Vol. 12 No. 4(48) (2014)
Published:
2014-12-10
Full Issue
Original Researches
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The structural optimization of [(2-R-quinazolin-4-ylidene)hydrazono]carboxylic acids and esters – approach for creating a new class of compounds with the anticancer activity
The strategies of the search of novel effective anticancer agents via optimization of [(2-R-quinazoline-4-ylydene) hydrazono]carboxylic acids and their esters are summarized in this article. To develop the most efficient synthetic approaches of initial substances the available information about chemical properties of [(2-R-quinazoline- 4-ylydene)hydrazono]carboxylic acids and their derivatives has been generalized and systematized. The basic approaches for optimization of the initial substances structure included variation of substituents in position 2, creation and removal of conformational constraints and introduction of substituents into the cyclisation products. It has been shown that (3H-quinazoline-4-ylydene)hydrazine easily interacts with α, β, γ-ketocarboxylic acids and their esters with formation of the corresponding hydrazonoderivatives. The given compounds are multicenter reagents, which are able to cyclize into the corresponding 3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones. 3-R- 2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones are a class of electron-deficient heterocyclic systems and may be cleaved under the action of strong nuleophiles, in particular hydrazine, followed by formation of the corresponding 3-(2-aminophenyl)-6-R-1,2,4-triazine-5(2H)-ones or 3’-(2-aminophenyl)-3-R-spiro[pirazoline-5,6’(1’H)-1,2,4- tiazine]-5’(4’H)-ones. A comparative description of spectral characteristics of the compounds synthesized has also been presented. The highest anticancer activities have been shown by compounds 2c, 3b and 3c against leukemia cell lines CCRF-CEM (logGI50 = -6.10; 6.05; 5.81, respectively), compound 3b and 3c against breast cancer cell lines HS 578T (logGI50 = -5.83; -6.43, respectively). The results of SAR-analysis have been discussed and directions of further modification of the structures studied have been proposed.
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Reactions of N-alkylhydrazones of aliphatic ketones
For the first time data concerning the reactions of N-alkylhydrazones of aliphatic ketones have been systematized. The possible reaction centres of hydrazones and the main lines of attack for electrophilic and nucleophilic reagents have been distinguished. Differences in the reactivity of N-alkyl and N-arylhydrazones have been studied. The types of tautomerism of hydrazones and their impact on the reactivity of these compounds have been considered. Most reactions occurring on the sp2-hybridized carbon atom lead to formation of azocompounds, which are generally aliphatic radical sources or initiators of radical processes. The interaction of hydrazones with oxidising reagents leading to the corresponding bisazocompounds has been studied. For a number of N-acylation hydrazones the ring-chain tautomerism has been described, as a result these compounds exist in cyclic and acyclic forms. The general methods for construction of heterocyclic compounds based on N-alkylhydrazones of aliphatic ketones due to cyclization of hydrazones with bis-functional reagents on both nitrogen atoms, as well as the nitrogen atom and the carbon atom have been considered. Hydrazone-enhyidrazine tautomerism is inherent to hydrazones of aliphatic ketones with the α-methylene group; it causes a simultaneous attack of dielectrophiles on the sp3-hybridized carbon atom and the nitrogen atom of hydrazone and can be used to construct derivatives of pyridazine and pyrazole, and the use of compounds of phosphorus and of silicon as dielectrophiles results in formation of phosphodiazoles and silapyrazolines, respectively. Reduction reactions for C=N bond of N-alkylhydrazones of aliphatic ketones have been studied.
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Synthesis and analgesic activity of N-(benzothiazol-2-yl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides
Continuing the search of new effective analgesics with improved properties the corresponding N-(benzothiazol- 2-yl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides have been synthesized in boiling xylene by the interaction of methyl ester of 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid with 2-aminobenzothiazoles. The structure of the substances synthesized has been confirmed by the data of elemental analysis, NMR 1H spectroscopy and mass-spectrometry. The peculiarities of the aromatic region interpretation in NMR 1H spectra of the structural class studied have been discussed. It has been shown that in ionization by electron impact the primary fragmentation of molecular ions of N-(benzothiazol-2-yl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides surprisingly occurs in a variety of ways. It starts with SO2 release in amide unsubstituted in the benzothiazole moiety of the molecule and its 6-methyl analogue, while for halogenated products the primary breaking of the terminal carbamide bond or the loss of halogen are characteristic. According to the results of the pharmacological research performed on the model of tail-flick procedure, N-(6-bromobenzothiazol-2-yl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide has been determined; it exhibits the analgesic effect at the level of Meloxicam.
