Pharmaceutical Chemistry Journal (v.48, #10)

Various ways of forming interspecies relationships between pharmacokinetic parameters were considered using drug substances as examples. The improvement of the statistical characteristics of the interspecies relationships including correction factors was estimated. The analysis was performed using examples of interspecies relationships for drug clearance, for which a large variety of correction factors was employed.
Keywords: interspecies pharmacokinetics; allometric scaling; interspecies relationships between pharmacokinetic parameters; clearance; distribution volume

Synthesis and Biological Activity of 2,3-Bis-(2-Oxoylidene)-1,2,3,4-Tetrahydroquinoxalines by S. S. Zykova; T. F. Odegova; O. G. Karmanova; R. R. Makhmudov (640-645).
Condensation of alkylmethylketones with diethyl oxalate and 1,2-diaminobenzene yielded 2,3-bis-(2-oxoylidene)-1,2,3,4-tetrahydroquinoxalines (IIIV). Four isomeric species were identified using spectral methods. Structural features of the synthesized compounds were discussed. The biological activity of the obtained compounds was investigated. It was observed that the synthesized compounds had low toxicity. It was found that (1Z,1′Z)-1,1′-(1,4-dihydroquinoxaline-2,3-diylidene)dibutan-2-one (II) exhibited antinociceptive activity that was greater than that of metamizole sodium. The antioxidant activity in an Escherichia coli BW 25113 oxidation resistance model in the presence of H2O2 solution (3 mM) was also most pronounced for II whereas V had pro-oxidant activity. The compounds showed high antiradical activity for diphenylpicrylhydrazyl (DPPH) binding that was comparable with that of trolox.
Keywords: 1,2,3,4-tetracarbonyl compounds; 2,3-bis-(2-oxoylidene)-1,2,3,4-tetrahydroquinoxalines; Escherichia coli BW 25113; antinociceptive activity; antioxidant activity; antiradical activity; acute toxicity

Antagonists of Serotonin 5-HT6 Receptors. VI. Substituted 3-(Phenylsulfonyl)Quinolines, Synthesis and Structure–Activity Relationships by A. V. Ivachtchenko; E. S. Golovina; M. G. Kadieva; O. D. Mitkin; I. M. Okun (646-660).
In continuation of research and development of new high-efficacy drugs based on 5-HT6 receptor antagonists for the treatment of CNS disorders, we synthesized a series of new 3-(phenylsulfonyl)quinoline derivatives, performed their molecular docking, and studied the receptor activity spectrum. It was found that the antagonist activity of the 3-(phenylsulfonyl)quinolines with respect to 5-HT6 receptors depended on the nature of the 4- and 8-substituents of the heterocycle. It was expedient for high activity of this type to introduce a tertiary nitrogen atom (dimethylamine or piperazine fragment) in the 8-position and a secondary nitrogen (methylamine fragment) or hydrogen in the 4-position. The most promising compounds were N,N-dimethyl-3-(phenylsulfonyl) quinoline-8-amine (IV, K i f  = 0.4 nM), 4-methylamino-8-dimethylamino-3-(phenylsulfonyl)quinoline (XXII, K i f  = 0.3 nM), and N-methyl-8-(piperazin-1-yl)-3-(phenylsulfonyl)quinoline-4-amine (XXIII, K i f  = 0.9 nM). Antagonist IV exhibited the maximum selectivity; XXIII, the maximum multimodality.
Keywords: 3-(phenylsulfonyl)quinoline; 5-HT6 receptors; antagonists; pharmacophore model; molecular docking; structure—activity relationship

