosemicarbazone becomes active against the indicated bacteria upon coordination to copper(II) ions. The antibacterial activity of the obtained complexes depends on neither the nature of the anion nor the form (molecular or anionic) of the ligand. Introduction of electron-accepting groups on the amide nitrogen atom of the thiosemicarbazide fragment leads to a substantial increase in the activity. 8-Quinolinealdehyde semicarbazone as well as its copper(II) complexes do not show appreciable antibacterial activity against the test species.All investigated compounds do not exhibit any antifungal properties.
Keywords: 8-quinolinealdehyde thiosemicarbazone; synthesis; copper(II) complexes; antibacterial and antifungal activity

Synthesis and pharmacological activity of 1-alkoxyaryl-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones by V. L. Gein; N. L. Fedorova; E. B. Levandovskaya; B. Ya. Syropyatov; E. V. Voronina; N. V. Danilova; M. Yu. Kovaleva (355-358).
A series of 1-alkoxyaryl-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones were synthesized by the reaction of methyl esters of acylpyruvic acids with a mixture of aromatic aldehyde and 2-, 3-, and 4-methoxyanilines. The structures of the compounds are determined by IR and PMR spectroscopy. Results of investigations of antibacterial, analgesic, antipyretic, and anti-inflammatory activities of the synthesized compounds are presented.
Keywords: 1-alkoxyaryl-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones; antibacterial; analgesic; antipyretic activities

Synthesis and effect of biguanide derivatives on biochemiluminescence and level of reduced glutathione in rat blood serum and brain under ischemia-reperfusion conditions by T. N. Popova; O. V. Sukhoveeva; A. V. Makeeva; A. A. Agarkov; E. D. Kryl’skii; S. M. S. Muhammad Amin (359-362).
We have studied the effect of the newly synthesized biguanides N-[amino(imino)methyl]morpholine-4-carboximidamide (I) and N-[amino(imino)methyl]piperidine-1-carboximidamide (II) on biochemiluminescence (BCL) parameters including (i) lightsum (S) and maximum flash intensity (I max), which characterize the level of free-radical processes, and (ii) the slope of the BCL kinetic curve (tan α2), which characterizes general antioxidant activity, and on the reduced glutathione level in rats brain and blood serum under post-ischemic reperfusion conditions. It was found that the investigated parameters, which increased in response to the development of oxidative stress with brain pathology, changed toward normalization under the influence of the biguanides. A dose-dependent action of these substances has been established. The administration of I and II in 25 and 50 mg/kg led to the most pronounced decrease in the BCL parameters and reduced glutathione concentration while 12.5 and 75 mg/kg doses did not lead to significant changes in the studied parameters. The results show that biguanides introduced in certain doses can decrease the free-radical oxidation level and produce a neuroprotective effect.
Keywords: biguanide derivatives; brain ischemia-reperfusion

Preparation of cation-exchange sorbent for 99mTc generator chromatographic column by N. S. Il’icheva; N. K. Kitaeva; V. R. Duflot (363-365).
A new cation-exchange sorbent based on polyethylene powder modified by polyacrylic acid was prepared for a technetium-99 m generator column. The dependence of the kinetics of polyethylene modification on the composition of the grafting solution was studied. The adsorption of manganese ions by the obtained sorbent has been studied. The new sorbent was tested in a technetium-99 m generator column with the maximum output activity. It is expedient to use the sorbent in a technetium-99 m generator column in order to improve the quality of the effluent, increase the consistency of the yield of pertechnetate ions, and maintain the eluate medium in a condition close to neutral.
Keywords: technetium-99 m generator; ionic adsorption; polyethylene; polyacrylic acid; modification; radiation- initiated graft polymerization

A new synthesis of 2-substituted-4H-chromen-4-ones (IVa-c) and 4-(2-hydroxyphenyl)-6-substituted pyrimidin-2(5H)-one/thiones (Va – Vc)/(VIa – VIc) derivatives is reported. First, benzoyloxy esters are converted into their 1,3-diones (IIIa – IIIc) by using dry KOH in pyridine via the Baker – Venkataraman transformation reaction. Then, 1,3-diones thus obtained are cyclised into 2-substituted-4H-chromen-4-ones (IVa – IVc) and 4-(2-hydroxyphenyl)-6-substituted pyrimidin-2(5H)-one/thiones (Va – Vc)/(VIa – VIc) by refluxing in acetic acid and urea/thiourea in ethanol, respectively. The newly synthesized compounds were characterized by IR, 1H NMR, and mass spectroscopy and elemental analysis and tested for their antibacterial and antifungal activity.
Keywords: Chromones; pyrimidinone/thiones; synthesis; antimicrobial properties

A series of new glycosyl imidothiocabamates were synthesized and charaterized and their antimicrobial properties were evaluated. These compounds were synthesized by the condensation of per-O-acetyl lactosyl isocyanate with N-aryl-S-benzyl isothiourea and per-O-benzoyl glucosyl aryl isothiourea and characterised using the IR, 1H NMR, and mass spectroscopy and elemental analysis. The synthesized compounds were screened for their in vitro antimicrobial activity against bacteria (S. aureus, E. coli, P. vulgaris, P. aeruginosa) and fungi (A. niger, Penicillium). Some of these compounds exhibited moderate to good activity, whereas some were inactive.
Keywords: per-O-acetyl lactosyl isocyanate; N-aryl-S-benzyl isothiourea; per-O-benzoyl glucosyl aryl isothiourea; imidothiocabamates; antimicrobial activity

Ion-selective electrode for quantitative determination of baclofen in pills by V. A. Nazarov; K. A. Andronchik; V. V. Egorov; S. A. Belyaev; T. L. Yurkshtovich (374-376).
The possibility of determining baclofen in the anionic and cationic forms has been investigated. The main analytical characteristics of a cation-selective electrode reversible to baclofen were determined. A rapid potentiometric technique for baclofen determination in pills without long and laborious sample preparation is proposed.
Keywords: baclofen; quantitative determination; ion-selective electrode

Pharmaceutical analysis and standardization of noopept tablets by L. N. Grushevskaya; N. I. Avdyunina; B. M. Pyatin; K. V. Alekseev; L. M. Gaevaya; M. S. Sergeeva; M. E. Dudenkova; V. S. Klumova; N. V. Tikhonova (377-380).
Procedures for pharmaceutical analysis and standardization of the new nootropic drug noopept in tablets manufactured by direct compression have been developed. The main quality tests were carried out. Ahigh performance liquid chromatography (HPLC) method for quantitative and qualitative analysis of noopept in tablets is developed and applied to determination of impurities, noopept content in tablets, uniformity of dosage, and dissolution rate.
Keywords: noopept; tablets; HPLC; chromatography; pharmaceutical analysis; amide; peptide