Pharmaceutical Chemistry Journal (v.48, #3)

Effects of Cytoflavin and its Components on Behavioral Disorders in Mice with Alloxan Diabetes by I. A. Volchegorskii; L. M. Rassokhina; S. G. Ermakova (143-148).
The effects of the combined formulation Cytoflavin and its individual components (meglumine sodium succinate, nicotinamide, riboflavin, and inosine) on depressive behavioral disorders (DBD) were studied in mice with alloxan diabetes. Cytoflavin was found to be effective in correcting deficits in the activity of animals in the open field test and significantly reduced “despair behavior” in a 6-min tail suspension test; it also produced a transient hypoglycemic effect. The DBD-correcting activity of Cytoflavin was shown to be associated mainly with meglumine sodium succinate. The effect was significantly less linked with nicotinamide, which also produced the transient hypoglycemic action of Cytoflavin. Riboflavin made an even smaller contribution to the positive psychotropic action of Cytoflavin. The most problematic component of Cytoflavin was inosine, courses of which significantly increased lethality in mice with alloxan diabetes. However, this effect of inosine was only apparent when used alone, and disappeared completely when used in Cytoflavin.
Keywords: Cytoflavin; alloxan diabetes; depressive behavioral disorders

Effects of Histochrome on P53 Expression in Mouse Red Bone Marrow Cells in a Model of Chronic Stress by E. N. Kareva; D. A. Tikhonov; N. P. Mishchenko; S. A. Fedoreev; N. L. Shimanovskii (149-152).
The clinical efficacy of the formulation Histochrome cannot be explained solely on the basis of its antioxidant properties. With the aim of identifying possible additional mechanisms of action of the medicinal substance (echinochrome A) in Histochrome, its effects on p53 expression were studied in bone marrow cells in SHK mice in a model of chronic stress. Echinochrome Aat a dose of 1 mg/kg (single daily i.p. doses for seven days prior of stress) normalized the level of p53 gene expression. The antioxidant formulation Histochrome had antistress properties in this experimental model in mice.
Keywords: antioxidant properties; 053 gene expression; Histochrome; chronic stress

Synthesis and Antibacterial Activity of 5-Thiomethylfuran-2-Carboxylic Acid Derivatives by M. A. Iradyan; N. S. Iradyan; R. A. Tamazyan; A. G. Aivazyan; G. A. Panosyan; R. V. Paronikyan; G. M. Stepanyan (153-158).
We report here the synthesis of methyl esters of 5-(1H-1,2,4-triazol-3-ylsulfanylmethyl)furan-2-carboxylic acids containing an alkyl or 2(4)-alkoxyphenyl substituent in position 5 of the triazole ring. Alkaline hydrolysis of these esters yielded the corresponding acids. X-ray diffraction studies showed that the oscillating hydrogen atom in the triazole ring of the methyl ester of 5-[5-(2-ethoxyphenyl)-1H-1,2,4-triazol-3-ylsulfanylmethyl] furyl-2-carboxylic acid was located on the N1 atom. The antibacterial properties of the esters and acids were studied.
Keywords: 5-(1H-1,2,4-triazol-3-ylsulfanylmethyl)furan-2-carboxylic acids; methyl esters; synthesis; oscillation; antibacterial activity

Synthesis and Chemico-Pharmaceutical Characteristics of a Somatostatin Analog with Antitumor Activity by Z. S. Shprakh; I. V. Yartseva; E. V. Ignat’eva; A. P. Smirnova; L. P. Sushinina; S. V. Ustinkina; L. I. Smirnova; A. P. Bud’ko; N. I. Zimakova (159-162).
An analog of somatostatin with hormonal and antitumor activity was synthesized. An optimum synthesis method was developed, yielding standard pharmaceutical somatostatin analog substance for preclinical and clinical studies. A quality control method was developed for inclusion in the draft manufacturer’s pharmacopeia monograph for pharmacological somatostatin analog substance.
Keywords: somatostatin (SST); peptide synthesis; antitumor activity; chemico-pharmaceutical analysis

