Vol. 11 No. 3(43) (2013)
Published:
2013-09-10
Original Researches
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The study of complexation of 5,17-bis-(n-tolyliminomethyl)- 25,27-dipropoxycalix[4]arene with benzoic acids by rp hplc and molecular modeling methods
The Host-Guest complexation of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with benzoic acids has been studied by reversed-phase high-performance liquid chromatography (RP HPLC) method (the mobile phase – MeCN/H2O, 86/14 v/v, the column support – LiChrosorb RP 18, UV detector, l = 254 nm). The study of the chromatographic behaviour of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene and benzoic acids, as well as determination of their main chromatographic characteristics – the retention times tR and capacity factors k’ have been performed. On the basis of the data obtained the lipophilicity log P, as well as the binding constants and Gibbs free energies of the complexes of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with benzoic acids have been calculated. The binding constants and Gibbs free energies of the complexes of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxycalix[4]arene with benzoic acids are in the range of 335-910 М-1 or -14.38 – -16.85 kJ/mol, respectively. The influence of the benzoic acids lipophilicity log P and pKa values on the binding constants KA of the complexes has been examined. It has been found that decrease of the log P and pKa values increases the binding constants KA of the complexes. Molecular modeling of the complexes revealed the presence of hydrogen bonds between carboxylic groups of the acids and nitrogen atoms of imino-groups at the upper rim or oxygen atoms of the hydroxyl groups at the lower rim of the calixarene macrocycle. A linear dependence of the binding constants from the acid lipophilicity log P indicates a significant role of solvatophobic interactions during the complexation process.
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Synthesis and the antimicrobial activity of ethyl 5-methyl-2-(alkylthio)-4-oxo-3,4-dihydrothieno [2,3-d]pyrimidine-6-carboxylates
By alkylation of the products of diethyl 3-methyl-5 {[(methylthio)carbonothioyl]amino}-2,4-thiophenedicarboxylate interaction
with benzylamines the novel derivatives of ethyl 5-methyl-2-(alkylthio)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylates have been obtained. It has been found that the signal of the CH2-group adjacent to the nitrogen atom in position 3 of thieno[2,3-d]pyrimidine system is always observed in the range of 5.35-5.40 ppm, while the position of the signal of methythylene-group connected with the sulfur atom much depends upon the structure of the radical attached to this group. IR-spectra of all the compounds contain the intensive С=О stretching band at 1721-1678 cm-1; the spectra of the compounds with amide function contain bands of stretching N–H of 3280-3263 cm-1, while nitriles have the band of stretching C≡N vibrations near 2250 сm-1. It has been determined that all of the compounds are mostly active against the strain of Candida aibicans fungi. The most resistant microorganism was found to be the strains of Staphylococcus aureus. The only exception is the derivative modified with the thioacetic acid residue in position 2 and unsubstituted benzyl in position 3, which appeared to be highly active against Staphylococcus aureus strain. Amides of thioactetic acid modified in position 3 with 3,4-dichlorobenzyl substituent and thioacetamide substituents in position 2 are active against Pseudomonas aeruginosa, as well as the compound, which contains 3-chlorobenzyl substituent in position 3 and p-chlorobenzotiol substituents in position 2 of thieno[2,3-d]pyrimidine. -
Synthesis and diuretic properties of n-aryl- 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1h-pyrrolo [3,2,1-ij]quinoline-5-carboxamides with electron-acceptor substituents in the anilide fragment
In numerous studies of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides it has been convincingly shown that amidation of quinoline-3-carboxylic acids esters with alkyl-, aryl- and hetarylamines is the best way to obtain these compounds. As a rule, syntheses proceed smoothly and efficiently under rather mild conditions. However, in those cases when for formation of amides the temperature of 120-150°C and above is applied, partial destruction of the ester fragment may occur and, as a result, it pollutes the target products with specific impurities – the corresponding 4-hydroxy-1,2- dihydroquinolin-2-ones or their analogues. Application of 1H NMR spectroscopy allows to prove that the cause of ester fragments destruction, which sometimes can be observed when alkyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates react with amines under harsh conditions, is water presented in the reagents or in the solvents. It becomes clear from this study that at the temperature of 95°C and higher the sensitivity of 4-hydroxy-2-oxo-1,2-dihydroquinoline- 3-carboxylic acids esters in a solution or a melt to hydrolysis increases significantly. Simple methods to minimize this undesirable process have been proposed – if the synthesis of N-substituted amides based on them requires such severe conditions, water should be removed from the reagents and solvents in order to avoid contamination of the final products with 4-hydroxy-1,2-dihydroquinolin-2-ones. The results of the diuretic properties study of new substituted anilides of 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid are discussed.
