Pharmaceutical Chemistry Journal (v.46, #2)

Interspecies correlations between the acute intravenous toxicity in mice and toxicities in several species of fish (guppy, fathead minnow, rainbow trout), infusorium Tetrahymena pyriformis, and the freshwater flea Daphnia magna have been studied. These correlations and relationships between the toxicity of chemical substances and their hydrophobicity and physicochemical descriptors lead to a conclusion that the toxicity of inert chemical substances to living organisms can be estimated using approaches based on the (i) toxicity to other living organisms, (ii) the hydrophobicity, and (iii) physicochemical descriptors of steric factors and the ability to form hydrogen bonds. The last approach is most promising because it does not involve laborious procedures and large expenditures for the synthesis and experimental evaluation of the lipophilicity and toxicity of compounds.
Keywords: toxicity; QSAR; physicochemical descriptors; interspecies correlation

A comparative analysis of blood plasma coagulation with the participation of terbium ions (Tb3+) and complexes of high-molecular-weight heparin with endogenous ligands (adenosine triphosphate, arginine, glycine, and proline) has been performed using published data on the computer simulations of chemical equilibria, results of biochemical experiments in vitro with blood plasma of laboratory rats, and the modern enzymatic theory of blood clotting. The participation of Tb3+ was investigated by computer simulation of chemical equilibria based on pH-metric data for the calcium chloride—terbium nitrate—unfractionated heparin system in physiological solution and by biochemical experiments in vivo with intraperitoneal injections of terbium heparinate and terbium chloride into laboratory rats. It is established that terbium heparinate at a concentration equivalent to 50 IU heparin and terbium chloride in the concentration range 1.5 × 10 – 5 – 1.5 × 10 – 2 act as coagulants. The hypothetical mechanism of competitive complexation of Tb3+ and Ca2+ with blood clotting factors is not confirmed by the results of biochemical experiments that are consistent with the modern enzymatic theory of blood clotting and the blood plasma component composition. Heparin complexes with blood plasma ligands were constructed by computer simulation of chemical equilibria based on pH-metric data for heparin-L and MCl2—heparin L (M = Ca2+ and Mg2+; L = ATP, Arg, Gly, Pro) systems in physiological solution and by biochemical experiments in vitro and in vivo with blood plasma of laboratory rats. Complexes of heparin with ATP, Arg, Gly, and Pro are non-toxic, contain organic cations of ligands bound to heparin sulfonates, and do not disrupt the enzymatic blood coagulation process. These complexes regulate the blood coagulation process by decreasing the equilibrium concentration of Ca2+ (through the formation of stable complexes) and produce a two- to three-fold increase in heparin activity.
Keywords: chemical equilibria; mathematical simulation; blood plasma; biochemistry of blood clotting; biochemical experiment; anticoagulant

Influence of hydrophobic properties of IKhFAN antioxidants on their membranotropic activity by E. Yu. Parshina; L. Ya. Gendel’; A. B. Rubin (82-85).
The echinocytogenic and stomatocytogenic action on erythrocytes, the structure-modifying effect on erythrocyte membranes, and the hemolytic activity of IKhFAN antioxidants were established as functions of their hydrophobicity. The functions are nonlinear. The echinocytogenic, stomatocytogenic, and hemolytic activities first increase, pass through a maximum, and then decrease as the hydrophobicity parameter increases whereas the microviscosity of erythrocyte membranes varies in the opposite manner. These results may be useful in developing approaches to the synthesis of hybrid biologically active compounds including drugs with controlled and targeted delivery to the corresponding cell membrane structures.
Keywords: IKhFAN antioxidants; echinocytogenic; stomatocytogenic; and hemolytic activity; hydrophobicity

Effect of cellulose sulfate on the induction of hydrolysis of plasmin-specific chromogenic substrate and anticoagulant activity in rabbit blood plasma by E. Yu. Savchik; T. B. Kalinina; I. D. Gurvits; M. A. Torlopov; N. N. Drozd; V. A. Makarov; A. V. Kuchin (86-91).
Rabbit plasma coagulation time in the APTT and ReaClot-heparin tests, antithrombin and anti-factor Xa activities of plasma, and the effective half-life and duration of action increase with dose (0.3 to 10 mg/kg, i.v.) of injected cellulose sulfate (molecular weight 10 – 30 kDa, degree of sulfonation 1.8, antithrombin activity 130 ± 12 IU/mg, anti-factor Xa activity 45 ± 3.3 IU/mg). Cellulose sulfate independently neither influences human platelet aggregation nor potentiates adenosinediphosphate-induced human platelet aggregation and fibrinolytic activity of plasma euglobulin fraction in vivo but it favors an increase in the fibrinolytic activity of plasma upon intravenous injection in rabbits.
Keywords: cellulose sulfate; plasma antithrombin (aIIa) activity; anti-factor Xa (aXa) plasma activity; fibrinolytic activity

Synthesis and AMPA-receptor modulating activity of benzodioxanecarboxylic and piperonylic acid derivatives by M. I. Lavrov; V. L. Lapteva; V. V. Grigor’ev; V. A. Palyulin; S. O. Bachurin; N. S. Zefirov (92-95).
A series of amides of benzodioxane-6-carboxylic and piperonylic acids have been synthesized. Biological studies showed that some of the synthesized compounds influence the central nervous system (in particular, AMPA receptors).
Keywords: AMPA receptors; neurodegenerative disorders; molecular modeling; benzodioxane-6-carboxylic acid; piperonylic acid

