Vol. 12 No. 3(47) (2014)
Published:
2014-09-12
Original Researches
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Synthesis of fused pyrimidine derivatives using NCNCC+C approach
The methods of synthesis of various substituted fused pyrimidine derivatives using NCNCC+C approach have been systematized and summarized in the review. Approaches based on the reaction of carbonyl compounds with NCNCC binucleophiles, in particular, N-aryl(thio)ureas, derivatives of aniline and aromatic heterocyclic amines, N-arylamidines and N-imidoylphosphoranes have been considered. Although these methods have been known for a long time, recent efforts in this area are put towards development of mild reaction conditions, in particular with the use of chlorotrimethylsilane or microwave irradiation. Besides, palladium-catalyzed cyclizations have been discussed, they involve N-arylamidines or N-arylcarbodiimides as the NCNCC components, and carbon(II) oxide or isocyanides – as single-carbon synthetic equivalents. These methods have received much attention in recent years. Most of them are three-component reactions, which involve an additional nucleophilic reagent; therefore, these approaches have some advantages in the view of diversity of the products obtained. Other methods for NCNCC+C cyclization have been also considered, including reactions of ketimines derived from aminoheterocycles with isocyanates, reactions of N-arylcarbodiimides with molybdenum carbonyl, Cu- and Rh-catalyzed processes, etc. It has been shown that [5+1] cyclization discussed in the review can be used for preparation of fused pyrimidines, which can bear moieties of annelated isoquinolines, thiazoles, pyridines, pyrazines, triazoles, pyrazoles, etc., apart from the simple ring.
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Investigation of sorption of calix[4]arene and calix[4]resorcinarene tetraalkyl derivatives with the LiChrosorb RP 18 surface by RP HPLC and molecular modelling methods
Tetrahydroxycalix[4]arene, tetraalkoxycalix[4]arenes and tetraalkylcalix[4]resorcinarenes are capable to reversible adsorption on the surface of the hydrophobic support LiChrosorb RP 18 under conditions of the reversed-phase high performance liquid chromatography. The main chromatographic characteristics of tetrahydroxycalix[4]arene, a series of tetraalkoxycalix[4]arenes and tetraalkylcalix[4]resorcinarenes have been determined. It has been found that in the conditions selected (the mobile phase is acetonitrile/water, 86/14, v/v) the retention times of the compounds studied are in the wide range from 4.67 min to 88.0 min depending on the nature of the substituents in the macrocyclic skeleton of the molecule. Thus, the retention times increase with increase of the length of the alkyl substituents at the lower rim of the calixarene macrocycle. According to the molecular modelling data the most effective sorption is explained by the inclusion of LiChrosorb RP 18 octadecyl groups into the lipophilic cavity formed by the alkyl substituents at the lower rim of the macrocycle of calixarene/calixresorcinarene. Thus, the molecular cavity formed by the benzene rings remains opened for the Host-Guest complexation with the analyte molecules. This sorption of tetraalkoxycalix[4]arenes and tetraalkylcalix[4]arenes on the LiChrosorb RP 18 surface can significantly improve its resolution ability in RP HPLC analysis. The influence of replacement of tetrahydroxycalix[4]arene hydroxyl protons with the alkyl groups on the conformation of the macrocycle has been studied.
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Improved synthesis, spectral characteristics and spatial structure of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate
The improved method for obtaining ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate being of interest as a base for synthesis of antiviral medicines has been suggested. The method involves a gradual addition of the solution of 2-amino-4-methylpyridine in triethylmethanetricarboxylate used as an acylating and condensing agent, as well as a high boiling heating agent simultaneously in the excess of triethylmethanetricarboxylate preheated to 150°C. This modification allows not only to reduce considerably regeneration of triethylmethanetricarboxylate taken in excess, but practically to avoid completely the undesirable formation of by-product – 2-hydroxy-8-methyl-N-(4-methypyridin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide. It has been found by X-ray diffraction analysis that in the crystal the ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate synthesized exists in the zwitterionic form with localization of the positive charge at the protonated nitrogen atom and the negative charge at the carbon atom in position 3 of the pyridopyrimidine ring. Based on the study of NMR 1H and 13C spectra the assumption that the test compound exits as an equilibrium mixture of two tautomeric forms in solution has been expressed.