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Synthesis of pyrazol-4-carbonitriles by thermal dehydratation of pyrazol-4-carbaldehyde oximes
A detailed literary analysis of the methods for synthesis, chemical and biological properties of 4-pyrazolcarboxylic acids nitriles, which are important synthetic building-blocks for purposeful obtaining of functional derivatives of pyrazole, has been conducted. A simple and effective method of obtaining of synthetically and pharmacologically perspective nitriles of 4-pyrazolecarboxylic acids has been developed. They are obtained by thermal dehydratation of oximes of easily available pyrazole-4-carbaldehydes in dimethylformamide. It has been determined that heating of these compounds in the boiling dimethylformamide for 3 hours is enough to produce pyrazole-4-carbonitriles with 56-86% yields. It has also been found that in comparison with aliphatic and aromatic aldoximes increase of the temperature of the reaction medium till it boils (by 17°C) in case of oximes of pyrazole-4-carbaldehydes allows to reduce 16 times the reaction time, thus making this synthesis to be economically effective and technological. It has been shown that in this transformation DMFA simultaneously plays roles of the solvent and reagent. The mechanism of the dehydratation discovered has been proposed. It includes consecutive elimination of dimethylamine and formate acid from the intermediate generated by nucleophilic addition of oximic hydroxyl to the electrophilic centre of dimethylformamide. The composition and structure of the nitriles synthesized have been confirmed by elemental analysis, chromatomass-spectrometry, IR- and 1H NMR spectroscopy.
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Reactivity of phenylanthranilic acids derivatives. Xxiii. Synthesis and acid-base properties of 4,5-dymethoxy-n-(2´-carboxyphenyl)anthranilic acids
The alternative ways of synthesis of new 4,5-dymethoxy-N-(2´ carboxyphenyl)anthranilic acids have been considered nad new ways for their obtaining have been suggested. The structure of the compounds synthesized has been proven by the elemental analysis, IR- and NMR-spectroscopy. The purity has been controlled by the method of thin-layer chromatography. The reactivity of 4,5-dymethoxy-N-(2´-carboxyphenyl)anthranilic acids has been researched by studying the acid-base properties in the binary solvent of dioxane-water (60 vol% of dioxane). It has been found that the substances synthesized are dibasic subacids, which strength depends upon the nature and position of substituents. The quantitative assessment of the influence of substituents on two reactive centres of the acids synthesized has been carried out by the method of correlative analysis according to the Gamete equation. It has been proven that the reactive centres sensitivity is substantially different and dependent on the substituent distance. In addition, appearance of another reactive centre does not practically influence on sensitivity of the first one. It has been determined that the substances synthesized reveal the anti-inflammatory, analgesic, diuretic, bacteriostatic, and fungistatic effects. According to the classification by K.K. Sydorov the substances synthesized when introducing intragastrically belong to low-toxic compounds (DL50>3000 mg/kg).
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"Green" synthesis of ethyl 4-hydroxy-2-oxo- 1,2-dihydroquinoline-3-carboxylates
One of the most convenient methods for obtaining ethyl of N-substituted 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates and their tricyclic analogues at present is condensation of the corresponding anilines with triethyl methanetricarboxylate. In spite of the fact that there are many methods describing the successful performance of this reaction in conditions of laboratory, but unfortunately, all of them appeared to be completely unusable for large production for a variety of reasons. The study of quality of the esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids by HPLC has shown that all of them contain from 2.4 to 5.6% of specific admixtures of 4-hydroxy-1,2-dihydroquinolin- 2-ones. In laboratory conditions these amounts can be neglected, but for industrial manufacture they can turn into great losses. The source of admixtures of 4-hydroxy-1,2-dihydroquinolin-2-ones appearing in crude esters can be only the esters themselves. It is obvious that ester grouping is partially destroyed not in the process of separation of the final products, but during the course of the basic reaction. It has been experimentally proven that the cause of contamination of the target products with the admixtures of the corresponding 4-hydroxy-1,2-dihydroquinolin-2-ones is water, which is present in reagents. Applying the principles of «green chemistry» the alternative for carrying out the syntheses of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates adapted for industrial manufacture has been suggested on the basis of N-substituted anilines and triethyl methanetricarboxylate.
