Pharmaceutical Chemistry Journal (v.44, #7)

Metabolism and pharmacokinetics of nibentan in human blood plasma by S. A. Appolonova; V. G. Valiev; M. A. Dikunets; A. V. Kukharenko; G. M. Rodchenkov; E. M. Zeltyn’; A. B. Bezprozvannyi; V. A. Gorshkov; A. E. Radzevich (341-344).
An HPLC method with electrospray ionization and ion-trap mass spectral detection (LC-ESI/MSD Ion Trap SL) for determining nibentan metabolites in human blood plasma is described. The proposed method provides simultaneous determination of nibentan and its metabolites in blood plasma. Three metabolites, hydroxylated, de-ethylated, and de-ethylated-hydroxylated, were found in human blood plasma after a single i.v. administration of nibentan (0.125 mg/kg, 1%). De-ethylated nibentan was the longest lived metabolite. The last two metabolites were found in human blood plasma for the first time. The results were verified and all metabolites were identified using LC—MS and LC—MS/MS. The major pharmacokinetic parameters were calculated.
Keywords: nibentan; metabolism; pharmacokinetics; HPLC—MS

Synthesis and pharmacological activity of 9-R-2-halogenophenylimidazo[1,2-a]benzimidazoles by V. A. Anisimova; A. A. Spasov; I. E. Tolpygin; V. I. Minkin; M. V. Chernikov; D. S. Yakovlev; A. Yu. Stukovina; I. I. Goryagin; O. Yu. Grechko; N. V. Kirillova; V. A. Kosolapov; E. V. Tibir’kova; O. A. Salaznikova; L. V. Naumenko; N. A. Gurova (345-351).
Taking into account the structure—activity relationship established previously for imidazobenzimidazole derivatives with high hemorheological activity, several new 9-R-2-halogenophenyl-substituted imidazo[1,2-a]benzimidazoles with C2 fluoro-, chloro-, dichloro-, or bromo-phenyl radicals have been synthesized. All substances were tested in vitro for various types of pharmacological activity characteristic of this class of drugs including hemorheological, antiplatelet, antiarrhythmic, antioxidant; 5-HT2-, 5-HT3-, P2Y1-, and H1-antagonist; and κ-opioid-agonist.
Keywords: imidazo[1; 2-a]benzimidazole; hemorheological activity; antiplatelet activity; antioxidant activity; antiarrhythmic activity; 5-HT2-antagonist activity; 5-HT3-antagonist activity; P2Y1-antagonist activity; H1-antagonist activity; κ-opioid-agonist activity

Synthesis and antineoplastic and antimonoamineoxidase properties of new benzo[H]quinazoline derivatives by A. I. Markosyan; S. V. Dilanyan; S. A. Gabrielyan; F. G. Arsenyan; R. S. Sukasyan; B. T. Garibdzhanyan (352-355).
N'-{[(2-cyano-3-ethyl-3-methyl-3, 4-dihydronaphthalen-1-yl)amino]carbonothionyl}benzamide (II) was synthesized by reaction of 1-amino-3-ethyl-3-methyl-3,4-dihydronaphthalene-2-carbonitrile (aminonitrile I) with benzoylisothiocyanate. Condensation of aminonitrile I with phenylchloroformate yielded carbamate III, which was converted into mono-and disubstituted ureas IV and V via reaction with ammonia and aniline, respectively. A series of 2-substituted condensed triazolobenzoquinazolines (VIXVI) was synthesized by condensation of carbamate III with hydrazides of aromatic and heteroaromatic carboxylic acids. The antineoplastic and antimonoamineoxidase properties of the synthesized compounds have been studied.
Keywords: aminonitrile; cyclization; triazolobenzoquinazoline; antineoplastic activity; antimonoamineoxidase activity

