Vol. 11 No. 4(44) (2013)

Published: 2013-12-02

Original Researches

  • Carbene variations of some classical reactions

    O. P. Shvaika, M. I. Korotkikh

    Carbene variations of a series of fundamental reactions, the features of their course in comparison with classical analogues have been first summarized and analyzed in the review. A number of carbene transformations described in the literature relates to classical name reactions being substantially their carbene variations acquiring the characteristics with the participation of carbenes. The attention in the review is drawn to such important analogies. Besides the carbene mechanism, they differ from the classical versions of the reactions because they mostly proceed under milder, sometimes considerably milder conditions. They always lead to specific products, the structure of which is conditioned by the nature of carbenes as ambiphilic reagents, and it affects certain stages and the final result of the reaction. In the above terms, such reactions are considered for the cases when carbenes are stoichiometrical components (carbene variations of Bodger, Michaelis-Arbuzov, Leuckart-Wallach reactions, Claisen condensation, Hoffman elimination), as well as for the cases when they are catalytic components (transesterification, Stetter reactions, benzoin condensation, nucleophilic aromatic substitution). At the present stage carbene variations of the classical reactions have become promising in the synthesis of some pharmaceutical substances, as well as in diesel fuel obtaining from vegetable oils. The review is intended to initiate further searches and deepening of such analogies.

    DOI: https://doi.org/10.24959/zofh.17.909
  • Synthesis and the antimicrobial activity 1-n-alkylated derivatives of 3-n-substituted 1H-thieno[3,2-d]pirimidine-2,4-diones

    O. V. Tkachenko, S. V. Vlasov, S. M. Kovalenko, I. O. Zhuravel’, V. P. Chernykh

    Two approaches for synthesis of a great variety of 3-N-substituted 1H-thieno[3,2-d]pyrimidine-2,4-diones have been investigated. The first one is based on the interaction of methyl 3-aminothiophene-2-carboxylate with isocyanates, which is a good way for preparation of 3-N-aryl-1H-thieno[3,2-d]pyrimidine-2,4-diones. The key step of the other one, which allows introduction of different alkyl substituents in position 3, is oxidation of 4-oxo-2-thioxo-2,3- dihydrothieno[3,2-d]pyrimidines prepared by interaction of 3-isothiocyanatothiophene-2-carboxylate and the primary aliphatic amines with hydrogen peroxide. Alkylation of the intermediates obtained in both ways resulted in 1-N-alkyl-3-N-substituted 1Н-thieno[3,2-d]pyrimidine-2,4-diones. 1H NMR spectra of the target molecules contain the signals of thiophene cycle protons H-6 (δ 8.02-8.18 ppm) and H-7 (δ 7.06-7.15 ppm) together with the signal of CH2 groups in position 1 of the heterocyclic system in the range of δ 4.70-5.20 ppm. The antimicrobial activity of the compounds synthesized has been investigated by the agar well diffusion method. It has been determined that the compound with phenyl substituents in position 3 and o-methylbenzyl substituent in position 1 is the most active antimicrobial agent. The 1-N-alkyl derivatives of 2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidine-3-yl)propanoic acid benzyl amide appeared to be active against the strains of Staphylococcus aureus and Bacillus subtilis.

    DOI: https://doi.org/10.24959/zofh.17.910
  • 2-amino-5-(4-chloro-1h-imidazol-5-yl)-1,3,4-thiadiazoles: synthesis, pyrimidoannulation and the bactericidal activity

    A. M. Grozav, V. O. Chornous, O. I. Gavrylyuk, M. V. Vovk

    This investigation is devoted to the synthesis of new representatives of 2-amino-5-imidazolil-1,3,4-thiadiazole systems, the study of some chemical transformations and the bactericidal activity. It has been shown that thiosemicarbazones obtained by condensation of 4-chloro-1H-5-formylimidazoles with thiosemicarbazide when heated with a triple surplus of iron (III) chloride hexahydrate in 80% acetate acid undergo oxidative cyclization with formation of new 2-amino-5-(4-chloroimidazole-5-yl)-1,3,4-thiadiazoles. The compounds synthesized are heterocyclic systems with two electrophilic centres that are widely used when obtaining biheterocyclic biologically active systems. While studying the chemical behaviour of 2-amino-1,3,4-thiadiazoles under research in reactions of annulation with series of bielectrophilic reagents it has been found that they do not react either with phenacylbromide or malononitrile, and with chloroacetylchloride the product of 5-aminoacylation is formed; it even when heated in the boiling DMF in the presence of K2CO3 is not prone to intramolecular cyclocondensation. At the same time heating of 2-amino-1,3,4-thiadiazoles with diethyl ether of acetylenedicarboxylic acid in the absolute boiling ethanol leads to formation of ethyl-7-oxo-[1,3,4]-thiadiazolo-[3,2-a]-pyrimidine-5-carboxylates. The results of studying the antibacterial properties of 2-amino-1,3,4-thiadiazoles have shown that the compounds synthesized possess a moderate bactericidal and fungicidal activity.