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Carbon-carbon and carbon-heteroatom conjugate addition of n-substituted maleimides to 4h-1,2,4- triazol-3-thioles, 2-amino-1,3-thiazoles, 1h-imidazole and 2-phenylindolizine catalyzed by lewis acids
In the paper the cheap and effective method of the synthesis of 3-heteryl substituted succinimides via catalytic Michael addition are presented. Lewis acids have been found to be effective catalysts for conjugate addition of N-aryl substituted maleimides to the heterocycles with donor-heteroatoms or CH-active function. Catalytic reactions proceed in mild conditions without formation of by-products that are often present in the classical Michael reaction. The compounds synthesized are promising and interesting substrates for biological evaluation since numerous natural products, drugs and drug candidates bear the succinimide core. Moreover, regioselectivity of addition of ambident heterocyclic nucleophiles such as 4H-1,2,4-triazole-3-thiole, 1H-imidazole and 2-amino- 1,3-thiazole to maleimides have been investigated. Lewis acids such as aluminium chloride, zinc chloride and lithium perchlorate have been tested on different heterocyclic substrates as catalysts. Interestingly, depending on nucleophilicity of the substrate different Lewis acids have shown significantly varying efficacy. In this respect aluminium chloride was identified as the most effective catalyst for C–C addition among the Lewis acids tested. Lithium perchlorate appears to be the most efficient in the case of C–N addition with the endocyclic nitrogen atom of the hererocycle. Zinc chloride shows a good catalytic efficacy in addition of maleimides to the exocyclic amino group of 2-aminothiazole. Finally, the advantages of the catalytic approach developed such as mild reaction conditions, easy handling, low toxicity of the catalysts and their low cost make this method useful for the synthesis of new 3-heteryl substituted succinimides, which, in turn, are interesting substrates in medicinal chemistry.
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The synthesis and investigation of vasoactive properties of new phosphorylated peptidomimetics
The paper presents the synthesis of new phosphorylated peptidomimetics and their action on the isolated rat aorta. It has been shown that derivatives of diethyl 5-amino-2-phthalimidoalkyl-1,3-oxazol-4-ylphosphonates can be employed in the synthesis of phosphorylated peptidomimetics containing a phosphonoglycine residue. For this purpose derivatives of 1,3-oxazol-4-ylphosphonates were decomposed hydrolytically in the acidic medium. The reaction of diethyl 5-alkylamino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates with unsaturated azlactones was used to obtain phosphorylated peptidomimetics with dehydroamino acid groups. The method developed is very convenient and preparative because reactions proceed in mild conditions without formation of undesirable byproducts. Peptidomimetics are isolated with high yields and their separation does not require chromatography. Biological research has revealed the vasodilating activity of new derivatives of phosphorylated peptidomimetics depending on their chemical structure when acting on the rat’s isolated aorta. The possible molecular mechanisms of this activity with participation of the plasma membrane Ca2+-channels of vascular smooth muscle cells are discussed. The data of impact of an inhibitor of voltage-dependent Ca2+-channels of L-type of nitrendipine on the vascular tone are reported. It has been found that the concentration dependences of the vasodilating activity of the diethyl esters of 5-alkylamino-2-{N-[N-benzoyl-(4-methylbenzylidene)glycyl]aminomethyl}-1,3-oxazol- 4-ylphosphonates synthesized and nitrendipine are similar. It can testify about the indirect detection of the vasodilatory effect of these compounds associated with inhibition of the calcium signal system. The study shows a direct effect of the compounds synthesized on the muscle cells of blood vessels.
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The structure and biological properties of (4-hydroxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)acetic acid and its esters
Continuing the search of new effective and safe means for pain relief in the range of different derivatives of 4-hydroxyquinoline-2-ones (4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetic acid and series of its alkyl esters have been involved in the objects of our research. All pharmacological experiments in studying the anti-inflammatory and analgesic activity of the compounds synthesized have been carried out in white mice using standard screening models – «carrageenan edema» and «acetic acid writhing», respectively. Compounds that are not inferior to the anti-exudative and analgesic action of the known non-steroidal anti-inflammatory drug Diclofenac have been identified. In addition, the important structural and biological regularities, which are of interest for further research as a starting basis have been found. With the help of X-ray analysis the peculiarities of the spatial structure of some products synthesized have been studied. A detailed comparative analysis of X-ray diffraction data of the most active analgesics identified among the tested substances – methyl (4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetate and its ethyl analogue has been performed. It is instrumentally confirmed that these two compounds have a substantially identical spatial structure, the same type of the intermolecular hydrogen bonds system and the same crystalline packing. However, they exhibit an analgesic effect approximately of the same level, but vary greatly in intensity of their anti-inflammatory properties. According to the results of the comprehensive analytical and biological studies the conclusion has been made that for all its undoubted importance the crystalline structure of substances is not the only factor that has a significant impact on their pharmacological properties.
