Pharmaceutical Chemistry Journal (v.49, #10)

Flavonoids as Potential Immunosuppressants Affecting Intracellular Signaling Pathways (a Review) by S. I. Pavlova; D. Z. Albegova; Yu. S. Vorob’eva; O. S. Laptev; I. G. Kozlov (645-652).
Flavonoids are a large group of polyphenolic compounds that are present in almost all higher plants. Recent research demonstrated a wide range of biological effects of these compounds under both normal and various pathological conditions. Apparently, the biological activity of most flavonoids is due mainly to their ability to penetrate into cells and block enzymes of signaling pathways and transcription factors, including those involved in the activation, proliferation, and realization of effector functions of immune system cells. Moreover, it should be noted that flavonoids were highly efficacious in several instances in experimental therapy of model immune pathologies, suggesting that they were promising as platforms for creating new pharmacological agents that suppress or “normalize” the immune response.
Keywords: flavonoids; immunotropic effects; intracellular signaling molecules

Synthesis and Pharmacological Activity of 2,9-Disubstituted Imidazo[1,2-a]Benzimidazole Phenyl- and Alkylthiocarbamides by V. A. Anisimova; O. N. Zhukovskaya; A. A. Spasov; V. A. Kuznetsova; V. A. Kosolapov; D. S. Yakovlev; O. A. Solov’eva; D. V. Sorotskii; A. A. Brigadirova; E. S. Vorob’ev (653-656).
A series of phenyl- and alkylthiocarbamides were synthesized by the reaction of 2,9-disubstituted imidazo-[1,2-a]benzimidazoles with phenyl- and alkylisothiocyanates. The structures of the products were confirmed by elemental analysis and PMR spectroscopy. Some of the synthesized compounds were capable of inhibiting non-enzymatic glycosylation of proteins. The concentration dependences of the antiglycation effect of the most active substances and aminoguanidine were studied.
Keywords: 2,9-disubstituted imidazo[1,2-a]benzimidazole-3-thiocarbamides; synthesis; 5-HT4-agonist effect; AT1-antagonist activity; antioxidant properties; antiglycation activity

Synthesis and Pharmacological Activity of Ethyl-2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)Pyrrolidine-3-Carboxylates by S. S. Zykova; A. A. Darovskikh; T. F. Odegova; M. A. Kiselev; N. M. Igidov (657-660).
Ethyl-2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)pyrrolidine-3-carboxylates (IIa-g) were synthesized via recyclization of 3-(2-benzoylhydrazono)-5-arylfuran-2(3H)-ones (I) through the action of ethylcyanoacetate. The synthesized compounds were screened for biological activity and were found to have low toxicity. Ethyl-2-amino-1-benzamido-5-[2-(3, 4-dimethoxyphenyl)-2-oxoethylidene]-4-oxopyrrolidine-3-carboxylate exhibited antiradical activity in a diphenylpicrylhydrazyl (DPPH)-binding assay that was greater than that of the reference drug trolox. This same compound showed anti-inflammatory activity in a carrageenan edema model that was greater than that of diclofenac sodium. Assessment of antihypoxic activity in an acute normobaric hypoxia test found that ethyl-2-amino-1-benzamido-5-[2-oxo-2-(4-methylphenyl) ethylidene]-4-oxopyrrolidine-3-carboxylate was comparable with the succinic acid standard.
Keywords: ethyl-2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)pyrrolidine-3-carboxylates; acute toxicity; antiradical activity; DPPH; antihypoxic activity; anti-inflammatory activity

