Pharmaceutical Chemistry Journal (v.47, #9)

Effect of Iron Nitrosyl Complexes, No Donors, on the Activity of Ca2+-Atpase of Sarcoplasmic Reticulum and Phosphodiesterase of Cyclic Guanosine Monophosphate by L. V. Tat’yanenko; O. V. Dobrokhotova; A. I. Kotel’nikov; N. A. Sanina; G. I. Kozub; T. A. Kondrat’eva; S. M. Aldoshin (455-458).
We studied the effect of iron nitrosyl complexes, NO donors, of various structural types on the activity of Ca2+-ATPase of sarcoplasmic reticulum (SR) and phosphodiesterase (PDE) of cyclic guanosine monophosphate (cGMP). It was established that iron nitrosyl complexes with organic ligands modulate functions of both enzymes. They effectively inhibited the hydrolytic and transport functions of Ca2+-ATPase SR at concentrations 0.1 – 0.01 mM and decoupled ATP hydrolysis and active Ca2+ transport at concentrations 0.01 – 0.0001 mM, thus disrupting the Ca2+ balance in cells. This influenced thrombogenesis and adhesion of metastatic cells to capillary endothelium. The compound [Fe(SC(NH2)2)2(NO)2]2[Fe2(S2O3)2(NO)4] produced non-competitive and reversible inhibition of Ca2+-ATPase SR functioning with K i = 0.70∙10–6 M. All studied iron nitrosyl complexes inhibited the activity of PDE-cGMP, which led to accumulation of cGMP, which is a secondary messenger influencing the in vivo anti-aggregation effect. The obtained results suggested that the studied iron nitrosyl complexes could be considered as potential drugs.
Keywords: Ca2+-ATPase; sarcoplasmic reticulum; phosphodiesterase of cyclic guanosine monophosphate; iron nitrosyl complexes

Synthesis and Anti-HIV-1 Activity of 1-[ω-(Phenoxy)Alkyl and -Alkenyl]Uracil Derivatives by M. P. Paramonova; D. A. Babkov; V. T. Valuev-Elliston; A. V. Ivanov; S. N. Kochetkov; C. Pannecouque; A. A. Ozerov; J. Balzarini; M. S. Novikov (459-463).
1-[ω-(Phenoxy)alkyl and -alkenyl]uracil derivatives were synthesized via condensation of equimolar amounts of 2,4-bis(trimethylsilyloxy)pyrimidine and 1-halo-ω-(phenoxy)alkane or -alkene in order to discover new non-nucleoside inhibitors of HIV-1 reverse transcriptase. Their anti-HIV-1 activity was studied in CEM-cell culture and against HIV-1 reverse transcriptase. It was found that several compounds exhibited marked activity.
Keywords: synthesis; anti-HIV-1 activity; 1[ω-(phenoxy)alkyl and -alkenyl]uracil derivatives

Synthesis and Antidepressant and Anxiolytic Activity of 1,2,4,5-Tetrahydro-3H-Pyrrolo[1,2-a][1,4]Diazepin-3-ones by G. V. Mokrov; A. M. Likhosherstov; V. I. Poseva; G. M. Molodavkin; V. P. Lezina; T. A. Gudasheva; T. A. Voronina (464-469).
A series of new 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one derivatives were synthesized from widely available furfurol, 3-aminopropionic acid, and amines. The antidepressant and anxiolytic properties of the obtained compounds were investigated. Results of Nomura and Porsolt forced swimming tests showed that some of the compounds exhibited antidepressant activity at doses of 7 μmol/kg (1.1 – 2.2 mg/kg). Use of the Vogel conflict test showed that several compounds possessed anxiolytic activity at the same doses. The activities of the most active compounds exceeded those of the reference drugs, antidepressant amitriptyline and daily tranquilizer medazepam, at doses of 10 mg/kg.
Keywords: anxiolytic activity; antidepressant activity; Nomura test; Porsolt test; pyrrolo-[1,2-a][1,4]diazepines; Vogel test