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Synthesis and antimicrobial activity of 4-chloro-5-(2-nitrovinyl)-1H-imidazoles and products of their interaction with 3-methyl-2-pyrazolin-5-one
The work is devoted to the synthesis of new derivatives of 5-(2-nitrovinyl)imidazole, investigation of their chemical behaviour in the Michael reaction with heterocyclic CH-acids and study of their antifungal and antibacterial action. It has been found that 1-substituted 4-chloro-5-(2-nitrovinyl)imidazoles can be prepared with 71-83% yields by heating 4-chloro-5-formylimidazoles with the excess of nitromethane or nitroethane in the presence of anhydrous ammonium acetate. The compounds synthesized are typical representatives of activated alkenes and react with 3-methyl-2-pyrazolin-5-one in the Michael reaction. It has been shown that when refluxing in water for 3 h the interaction proceeds regioselectively with the most nucleophilic C4 atom of pyrazolinone giving 4-[1-(4-chloro-1H-imidazole-5-yl)-2-nitroalkyl]-5-methyl-1H-pyrazol-3-oles. In the case of the spatially hindered exocyclic part of the molecule 1H NMR spectra have characteristic features. The biological screening results of the compounds obtained have confirmed a high bactericidal and fungicidal effect. It has been found that antimicrobial properties are dependent on the nature of the substituent in the position 1 of the imidazole cycle and the structure of the exocyclic fragment. In particular, the condensation products of 4-chloroimidazol-5-carbaldehyde with nitroethane showed 4-6 times higher bactericidal activity compared to the analogous compounds obtained from nitromethane.
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Synthesis of new 4,4-spirocycloalkenic 1,2-diphenylpyrazolidine-3,5-dione derivatives by ring-closing metathesis reactions
The present article describes the synthesis of new 4,4-spiroalkenic 1,2-diarylpyrazolidine-3,5-diones by ring-closing metathesis reactions (RCM). They may be potential biological active compounds since a great quantity of 1,2-diazoles show a wide spectrum of both biological and pharmacological activities, and therefore, they are successfully used in biology, medicine, veterinary medicine. The initial compounds for ring closing metathesis cyclization were synthesized by the corresponding hydrazobenzenes condensation with various allylmalonic acid derivatives, whereupon monoallylpyrazolidinediones obtained were alkylated by some halogenoalkenes to form unsaturated disubstituted 1,2-diarylpyrazolidine-3,5-dione with subsequent ring-closing metathesis. The most appropriate catalyst for carrying out the aforementioned conversion appeared to be the ruthenium carbene Grubbs complex of the second generation used in the concentration not more than 3 mol.%. The yield of the metathesis products was 75-91%. The preliminary computer prognosis of the biological activity of the new spirocycloalkenic 1,2-diazoles by means of Prediction of Activity Spectra for Substances programme has shown that the substances obtained with the high probability may be inhibitors of L-glutamate oxidase and testosterone 17-beta-dehydrogenase (NADP+), nicotine 2alpha2beta receptor antagonists, as well as they can have the anti-inflammatory properties.
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Synthesis and cytotoxicity of aminoethoxydiphenyls
The implementation mechanism of the antiviral activity (AA) and interferon induction (IFI) by planar polycyclic compounds has not yet been determined. However, our hypothesis of the priority role of intercalation in double strand nucleic acids (NA) has gained strong arguments in its favour in our works and the works of foreign colleagues.
On the other hand, the presence of AA and the ability to induce IFI in biphenyl derivatives that are incapable to intercalate in NA indicates the possibility of implementing alternative mechanisms. This determined our interest to the study of aminoethoxydiphenyls (AED), which synthesis and investigation of cytotoxicity become the subject of this article. 4,4’-Bis-(2-chloroethoxy)diphenyl was obtained by alkylation of dihydroxydiphenyl with dichloroethane in its mixture with aqueous sodium hydroxide (20%) in the presence of tetrabutylammonium chloride (TBAC). Series of AED were synthesized by substitution of chlorine by iodine in the mixture of xylene with the aqueous solution of sodium iodide in the presence of TBAC with subsequent amination with primary and secondary amines. The protonated molecular ions (MI) intensive peaks of the compounds synthesized are observed in the mass spectra with FAB ionization. The most common way of MI fragmentation is PhO-CH2-bond cleavage following the side aminoalkyl fragment detachment. Absorption bands typical for CH (arom.), CH (aliph.), COC bonds and NH protonated terminal amino groups are present in IR spectra. In the 1H-NMR spectra signals from aromatic and aliphatic protons present, multiplicity and integral intensity correspond to the attributed structures. Cytotoxicity of the compounds synthesized was tested using EPT cells in vitro. All AED tested appeared to be comparable to amixine and are in the range from low to moderate cytotoxicity. -