Synthesis and pharmacological activity of analogs of the endogenous neuropeptide cycloprolylglycine by K. N. Kolyasnikova; M. V. Vichuzhanin; M. A. Konstantinopol’skii; S. S. Trofimov; T. A. Gudasheva (96-102).
A series of analogs and homologs of the endogenous cyclic dipeptide cycloprolylglycine were synthesized. The nootropic properties of the synthesized compounds were investigated on an experimental model of a passive avoidance test with electroshock- or scopolamine-induced amnesia. The anxiolytic activity was examined by an elevated plus-maze test. It is established that the pharmacophores responsible for the nootropic and anxiolytic activities are different. Hypotheses concerning the structure of the binding regions with the corresponding pharmacological targets are formulated.
Keywords: cyclic dipeptides; cycloprolylglycine; nootropic activity; anxiolytic activity

Synthesis and radioligand activity of hydrogenated azepino[4,3-b]indoles by O. D. Mit’kin; A. V. Ivachtchenko; E. B. Frolov; S. E. Tkachenko; V. I. Kazey; I. M. Okun’ (103-113).
Indole-containing compounds are found to interact with many therapeutically relevant targets that belong to different types of cell membrane receptors. They represent a very promising class of potential drugs. The synthesis of novel 1,2,3,4,5,5a,6,10b-octahydroazepino[4,3-b]indoles and their interaction profiles measured on a series of 66 therapeutic targets including receptors, enzymes, and neuromediator transporters are described. The target recognition patterns of the compounds are compared with those of their bioisosteric analogs, diazoline (I) and Dimebon™ (II), which are 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, in addition with those of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indoles VIII and X. We show that different therapeutic targets exhibit different levels of sensitivity toward cis- and trans-configurations of the new structures. The new compounds exhibit affinity predominantly toward histamine H1 and serotonin 5-HT2C receptors.
Keywords: azepinoindoles; Dimebon; dizaoline; histamine receptors; serotonin receptors

Synthesis and antimicrobial activity of N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides by V. L. Gein; I. V. Kholkin; T. M. Zamaraeva; E. V. Voronina; M. I. Vakhrin (114-116).
A series of N,6-diaryl-2-thioxo-4-methyl-1,2,3,6-tetrahydropyrimidine-5-carboxamides were synthesized by a three-component reaction of acetoacetanilide (2-methylacetoacetanilide; 2,4-dimethylacetoacetanilide; 4-chloroacetoacetanilide) with a mixture of aromatic aldehyde and thiourea. All structures are confirmed by IR, PMR, and 13C NMR spectroscopy and mass spectrometry. All synthesized substances are characterized with respect to antimicrobial activity.
Keywords: synthesis; 2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide derivatives; antimicrobial activity

Thiopyrimidine derivatives: synthesis and antibacterial activity by S. Baluja; N. Kacchadia; S. Chanda (117-121).
Eleven thiopyrimidine derivatives have been synthesized and their antibacterial activity has been studied against four Gram positive (Bacillus cereus ATCC11778, Staphylococcus aureus ATCC29737, Staphylococcus epidermidids NCIM2493, and Micrococcus luteus ATCC10240) and three Gram negative (Proteus mirabilis NCIM2241, Escherichia coli ATCC25922, and Klebsiella aerogenes NICM2098) bacteria. The antibacterial activity was evaluated using the agar well diffusion method. The thiopyrimidine derivatives showed various activity against different bacterial strains, depending on their structural formula. Gram positive bacteria were more susceptible than Gram negative bacteria; E. coli was the most resistant, and B. cereus was the most susceptible bacteria. A thiopyrimidine derivative with methoxy group at the para position showed the best antibacterial activity, while the substitution of chloro, bromo, and methyl groups decreased the activity.
Keywords: Thiopyrimidine derivatives; antibacterial activity; Gram positive bacteria; Gram negative bacteria; E. coli ; B. cereus

Stability of nanodispersions based on perfluorohydrocarbons and phospholipids by I. N. Kuznetsova; V. S. Yurchenko; G. A. Kochetkova (122-126).
Series of nanodispersions—emulsions with identical compositions based on perfluorohydrocarbons (PFH) and phospholipids (PL) were prepared. Extensive experimental results for the size (~100 nm) and structure of the particles, the viscosity, the pH and pF values, and the osmolarity level showed that the PFH/PL emulsions corresponded to the physicochemical parameters established for medical and biological PFH emulsions. The final drug form of the emulsion (in a vial) withstood thermal sterilization. The PFH/PL emulsions retained their particle size and structure during controlled storage at +4°C to +10°C for 12 months, i.e., the obtained nanodispersion was stable on storage in an unfrozen state for one year.
Keywords: nanodispersions; emulsions; perfluorohydrocarbons; phospholipids; particle size and structure; stability

A new high performance liquid chromatography (HPLC) method for the simultaneous determination of pentoxifylline and its main related substances – theophylline, theobromine and caffeine – in pharmaceuticals has been developed. Chromatographic separation was achieved within 5 min on a monolithic column eluted with a mobile phase consisting of methanol – water (35/65 v/v) mixture in an isocratic mode at a flow rate of 1 mL/min. The detection wavelength was set at 272 nm. The proposed method was validated over a concentration range of 0.5 – 14 μg/mL for pentoxifylline and 0.1 – 3.0 μg/mL for the related impurities. Calibration plots were linear for pentoxifylline and all other compounds with a correlation coefficient greater than 0.99. Relative variation coefficients for reproducibility and repeatability were below 2.0%. Recoveries from standard addition assay of an individual component in pharmaceutical formulations varied from 95.0% to 102.9%. The proposed method was successfully applied for the determination of pentoxifylline, theophylline, theobromine, and caffeine in pharmaceutical formulations (tablets and injections). Recoveries with respect to label amount in pharmaceutical formulations varied from 94.0% to 105.9%.
Keywords: Monolithic column; isocratic elution; pentoxifylline; theophylline; theobromine; caffeine