Vol. 12 No. 2(46) (2014)
Published:
2014-06-10
Original Researches
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The structure of 2-arylhydrazones 1R-3-(4-pyridinyl)-1,2,3-propanetrione
For the first time 2-arylhydrazones of 1R-3-(4-pyridinyl)-1,2,3-propanetrion have been synthesized with the help of Japp-Klingemann reaction. They are characterized by the keto-hydrazone structure, but since the initial dicarbonyl compound is asymmetric, there is a real possibility of formation of two tautomer forms – form A (where the fragment with acetyl group acts as the acceptor of the hydrogen bond) and form B (where 4- the pyridoyl fragment acts as the acceptor of the hydrogen bond). In the solid state 2-arylhydrazones of 1R-3-(4-pyridinyl)-1,2,3-propanetriones exist in the form of tautomer A. In the solid state the structure of the initial 1R-3-(4-pyridinyl)-1,2,3-propanetriones, as well as the structure of 2-arylhydrazones of 1R-3-(4-pyridinyl)-1,2,3-propanetriones obtained from of them has been studied with the help of IR spectroscopy (in the range of 1500-1600 cm-1 where the intensive absorption is observed). In this part of the spectrum the hyrazones absorption differs from the initial compounds. Distinctive intensive bands appear in the ranges of 1508-1516 cm-1 and 1640-1665 cm-1. Besides, none of the carbonyl groups of 2-arylhydrazones of 1R-3-(4-pyridinyl)-1,2,3-propanetriones is enolized. Both forms (A and B) may exist in solutions. The proportion of forms is controlled by the nature of the solvent. In all compounds of CDCl3 the concentration of isomer A is higher than that of isomer B. In the spectrum of 1-(4-pyridinyl)-1,2,3-butantrion-2-[(4-methylphenyl) hydrazone) there are no signals, which could be attributed to isomer B. It testifies the predominant coordination of the hydrogen bond by the fragment with the acetyl group and formation of strong intramolecular hydrogen bonds. The ratio of isomers in solution of the polar solvent (DMSO-d6) changes in favour of accumulation of more polar minor tautomer B. Factors affecting the isomers equilibrium position have been evaluated together with determination of the dependence between the electronic effect of the substituent in the para-position of the phenylhydrazone fragment and the ratio and characteristics of A and B isomers. The intramolecular hydrogen bond strengthens with the presence of electron-donating substituents, while the thermodynamic efficiency of tautomer A increases. Quaternization of 2-arylhydrazones of 1R-3-(4-pyridinyl)-1,2,3-propanetrion by iodic methyl occurs only by the pyridine atom of nitrogen, thus decreasing the content of compounds that are derivatives of minor tautomer B.
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Synthesis of 4,4,6-trimethyl-8-R-4H-pyrrolo [3,2,1-ij] quinoline-1,2-diones
The features of the Stolle reaction in a series of substituted 2,2,4-trimethyl-1,2-bis (tetra) hydroquinoline have been investigated. When carrying out the reaction of oxalyl chloride not with 2,2,4-trimethyl-1,2-dihydroquinoline and 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline themselves, but with their hydrochlorides we have succeeded in avoiding the side formation of oxalic diamides 2 and increased the yields of pyrrolo[3,2,1-ij]quinoline-1,2-dione 3a-g up to 90%. It has been determined that carrying out the reaction in methylene chloride requires boiling for 1.5-2 h, in carbon tetrachloride it is 40-50 min, and in toluene it is only 20-30 min. It has been found that in the abovementioned conditions methoxy and benzyloxy groups are not hydrolyzed and, thus, the previously unknown 4,4,6-trimethyl-8-R-4H-pyrrolo [3,2,1-ij]quinoline-1,2-diones containing alkoxy, acyloxy and hydroxy groups have been synthesized. When studying the Stolle reaction for bifunctional 6-hydroxy-2,2,4-trimethyl-1,2- dihydroquinoline it has been found that acylation with oxalyl chloride and the subsequent cyclization proceed selectively only by the secondary amine group of the hydroquinoline ring with saving the hydroxyl group. It has been shown that the use of a two-stage modification of the Stolle method for the synthesis of pyrrolo [3,2,1-ij] quinoline-1,2-diones brings no advantages compared to the classical method of direct interaction of the substrates with oxalyl chloride. The structure of the compounds obtained have been confirmed by IR and 1H NMR spectroscopy and elemental analysis. -