Synthesis, Antimicrobial, and Protisticidal Activity of 3-Aryloxyethyl(Benzyl)-1-Carbamoylmethyl-2-Iminobenzimidazoline Hydrochlorides by L. N. Divaeva; A. S. Morkovnik; A. A. Zubenko; T. A. Kuz’menko; L. N. Fetisov; A. N. Bodryakov; M. A. Bodryakova (661-664).
Alkylation of 2-aminobenzimidazole by methyliodide and benzyl- or 2-aryloxyethylbromides produced 1-substituted 2-aminobenzimidazoles that were quaternized by chloroacetamide to previously undescribed 3-aryloxyethyl(benzyl)-1-carbamoylmethyl-2-iminobenzimidazoline hydrochlorides. These compounds were shown to possess antibacterial activity against several pathogenic Gram-positive and Gram-negative microbes (Staphylococcus aureus, Escherichia coli) combined with pronounced protistocidal activity against the protozoa Colpoda steinii that was on the level of the clinical reference drugs.
Keywords: 1-substituted 2-aminobenzimidazoles; 3-aryloxyethyl(benzyl)-1-carbamoylmethyl-2-iminobenzimidazoline hydrochlorides; antibacterial activity; Staphylococcus aureus ; Escherichia coli ; protistocidal activity; Colpoda steinii

A series of 2-(3-methyl-6-methoxy-7-ethoxy-3,4-dihydroisoquinolyl-1)ethanoic acid amides were synthesized via cyclocondensation of O-ethylated eugenol with cyanoacetic acid amides. Hydrochlorides of the synthesized compounds were shown to exhibit anthelmintic activity. The unsubstituted amide was the most active and exhibited activity equal to that of levamisole and significantly greater than that of pyrantel. The insecticidal activity of the synthesized compounds was inferior to that of imidacloprid.
Keywords: 2-(3-methyl-6-methoxy-7-ethoxy-3,4-dihydroisoquinolyl-1)ethanoic acid amides; anthelmintic and insecticidal activity

Hypoglycemic Activity of Substituted Haloanthranilic Acid Amides by E. R. Kurbatov; T. A. Chupina; L. M. Korkodinova; V. P. Kotegov; N. A. Vlasova; O. L. Vizgunova (669-670).
A series of NH-aroyl-5-bromo(iodo)anthranilic acid amides were synthesized by amidation of 2-substituted 6-bromo(iodo)-3,1-benzoxazin-4-ones with various amines in EtOH (95%). The structures of the compounds were confirmed by PMR spectral data. The synthesized compounds were tested for hypoglycemic activity as estimated by the glucose oxidase method. It was found that NH-aroyl-5-bromo(iodo)anthranilic acid amides exhibited a sugar-reducing effect. Several of the synthesized compounds exhibited hypoglycemic activity comparable to that of carbutamide.
Keywords: NH-acylanthranilic acids; hypoglycemic activity; 6-bromo(iodo)-3,1-benzoxazin-4-ones

Accumulation of Ascorbic Acid in Fresh Echinacea Purpurea Plants and Their Processing Products by V. B. Zagumennikov; A. V. Molchanova; E. Yu. Babaeva; A. L. Petrova (671-674).
The accumulation of vitamin C (ascorbic acid) in fresh Echinacea purpurea plants grown in a non-chernozem zone of Russia in 2009 – 2010 in addition to its component parts, juice, and pulp was analyzed as a function of age (2 – 7 years) and year of collection. Leaves accumulated the most ascorbic acid; stems, the least. The vitamin C concentration in juice from fresh plants collected in 2009 was much greater than that in the herb. The vitamin C content in juice from 3-, 4-, and 5-year-old plants collected in 2010 was the same as in the herb. Fresh pulp was characterized by a lower vitamin C content than the fresh plant and juice according to results from a two-year experiment.
Keywords: vitamin C; ascorbic acid; Echinacea purpurea ; herb; juice; pulp