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Synthesis and study of the antimicrobial activity of N-alkyl(dimethylaminoalkoxyacetammoniumchloride)-N′-[4-(hydroxymethyl)-1H-pyrazol-3-yl]ureas
A number of the quaternary ammonium salts previously unknown with polyfunctional pyrazole base have been obtained. The structure of these pyrazoles contains highly polar ammonium, ureide and hydroxymethyl groups. The compounds under study were synthesized by quaternization of N-dimethylaminoalkyl-N 4- ]-׳ (hydroxymethyl)-1H-pyrazol-3-yl]ureas by chloroacetic acid esters containing the lipophilic alcohol residue of various length. The structure of the substances obtained has been strictly confirmed by the data of elemental analysis, as well as by IR- and NMR 1H-spectral measurements. A wide range of the antimicrobic action for each substance synthesized has been found in their microbiological study. Gram-positive microorganisms, in particular coccal bacteria group, revealed the highest sensitivity to the inhibiting action of the substances. The culture of yeast-like fungi f Candida genus was less sensitive. Quaternary ammonium salts had less expressed action on gram-negative bacteria of enteritis group, e.g. E. coli, Proteus vulgaris and Pseudomona saeruginosa. Analysis of the structureactivity relationship of a number of compounds makes clear that the length of the alkoxyacetyl fragment near the ammonium centre has the greatest effect on the antimicrobic action. At the same time there is virtually no dependence of the biological effect from the distance between ureide and amide nitrogen atoms in the exocyclic fragment. The study of the antimicrobic action depletion of the most active substances by tenfold addition of inoculation doses of test cultures of St. aureus has shown their cumulatively high bactericidal action.
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The multi-component condensation in the synthesis of the substituted 2-alkylsulphanil-4,6-diarilpyridine-3-carbonitriles and their derivatives
The multi-component condensation of chalcones, malononitrile, alkylhalides, hydrogen sulphide and N-methyl-morpholine completes with forming 2-alkylsulphanil-4,6-diarylpyridine-3-carbonitriles, which are used in the synthesis of the substituted 1,4-bis(3-cyano-6’-methoxyphenyl-4’-phenylpyridin-2-ylthio)butane, 3-amino-4,6-diaryl-2-R-thieno[2,3-b]pyridine, pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine. During the reaction the interaction of malononitrile with hydrogen sulfide forms cyanothioacetamide, which is reactive with chalcone by Michael reaction. The corresponding adduct intramolecularly cyclizes into the substituted pyridine-2-thiolate N-methylmorpholinium. The latter can be alkylated in situ by alkyl halides into the aforementioned heterocyclic ring systems. The substituted 2-alkylsulphanil-pyridines with a labile hydrogen atom in the SCH2 fragment are capable to cyclize by Thorpe-Ziegler under alkaline conditions in direction to the intramolecular interaction with the cyano group of the pyridine ring vicinally located towards the methylensulphanil fragment. 3-Amino-6-(4-methoxyphenyl)-4-phenyl-2-cyanotieno[2,3-b]pyridine in refluxing in formamide easily forms 4-amino-7-(4-methoxyphenyl)-9-phenylpyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine previously unknown. The composition and structure of the newly synthesized compounds have been confirmed by elemental analysis, infrared spectroscopy (IR), nuclear magnetic resonance of protons (1H NMR) and mass spectrometry.
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The synthesis of bisphosphonate analogues of nucleotides – derivatives of (α-phenyl)(α-fluoro)methylenebisphosphonic acids
The synthetic methods of fluorine-containing mimetics of nucleozide-diphosphates based on the derivatives of (α-fluoro)(α-phenyl) methylenebisphosphonic acid containing the residues of 2-{1-[4-(toluene-4-sulfonyl)-5-per-fluoroalkyl-[1,2,3]triazol-2-yl]-ethoxy}-ethelene and {2,2-dimethyl-6-[4(toluene-4-sulfonyl)-5-pentafluoroethyl-[1,2,3] triazol-2-yl]-tetrahyro-furo[3,4-d][1,3]dioxol-4-yl}-methylene as ester groups have been developed. Selective mono-and bisdealkylation of methoxy-groups in the tetramethyl ester of (α-fluoro)(α-phenyl)methylenebisphosphonic acid allows to prepare in high yields the corresponding trimethyl or symmetrical dimethyl esters containing one or two free reactive phosphonic acids groups. These compounds are convenient starting materials for the synthesis of mixed esters of (α-fluoro)(α-phenyl)methylenebisphosphonic acid by esterefication of acidic functionalities using simple aliphatic alcohols (n-butanol) and such analogues of nucleosides as 2-{1-[4-(toluene-4-sulfonyl)-5-perfluoroalkyl-[1,2,3]triazol-2-yl]-ethoxy}-ethanols and {2,2-dimethyl-6-[4(toluene-4-sulfonyl)-5-pentafluoroethyl-[1,2,3]triazol-2-yl]-tetrahyro-furo[3,4-d][1,3]dioxol-4-yl}-methanol. The structure of the compounds obtained has been proven using the methods of IR, NMR (1H, 13C, 19F, 31P) spectroscopy, mass-spectra, and elemental analysis. The cytotoxicity and antiviral activity of the compounds synthesized have been studied on the model of the Epstein-Barr virus. The compound possessing a significant inhibitory effect on the Epstein-Barr virus reproduction has been found.