Complexation of calix[4]arene hydroxymethyl-phosphonic acid with tryptophan and N-acetyl-tryptophan amide
The Host-Guest complexation of calixarene hydroxymethylphosphonic acid with tryptophan and N-acetyltryptophan amide has been investigated by the RP HPLC method in H2O/MeCN (99/1) solution (column support Hypersil CN, UV-detector, λ = 254 nm). Adsorption of calixarene hydroxymethylphosphonic acid on the Hypersil CN surface has been studied. It has been found that hydroxymethylphosphonic acid is characterized by reversible sorption on the Hypersil CN surface. The binding constants (KA = 23000 M-1 and 39000 M-1 for tryptophan and N-acetyltryptophan amide, respectively) of the supramolecular complexes have been calculated from the ratio between the capacity factors k’ of the Guest and the calixarene hydroxymethylphosphonic acid Host concentration in the mobile phase. The Gibbs free energies of the tryptophan and N-acetyltryptophan amide complexes are -24.84 and -26.15 kJ/mol, respectively. The molecular modelling of calixarene hydroxymethylphosphonic acid and its complexes with tryptophan and N-acetyltryptophan amide (Hyper Chem, version 8, force field PM3) has indicated that the complexes are stabilized by hydrogen bonds, electrostatic, π-π, and solvatophobic interactions. The geometric parameters of the energy minimized calixarene macrocycle and its complexes with tryptophan and N-acetyltryptophan amide have been calculated. According to the calculations it has been shown that the Host-Guest complexation does not change the flattened-cone conformation of calixarene. Finally, the inverse correlation has been found between the KA values of the complexes and the Log P values of the guest molecules.
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Synthesis of 7-carboxyalkylthio-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-e]diazepin-4-ones
The article describes the method of synthesis of a new type of pyrazolo[3,4-e][1,4]diazepin-4-ones substituted in position 7 by fragments of thioalkane carboxylic acids. The literature reference considers the synthetic and biological studies of heterocyclic compounds with exo-functionalized fragments of thioalkan carboxylic acids and it substantiates the expediency of our investigation. The results of the research are development of an effective one pot method for the target compounds, which is based on the intramolecular cyclization of 5-amino-N-(2,2-dialkyloxyethyl)pyrazole-4-carboxamides in the solution of formic acid with thioalkan carboxylic acids. The synthesis of the starting 5-aminopyrazolo- 4-carboxamides has been performed by condensation of 2-cyano-N-(2,2-dimethoxy)-3-dimetylaminoacryl(croton) amides with alkyl hydrazines or hydrolytic cleavage of 5-(2,2-dietoxyethyl)-1,5-dihydropyrazolo-4Н-[3,4-d]pirimidin- 4-ones. The scheme of this reaction proposed involves the intramolecular cyclocondensation with the initial formation of the corresponding 7-hydroxy-5,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-4(1H)-ones, and further replacement of the hydroxyl group for the carboxyalkylthiol residue in the acidic medium. The structure of the compounds obtained has been proven using the methods of IR-, NMR 1H 13C-spectroscopy, mass-spectra and elemental analysis. The substantial evidence of the diazepine cycle formation is the presence of multiplets of protons H6 in the range of 3.16- 3.50 ppm and multiplets of protons H7 in the range of 4.89-5.17 ppm in the 1Н NMR spectra.