Differences Between Cerebrovascular and Anti-Ischemic Effects of Dopamine, Docosahexaenoyldopamine, and GABA–Docosahexaenoyldopamine Conjugate by R. S. Mirzoyan; T. S. Gan’shina; A. V. Topchyan; N. A. Khailov; I. N. Kurdyumov; G. I. Kovalev; I. A. Zimin; Yu. Yu. Firstova; E. V. Vasil’eva; N. M. Gretskaya; V. V. Bezuglov (661-666).
The cerebrovascular and anti-ischemic effects of dopamine and synthetic docosahexaenoyldopamine (DHA-DA) and the GABA–DHA-DA conjugate (OXL1220) were compared and found to differ. Dopamine and DHA-DA increased blood flow in intact and ischemic brain that was associated with pronounced hypertensive reactions. The latter inhibited dopamine transporter with IC50 = 29 μM but was practically inactive as a ligand for dopamine receptors. OXL1220 produced a selective vasodilating effect on blood flow in brain subjected to transient global ischemia. Only OXL1220 competed in vitro for specific binding sites of [3H]-gabazine in rat-brain GABAA-receptors. Therefore, conjugation of a neuromediator (GABA) to the DHA-DA changed the dopaminergic activity of the compound to GABA-ergic with respect to vascular tone in ischemic brain.
Keywords: dopamine; docosahexaenoyldopamine (DHA-DA); GABAconjugate with DHA-DA(OXL1220); cerebral blood flow; brain ischemia; bicuculline; dopamine receptors; GABAA-receptors; dopamine transporter

Complexes of Glucosamine Hydrochloride and Phytic Acid in Aqueous Medium and Their Antioxidant Properties in Human Blood Plasma by N. B. Mel’nikova; M. V. Sidorova; A. R. Sorokina; A. K. Martusevich; S. P. Peretyagin; A. V. Kochubeinik; M. V. Gulenova; A. E. Bol’shakova (667-671).
The reaction in aqueous medium of phytic acid (myo-inositol hexakisphosphate) and glucosamine hydrochloride (2-amino-2-deoxy-β-D-glucopyranose hydrochloride) formed phytic acid—glucosamine complexes of formula InsP6 5GA. Their compositions were proved by elemental analysis for C, H, N, and P. IR, PMR, 13C NMR, and 31P NMR spectroscopy and potentiometric titration showed that the complexes of phytic acid and glucosamine were formed by H-bonds and electrostatic salt interactions. High antioxidant activity against lipid peroxidation and a positive effect on superoxide dismutase activity were found for complexes of InsP6H12 and glucosamine in in vitro studies of human blood plasma under oxidative stress.
Keywords: phytic acid; glucosamine hydrochloride; antioxidant activity; superoxide dismutase

Synthesis of New 2-Amino-6-Ethoxybenzothiazoles and Their Influence on Physical Work Capacity by E. G. Tsublova; T. N. Ivanova; Vik. V. Yasnetsov; M. V. Troshina; V. V. Yasnetsov (672-676).
New 2-amino-6-ethoxybenzothiazole derivatives were synthesized and tested for their influence on physical work capacity in mice. It was shown that a pyridylidene or furylidene radical on the amine or a formulation with carboxypentanoate were important for producing effective new 2-amino-6-ethoxybenzothiazole derivatives. These compounds were either more effective or comparable with the well-known actoprotectors metaprot and ladasten, which are used at significantly higher doses.
Keywords: new 2-amino-6-ethoxybenzothiazole derivatives; physical work capacity

Synthesis and Antibacterial and Immunobiological Activity of Ethyl-1-(4-Aminosulfonylphenyl)-5-Aryl-3-Hydroxy-2-Oxo-3-Pyrroline-4-Carboxylates by V. L. Gein; O. V. Bobrovskaya; T. F. Odegova; I. V. Krylova; O. N. Gein; E. É. Sopova; S. V. Gein (677-679).
A series of ethyl-1-(4-aminosulfonylphenyl)-5-aryl-3-hydroxy-2-oxo-3-pyrroline-4-carboxylates were synthesized via a three-component reaction of sodium diethyloxalylacetate and a mixture of an aromatic aldehyde and 4-aminobenzenesulfonamide. The structures of the compounds were established using IR and PMR spectroscopy and mass spectrometry. The antibacterial and immunobiological activities of the synthesized compounds were studied.
Keywords: synthesis; ethyl-1-(4-aminosulfonylphenyl)-5-aryl-3-hydroxy-2-oxo-3-pyrroline-4-carboxylates; antibacterial and immunobiological activity