Synthesis and Anticholinesterase Properties of Choline esters of α-Amino Acids by V. O. Topuzyan; I. R. Karapetyan; G. P. Alebyan (163-165).
2-(Dimethylamino)ethyl esters of a number of N-substituted α-amino acids and their quaternary ammonium salts were synthesized and their physiochemical properties were determined. We report here studies of their interactions with erythrocyte acetylcholinesterase and human plasma butyrylcholinesterase. IC50 values (the concentrations of study compounds producing 50% inhibition of the rate of cholinesterase hydrolysis of 0.1 mM acetylcholine) were measured for all the compounds synthesized. The results showed that all the choline esters of N-substituted amino acids synthesized here had anticholinesterase properties, mainly specific for butyrylcholinesterase.
Keywords: amino acids; choline esters; anticholinesterase properties

3-O-benzyl-1,2-O-isopropylidene-xylopentadialdose has emerged as structurally new antibacterial and anti-inflammatory agent. Therefore, various substituted bis-indolyl-(3-O-benzyl-1,2-O-isopropylidene-xylopentadialdose glucofuranose) derivatives were synthesized by addition of substituted xylopentadialdose with various substituted indoles. The structures of the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectroscopy techniques. All the synthesised compounds showed maximum zone of inhibition againt both Gram-positive and Gram-negative organisms. In the anti-inflammatory activity test, three compounds (1, 3 and 5) produced significant activity in a dose-dependent manner.
Keywords: 3-O-benzyl-1,2-O-isopropylidene-xylopentadialdose; antibacterial activity; anti-inflammatory activity

A series of new pyrimidine analogs carrying 1,4-naphthoquinone and uracil moiety were prepared as hybrid compounds 1-(3′-chloro-1′,4′-dioxo-1′,4′-dihydronaphthalen-2′-yl)-5-substitued-1H-pyrimidine-2,4-diones (6 – 9), which might possess biological activity. The structures of new products were confirmed by IR, 1H and 13C NMR, and mass spectroscopy data. All synthesized compounds were also evaluated for their antibacterial activity. The structure – activity relationship for these compounds was studied and the results showed that 1-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-5-fluoro-1H-pyrimidine-2,4-dione (9) containing a fluorine atom exhibited in vitro potent antibacterial activity (MIC50 = 1.0 μg/mL) comparable with that of the clinically useful antibacterial drug gentamicin (MIC50 = 2.0 μg/mL) against S. aureus and B. subtilis. Compound 9 also exhibited the same antibacterial activity with MIC50 = 1.0 mg/mL compared to gentamicin and ciprofloxacin against P. aeruginosa and with MIC50 = 0.5 mg/mL compared to Gentamicin (MIC50 = 0.5 mg/mL) against E. coli.
Keywords: 1H-pyrimidine-2,4-dione; 2,3-dichloro-1,4-naphthoquinone; antimicrobial activity

Docking and Synthesis of 2-Arylisoindoline-1,3-dione Derivatives as Anticonvulsant Agents by Asghar Davood; Liela Azimidoost; Hamed Shafaroodi; Mohsen Amini; Maryam Iman; Abdollah Ansari; Ali Nikbakht; Somaieh Rahmatpour; Ali Reza Nematollahi (175-180).
Antiepileptic drugs are used to prevent or reduce the occurrence of epileptic seizures, but up to 30 % of patients are resistant to the available medical therapies. Ten new analogs of 2-aryl substituent of isoindoline-1,3-dione have been synthesized and evaluated for their anticonvulsant activities. The in vivo screening data acquired indicate that all the analogs have the ability to protect mice against pentylenetetrazole-induced seizures. These compounds exerted their maximal effects 30 min after administration. The most potent compound was 4-triazolyl derivative (compound VIII). Using a model of the open pore of the Na channel, we have docked compound VIII. Docking studies have revealed that this ligand (i) interacts mainly with residues II-S6 of NaV1.2 by forming hydrogen bonds and (ii) has additional hydrophobic interactions with domains I and II in the channel inner pore.
Keywords: anticonvulsant; arylisoindoline; design; phenytoin; seizure

