Pharmaceutical Chemistry Journal (v.46, #8)

Synthesis and biological activity of O-carbamoylated 1,1,1,3,3,3-hexafluoroisopropanols as new specific inhibitors of carboxylesterase by G. R. Mukhamadieva; N. P. Boltneva; T. G. Galenko; V. B. Sokolov; T. A. Epishina; G. F. Makhaeva (461-464).
A series of O-carbamoylated 1,1,1,3,3,3-hexafluoroisopropanols of general formula RNHC(O)OCH(CF3)2, where R = CH3, n-C3H7, tert-C4H9, cyclo-C6H11, C6H5–CH2, C6H5, 4-Cl-C6H4, 3-Cl-C6H4, 3,4-Cl2-C6H3, and naphthylen-2-yl were synthesized. The reaction kinetics of the synthesized carbamates with human erythrocyte acetylcholinesterase (EC, horse serum butyrylcholinesterase (EC, and porcine liver carboxylesterase (EC were studied. It was shown that the synthesized carbamates did not inhibit acetylcholinesterase, inhibited weakly butyrylcholinesterase, and inhibited selectively the activity of carboxylesterase. A new selective irreversible inhibitor of carboxylesterase, 2,2,2-trifluoro-1-trifluoromethylethyl cyclohexylcarbamate, which had low acute toxicity, was obtained.
Keywords: O-carbamoylated 1,1,1,3,3,3-hexafluoroisopropanols; carbamates; isocyanates; 1,1,1,3,3,3-hexafluoroisopropanol; carboxylesterase; butyrylcholinesterase; acetylcholinesterase; inhibition

A new method for constructing QSAR models that was based on the joint application of linear discriminant and regression analysis was proposed. A molecular cluster, the size and structure of which was close to a group of molecules with an inert mode of action, was obtained using data on the acute toxicity of aqueous chemical compounds with respect to Guppy. The resulting regression equation describing the toxicity of the chemicals as a function of the n-octanol:water distribution coefficient corresponded to models known from the literature. The proposed approach was recommended as a tool for carrying out QSAR investigations.
Keywords: acute toxicity; Guppy; QSAR; HYBOT

Synthesis and antimicrobial activity of 3-aryl-4,5,6,7-tetrahydroindazoles by A. A. Pantyukhin; A. G. Mikhailovskii; G. A. Aleksandrova; R. R. Makhmudov; N. N. Pershina; M. I. Vakhrin (470-472).
Acylation of 1-piperidinocyclohexene by aroylchlorides yielded 2-aroylcyclohexanones. The obtained 1,3-diketones reacted with hydrazine hydrate to yield 3-aryl-4,5,6,7-tetrahydroindazoles, which formed stable hydrochlorides showing a high level of activity against Staphylococcus aureus and Candida albicans. The maximum activity against the bacterial strain was observed for the compound containing a 4-bromophenyl radical (the inhibition and bactericidal effects were produced at concentrations of 2 and 7.8 μg/mL, respectively). The maximum activity against the fungal strain was observed for the compound with a p-tolyl radical (the corresponding concentrations being 3.9 and 31.2 μg/mL).
Keywords: 1-piperidinocyclohexene; aroylchlorides; 2-aroylcyclohexanones; hydrazine hydrate; 3-aryl-4,5,6,7-tetrahydroindazoles; hydrochlorides; activity against Staphylococcus aureus and Candida albicans at concentrations 2 and 3.9 μg/mL, respectively

Synthesis of Betulin Derivatives: N’{N-[3-OXO-20(29)-Lupen-28-OYL]-9-Aminononanoyl}3-Amino-3-Phenylpropionic Acid by S. V. Sysolyatin; V. N. Surmachev; V. V. Malykhin; A. I. Kalashnikov; I. A. Surmacheva; E. G. Sonina; A. S. Dubkov; G. A. Tolstikov; E. E. Shul’ts; N. F. Salakhutdinov; U. M. Dzhemilev (473-477).
A method for synthesizing N’-{N-[3-oxo-20(29)-lupen-28-oyl]-9-aminononanoyl}-3-amino-3-phenylpropionic acid, a compound that exhibited immunostimulating and antiviral activities, by adding the methyl ester of N-(9-aminononanoyl)-3-amino-3-phenylpropionic acid to betulonic acid was described.
Keywords: betulonic acid derivatives; 3-amino-3-phenylpropionic acid; anti-HIV agent; N-benzylcarboxy9-aminononanoic acid; 9-phthalimidononanoic acid