Analgesic Effect of Several Nonsteroidal Anti-Inflammatory Drug Nanoaerosols by S. V. An’kov; T. G. Tolstikova; A. A. Onishchuk; M. V. Khvostov; I. V. Sorokina; A. M. Baklanov; V. M. Fomin; V. V. Boldyrev (680-682).
The analgesic activities of nanoaerosols of the nonsteroidal anti-inflammatory drugs indomethacin, butadion, and diclofenac were studied. It was found that nanoaerosol delivery of these drugs gave analgesic activities that were comparable to those of oral delivery 5 – 8 min after administration at doses that were 3 – 5 orders of magnitude lower.
Keywords: nonsteroidal anti-inflammatory drugs; nanoaerosols; indomethacin; butadion; diclofenac

New highly active N 1-substituted uracil derivatives of the HIV-1 nonnucleoside reverse transcriptase inhibitor class were designed. The structure—activity relationship provided a basis for building a computer model of the inhibitory activity against reverse transcriptase of HIV-1 mutant K103N/Y181C. New compounds that were more active than nevirapine were synthesized.
Keywords: anti-HIV-1 activity; mutant strains; nonnucleoside reverse transcriptase inhibitors; uracil derivatives; molecular docking

Design, Synthesis and Evaluation of New Azoles as Antifungal Agents: a Molecular Hybridization Approach by Maryam Iman; Talin Peroomian; Asghar Davood; Mohsen Amini; Soroush Sardari; Parisa Azerang (687-693).
Two benzimidazole derivatives and one nitroimidazole derivative were designed using molecular hybridization approach. The designed compounds were synthesized and their in vitro antifungal activities were tested against Candida albicans and Saccharomyces cerevisiae strains. Based on the antifungal activity data, compound 9 containing 2-methyl-5-nitroimidazole moiety proved to be the most potent compound. It was more active than the reference drugs fluconazole and ketoconazole against S. cerevisiae.
Keywords: benzimidazole; nitroimidazole; azole; antifungal activity

Despite advances in anticancer drug development and discovery, the survival of patients is so poor. A deep need for discovery of novel anticancer drugs is among priority issues in medicinal chemistry now. A new series of 1,2,4-triazole derivatives were designed and synthesized by means of bioisosteric replacement. In vitro cytotoxicity evaluation was carried out with respect to PC3 (prostate carcinoma), HT29 (colorectal cancer) and SKNMC (neuroblastoma) cell lines using MTT assay, and the obtained results were compared to imatinib as a reference drug. Spectroscopic methods including 1H NMR, IR, and MS were used for characterization of the synthesized compounds. Generally, none of the tested compounds showed superior activity in comparison to imatinib against PC3 and SKNMC cell lines. However, compound 3b (IC50 = 3.69 ± 0.9 μM) and 3e(IC50 = 15.31 ± 2.1 μM) exhibited higher activity than imatinib (18.1 ± 2.6) against HT29 cells. Some of the obtained 1,2,4-triazole derivatives can be proposed as potential anticancer agents – in particular, against colorectal cancer – but further structural modifications and experimental tests are needed to increase the anticancer activity.
Keywords: synthesis; 1,2,4-triazole; cytotoxicity; anticancer activity