    DOI: https://doi.org/10.24959/zofh.17.911
  • Synthesis of n-acetylglucosaminides dimers

    O. Ye. Zemlyakov, V. M. Tsykalova, S. O. Zemlyakov, V. Ya. Chirva

    Glycosylation of aliphatic and aromatic α,ω-diols by the oxazoline method and by peracetylated α-D-glucosaminylchloride in the presence of zinc chloride and co-promoters (quaternary ammonium salts or trityl chloride) have been investigated. The highest yield of bis-glucosaminides in the conditions of oxazoline synthesis (the solvent is dichloroethane, the temperature of the reaction mixture is ~100°C, catalytic quantities of p-toluenesulfonic acid) has been observed for octane-1,8-diol. The products of monoglycosylation of butane-1,4-diol and dodecane-1,12-diol have been also obtained. The influence of the nature of a со-promoter has been studied on the model glycosylation reaction of octane-1,8-diol with peracetylated α-D-glucosaminylchloride in reflux dichloromethane (the ratio of glycosyl-acceptor : glycosyl-donor : zinc chloride : quaternary ammonium salt = 1 : 2,5 : 2,5 : 2,5). The best yields of dimeric glycoside have been obtained using tetrabutylammonium bromide. Increase of the amount of zinc chloride up to 1.5 equivalents in relation to the glycosyl donor has not led to significant changes of the reaction product yield. The yields of bis-glycosylation have been increased using peracetylated α-D-glucosaminylchloride as a glycosyl-donor for all aglycones. The corresponding mono- and bis-glucosaminides of 2,2’-(1,2-phenylenedioxy)diethanole have been synthesized by glycosylation in these conditions. The structure of the glycosides synthesized has been proven by 1H-NMR-spectroscopy.

    DOI: https://doi.org/10.24959/zofh.17.913
  • The search for new biologically active substances among derivatives of 3-mercapto-4-amino- 5-cyclohexyl-1,2,4-triazole(4h)

    N. B. Saidov, V. A. Georgiyants, N. V. Garna

    Synthesis of the series of new 4-phenyl-5-cyclohexyl-1,2,4-triazole(4H)-3-yl thioacetanilides is described. The key intermediate – 4-phenyl-5-cyclohexyl-3-mercapto-1,2,4-triazole(4H) has been synthesized started from cyclohexane carboxylic acid through its methyl ester, then hydrazide and the corresponding potassium 3-cyclohexyl dithiocarbazate after cyclisation with hydrazine hydrate. The end products 6a-u have been obtained by alkylation of the key intermediate 5 with chloroacetic acid anilides in the presence of basic catalysts. The purity of the compounds synthesized has been monitored by TLC. The structure of compounds synthesized has been proven by elemental analysis data and NMR spectra. In NMR-spectra the result of alkylation has been proven by disappearence of the chemical shift of the mercaptogroup. All compounds – both intermediate 5 and end products 6a-u contain signals of the cyclohexane system protons as two multiplets near 2.80 ppm (CH) and at 1.92-1.11 ppm (CH2)5; 4-aminogroup protons as a singlet signal at 5.92-5.87 ppm. The preliminary prediction of the possible pharmacological activity by computer prognosis (PASS programme) has been carried out. Among activities, which are the most probable for some of the substances synthesized, are ligase inhibitor, interferon agonist, antihypertensive, thyroid hormone antagonist, sedative, antiviral (Pa = 0.554-0.729). Due to prognosis and analysis of logical data the substances synthesized will be examined as possible antiviral agents.