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Enhancement of the base for 3,7-disubstituted [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one derivatives as promising pharmaceutical agents
A suitable and effective scheme for the synthesis of 3,7-disubstituted [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-ones has been suggested and tested. It can provide a wide chemical diversity of the final products containing practically any substituent in position 3. The scheme previously developed starts from esters of oxalamic acid following with the cyclization of intermediate 3-hydrazinopyrazin-2-ones with carbonyl-containing compounds (ortho-esters or alkylcarbonic acid anhydrides). To introduce aryl or heteryl substituents in position 3 of the heterocyclic system we propose to use the reaction of 3-hydrazinopyrazin-2-ones with the corresponding carbonic acids preliminary activated by carbonyldiimidazole (CDI). The further cyclization is carried out by reflux for 24 hours in anhydrous DMFA. The structure of the compounds obtained has been proven by elemental analysis and 1H NMR spectroscopy data. Formation of [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one condensed system is in good correlation with spectral data, and is confirmed by the presence of signals of H-5 and H-6 protons of the pyrazinone fragment as doublets at d 7.15-7.28 ppm and d 7.50-7.59 ppm, respectively. The compounds synthesized are of particular interest as potential pharmacological objects with the cytotoxic, membrane-stabilizing, cerebroprotective, cardioprotective activity. -
Synthesis and the antimicrobial activity of precarbene and metalcarbene compounds of the imidazole series
Precarbene and metalcarbene compounds of a series of imidazole have been synthesized to study their antimicrobial activity. Calix[4]arene imidazolium salts 3,4a,b have been obtained from the corresponding chloromethyl derivatives of calix[4]arenes and N-substituted imidazoles in dimethylformamide or tetrahydrofuran, and salt 5 – from p-xylylenediimidazoles and 1-bromoadamantane in o-dichlorobenzene. Monocarbene complexes of palladium 8a-c, copper(I) 8d and biscarbene complexes of nickel 9a and cobalt 9b have been synthesized by the direct interaction of stable carbenes with transition metal salts or by the analogous reactions in situ in tetrahydrofuran. The NMR spectra data of the compounds synthesized are given. The most characteristic signals of the carbenoid carbon atoms are detected in the 13С NMR spectra of complexes 8a-d, 9a in the range of 165-178 ppm. A high antimicrobial activity has been found for carbenoid salts 4a,b, 5 on the test-culture of M. Luteum. It corresponds to the minimal bacteriostatic concentration (MBsC) of 15.6 mkg/mL and the minimal bactericidal concentration (MBcC) of 62.5 mkg/mL for compound 2. The higher activity has been found for carbene complexes of nickel 9a and cobalt 9b on the test-culture of M. luteum (MBsC is 7.8 mkg/mL and MBcC is 15.6 mkg/mL), and the highest 9b on the test-cultures of M. luteum and C. tenuis (the minimal fungistatic concentration is 1.9 mkg/mL and the minimal fungicidal concentration is 3.9 mkg/mL).