Synthesis and Analgesic Activity of Reaction Products of Hetareno[e]pyrrolo-2,3-diones with aryl- and Hetarylhydrazines by N. V. Suchkova; R. R. Makhmudov; I. V. Mashevskaya; L. V. Kuslina; A. N. Maslivets (470-473).
The analgesic activity of reaction products of hetareno[e]pyrrolo-2,3-diones with arylhydrazines and 2-pyridylhydrazine was investigated by the thermal stimulation (hot plate) test. Compounds that showed the maximum activity were also studied using the acetic acid writhing test. The investigated compounds showed pronounced analgesic activity at low toxicity.
Keywords: hetareno[e]pyrrolo-2,3-diones; aryl- and hetarylhydrazines; analgesic activity

Silver-containing nanocomposites based on copolymers of 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride with vinyl acetate and N-vinylpyrrolidone were obtained by the borohydride method. The antimicrobial activity with respect to bacteria, spores, and fungi was determined by the double serial dilution method.
Keywords: silver-containing nanocomposites; 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride; antimicrobial properties

Synthesis and Antibacterial Properties of Several Unsaturated Quaternary Ammonium Salts by J. V. Grigoryan; G. T. Sargsyan; A. Kh. Gyulnazaryan; R. V. Paronikyan; G. M. Stepanyan (477-480).
A series of ammonium salts with various functional groups were synthesized by the reaction of the corresponding tertiary amines and alkyl halides. It was established that nine compounds (of ten synthesized) displayed bactericidal activity.
Keywords: ammonium salts; quinolinium; antibacterial activity; Gram-positive Staphylococcus (209 p,1); Gram-negative Bacillus (Sh. dysenteriae, flexneri 6858, E. coli 0 − 55)

Synthesis and Some Biological Properties of Aminoalkyl Ester Methyliodides of Substituted Acetic and Propionic Acids by A. U. Isakhanyan; G. A. Gevorgyan; N. S. Arutyunyan; G. G. Tokmadjyan; R. V. Paronikyan; A. A. Tatevosyan; A. A. Shakhatuni (481-484).
The reaction of some aminoalkanols with substituted acetic and propionic acid chlorides was used to synthesize the corresponding (2-dimethylamino-1-methyl and 2-azepan-1-yl)ethyl esters, the methyliodides of which were prepared in order to conduct antibacterial tests of the resulting salts. High antibacterial activity was found for the methyliodides of the aminoalkyl esters of substituted propionic acids, some of which also exhibited strongly pronounced peripheral n-cholinolytic activity.
Keywords: aminoalkanols; methyliodides; (2-dimethylamino-1-methyl- and 2-azepan-1-yl)alkyl esters; substituted acetic and propionic acid chlorides; antibacterial and peripheral n-cholinolytic activity

Synthesis and Biological Activity of 5-aryl-4-acyl-3-hydroxy-1-(2-piperazin-1-ylethyl)-2,5-dihydropyrrol-2-ones and their Derivatives by V. L. Gein; B. Ya. Syropyatov; N. N. Kasimova; N. V. Dozmorova; E. V. Voronina; M. I. Vakhrin (485-489).
5-Aryl-4-acyl-3-hydroxy-1-(2-piperazin-1-ylethyl)-2,5-dihydropyrrol-2-ones (I) were synthesized by reactions of acylpyruvate methyl esters with a mixture of aromatic aldehyde and 2-(1-piperazino)-1-ethylamine. Then, the corresponding hydrochlorides (II) were obtained. Compounds I were transformed into 3,4-diaryl-4,6-dihydro-5-(2-piperazin-1-ylethyl)pyrrolo[3,4-c]pyrazol-6-ones (III) by reaction with hydrazine hydrate. The antimicrobial activity of compounds I and the influence of compounds II and III on blood coagulation were studied. The acute toxicity of two compounds was evaluated.
Keywords: 5-aryl-4-acyl-3-hydroxy-1-(2-piperazin-1-ylethyl)-2,5-dihydropyrrol-2-ones; 3,4-diaryl-4,6-dihydro-5-(2-piperazin-1-ylethyl)pyrrolo[3,4-c]pyrazol-6-ones; synthesis; antimicrobial activity; influence on blood coagulation; acute toxicity

