Pharmaceutical Chemistry Journal (v.45, #1)

A new group of 1-and 7-[ω-(benzhydryl-1-alkyl]-3methylxanthine derivatives with antihistamine activity by R. G. Glushkov; S. D. Yuzhakov; M. V. Alekseev; O. S. Fominova; V. A. Shorr; G. F. Zhdanov; E. M. Dolginova; N. M. Sazonova; N. I. Andreeva; E. N. Salin; V. V. Asnina (1-11).
Directed synthesis using the accessible compound 3-methylxanthine was used to obtain a new group of 1-and 7-[ω-(benzhydryl-1)alkyl]-3-methylxanthine derivatives which functioned as histamine receptor blockers. The compound which was most active, had the longest duration of action, and the lowest toxicity was 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate, and this compound was selected for clinical trials.
Keywords: 1-and 7-[ω-(benzhydryl-1)alkyl]-3-methylxanthine derivatives; synthesis; antihistamine activity; acute toxicity; further pharmacological study of 7-[4-(4-benzhydrylpiperazinyl-1)butyl]-3-methylxanthine succinate

Synthesis and hemostatic and antimicrobial activities of the sodium salts of N-acyl-5-bromo(3,5-dibromo)anthranilic acids by K. V. Andryukov; N. G. Ismailova; M. V. Tomilov; L. M. Korkodinova; B. Ya. Syropyatov; T. F. Odegova; M. I. Vakhrin; Yu. V. Kozhevnikov (12-14).
Acylation of 5-bromo(3,5-dibromo)anthranilic acids with the corresponding anhydrides yielded 10 N-acyl-5-bromo(3,5-dibromo)anthranilic acids. The resulting compounds were reacted with 10% sodium hydroxide to convert them to the corresponding sodium salts. The hemostatic and antimicrobial activities against Staphylococcus aureus and Escherichia coli of the resulting compounds were studied. Compound IV, containing a phenyl residue in the acyl fragment, was found to have marked hemostatic activity (18.2%) and weak antimicrobial activity. The minimum inhibitory concentration for this compound was 500 μg/ml against S. aureus and E. coli. The other sodium salts were significantly less active.
Keywords: Sodium salts of N-acyl-5-bromo(3,5-dibromo)anthranilic acids; hemostatic and antimicrobial activities; synthesis

Synthesis and antibacterial and antifungal activities of thiourea derivatives of the alkaloid anabasine by I. V. Kulakov; O. A. Nurkenov; S. B. Akhmetova; R. B. Seidakhmetova; Z. M. Zhambekov (15-18).
A series of new N-acyl-substituted derivatives of the physiologically active alkaloid anabasine were synthesized and described. Their compositions and structures were identified using IR and 1H NMR spectroscopy. These compounds were found to have moderate antibacterial and antifungal activities.
Keywords: Anabasine; antibacterial and antifungal activities

A series of quaternary salts of adamantane-containing alkoxydialkylaminopropanols was synthesized. The structures of the reaction products were confirmed by IR and PMR spectroscopy. Some compounds were found to have high levels of antimicrobial activity.
Keywords: Adamantane derivatives; antimicrobial activity; antifungal activity

Synthesis and antimicrobial activity of a number of pyrroloindole derivatives by Sh. A. Samsoniya; D. O. Kadzhrishvili; I. Sh. Chikvaidze (22-25).
A method for the predominant synthesis of linear pyrroloindoles was developed, based on the attachment of the pyrrole ring to indoline and including diazo coupling of 5-and 6-aminoindolines followed by reduction, condensation with pyruvic acid ethyl ester, and indolization of the resulting 5-and 6-indolinylhydrazines. The in vitro antimicrobial, tuberculostatic, and antifungal activities of a number of 3H,6H-pyrrolo[3,2-e]indole, 1H,7H-pyrrolo[3,2-f]indole, and 1H,5H-pyrrolo[3,2-f]indole derivatives were studied. 1-(p-Chlorophenylazo)-3H,6H-pyrrolo[3,2-e]indole (XIX) and 3,5-di(p-chlorophenylazo)-1H,7H-pyrrolo[3,2-f]indole (XXIII) had high, 1-(p-nitrophenylazo)-3H,6H-pyrrolo[3,2-e]indole (XX) had moderate, and 2,7-diethoxycarbonyl3H,6H-pyrrolo[3,2-e]indole (XVIII) had weak tuberculostatic activity. 3,5-p-Chlorophenylazo)-1H,7H-pyrrolo[3,2-f]indole (XXIII) had high activity against Gram-negative bacteria.
Keywords: Pyrroloindole derivatives; synthesis; antimicrobial activity