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Synthesis and the antimicrobial activity of metalcarbene compounds of the triazole series
Мetalcarbene compounds of a series of [1,2,4] and [1,2,3]triazoles have been synthesized to study their antimicrobial activity. Monocarbene complexes of palladium (9a) and copper(I) (9b,12,15), biscarbene complexes of palladium (4a) and copper(I) (4b,14), a carbenoid complex of cobalt (5) have been synthesized by the direct interaction of stable carbenes with transition metal salts or by analogous in situ reactions. The intermediate sterically hindered carbenes – [1,2,4]triazol-5-ylidenes 3a-c have been isolated in the individual state. Being intermediate in the synthesis of mesoionic complexes 9a,b 1-adamantyl-4-phenyl-[1,2,3]triazole has been synthesized by [3+2]-cycloaddition of 1-adamantylazide to phenylacetylene in the presence of the biscarbene complex of copper(I) iodide 14. Characteristic signals of the carbenoid carbon atoms are detected in the 13С NMR spectra of complexes in the range of 165-203 ppm. A high antimicrobial activity has been found for complexes 5.12; for compound 12 it corresponds to the minimal bacteriostatic concentration (MBsC) 15.6 mkG/mL, the minimal bactericidal concentration (MBcC) 31.2 mkG/mL (М. luteum), and MBsC 31.2 mkG/mL, MBcC 62.5 mkG/mL (S. aureus). The highest activity in the series studied is observed for the carbenoid complex of cobalt (5) on the test-culture of M. luteum (MBsC 15.6 mkG/mL and MBcC 31.2 mkG/mL), and on the test-culture of C. tenuis (the minimal fungistatic concentration is 7.8 mkG/mL and the minimal fungicidal concentration is 31.2 mkG/mL). -
Methyl-substituted anilides of 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carb-oxylic acid. Synthesis, spectral characteristics and biological properties
The synthesis of a series of methyl-substituted anilides of 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine- 3-carboxylic acid has been carried out by the reaction of methyl 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and the corresponding anilines in boiling xylene. To confirm their structure elemental analysis and NMR 1H spectroscopy have been used. The central component in the mechanism of analgesic properties of the compounds obtained has been studied in non-pedigree rats on the standard model of the thermal tail-flick in parallel and in comparison with the structurally related drugs – Meloxicam and Piroxicam. Furthermore, among the substances studied the potent analgesics have been found. When administered orally in the dose of 20 mg/kg they significantly exceed the reference medicines in their analgesic effect. Being sulfo analogues of quinolone diuretics all the anilides obtained have been subjected to the pharmacological screening to reveal the diuretic properties. Some of these substances stimulate diuresis at the level of Hydrochlorothiazide in much lesser dose. According to the results of biological tests the structural and biological regularities that are important for further research have been revealed. In fact, they appeared to be practically identical for analgesic and diuretic properties: 2 - and 2,4-dimethylsubstituted derivatives exhibit the highest effect, and 3-methyl group inactivates the molecule.
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Synthesis of new pyrazoline-thiazoles and their biological activity
The application of the [2+3]-cyclocondensation reaction for the synthesis of 2-pyrazoline substituted thiazolidinones, as well as bioisosteric pyrazoline-thiazoles has been analyzed. Following the literature data 4,5-dihydro- 1-carbothioamides are used as S,N-binucleophiles in the [2+3]-cyclocondensation reaction with different equivalents of the dielectrophilic synthon [C2]2+ (α-halogencarboxylic acids, derivatives of maleic acid, aroylacrylic acids, dimethyl ester of acetylenedicarboxylic acid, α-bromoacetophenones and ethyl 4-chloroacetoacetate). It has allowed to identify the highly active compounds with the antimicrobial, antiviral, anti-inflammatory, antitumor and antiparasitic activities. Aiming to enlarge a scope of 3,5-diaryl-4,5-dyhidropyrazol-1-carbothioamides as S,N-binucleophiles in [2+3]-cyclization and to find a new chemotherapeutic agents the synthesis of new pyrazoline-thiazoles has been carried out; it is based on the reaction between the carbothioamides mentioned and ethyl 2-chloroacetoacetate or 3-chloroacetyl acetone in the presence of fused sodium acetate in refluxing acetic acid. The structure of the compounds synthesized has been confirmed by 1H NMR spectra. The screening of the antitumor and antitrypanosomal activities of some compounds synthesized has been conducted. As a result of in vitro experiments their moderate cytotoxicity in the concentration of 10-5 mol/l for individual cancer cell lines has been identified. At the same time a high trypanocidal activity of compounds 2h and 2j has been determined against Trypanosoma brucei gambiense strain with the values of ІC50 of 3.82 and 2.61μM, respectively; and it exceeds the activity of the reference medicine nifurtomox.