Studies of the Lipophilic Components of a Dense Extract of the Herb Alfredia Cernua and its Nootropic Properties by I. V. Shilova; T. P. Kukina; N. I. Suslov; O. I. Sal’nikova; R. N. Mustafin (181-185).
Chromato-mass spectrometry (GC/MS) studies of the chemical composition of a dense extract of the herb Alfredia cernua (L.) Cass. prepared by processing raw material with 95 % ethanol identified 31 aliphatic, including 2-hydroxy- and dicarboxylic, acids, three phenolcarboxylic acids, one di- and two triterpenoic acids, and 16 neutral lipophilic components. A total of 40 compounds were detected in Alfredia cernua for the first time. T maze experiments showed that the plant extract promoted changes in the motivational domain in normal animals, activating appetitive and consumatory behavior due to nootropic and anxiolytic actions, which were greater than those of piracetam.
Keywords: Alfredia cernua herb; dense extract; chromatomass spectrometric analysis; aliphatic acids; phenolcarboxylic acids; di- and triterpenoic acids; neutral lipophilic compounds; nootropic activity; T maze

The Atropomer Composition of Iopromide as an Indicator for Assessment of the Quality of its Substance and Medincal Formulations by R. G. Glushkov; M. S. Goizman; D. A. Arantseva; N. N. Demidova; E. K. Kulaeva; M. B. Zagudailova; D. E. Dmitriev; A. S. Trifilenkov; A. A. Korlyukov; D. E. Arkhipov; K. Yu. Suponitskii; N. L. Shimanovskii; S. A. Zaitsev; E. V. Degterev (186-195).
The atropisomer composition of iopromide substance and formulations is discussed. At 120 °C in aqueous iopromide solution, its atropisomers were found to be converted to conformers, which reached equilibrium with each other in 15 min at this temperature. Thus, the atropisomer composition of iopromide substance in solutions prepared using the technical method as described inevitably consists of the equilibrium between conformers formed at 120 °C. The equilibrium composition of these solutions persists after cooling, i.e., after return of conformers to the state of atropisomers. The relative content of the E1 and E2 (USP terminology) atropisomers (ΣE) is an important quality indicator for iopromide formulations; only compliance with the inequality ΣE ≥ 20 % guarantees phase stability of solutions with working concentrations of iopromide ( ≤ 769 mg/ml) over a wide range of temperatures (0 – 120 °C). The inequality ΣE ≥ 20 % is inevitably reached during heat sterilization of iopromide.
Keywords: iopromide; conformer; atropisomer; thin-layer chromatography (TLC); high-performance liquid chromatography (HPLC); proton magnetic resonance (PMR); x-ray diffraction studies; quantum chemistry; conformational studies

Preparation of an Inclusion Complex of 1-(3-n-butoxypropyl)-4-vinylacetylen-4-benzoyloxypiperidine with B-cyclodextrin and its Local Anesthetic Activity by G. M. Kaldybekova; U. S. Kemel’bekov; A. A. Abdildanova; K. D. Praliev; V. A. Volynkin; S. R. Nasyrova; Sh. O. Imashova; G. M. Pichkhadze (196-200).
Complex formation of 1-(3-n-butoxypropyl)-4-vinylacetylene-4-benzoyloxypiperidine with β-cyclodextrin was studied by NMR spectroscopy. The structural characteristics and composition (1:2) of the resulting inclusion complex of 1-(3-n-butoxypropyl)-4-vinylacetylene-4-benzoyloxypiperidine with β-cyclodextrin in aqueous solution were identified. The local anesthetic activity of the resulting preparation was assessed; the complex was found to have greater anesthetic activity greater than reference agents.
Keywords: 1-(3-n-butoxypropyl)-4-vinylacetylene-4-benzoyloxypiperidine; β-cyclodextrin; inclusion complex; anesthetic activity