    DOI: https://doi.org/10.24959/zofh.17.916
  • A new method for synthesis of atomoxetine and its interaction with with azole-con¬taining sulfonyl chlorides

    M. K. Korsakov, L. O. Shumilova, V. O. Postnov, M. V. Dorogov, M. Yu. Solovyov

    A new approach to the synthesis of atomoxetine using the methods of enzymatic catalysis has been developed;
    the interaction of atomoxetine with a number of azole-containing heterocyclic sulfochlorides has been studied. The
    carbonyl group of 3-chloro-1-phenyl-propane-1-one was region-specifically reduced with NADPH-dependent
    carbonylreductase (SSCR) in phosphate buffer solution. In Mitsunoby reaction with o-methylphenole the inversion
    of the final product configuration takes place and [R]-1-(3-chloro-1-phenypropoxy)-2-methylbenzene is formed.
    Its further treatment with methylamine results in the base of atomoxetine, which may be isolated from the solution
    as a chloride. In order to develop the novel biologically active compounds the series of sufonyl chlorides with
    oxazole and isoxazole substituents were reacted with atomoxetine. The sulfonamides obtained fully comply with
    all criteria for the molecules – candidates for the biomedical study.

    DOI: https://doi.org/10.24959/ophcj.13.765
  • Synthesis of new n,n’-disubstituted 5-spirocyclopenten-3-yl 2,4,6-trioxyhexahydropy-rimidines

    N. I. Kobyzhcha, V. M. Holovatiuk, Yu. V. Bezugly, V. I. Kashkovsky

    The synthesis of new N, N`-disubtituted 5-spiro-2,4,6-trihydropyrimidinetriones by ring-closing metathesis reactions has been presented in this work. Starting compounds for obtaining of spirocycles (5,5-diallyl-1,1-dioxythiolanyl-2,4,6-trihydropyrimidinetriones) have been synthesized by two pathways, one of them is condensation of carbamides with malonic acid in the presence of dehydrating agents, whereas the other path consists in the condensation of dicyanodiamide with diallylcyanoacetic ester in the presence of sodium alkoxide, and the resulting products are subjected to alkylation with the following acid hydrolysis. It has been found that imidazolidine containing the isopropoxybenzylidene ruthenium complex is the most suitable for carrying out of ring-closing metathesis reactions since it has the high thermal stability; it allows to obtain the target products with a high yield due to carrying out these reactions at the higher temperatures. The preliminary computer prognosis of the biological activity of new 1,1-dioxythiolan derivatives with the help of PASS (Prediction of Activity Spectra for Substances) programme has shown that some of these compounds can be ATPase proteasome inhibitors. Moreover, new spirocyclopenten containing derivatives may be promissing as precursors for obtaining of biologically active substances.

    DOI: https://doi.org/10.24959/ophcj.13.770
  • Synthesis and the antimicrobial activity of 2-(1-acyl-3-piperidinyl)-1h-benzimidzoles de-rivatives

    S. M. Kovalenko, S. V. Vlasov, K. Yu. Krolenko, O. V. Zaremba, V. P. Chernykh

    An effective and simple method for liquid-phase combinatorial synthesis of structural analogues of compounds with the mechanism of action being similar to aminoglycoside antibiotics – 2-(1-acyl-3-piperidinyl)-1H-benzimidazoles
    based on acylation of the starting 2-(3-piperidinyl)-1H-benzimidazole with aromatic carboxylic acids imidazolides has been developed. The starting 2-(3-piperidinyl)-1H-benzimidazole has been obtained by interaction
    of o-phenylenediamine with nipecotic acid heating in the polyphosphoric acid medium. The application of polyphosphoric acid in this case allows keeping high temperature of the reaction medium without any other additional solvent because it well dissolves both of the components. The structure of the compounds obtained has been confirmed by 1H NMR and IR-spectroscopic methods. Unlike the starting 2-(3-piperidinyl)-1H-benzimidazole the products of its acylation contain additional signals in the region of aromatic proton resonance, produced by aromatic protons of acyl radicals. The signal of imidazole NH, which is not observed for the starting amine because of proton exchange is cleanly identified as the broad singlet at 12.14-12.30 ppm. IR-spectra of 2-(1-acyl- 3-piperidinyl)-1H-benzimidazoles are characterized by the n N–H stretching bands in the region of 3526-3417 cm-1, and the bands of n C–H vibrations (3199-2766 cm-1). An intensive band of n C=O vibrations is observed at 1672-1601 cm-1. The study of the antimicrobial activity for the compounds obtained performed by the serial dilution method has proven that the most bactericidal properties against Staphylococcus aureus strains are shown by the compounds with hydrophobic electron-donating substituents (Me-, F-) in the benzoyl fragment (MBC = 37.5 μg/ml); while the compound with the methoxy-group in meta-position of the benzoyl moiety has appeared to be active against the strain of Escherichia coli, however, it inhibits the growth of this microorganism at higher concentrations (MBC = 75 μg/ml).