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N-phenethyl-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides as possible anti-viral agents
Based on the preliminary calculated screening performed by the PASS programme the synthesis of the group of the corresponding N-phenethyl-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides as potential antiviral agents has been carried out by the interaction of ethyl esters of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acids with 2-arylethylamines in boiling ethanol. Their structure has been confirmed by the data of elemental analysis and NMR 1H spectroscopy. Of the Herpesviruses family such viruses as Herpes Simplex Viruses Type 1 and 2, Varicella-Zoster Virus, Epstein-Barr Virus, as well as Cytomegalovirus have been involved in the screening research. Influenza Virus was presented by two types: A (subtypes H1N1, H3N2, H5N1) and B. The group of viruses affecting different sections of the respiratory tract included Parainfluenza Virus, SARS Virus, Rhinovirus, Adenovirus and Respiratory Syncytial Virus. Besides, Measles Virus, Vaccinia Virus and related Cowpox Virus, Hepatitis B and C Viruses, as well as Venezuelan Equine Encephalitis Virus were involved. The group of viruses causing febrile states of varying severity in human was presented by Rift Valley Fever Virus, West Nile Virus, Yellow Fever Virus, Dengue Virus and Tacaribe Virus. According to the results of the tests performed N-(4-chlorophenethyl)- 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide has been recommended for further research. Having a low cytotoxicity this compound revealed a high antiviral activity in relation to the West Nile fever virus agent.
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Targeted synthesis of a series of 4-o-aryl- and 4-N-alkyl/arylquinazolines for stu-dying the JNK-kinase activity
To study the JNK-kinase activity of quinazoline derivatives a series of 4-O-aryl- and 4-N-alkylquinazolines have been synthesized in standard condition of nucleophilic substitution of 4-chloroquinazolines in the presence of potassium carbonate. 4-Chloroquinazolines have been obtained by the reaction of POCl3 with 3H-quinazolin-4-оnes using DMFA as a solvent. The abovementioned conditions have not yielded the desired results for the synthesis of 4-N-arylquinazolines, so acetic acid is used for the reaction catalysis. Therefore, 40 compounds of 4-(O)N-(aryl) alkylquinazolines class have been obtained. The structures of the compounds synthesized have been confirmed by NMR 1H-spectroscopy data. Characteristic signals of quinazoline protons in the second position are observed in the spectra of the compounds obtained. The signals of other protons are in good correlation with the expected structures. The melting points and purity of the compounds synthesized have been also determined. Using the PASS Professional programme the computer prediction of the biological activity of the compounds synthesized has been conducted; according to its results the compounds with the potential kinase activity have been selected. They are 4-N-arylquinazolines. The biological examination have been conducted under conditions in vitro in the culture medium of hepatocytes. The impact of substances on the activity of alanine aminotransferase has been determined and the activity of 4-N-(cyanoaryl)quinazolines as JNK-kinase inhibitors has been confirmed. -
The antioxidant activity of pyridylhydrazones of aromatic aldehydes
The kinetic parameters of the antioxidant activity of pyridylhydrazones derivatives of aromatic aldehydes in the initiated oxidation of ethylbenzene have been determined by the chemiluminescent method. The antioxidants studied have higher values of the reaction rate constants with peroxy radicals k7 compared to ionol. In the conditions of autooxidation of ethylbenzene the efficiency of the antioxidants studied reduces. It has been found that 3-pyridylhydrazon-3,5-dimethyl-4-hydroxybenzaldehyde interacts with cumene hydroperoxide. The regularities of the inhibitory effect of pyridylhydrazones in heterogeneous systems have been studied. Interaction of pyridylhydrazones with НО• radicals has been investigated by the chemiluminescent method in water solution. It has been determined that pyridylhydrazones show a high activity towards НО• radicals. In the initiated azodiisobutyronitrile oxidation the emulsion of ethylbenzene : water derivative of pyridylhydrazones has revealed a high antioxidant activity. In the presence of hydrophobic derivatives in molecules of antioxidants the values of log P and the induction period (τ/τ0) increase. When inhibiting the initiated oxidation of phosphatidylcholine dispersion pyridylhydrazones show practically twice higher antioxidant activity in comparison with ionol.