The clouding behaviour of an amphiphilic antidepressant drug imipramine hydrochloride (IMP) with several additives (hydrotropes, bile salts, fatty acids and sugars) over the entire composition range at pH = 7.6 was investigated in the present study. The magnitude of clouding (increase or decrease) of IMP in the presence of additives (pharmaceutical excipients) depends on the nature and types of additives. Bile salts and fatty acids showed peak behaviour i.e., cloud point (CP) increases at lower concentrations while decrease in cloud points was observed at higher concentrations. Thermodynamics at the CP were also evaluated (except for sugars, because sugars does not form mixed micelles with IMP), assuming that the clouding indicates the solubility limit when phase separation occurs. Thus, the various thermodynamic parameters e.g., standard Gibbs free energy (ΔG s o ), the enthalpy (ΔH s o ) and entropy (TΔS s o ) were calculated at this point. The results showed that the ΔG s o , was found to be negative for all the additives, however ΔH s o and TΔG s o of the clouding phenomenon were found to be positive or negative depending upon the types and nature of additives.
Keywords: Amphiphilic drugs; imipramie hydrochloride; cloud point; bile salts; hydrotropes; fatty acids

Solubilization of Hydrophobic Antitumor Drugs (Review) by I. D. Gulyakin; N. A. Oborotova; V. M. Pechennikov (209-213).
Advances in chemotherapy always depend on the physician’s correct selection of a medicinal formulation in which the main active ingredient or complex of substances has the greatest therapeutic effect. From this point of view, the pharmacokinetics of injectable medicinal formulations are optimal in terms of achieving the required dose in the systemic circulation, as the bioavailability of an agent given intravenously reaches 100%. However, major problems in creating medicinal formulations are posed by medicinal substances with low solubility and the high lability of aqueous solutions of such substances. This review discusses the properties of current solubilizers used in the production of known hydrophobic antitumor formulations for parenteral use and in the development of new medicinal formulations of experimental compounds with cytotoxic effects and undergoing preclinical and clinical studies.
Keywords: injectable medicinal formulations; solubilizers; polyvinylpyrrolidone; CremophorR EL; dimethylsulfoxide

Effects of Processing Regimes on the Loss of Disperse Pharmaceutical Materials from Pulsatile Layers by M. S. Vasilishin; O. S. Ivanov; A. A. Kukhlenko; S. E. Orlov; A. G. Karpov (214-216).
The effects of pulsation frequency, fluidizing agent speed, and layer height on the loss of medicinal ascorbic acid and gamma-aminobutyric acid (Aminalon) from a pulsatile layer device were studied. An empirical relationship is proposed for estimation of loss.
Keywords: medicinal ascorbic acid; Aminalon; pulsatile layer; loss

Synthesis of Leuprorelin Acetate by A. N. Balaev; V. N. Osipov; K. A. Okhmanovich; V. E. Fedorov (217-219).
A method for preparing leuprorelin acetate – a synthetic agonist of natural gonadotropin-releasing hormone - was developed, using liquid-phase peptide synthesis. The new method yields target peptide with a main substance content of > 99% on a semi-industrial scale.
Keywords: leuprorelin; liquid-phase synthesis; manufacture

An alternative efficient road for the synthesis of 16α,17α-epoxy-pregn-4,9(11)-dien-21-ol-3,20-dione from 9α-hydroxy-androst-4-ene-3,17-dione via its Δ9-analog has been studied.
Keywords: Synthesis; 16α,17α-epoxy-pregn-4,9(11)-diene-21-ol-3,20-dione