    DOI: https://doi.org/10.24959/ophcj.13.755
  • Synthesis and the biological action of thiosemicarbazones and (1,3-thiazol-2-yl)hyd-razones of [(1-aryl-5-formylimidazol-4-yl)thio]-acetic acids

    V. O. Chornous, A. O. Palamar, A. M. Grozav, I. M. Yaremiy, M. V. Vovk

    This research focuses on the synthesis of thiosemicarbazones [(1-aryl-5-formylimidazol-4-yl)thio]acetic acids and the study of some of their chemical transformations and biological activity. By condensation of [(1-aryl-5-formylimidazol-4-il)thio]acetic acids with thiosemicarbazide in boiling acetic acid the corresponding thiosemicarbazones have been obtained with high yields. They were used as effective N,S-binucleophiles in reactions of cyclocondensation with electrophilic reagents. In particular, heating of these thiosemicarbazones with monochloroacetic acid in the acetic acid medium results in formation of (1,3-thiazol-2-il)hydrazones [(1-aryl-5-formylimidazol-4-yl)thio]acetic acids. By the reaction of maleic anhydride with thiosemicarbazones of [(1-aryl-5-formylimidazol-4-il)thio]acetic acids in boiling dioxane 2-[(1H-imidazol-5-yl)methylenehydrazino)-4-oxo-1,3-thiazole-5-il]acetic acids have been synthesized. The compounds obtained show a moderate antioxidant effect. The maximum level of inhibition of free radical lipids oxidation in vitro is observed in final concentrations of 10-1M and is 31.94% compared to the control. The results of the bactericidal and fungicidal activity obtained show that the compounds studied are characterized by the moderate antimicrobial action: the minimal bacteriostatic and fungistatic concentrations are in the range of 62.5-2000 mcg/ml.

    DOI: https://doi.org/10.24959/ophcj.13.774
  • Synthesis and biological properties of 3-(3-cycloalkylcarbamoyl-4-hydroxy-2-oxo- 1,2-dihydroquinolin-1-yl)propanoic acids and their nitriles

    I. V. Ukrainets, O. V. Gorokhova, X. V. Andreeva

    Based on the generally recognized in modern medical chemistry methodology of the chemical modification of substances, which are promising in the pharmacological respect, the preparative methods for their obtaining have been suggested and the synthesis of a series of new 3-(3-cycloalkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic acids and their nitriles has been carried out. At the same time the alternatives of the synthesis of both intermediate cycloalkylamides of 4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxylic acid and final quinolinylpropanoic acids are considered. It has been demonstrated that in the first case the choice of one or another method is determined by the physical characteristics of amine. So, it is expedient to perform amidation of ethyl 1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate with low boiling cycloalkylamines by the excess of amine in boiling alcohol, whereas with high boiling or crystalline amines thermolysis of equimolar amounts of reagents is more preferable. Transformation of quinolinylpropionitriles obtained into the corresponding quinolinylpropanoic acids without destruction of cycloalkylamide moieties can be performed by long-term heating in the mixture of hydrochloric and acetic acids with the low content of water. However, as the experiments carried out show, alkaline hydrolysis being more available and simple in its performance is suitable for the given trasformation. Thus, undesirable destruction of cycloalkylamide groupings occurs to only a small extent, and it can be neglected. The peculiarities of NMR 1H spectra of the compounds synthesized allowing to control easily the course of both side and planned reactions are discussed. Using standard screening models the analgesic and diuretic properties of all substances obtained have been studied. It has been found that transfer from 3-(3-R-carbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic acids and nitriles with alkyl substituents in the amide moieties to their cyclic analogues with the same number of carbon atoms does not lead to increase in the biological activity, and therefore, it is unpractical.

    DOI: https://doi.org/10.24959/ophcj.13.764
  • Ternary rhenium (i) complexes: from fluorescent reporters to interesting scaffolds for dual-imaging heterobimetallic probes

    Louise Marty, Alison François, Tetiana Krachko, Chantal Galaup, Claude Picard, V. M. Amirkhanov, Eric Benoist

    In this paper, five new ternary tricarbonylrhenium(I) complexes based on a pyridinetriazole moiety, the so-called pyta, have been investigated. These cationic complexes of the general formula [Re(CO)3(pyta-COOMe)L] (L = substituted pyridine derivatives) combine a carboxylate functionalization, for further biomolecule conjugation, with a metal chelating site – a pyta-based tricarbonylrhenium moiety – which can act as a fluorescent reporter. The complexes have been prepared using a two-steps pathway involved the activation of [Re(CO)3Cl(bipy)] with triflate silver salts in the presence of acetonitrile followed by the thermally activated substitution of the acetonitrile adduct by commercially available substituted pyridine derivatives. They have been prepared from modest to good yields, fully characterized by means of NMR, IR and mass spectrometry, and their photophysical properties have been investigated. Upon excitation into the MLCT band of each complex (absorption band at ca. 300 nm), three of them exhibit a bright green luminescence centered at c.a. 494 nm, with a quantum yield of 0.60% in acetonitrile. These interesting photophysical features make them potential fluorescent cellular imaging agents. Moreover, thank to their ancillary ligand, they could be also considered as interesting scaffolds for the preparation of dual-imaging heterobimetallic species.