Synthesis, the antioxidant and antibacterial activity of fluoroalkyl substituted thiazolidinones and thiazinanones incorporating an aminophosphonate or aminocarboxylate fragment
2-R-2-RF-4-оxo-thiazolidines, thiazinanes, and bezothiazinanes incorporating a fragment of aminophosphonic or aminocarboxylic acid and a fluoroalkyl group at C-2 atom of the heterocycle have been prepared by cyclocondensation of the corresponding iminophosphonates or iminocarboxylates, RFCH(R)=NH [R = (EtO)2P(O), COOMe, RF = CF3, CHF2], with mercaptoacetic, 3-mercaptopropionic or thiosalicylic acid. The primary screening of the compounds on the antioxidant and antibacterial activity has been carried out. The antioxidant activity has been determined by the method based on auto-oxidation of adrenaline; the antibacterial activity has been investigated by the method of double serial dilution with the use of Hottinger broth. The compounds investigated show only an insignificant antioxidant effect and the low activity towards the strains of such bacteria as E. coli, Ps. aeroginosa, B. subtilis and St. aureus. Compounds bearing diethoxyphosphonyl or methoxycarbonyl group at C-2 atom of a five- or six-member heterocycle show the similar activity in general. For 2-fluoroalkyl substituted 4-thiazolidinon- or 4-bezothiazinanones a considerable growth of the culture biomass has been revealed, and it can find application for growth stimulation of producers of biologically active compounds. Compounds incorporating the thiazinanones or bezothiazinanones fragment reveal the prooxidant effect, and it can become a basis for manifestation of the antineoplastic or antimicrobic activity.
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Methods of synthesis, structure and biological activity of 5-nitro-9-N-arylaminoacridines
With the purpose of search of new biologically active substances the synthesis of nine derivatives of 5-nitro-9-Narylaminoacridinium (2a-i) has been carried out by interaction of the corresponding 5-nitro-9-chloracridines and aromatic amines in two ways: in the phenol medium (method A) and in the dioxane medium in the presence of hydrochloric acid (method B). It has been experimentally proven that method B is more expedient because it is characterized by the absence of toxic phenol in the synthesis, reduction of the experiment time, a high yield of the desired product (87-94%). The structure and individuality of compounds synthesized that are undescribed in the literature have been confirmed by IR-, NMR-spectral and chromatographic analysis. The choice of the pharmacological screening spectrum has been conducted using data of PASS-prognosis, scientific and patent literature. It has been found experimentally that the substances synthesized possess a moderate bacteriostatic and fungistatic, expressed anti-inflammatory and analgesic, high diuretic (compounds 2d-f) and antidiuretic (compounds 2h-i) activities. According to the classification by K.K.Sydorov the compounds synthesized when introduced intragastrically belong to low toxic compounds. Some regularities of the “structure – biological activity – toxicity” dependence have been analyzed, and it is an important element in determining the areas for further research to develop new biologically active substances.
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Selective reduction and oxidation of 1-aryl-5-aryl-sulfanyl-6-phenylpiperidine-2-ones
The work is devoted to investigation of reactions of selective reduction and oxidation of a new type of piperidine systems – trans-5-arylsulfanyl-6-phenylpiperidine-2-ones. It has been found that the use of the reduction system LiAlH4-AlCl3 onto 1,6-diphenyl-5-(4-tolyl)sulfanylpiperidine-2-one provided a selective reduction of the carbonyl group and formation of 3-(4-tolyl)sulfanyl-1,2-diphenylpiperidine isolated as a hydrochloride with the yield of 83%. At the same time, reduction of 1-aryl-5-phenylsulfanyl-6-phenylpiperidine-2-ones by Ni-Raney runs with decomposition of the phenylsulfanyl group and leads to 1-aryl-6-phenylpiperidine-2-ones. Processing the latest by LiAlH4 in the presence of AlCl3 gives 1-aryl-2-phenylpiperidines isolated as hydrochlorides with the yields of 85-88%. It should be noted that hydrogen peroxide in acetone oxidates the arylsulfanyl moiety of 5-arylsulfanyl-6-phenylpiperidine-2-ones to the arylsulfinyl group at room temperature. As a result, a mixture of diastereomeric 5 sulfinilderivatives is formed with almost the same content of each isomer differing by quantity of chemical shifts of protons at the chiral carbons. The selective oxidation of 1,6-diphenyl-5-arylsulfanylpyperidin-2-ones to the corresponding sulfones has been successfully conducted using oxone as an oxidizer in methanol solution. The composition of all compounds synthesized has been proven by elemental analysis and chromatomass-spectra, their structure has been confirmed by IR and 1H NMR (13C) spectroscopy.