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Heterocyclisation on the basis of ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1h-pyrazo-le-3-carboxylates
Ethyl 1-aryl-5-methyl-4-(2-R-1,3-thiazol-4-yl)-1H-pyrazole-3-carboxylates, ethyl 1-aryl-4-(imidazo[1,2-a]pyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxylates, ethyl 1-aryl-4-(imidazo[2,1-b][1,3]thiazol-6-yl)-5-methyl-1H-pyrazole-3-carboxylates, ethyl 1-aryl-4-{3-aryl(hetaryl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl}-5-methyl-1H-pyrazole-3-carboxylate have been synthesized by heterocyclisations of ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazole-3-carboxylates with thiobenzamide, 1-(6-methylpyridin-2-yl)thiourea or 1-carbamidoylthiourea, pyridin-2-amine, 1,3-thiazol-2-amine and 4-amino-5-aryl(hetaryl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones, respectively.
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The study of the structure – anticancer activity relationship of 4-thiazolidinone derivatives using multivariate adaptive regression splines
Combining the bagging method with multivariate adaptive regression splines the complex QSAR-model that incorporates 200 submodels has been developed. The predictive ability of the new model has the superiority over already known 4-thiazolidinones anticancer activity models. The interpretation of the most significant descriptors used in the model reveals promising templates for the design of new anticancer agents. The earlier conclusion that small sizes of molecules together with the absence of bonds with high dipole moments increase the antitumor activity has been confirmed. The influence of 3D-MoRSE descriptors values on the capability of compounds to inhibit the cancer cells growth has been found.
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The synthesis of 1-(triethylsilyl)-3-[4-(hetaryl)phenyl]-5-(trimethylsilyl)penta-1,4-diyn-3-ols
The method of synthesis of 1-(triethylsilyl)-3-[4-(hetaryl)phenyl]-5-(trimethylsilyl)penta-1,4-diyn-3-ols based on the interaction between 1-(triethylsilyl)-5-(trimethylsilyl)penta-1,4-diyn-3-one and lithium derivatives of 1-(4-bromophenyl)-1H-indole or 9-(4-bromophenyl)-9H-carbazole has been developed.
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One-pot synthesis of the substituted imidazolidin-2-ones with participation of thiobarbituric acid, ureas and arylglyoxals
Derivatives of imidozoline-2-ones containing the pyrimidinthionic moiety in position 4 have been synthesized by three-component one-pot condensation of thiobarbituric acid, arylglyoxal hydrates and ureas. It has been found that these compounds exist in the solution of DMSO-d6 as a mixture of two tautomeric forms: for products obtained from N-substituted ureas the imidazolidin form predominates; and in the case of urea the imidazolidin and imidazolin forms are present in the ratio of 1:1.
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New steroidal glycoside of allium cyrilіlii racemes
Steroidal glycosides are the vast class of natural compounds from the group of saponins that attract attention of researchers due to the wide spectrum of their biological activity and ecological safety. Plants from Allium genus growing in the Crimea are promising as to search of species with saponins. As a result of research of steroidal glycosides of Allium cyrillii Ten. racemes a new spirostanol glycoside has been isolated. The 1H- and 13C-NMR spectral data testify that this compound is a derivative of spirostan series. After acidic hydrolysis with the help of TLC only glucose has been identified by comparing to the samples of monosaccharides known beforehand. The chemical shifts of all protons of the carbohydrate residue have been determined by means of combination of two-dimensional TOCSY and COSY spectra. The 13C-chemical shifts of signals of their corresponding atoms are simply taken by means of the HSQC spectrum. The hydroxy groups position at C-2 and C-6 atoms of aglycone have been determined by the analysis of chemical shifts of C-atom signal comparing to the literary data for unsubstituted for aglycon parts and taking into account considerable positive α-effects of hydroxylation and little, usually negative, β-effects. Analysis of NMR 13C spectra of the compound isolated and 24 hydroxy derivative has shown that the signal of C-24 undergoes paramagnetic displacement in +10.8 ppm. The strong field change of signals of C-23 and C-25 also takes place. Correlation between the signal of the anomeric proton of glucose and C-24 aglycone in the HMBC spectrum confirms the site of addition of the glucose residue to aglycone. Thus, the glycoside isolated from Allium cyrillii racemes is (24S,25S)-5α-spirostan-2α,3β,6β,24-tetraol-24-O-β-D-glucopyranoside and it is a new compound.