    DOI: https://doi.org/10.24959/ophcj.13.773
  • N-(arylpiperazinyl)butylimides of bicyclo [2.2.1]gept-5-en-endo-endo-2, 3-dicarbonic acid – ligands of 5-ht1a and d2 receptors, their neurotropic properties

    S. A. Andronati, T. L. Karasyova, A. V. Zamkova, S. G. Soboleva, I. A. Boyko, L. I. Kasyan, D. I. Tsimbal

    It is known that hetaryl(aryl)piperazines possess important neuropharmacological (anxiolytic, antidepressant, neuroleptic, etc.) properties. In the process of studying the relationship between the structure and properties of N-(arylpiperazinyl) butylimides bicyclo[2.2.1]gept-5-en-endo-endo-2,3-dicarbonic acid (compounds 1-5) the neuropharmacological properties and their affinity for D2 and 5-HT1A receptors have been studied in this work. It has been determined by the radioligands method that arylpiperazines 1-5 possess the high affinity for D2 and 5-HT1A receptors. Compounds 1-5 have been found to have the marked sedative and neuroleptic properties. The compounds (1-5) synthesized revealed a dose-dependent pharmacological effect. In lower doses (5 mg/kg) on the model of the conflict test in rats m-tolyl derivatives had the same anxiolytic effect as buspirone (10 mg/kg); in higher doses (10 mg/kg) all compounds revealed the neuroleptic activity on the model of “Waxy flexibility” catalepsy induction. Compounds of this series in the dose of 10 mg/kg reduced the apomorphine-induced stereotypic behaviour by 33.7-86.5% in rats, as well as a refrence drug haloperidol. All of these compounds are nontoxic, the value of their LD50 ≥ 300 mg/kg.

    DOI: https://doi.org/10.24959/ophcj.13.775
  • Carboxylic group modification as a method of intensification of diuretic properties of 7-hydroxy-5-oxo-2,3-dihydro-1h,5h-pyrido[3,2,1-ij]quinoline-6-carboxylic acid 2-carboxyanilide

    I. V. Ukrainets, M. Yu. Golik, I. M. Chernenok, V. O. Parshikov

    The intensive and purposeful search of fundamentally new diuretics conducted by our research laboratory among the derivatives of 4-hydroxyquinolin-2-ones has found 7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij] quinoline-6-carboxylic acid 2-carboxyanilide as an intermediate lead compound. The basis for it is a high diuretic activity and a low toxicity of this substance. However, a free carboxylic group, which is often conductive to appearance of an extremely undesirable ulcerogenic action in relation to the gastro-intestinal tract, can be a serious obstacle for using the given compound as a drug. That is why we attempted to block the carboxylic group of 2-carboxyanilide by one of the known methods. For this purpose the methodology of both classical and non-classical bioisosteric replacements has been used. When conducting the synthetic part of the research the alternative ways of close structural analogues of the basic molecule were considered. As a result the optimal method for their obtaining has been offered; it differs by the minimal time costs and preparative high yields and purity of the target products. The structure of all substituted 7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij] quinoline-6-carboxanilides synthesized has been confirmed by the data of elemental analysis, counter synthesis and NMR 1Н spectra. The primary pharmacological screening in studying the effect of the compounds obtained on the excretory function of the kidneys has been carried out in white outbread rats using the standard method. The testing has been performed in parallel and in comparison with Hydrochlorothiazide, as well as the abovementioned 2-carboxyanilide. It has been determined that some compounds under study in the dose of 10 mg/kg when introduced orally exceed not only Hydrochlorothiazide, but the basic molecule as well. By the results of the experiments carried out the structural and biological regularities that are important for further research have been found. As a new lead compound 7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylic acid 2-carbamoylanilide has been suggested. It has no free COOH-group and, therefore, is not capable of having an great effect on the gastro-intestinal tract.

    DOI: https://doi.org/10.24959/ophcj.13.766