Aquatic extracts of Heracleum (family: Apiaceae (Umbelliferae)) collected from Norway and Netherlands were tested against three bacterial strains isolated from humans, three fish pathogens, four non-pathogens, and three lactic acid bacteria (LAB) isolated from fish intestine in an in vitro growth inhibition assay. Highest in vitro growth inhibition of the test bacteria was noticed in the sterile supernatant of 5 g H. persicum and 5 g H. mantegazzianum)collected from Netherlands) boiled in 500 ml water for 2 h. Generally, highest growth inhibition was observed on Gram-positive test bacteria but lesser effect was noticed on LAB isolated from fish intestine. The aqueous extracts of H. persicum showed highest activities over Bacillus megaterium, Micrococcus sp., Pseudomonas sp. and Staphylococcus aureus.
Keywords: Aquatic extract; Heracleum ; antibacterial effect; in vitro growth inhibition

Azeolite ZSM-5 catalyzed simple, one-pot solvent-free, cost-effective and environmental benign protocol for the synthesis of dihydropyrimidines (DHPMs) have been developed. Aseries of substituted 1,4-DHPM derivatives have been synthesized by one-pot Biginelli type cyclocondensation of ethylacetoacetate, aromatic/heteroaromatic aldehydes, and urea/thiourea with a catalytic amount of zeolite under solvent-free protocol in a sufficiently high yield. The catalyst is recyclable and can be used repeatedly.
Keywords: zeolite ZSM-5; dihydropyrimidines (DHPMs); Biginelli reaction; solvent-free reaction; recyclable catalyst

General Principles for Composing Dosage Form Names by E. L. Kovaleva; L. I. Mit’kina; L. A. Kolganov; A. N. Novichenko (683-686).
Recommendations were given that will help to compose dosage form names of particular medical products by combining the basic and additional elements so as to specify more correctly the dosage form characteristics.
Keywords: drugs; dosage form; name

Development of an HPLC Method for Determining Baclofen by O. A. Dukova; E. A. Krasnov; A. A. Efremov (687-689).
A method for quantitative and qualitative determination of baclofen was developed based on high-performance liquid chromatography (HPLC) with UV detection. Conditions for maximum sensitivity of baclofen detection by HPLC were selected. The optimum regime of baclofen determination by HPLC on a nonpolar column employed triethylamine solution (10 mM) as the aqueous component of the mobile phase.
Keywords: baclofen; HPLC; mobile phase modifiers

Determination of Buprenorphine and Naloxone in Patient Blood Plasma Using HPLC-MS by I. K. Zhurkovich; A. O. Rudenko; V. V. Chelovechkova; I. A. Merkusheva; N. V. Lugovkina; N. G. Kovrov; M. V. Pchelintsev; E. V. Verbitskaya; É. É. Zvartau (690-695).
A method for determining buprenorphine and naloxone in human plasma using liquid chromatography and high-resolution time-of-flight mass spectrometry (LC-MS Q-TOF) was developed. The sample preparation technique included liquid extraction with salting out of the analytes in Toxi-Tubes Aintended for the determination of neutral and basic compounds. Quantitative analysis was carried out by the internal standard method. Naltrexone, which was structurally similar to the analytes, was used as the internal standard. The proposed method was developed for clinical trials of the new drug bupraxone, a sublingual dosage form containing buprenorphine and naloxone at doses of 0.2 mg each. The bioavailability of the drug components upon sublingual administration was studied. The buprenorphine concentrations in human plasma after administration at a dose of 0.4 mg via two routes (intravenous and sublingual) were compared.
Keywords: buprenorphine; naloxone; blood plasma; HPLC; mass spectrometry

Erratum to: Computerized Prediction, Synthesis, and Antimicrobial Activity of New Amino-Acid Derivatives of 2-Chloro-N-(9,10-Dioxo-9,10-Dihydroanthracen-1-yl)Acetamide by V. I. Zvarych; M. V. Stasevych; O. V. Stan’ko; E. Z. Komarovskaya-Porokhnyavets; V. V. Poroikov; A. V. Rudik; A. A. Lagunin; M. V. Vovk; V. P. Novikov (697-697).