Synthesis and antibacterial activity of 2-hydrazino5-bromomethyl-4,5-dihydrothiazole hydrazones by M. A. Iradyan; R. A. Aroyan; D. A. Avakimyan; G. M. Stepanyan (26-29).
A series of 2-hydrazino-5-bromomethyl-4,5-dihydrothiazole hydrazones based on substituted N4-allylthiosemicarbazones was synthesized. Some of these hydrazones were found to have moderate antibacterial activity against Staphylococcus aureus 209P, 1 and Shigella flexneri.
Keywords: N4-allylthiosemicarbazones; 2-hydrazino-5-bromomethyl-4,5-dihydrothiazole hydrazones; antibacterial activity

Synthesis and antitumor properties of new 2,4-dichlorophenoxy ethers by B. F. Abdel-Wahab; M. Farghaly; F. A. Badria (30-35).
A series of new compounds incorporating 2,4-dichlorophenoxy nucleus have been synthesized. Reaction of 2,4-dichlorophenoxyacetic acid with thiosemicarbazide in the presence of phosphoryl chloride followed by treatment with phenacylbromides led to the formation of imidazo[2,1-b][1,3,4]thiadiazoles (3). Bischlorophenoxyallyl hydrazides (4) reacted with some of alkenes, azo dyes, aldehydes, and hydrazonoyl chlorides to produce pyrazoles, Schiff bases, and bis-diazo compounds, respectively. 1,3,4-Thiadiazole (10) was obtained by reaction of dichlorophenoxyallyl hydrazides (4b) with carbon disulphide followed by hydrazonoyl chlorides. All compounds were tested for their preliminarily antitumor activity on transplantable murine tumor cell line [Ehrlich ascites carcinoma (EAC)]. Compound 2-{2-[2-(2,4-dichlorophenoxy)acetyl]hydrazono}-N'-(4-fluorophenyl)propanehydrazonoyl chloride (8c) has remarkably decreased the viable EAC cell count as indicated by Trypan Blue dye exclusion test (3%) in comparison to the well known antitumor agent 5-FU (0%).
Keywords: 2,4-dichlorophenoxyacetic acid; imidazo[2,1-b][1,3,4]thiadiazoles; pyrazoles; hydrazonoyl chlorides; thiosemicarbazides; 1,3,4-thiadiazoles; antitumor activity

In order to understand the essential structural features of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) inhibitors, three-dimensional (3D) pharmacophore hypotheses were built based on a set of known HIV-1 RT inhibitors selected from literature using PHASE program. Ten four-point 3D pharmacophore models, each with one hydrogen bond acceptor (A), one hydrogen bond donor (D), one hydrophobic group (H), and one aromatic ring (R) as pharmacophore features were developed. Among these, the hypothetical pharmacophore ADHR1 yielded a statistically significant hypothesis with correlation coefficient R2 = 0.918 value, which was considered to be the best pharmacophore hypothesis. The developed pharmacophore hypothesis was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.743 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore hypothesis were expected to be useful for the design of selective HIV-1 RT inhibitors.
Keywords: HIV-1 reverse transcriptase; pyridinone; pharmacophore model; regression coefficient; squared predictive correlation coefficient

A method for assaying total flavonoids in common agrimony (Agrimonia eupatoria L.) herb based on differential spectrophotometry (analytical wavelength 403 nm) and cynaroside State Reference Compound (SRC) was developed. This method was used to analyze a series of raw material samples, which demonstrated that the flavonoid content of common agrimony herb ranged from 1.22% to 1.40% (expressed as cynaroside). Statistical analysis of these experiments showed that the error in single assays of total flavonoids in common agrimony herb was ± 4.02% at the 95% confidence level.
Keywords: Common agrimony herb; flavonoids; differential spectrophotometry; assay