Synthesis and antituberculosis activity of O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes by L. A. Kayukova; M. A. Orazbaeva; V. L. Bismilda; L. T. Chingisova (356-359).
The search for new tuberculostatics is an important task for medicinal chemistry. A series of new O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes were synthesized and tested in vitro for antituberculosis activity. The synthesis of the target substances consists of 3 – 4 steps. In the first step, β-(4-phenylpiperazin1-yl)propionitrile was obtained in 79% yield; the second step yields β-(4-phenylpiperazin-1-yl)propioamidoxime in 75% yield. Subsequent aroylation of this amidoxime by substituted benzoic acid chlorides in the presence of Et3N leads to the target O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes in 61 – 93% yields. Hydrochlorides of the O-aroylated products were obtained in 72 – 94% yields by the action of ethereal HCl on solutions of the bases. PMR spectra of hydrochlorides of the O-aroylated products show evidence of slow inversion of the heterocycle at the β-position and coordination of HCl at the N1 atom of the 4-phenylpiperazine fragment. Some bases and hydrochlorides of O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes exhibited interesting antituberculosis properties when tested in vitro on sensitive, resistant, and multi-drug resistant strains of M. tuberculosis.
Keywords: O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes; synthesis; antituberculosis activity

Indices of reactivity with respect to active oxygen species that resulted from quantum-chemical calculations (PM3 and AM1) have been studied in a series of hydroxyl-and methoxy-derivatives of cinnamic acid. The high antioxidant activity of 4-hydroxy-3,5-di-tert-butylcinnamic acid has been predicted and then experimentally confirmed, which can be of interest for the creation of new drugs.
Keywords: cinnamic acid derivatives; sterically hindered phenols; chemical structure—activity relationship

Synthesis and antimicrobial activity of n,7-diaryl-5-methyl-4,7-dihydrotetrazolo[1,5-a] pyrimidine-6-arboxamides by V. L. Gein; T. M. Zamaraeva; A. A. Kurbatova; E. V. Voronina; M. I. Vakhrin (366-369).
N,7-Diaryl-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamides were synthesized by three-component reaction of acetoacetanilides (2-methylacetoacetanilide, 2,4-dimethylacetoacetanilide, 4-chloroacetoacetanilide, o-acetoacetanilide) with a mixture of aromatic aldehyde and 5-aminotetrazole. The proposed structures are confirmed by IR and PMR spectroscopy and mass spectrometry. The synthesized compounds are characterized with respect to antimicrobial activity.
Keywords: N,7-Diaryl-5-methyl-4,7-dihydrotetrazolo[1,5-a] pyrimidine-6-carboxamides; synthesis; antimicrobial activity

Synthesis and antibacterial and analgesic activity of 5-aryl-4-acyl-3-hydroxy-1(2,2-dimethoxyethyl)-3-pyrrolin-2-ones by V. L. Gein; V. N. Vychegzhanina; E. B. Levandovskaya; B. Ya. Syropyatov; M. I. Vakhrin; E. V. Voronina; N. V. Danilova (370-373).
5-Aryl-4-acyl-3-hydroxy-1-(2,2-dimethoxyethyl)-3-pyrrolin-2-ones were synthesized by the reaction of acylpyruvic acid methyl esters with a mixture of an aromatic aldehyde and aminoacetaldehyde dimethylacetal. The proposed structures are confirmed by IR and PMR spectroscopy. The results of an investigation of the antibacterial and analgesic activity of the synthesized compounds are presented.
Keywords: 5-Aryl-4-acyl-3-hydroxy-1-(2,2-dimethoxyethyl)-3-pyrrolin-2-ones; synthesis; antibacterial activity; analgesic activity

Novel bioactive 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones 12–22 were synthesized with good yields in a short reaction time by the “one-pot” multicomponent reaction of the appropriate 2-amino-4,6diarylpyrimidines, benzaldehyde and thioglycolic acid under microwave irradiation in the presence of an activated fly ash catalyst in dry medium. The characterization of these compounds was confirmed by melting point, elemental analysis, mass spectrometry, FT-IR spectroscopy, and one-dimensional NMR (1H and 13C) spectroscopic data. In search for new leads toward potent antimicrobial agents, all the synthesized compounds have been tested in vitro for their antibacterial activity against Bacillus subtilis and Micrococcus luteus and antifungal activity against Aspergillus niger, Candida albicans, Candida 6 and Candida 51, and the results are discussed.
Keywords: One-pot synthesis; 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones; activated fly ash; antibacterial activity; antifungal activity