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Enzymatic resolution of 2-cycloalkylethanols
Kinetic enzymatic resolution is a convenient modern method for obtaining optically pure compounds. The behaviour of 2-cyclopropyl- and 2-cyclobutyl methylcarbinols under conditions of the biocatalytic acylation reaction has been investigated. The comparative analysis of efficiency of enzymes of Burkholderia Cepacia Lipase (BCL) and Candida Antarctica Lipase B (CAL-B) in the reactions of acylation in the presence of vinyl acetate and hydrolysis in the buffer solution has been carried out. The progress of the reaction was monitored by 1H-NMR. It has been found that in 50% conversion the selectivity of enzymatic acylation of both 2-cycloalkylethanols in the presence of BCL is low and increases with increasing the cycle ring due to the small difference in size between alkyl substituents at the chiral carbon atom. By using biocatalysis (2-cyclopropyl) – and 2-cyclobutylethanols in an optically pure (ee ≥ 95%) form have been synthesized. The comparison of the results obtained with the literature data shows that reactions of enzymatic acylation and deacylation proceed in accordance with Kazlauskas rule stating the predominant acylation of (R)-enantiomer and deacylation of (R)-acetate. To study the possibilities of application of the compounds obtained as building blocks the enantioselective synthesis of both enantiomers of (2-cyclobutyl)ethylamine has been conducted using Mitsunobu reaction with hydrazoic acid at the key stage. The optical purity of the compounds studied has been determined by analyzing the 19F-NMR spectra of their derivatives obtained as a result of interaction with Mosher’s acid chloride.
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Synthesis and some transformations of alkyl N-(2-aryl-3-nitro-1,1,1-trifluoropropan-2-yl)carbamates
The paper is devoted to preparation and study of the transformations of novel multifunctional fluorinated synthetic building blocks – alkyl N-(3-nitro-1,1,1-trifluoropropan-2-yl) carbamates. In order to obtain them in high yields the aza-Henry reaction of 2,2,2-trifluoroethylidencarbamates with nitromethane catalyzed by triethylamine has been proposed. The structure of the compounds obtained has been confirmed by spectral methods. Essential elements of the structure corroboration are 13C NMR spectra, in which a signal of the newly formed stereogenic carbon atom is found as a quartet at 63 ppm. It has been shown that the interaction of sodium borohydride with alkyl N-(3-nitro-1,1,1-trifluoropropan-2-yl)carbamates in the presence of the equimolar amount of NiCl2.6H2O leads to selective reduction of the nitro group and formation of the corresponding alkyl N-(3-aminopropan-2-yl)carbamates. The presence of amino group in their structure considerably affects the chemical shifts of diastereotopic methylene protons. Their signals in the 1H NMR spectra are upfield (about 2 ppm difference in comparison with nitro derivatives). Alkyl N-(3-aminopropan-2-yl)carbamates in refluxing toluene in the presence of DBU were easily transformed into 4-trifluorometylimidazolidyn-2-ones by intramolecular cyclization. In its turn, tert-butyl N-(3-aminopropan-2-yl)carbamates when treating with hydrogen chloride in dioxane readily gave 3,3,3-trifluoropropan-1,2-diamines through Boc protecting group cleavage.
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Synthesis and the antiresistant activity of acylated and supramolecular derivatives of ellagic acid
The aim of our research was to obtain new, more soluble and biologically active derivatives of ellagic acid through acylation of phenol hydroxyls and obtaining supramolecular complexes with cyclodextrins, as well as to study the ability of the derivatives synthesized to eliminate the microorganism resistance to aminoglycoside antibiotics (by the example of gentamicin). The article represents the research results of the acylated derivatives of ellagic acid and its supramolecular derivatives with β-cyclodextrins. The structure of the compounds synthesized has been confirmed by NMR1H -spectroscopy and HPLC with a multiwave ultraviolet-detector. It has been shown that in sub-effective concentrations (0.001% solution) in the absence of direct antimicrobial and antifungal properties, tetrasuccinyl-digallic acid (5) reveals the ability to reduce sensitivity to gentamicin in polyresistant strains of microorganisms and sensitivity to nystatin in fungi resistant to it. It has been found that clathrate complexes of ellagotanin with β-cyclodextrins have no antiresistant activity, as well as other acylated derivatives of ellagic acid.