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Complexation of 4-amino-N-hydroxybenzamide with Ru(III), Rh(III) and Pd(II) ions
A series of hydroxamate and hydroximate complexes of Ru(III), Rh(III) and Pd(II) with 4-amino-N-hydroxybenzamide (AHBA) has been synthesized, and their IR, UV-Vis and NMR 1H spectral characteristics have been studied.
It has been found that AHBA interacts with metal ions mainly by the type of O,O’-coordination, wherein the structure of the complexes is largely dependent on the pH of medium. In acidic and weakly acidic media AHBA predominantly forms hydroxamate complexes with coordination of hydroxamic acid in neutral or mono deprotonated states. In NMR 1H spectra of hydroxamate complexes a singlet of NH protones is shifted upfield, which is associated with formation of cyclic metal chelates. In alkaline or near neutral media AHBA reacts as dianion to form anionic type hydroxamate complexes. In NMR 1H spectra of such complexes the singlets of NH and OH are absent. Depending on the nature of the metal, the central ion forms a square-planar [complexes of Pd(II)] or octahedral [complexes of Ru(III)] coordination unit, and it confirms the presence of d-d transition in electronic absorption spectra. The most characteristic of absorption bands in IR-spectra of the complexes are oxime group N–O of stretching vibrations that undergo low frequency offset by Dν = -(24–44) cm-1. The results obtained, as well as analysis of the published data show that increase of pH in the complexation reactions of hydroxamic acids leads to bidentate coordination of AHBA with formation of five-membered metallocycles. -
Synthesis of substituted 2-hydrazinoquinazolin-4-ones as intermediates for heterocyclic compounds synthesis
A suitable and effective scheme for the synthesis of 2-hydrazinoquinazolin-4-ones has been suggested and tested. It can provide a wide chemical diversity of the final products. The scheme developed starts from esters of 2-isothiocyanobenzoic acids, which easily form 3-substituted 2-thioxoquinazolin-4-ones with a high yield in the reaction with primary amines. When refluxing the latter in a heterogenic emulsion of dioxane and hydrazine hydrate the nucleophilic substitution of the sulfur atom occurs with 3-substituted 2-hydrazinoquinazolin-4-ones formation accumulated in the dioxane phase. After separation of the dioxane layer and dilution with water the precipitate of sufficiently pure target 2-hydrazinoquinazolin-4-ones is formed. Under these conductions there is no splitting of the amide group, which can be a part of substituents. But in case of amides of (4-oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid after inserting of the hydrazine substituent the cyclization occurs as a result of the intramolecular substitution of the amine residue of the amide fragment with formation of 2H-[1,2,4] triazino[3,4-b]quinazoline-3,6(1H,4H)-dione. The structure of the compounds synthesized has been proven by elemental analysis and 1H NMR spectroscopy data. The compounds obtained are promising synthones for construction of diversified heterocyclic systems, which can be of interest as potential pharmacological substances.
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Chemical properties of 3-(5-amino-1H-1,2,4-triazol-1-yl)- and 3-(2-amino-1H-benzo[d]imidazol-1-yl)-3-phenylpropanehydrazides
Reactions of 3-(5-amino-1H-1,2,4-triazol-1-yl)- and 3-(2-amіno-1H-benzo[d]іmіdazol-1-yl)-3-phenylpropanehydrazides with carbonyl electrophiles such as acetylacetone, aromatic and heterocyclic aldehydes in the alcoholic medium complete by formation of the corresponding hydrazones as a E-geometric isomers and s-trans/cis conformers with respect to the amide bond. In more severe conditions elimination of hydrazone fragments and retrocondensation of aminoazolophenylpropionyl residues in dihydroazolopyrimidinones have been observed.
The composition and structure of the hydrazones synthesized for the first time have been proven by data of elemental analysis, infrared spectroscopy (IR), nuclear magnetic resonance on protones (1H NMR) and mass spectra.
Virtual screening of the substances obtained carried out by using the PASS programme for 780 types of pharmacological action has shown that these compounds are advisable to test for the presence of their antibacterial and fungicidal properties. However, the experimental evaluation of the antimicrobial activity of N1-ylidene derivatives of 3-phenylpropanehydrazides performed on five museum strains of test cultures has revealed a weak activity against Staphylococcus aureus only in 3-(5-amіno-1H-1,2,4-triazol-1-yl)-N1 benzilіdene-3-phenylpropanehydrazide.