Synthesis and molecular-weight characteristics of n-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymers by S. A. Kedik; A. V. Panov; I. V. Sakaeva; Yu. V. Kochkina(Cherta); D. V. Eremin; V. V. Suslov (478-481).
N-Vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymers with various ratios of monomer units and molecular weights were synthesized by radical copolymerization using an injection method. The ratio of monomer units was determined by non-aqueous potentiometric titration and 13C NMR methods. The viscosity-average molecular weights of copolymers containing 35 – 39 mol% of 2-methyl-5-vinylpyridine were in the range 15.2 – 27.6 kDa. Copolymers with 2-methyl-5-vinylpyridine content up to 75 ± 5 mol% exhibited good solubility in water.
Keywords: copolymer synthesis; N-vinylpyrrolidone; 2-methyl-5-vinylpyridine

A series of coumarin derivatives with attached heterocyclic pyrazoline rings have been synthesized from ethyl acetoacetate and salicylaldehyde. All the final products were characterized and screened for their in vitro activities as antioxidants and anti-inflammatory agents. The antioxidant activity was studied by DPPH free radical scavenging method and the IC50 values were calculated for comparison with a standard (ascorbic acid) at the same dose. Several compounds (C1, C4, C7, C8, C9 and C10) have shown promising results. RBC membrane stabilization model was used to evaluate the in vitro anti-inflammatory activity, and compounds C1, C3, C7 and C9 showed effective inhibition of hemolysis in comparison compared to acetylsalicylic acid as the standard. Upon studying the structure – activity relationship (SAR), it has been concluded that electron withdrawing substitutions at para position are most potent as antioxidants as well as anti-inflammatory agents.

The polyphenol complex (maksar) from the Far-Eastern tree Maackia amurensis and its phenolic constituents were tested for their ability to (1) scavenge 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH), (2) reduce Folin—Ciocalteau reagent (FCR), (3) reduce radical cations of 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS∙+), and (4) inhibit peroxide-induced oxidation of linoleic acid (LA). It was established that the main components of maksar that contribute to the antioxidant potential of the polyphenol complex were the stilbenes resveratrol, piceatannol, scirpusin A, scirpusin B, maackiazine, and maackoline; the isoflavonoids retusin, tectorigenin, and genistein, and the minor isoflavonoids calycosin and vestitol, the stilbene dihydroresveratrol, and the chalcones isoliquiritigenin and α,2′,4′,4-tetrahydroxydihydrochalcone.
Keywords: maksar; phenolic constituents; antioxidants; Maackia amurensis

Anxiolytic activity of biologically active compounds from Filipendula vulgaris by V. V. Udut; A. I. Vengerovskii; N. I. Suslov; I. V. Shilova; A. V. Kaigorodtsev; N. Yu. Polomeeva; A. M. Dygai (492-494).
The composition of biologically active compounds in Filipendula vulgaris aqueous extract and its EtOAc and BuOH fractions was studied. The total extract and its fractions contained phenols, coumarins, triterpenes, carbohydrates, and amino acids. The influence of the aqueous extract of F. vulgaris and its fractions on the behavior of mice in the elevated plus-maze and open-field tests was studied. It was established that the EtOAc fraction had the most pronounced anxiolytic effect.
Keywords: Filipendula vulgaris ; aqueous extract; biologically active compounds; anxiolytic action; anxiety models

Synthesis of L-ornithine L-aspartate from L-arginine by Z. I. Kuvaeva; D. V. Lopatik; M. M. Markovich; L. G. Vinokurova; O. P. Popova (495-497).
The synthesis of L-ornithine L-aspartate that involved basic hydrolysis of L-arginine by barium hydroxide, precipitation of barium cations as barium carbonate, addition of L-aspartic acid, and direct precipitation of L-ornithine L-aspartate was described. The obtained compound could be used as a hepatoprotective drug.
Keywords: α-amino acids; L-arginine; L-ornithine; L-citrulline; L-aspartic acid; L-ornithine L-aspartate; hydrolysis; barium hydroxide; barium carbonate; hepatoprotective drug

Development of the pharmaceutical composition micephosphone containing dimephosphone and its study by modeling osteoporosis by N. B. Melnikova; A. E. Bolshakova; M. V. Sidorova; I. P. Pyanzina; I. V. Guljaev; O. P. Tikhobrazova; T. I. Solov’eva; I. V. Mukhina (498-503).
The effectiveness of the developed combined drug as capsule and suspension dosage forms based on dimephosphone® (dimethyl 1,1-dimethyl-3-oxobutylphosphonate) and calcium carbonate was demonstrated for treatment and prophylaxis of bone diseases. According to IR spectra, dimephosphone® was chemisorbed to calcium ions on the surface of calcium carbonate to form surface calcium phosphonates. Dimephosphone® adsorption (A) as a function of its concentration (C) in aqueous solutions obeyed formally the Langmuir equation. The remodeling action for bone tissue by the suspension dosage form was verified using a glucocorticoid-induced osteoporosis model in rats.
Keywords: dimephosphone; calcium carbonate; bone diseases; glucocorticoid-induced osteoporosis model