Synthesis and Antibacterial Activity of Oxalates and Acetamides of {2-[2-Sopropyltetrahydropyran-4-yl-4-(4-Fluorophenyl)]Ethyl}Arylamines by N. S. Arutyunyan; L. A. Akopyan; R. L. Nazaryan; G. A. Gevorgyan; G. M. Stepanyan; R. V. Paronikyan; G. A. Panosyan (490-493).
The reaction of cyano(2-isopropyltetrahydropyran-4-ylidene)acetic acid ethyl ester and 4-fluorophenylmagnesium bromide produced the cyanoester that was decarboxylated to the corresponding nitrile. Reduction of the latter by LiAlH4 formed 2-[4-(4-fluorophenyl)-2-isopropyltetrahydropyran-4-yl]ethylamine, reaction of which with aromatic aldehydes synthesized azomethines that were then reduced by NaBH4 to secondary amines. The last were transformed to oxalates and acetamides. It was shown that the secondary amine oxalates possessed high antibacterial activity.
Keywords: azomethines; reduction; secondary amine oxalates; antibacterial activity

A reversed-phase microcolumn HPLC method with UV detection (303 nm) for quantitative analysis of aloenin using a ProntoSIL-120-5-C18 (2 × 75 mm) column and gradient elution system LiClO4 (4.1 M)/HClO4 (0.1 M):CH3CN was developed. Validation analysis showed that the proposed method was characterized by satisfactory metrological parameters. The limit of detection (LOD) and limit of quantitation (LOQ) of aloenin were 35 and 105 μg/mL, respectively. The accuracy for aloenin content levels 80 – 120% was less than 98.16 – 101.34%. The method was used for the analysis of Aloe arborescens Mill. leaves and some related preparations (dry aloe extract, liquid aloe extract for subcutaneous injection, aloe juice, aloe extract tablets).
Keywords: aloenin; Aloe arborescens Mill; reversed-phase microcolumn HPLC with UV detection

New Opportunities for the Synthesis of Quinoxaline-Substituted Heterocyclic and Aryl Moieties by Yu. A. Azev; M. I. Kodess; M. A. Ezhikova; A. M. Gibor; V. I. Baranov; O. S. Ermakova; V. A. Bakulev (498-502).
6.7-Difluoroquinoxaline (I) reacted with dimedone, indandione, and 3-methyl-1-phenylpyrazol-5-one in DMSO solution in the presence of acid to form mono-substituted products IIa – c. Heating I with resorcinol in EtOH in the presence of acid gave resorcinol derivative IId. 6.7-Difluoroquinoxaline in the presence of base reacted with 3-methyl-1-phenylmethylpyrazol-5-one to form dipyrazolylmethane III and tetrapyrazolylethane derivative IV. Heating products IIa – c with N-methylpiperazine produced 7-methylpiperazine derivatives Va – c of 2-substituted quinoxalines.
Keywords: 6.7-difluoroquinoxaline; reactions with nucleophiles

Optimizing Quality Control of Docetaxel Drug Substance and its Parenteral Dosage Forms by M. S. Goizman; D. A. Arantseva; I. I. Demidova; M. B. Zagudailova; E. K. Kulaeva; M. G. Chernobrovkin; E. V. Degterev (503-508).
An HPLC method for quantitative determination of docetaxel and impurities in docetaxel drug substance and related dosage forms was developed for their quality control. Validation of the proposed method during the course of drug analysis stipulated separate statistical analysis of two groups of intermediate values with checking for the homogeneity of each group. Values in the first group were calculated as the ratio of areas under peaks of docetaxel in the chromatograms of test solutions to the chromatographed amounts of analyte. Values in the second group were calculated as the ratio of chromatographed amounts of docetaxel standard to the areas under peaks of docetaxel on the corresponding chromatograms. The docetaxel content was calculated as the product of the averaged intermediate values of the first and second groups. This increased the reliability of the results and decreased the amount of labor and consumption of standards. The confidence interval of docetaxel quantitative determination by the proposed method with reliability degree α = 0.05 was less than 1.5% for three analyses each of two test and two standard solutions. The average peak area of each impurity was determined on chromatograms of test solutions. The ratios of these values to the average docetaxel peak area in chromatograms of reference solutions prepared by diluting test solutions (1:1000) were found and were proportional to the contents of the corresponding impurities in the analyte to that of docetaxel (proportionality coefficient 0.1%). The confidence interval of the determination of an individual impurity for α = 0.05 was less than 6.5%.
Keywords: docetaxel; authenticity; quantitative determination; taxane; HPLC; drug substance; dosage form; validation