Identification of flavonoids in plants by HPLC by D. V. Moiseev; G. N. Buzuk; V. L. Shelyuto (47-50).
The HPLC capacity factors of 27 flavonoids were determined using the following chromatographic conditions: Zorbax SB 250 × 4.6 mm analytical columns containing C-18, C-8, and CN sorbents with particle size 5 μm, mobile phase consisting of 0.01 M potassium dihydrogen phosphate pH 3.0 and acetonitrile at a ratio of 80:20 (v/v), column temperature 30°C; absorption spectra were recorded over the range 190 – 400 nm. This chromatography system can be used for preliminary identification of flavonoids in plant materials.
Keywords: Flavonoids in plants; identification by HPLC

Poly(3-hydroxybutyrate)-chitosan: a new biodegradable composition for prolonged delivery of biologically active substances by E. L. Ivantsova; A. L. Iordanskii; R. Yu. Kosenko; S. Z. Rogovina; A. V. Grachev; É. V. Prut (51-55).
A new polymer composition based on bacterial poly-3-hydroxybutyrate and chitosan encapsulating the wide-spectrum antibiotic rifampicin was developed. Both biopolymers are biocompatible and can undergo enzymatic and hydrolytic degradation. Variations in the ratio of poly-3-hydroxybutyrate and chitosan in the mixture, altering the ratio of hydrophilic and hydrophobic components, influenced not only the sorption capacities for water and drug but also the controlled release profile of the drug. Analysis of kinetic curves for rifampicin release showed that drug release was determined by the superimposition of two processes: drug desorption by a diffusional mechanism and hydrolytic degradation of poly-3-hydroxybutyrate, which was most marked after the initial diffusional stage. Kinetic parameters (the constant of hydrolysis of poly-3-hydroxybutyrate k and the coefficient of diffusion of rifampicin D) were required for a full description of the poly-3-hydroxybutyrate-chitosan-rifampicin system. The fact that the kinetic curves had a prolonged linear region suggests that this composition may have value as a biodegradable therapeutic system for local controlled drug release.
Keywords: Poly-3-hydroxybutyrate; chitosan; rifampicin; polymer composition; biodegradable therapeutic system; controlled release

The antithrombin activity of fucoidan fractions from the brown seaweed species Fucus evanescens, Laminaria gurjanovae, Undaria pinnatifida, Laminaria japonica, Laminaria cichorioides, and Costaria costata was found to depend on the Man/Fuc and Gal/Fuc monosaccharide ratios. Fucoidans with lower xylose contents had greater anticoagulant activity. The mechanism of the anticoagulant actions of the fucoidans studied here depended not only on antithrombin, but also on other plasma inhibitors of serine pro-teases. Fucoidans from F. evanescens, U. pinnatifida, L. gurjanovae, and L. cichorioides had the greatest levels of antithrombin (30 – 50 U/mg) and anti-activated factor X (10 – 20 U/mg) activity and had the greatest potential for creating new anticoagulant drugs. Biospecific agarose gel electrophoresis with protamine sulfate could be used to evaluate the anticoagulant activity of fucoidans with levels of greater than 5 U/mg.
Keywords: Fucoidans; seaweed; anticoagulant activity; inhibition of thrombin; inhibition of factor Xa

Effects of liposomal “Bien” on the functional activity of alveolar macrophages by I. M. Bushmakina; N. I. Drozdova; M. A. Martynova (62-64).
In vitro experiments were performed to study the functional state of pulmonary macrophages interacting with multilamellar macrophages containing Bien, a complex of unsaturated fatty acids, pure therapeutic agent, and liposomes without the active ingredient. The effects identified during these studies should be taken into consideration when creating liposomal preparations containing active fatty-acid substances for the treatment of bronchopulmonary pathology.
Keywords: Alveolar macrophages; Bien complex of fatty acids; multilamellar liposomes; liposomal Bien; phagocytic activity