Adrenocorticolytic activity of o,p′-DDD (chloditan) solution in in vitro and in vivo tests by Ya. G. Bal’on; A. V. Simurov; I. P. Paster; L. I. Vakulenko; L. M. Tochilkina; L. A. Kuzminskaya; N. I. Levchuk (504-506).
A new drug formulation of the adrenal cortex (AC) inhibitor o,p′-DDD (chloditan) was developed as a solution for i.v. injection. Its effects on glucocorticoid hormone production by human AC tissue culture and AC function in dogs were studied. A concentration range of 0.005 – 5.0 mg/mL was established by adding 5% o,p′-DDD solution to the culture medium. Cultivation of specimens of human adrenocortical tissue in the presence of o,p′-DDD solution caused after 24 h a dose-dependent decrease of 11-hydroxycorticosteroid (11-HCS) content by 11.0 – 69.8%. The 11-HCS content in dog blood plasma decreased by an average of 3.5 times; the response to synthetic 1 – 24-corticotropin stimulation, by three times, with daily administration for 3 d of 10 mL of the solution. The 11-HCS blood level was still reduced two weeks after withdrawal of the drug. The proposed o,p′-DDD solution showed adrenocorticolytic activity and could be recommended for clinical trials.
Keywords: o,p′-DDD; chloditan; adrenal cortex; adrenocorticolytic activity

Comparative evaluation of new carriers for controlled drug delivery based on Eudragit EPO/L100 interpolyelectrolyte complexes by R. I. Moustafine; A. V. Bukhovets; V. R. Garipova; A. Y. Sitenkov; A. R. Shamsutdinova; V. A. Kemenova; P. Rombaut; G. Van den Mooter (507-511).
New interpolyelectrolyte complexes (IPECs) between oppositely charged Eudragit® EPO and Eudragit® L100 were investigated with a view to the development of oral controlled drug delivery systems (DDS). Structural features of the samples were evaluated by modulated-temperature differential scanning calorimetry (MTDSC). The results confirmed that all IPECs were chemically homogeneous and were characterized by only one glass-transition temperature. Evaluation of the diffusion-transport properties of the investigated IPECs revealed the basic mechanisms responsible for the controlled delivery of drugs with different physicochemical properties. The results showed that the synthesized IPECs have great potential to be used as pH-sensitive oral controlled DDS.
Keywords: interpolyelectrolyte complex; Eudragit® EPO; Eudragit® L100; MTDSC; polycomplex matrix; diclofenac sodium; theophylline

A combination of physical, chemical, and technical studies was carried out in order to support the technology of vaginal suppositories called Climedex. The technology was developed and the critical parameters for preparing the suppositories under pharmacy conditions were determined to be the temperature, rate and time of mixing of the suppository mass, degree of grinding, and method of adding the active ingredients, in addition to their loss in the mortar pores and the displacement coefficients in the suppository bases.
Keywords: metronidazole; dexamethasone sodium phosphate; clindamycin phosphate; sea-buckthorn oil; vaginal suppositories; technology; gynecological diseases

Configurations of polyvalent central metals in pectinates and alginates were established as octahedral with a coordination number of six for the central metal in Cu(II) alginate; square-planar, tetrahedral, and pyramidal with coordination number 4 or 5 (for Cr) in Cu(II) pectinate and Cr(III), Mn(II), Co(II), and Ni(II) polyuronates. The polyuronates were formed by interchain dinuclear complexes. The metal atoms were coordinated to O atoms of polymer carboxyls and hydroxyls and H2O molecules. The results provided justification for the mechanism of action of polyuronates as antidotes.
Keywords: polyuronates; EPR spectroscopy; pectins; alginates

Features of aminalon drying in a pulsed bed reactor by M. S. Vasilishin; O. S. Ivanov; A. A. Kukhlenko; Z. B. Podsevalova; A. G. Karpov (519-521).
The influence of various processing parameters on the drying kinetics of pharmaceutical aminalon in a pulsed bed apparatus was investigated. The results could be used to design commercial drying equipment.
Keywords: aminalon (γ-aminobutyric acid); drying; pulsed bed reactor

Erratum to: Synthesis and characterization of polysulfanilamide and its copolymers: bioactivity and drug release by Abdulhakeem Alsughayer; Abdel-Zaher A. Elassar; Fakhreia Al Sagheer; Seham Mustafa (522-522).