The key intermediates 3H-imidazo[4′,5′:3,4]benzo[c]isoxazoles were synthesized by the reaction of N-alkyl-5-nitrobenzimidazoles with aryl acetonitriles under basic conditions. These compounds were converted to 3H-imidazo[4,5-a]acridin-11(6H)-ones by the Tanasescu reaction in excellent yields. The structures of all newly synthesized compounds were confirmed by IR, 1H NMR, and mass spectroscopic data. The interactions of 3H-imidazo[4,5-a]acridin-11-ones with human serum albumin (HSA) have been studied by fluorescence spectroscopy. The binding of 3H-imidazo[4,5-a]acridin-11(6H)-ones quenches the HSA fluorescence, revealing a 1 : 1 interaction with a binding constant of about 4.50 × 104 – 1.25 × 105 M-1. A decrease in the fluorescence intensity at 339.41 nm, when excited at 280 nm, is attributed to changes in the environment of protein fluorophores caused by the presence of the ligands. Differences in the interactions of 3H-imidazo[4,5-a]acridin-11(6H)-one derivatives with HSA were observed using the spectrofluorimetry technique. Thermodynamic characteristics and the parameters of HSA binding with these compounds are in accordance with the antibacterial activity of various derivatives of 3H-imidazo[4,5-a]acridin-11(6H)-one.
Keywords: 3H-imidazo[4′,5′:3,4]benzo[c]isoxazole; 3H-imidazo[4,5-a]acridin-11(6H)-one; human serum albumin; interaction; fluorescence spectroscopy

Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance by A. K. Nazarov; I. V. Zavarzin; G. V. Nazarov; A. V. Aksenov; I. S. Levina (706-710).
Microcrystals of 6α-methyl-16α,17α-cyclohexapregn-4-ene-3,20-dione (mecigestone) that differed from the starting drug substance by decreased sizes and altered morphologies were produced using a Nano Spray Dryer B-90 (Buchi, Switzerland) that allowed operation with organic solvents in a closed cycle. The bioavailability of starting crystalline and micronized mecigestone drug substance was studied by oral administration to laboratory white rats. Mecigestone was extracted from rat blood serum using solvent extraction. The extraction coefficient was 64%. The detection limit of the drug substance was 0.08 ng/mL. The content of unaltered mecigestone in the extracts was determined using HPLC with high-resolution mass spectrometric detection. Micronized mecigestone was 7.5 times more bioavailable than the starting drug substance.
Keywords: mecigestone; micronization; HPLC-MS; bioavailability

Amperometric Detection Under Batch-Injection Analysis Conditions of Caffeine on an Electrode Modified by Mixed-Valence Iridium and Ruthenium Oxides by L. G. Shaidarova; I. A. Chelnokova; M. A. Degteva; G. F. Makhmutova; Yu. A. Leksina; A. V. Gedmina; G. K. Budnikov (711-714).
Mixed-valence Ir–Ru oxides (IrOx—RuOx) electrodeposited on a glassy-carbon electrode surface were found to exhibit catalytic activity for caffeine oxidation. An amperometric method for caffeine detection at this modified electrode under batch-injection analysis conditions was developed. The analytical signal was linearly dependent on the caffeine concentration in the range 5 × 10−8 – 5 × 10−3 M. The developed method was tested for caffeine determination in tablets, solutions for injection of caffeine—sodium benzoate, and coffetamin tablets.
Keywords: chemically modified electrodes; mixed-valence Ir–Ru oxides; caffeine electrochemical oxidation; batch-injection analysis

Solutions: Characteristics, Classification, and Basic Quality Requirements by O. A. Mochikina; E. I. Sakanyan; T. B. Shemeryankina (715-718).
Solutions containing pharmaceuticals of various origins are one of the most popular dosage forms. Pharmaceuticals for parenteral, ophthalmic, internal, and external use, among others, are prepared as solutions. However, a general monograph for the Solutions dosage form has not yet appeared in the Russian State Pharmacopoeia. The principal regulations, including relevant monographs of leading global pharmacopoeias, for the quality requirements of the Solutions dosage form were analyzed and enabled a list of the principal quality parameters of solutions, the techniques and methods for their determination, and the normalized ranges that would be used subsequently to compose a general pharmacopoeial monograph Solutions to be compiled.
Keywords: general pharmacopoeial monograph; dosage form; quality parameters; solutions; analytical methods