Methods of synthesis of halogenonitroimidazoles (review) by E. V. Aleksandrova; P. M. Kochergin (381-386).
Published data on methods of synthesis of halogenated nitroimidazoles are summarized and systematized.
Keywords: halogenonitroimidazoles; synthesis; practical application

Using rheology for optimization of adsorptive vaginal gel technology by T. V. Romanko; G. V. Ayupova; A. A. Fedotova; Yu. I. Murinov; V. G. Romanko (387-390).
The quality assurance system of soft medicinal preparations (SMPs) is based on standardization of the rheological parameters of compositions used in clinical practice. These rheological parameters influence the quality of pharmacological action. Biopharmaceutical studies demonstrate that the rheological properties of SMPs are closely correlated with the intensity of the drug release and absorption. The structural and mechanical properties of an adsorptive vaginal gel based on styrene copolymer with maleic anhydride have been studied. The active substance was the adsorbent “Enterosgel.” Rheological data were used to determine the optimum combination of active substance and structural component concentrations in preparing the adsorptive gel composition.
Keywords: soft medicinal preparations; adsorptive vaginal gel; composition optimization; rheological optimum of extrusion

New interpolyelectrolyte complexes (IPECs) between oppositely charged types of Eudragit® EPO and Eudragit® L100 – 55 were investigated with a view to their application in oral controlled drug delivery systems. Monitoring of microenvironmental changes of polycomplex matrices in simulated gastro-intestinal fluids showed that all IPECs could have different pH-sensitivity characteristics. Evaluation of the diffusion transport properties of the investigated IPECs with diclofenac sodium confirmed that their swellability and release characteristics were closely correlated. The main possible mechanisms of control over the delivery of drugs to the desired regions of the gastro-intestinal tract are found. The results confirm that the proposed IPEC matrices have great potential to be used for controlled drug delivery.
Keywords: interpolyelectrolyte complexes; diffusion transport properties; Eudragit® EPO and L100-55

Developing analytical methods for afobazole in injection forms by L. N. Grushevskaya; N. I. Avdyunina; S. E. Milkina; O. B. Stepanenko; B. M. Pyatin; K. V. Alekseev; S. A. Sizyakov (396-400).
This investigation was aimed at elaborating procedures for the pharmaceutical analysis of the parenteral dosage form of afobazole, a novel domestic drug with anxiolytic and neuroprotective action. The physicochemical properties of afobazole parenteral dosage form have been studied. Methods for the determination of impurities (TLC, HPLC) and identification and assay of the drug (UV spectrophotometry, HPLC) have been developed.
Keywords: afobazole; parenteral dosage form; pharmaceutical analysis; thin-layer chromatography; high performance liquid chromatography

The melting point of lipophilic base mixtures for suppositories comprising confectionary fats with various surfactants including emulsifying cetostearyl alcohol type B (1 – 10%), emulsifier T-2 (1 – 5%), sodium lauryl sulfate (0.2 – 5%), and phospholipid concentrate (0.1 – 1%) has been investigated. It is established that these surfactants added in the indicated concentrations lead to depression of the melting point of confectionary fat. Introduction of suspended nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac sodium, analgin, paracetamol, naproxen, acetylsalicylic acid, and sodium salicylate to the aforementioned mixtures changed their melting points within 0.5 – 3°C depending on the nature of the drug and excipient. The melting points of all investigated suppositories fell within 31.0 – 36.3°C, thus obeying pharmacopoeial requirements. The softening time of all anti-inflammatory suppositories varied within 2 – 11 min depending on the particular types of components and was within the pharmacopoeial limits. A comparative analysis of the variation of melting point and softening time of the NSAID suppositories showed no clear correlation between the two parameters in the indicated limits. The reported data can be used for selecting the optimum bases for suppositories and developing a common approach to the evaluation of the quality and performance characteristics of suppositories.
Keywords: suppositories with nonsteroidal anti-inflammatory drugs (NSAIDs); melting point; softening time