Vol. 17 No. 4(68) (2019)
Published:
2019-11-29
Original Researches
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Pyrido[2,3-d]pyrimidin-7-ones: synthesis and biological properties
The review summarizes and systematizes data of the last twenty years on the synthetic methods and biological properties of pyrido[2,3-d]pyrimidin-7-ones, promising objects of organic and pharmaceutical chemistry. Two main approaches to the formation of the pyrido[2,3-d]pyrimidine system are considered. The first of them involves the cyclization of substituted pyridines containing functional groups in positions 2 and 3 of the heterocyclic ring. The second approach is based on the formation of a bicyclic system by adding a pyridone moiety to the pyrimidine ring. The methods developed allow to introduce various functional groups and aromatic substituents into the pyrido[2,3-d]pyrimidine system, as well as to obtain most of the target products with high yields. The effective three-component one-pot synthetic approaches to the formation of pyridine ring with the participation of functionalized pyrimidines and compounds with an active methylene group have been proposed. The analysis of the literature has shown that functionalized pyrimidines are the most common starting reagents, which structural modification is useful for the further annelation of the pyridine cycle. Much attention is paid to the biological properties of pyrido[2,3-d]pyrimidin-7-ones. The prospect of using pyrido[2,3-d]pyrimidin-7-one derivatives as tyrosine kinase inhibitors has been shown. Data on the biological effects of pyrido[2,3-d]pyrimidin-7-one derivatives indicate the possibility of detecting new biologically active compounds among pyridopyrimidines.
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New approaches to assessing the stability of carbenes
Carbenes are known to be highly reactive compounds, which can, in turn, spontaneously transform to dimers and products of rearrangements. Therefore, the question about the estimation of stability of carbenes is fundamental in the design of compounds for their subsequent synthesis and application.
Aim. To consider the known methods for assessing the stability and stabilization of carbenes, first of all, created by the authors of the article, and show their possibilities in predicting the properties of carbenes.
Materials and methods. The study was performed using the DFT method (B3LYP5, 6-311G**, RHF) to estimate the stabilization energies, and the DFT (B3LYP5, 6-31G, RHF) to obtain dimerization energies.
Results and discussion. The ways of solving the problem of stability of carbenes by the methods of quantum chemistry are discussed, in particular the application of new criteria for the stabilization of cyclic compounds – energies of the general and cyclic stabilization, energies of non-aromatic conjugations. To assess the possibility of isolating compounds the study of standard dimerization enthalpies (according to the ESP electronic and steric parameter proposed) for different classes of heterocyclic carbenes has been performed taking into account conformational factors. The scale of substituent effects on the stability of carbenes has been developed. It has been shown that sterically shielding substituents cause not only the kinetic stabilization, but also the thermodynamic one. The skeletons of the molecules have been estimated for their degree of influence on the stability of the compounds.
Conclusions. The parameters proposed for assessing the energies of the total and cyclic stabilization of carbenes, the dimerization energies of complex carbenes (electronic and steric parameter) allow identifying the most stable structures in the design of compounds for their subsequent synthesis and application. -
The electronic properties of carbenes
For carbenes as ambiphilic compounds there is no single scale for estimating their electron properties.
Aim. To consider the known methods of estimating the electron-donating and electron-withdrawing properties of carbenes, first of all, created by the authors of the article, and show their possibilities in predicting the properties of carbenes.
Materials and methods. The studies were performed using the DFT (B3LYP5/6-311G/RHF) method to estimate proton affinity, DFT (B3LYP5/3-21G/RHF and B3LYP5/3-21G/UHF) to determine chemical hardness and electronic indices.
Results and discussion. The electronic properties of carbenes, including thermodynamic parameters, such as proton affinity (PA), chemical hardness η, and new electronic indices Ie, are discussed in the paper. With their help, the electron-donating and electron-withdrawing ability of a wide range of carbenes of both nucleophilic and electrophilic type has been estimated. It has been shown quantitatively that the electronic properties of carbenes depend both on the backbone of the molecule (for example, the type of the heterocyclic nucleus) and on substituents. The above data show the ways of regulating the structure of carbenes to achieve certain characteristics, which together with stability factors can be used in the design of structures for the synthesis and practical application.
Conclusions. The author’s results of estimating proton affinity, chemical hardness and electronic indices for the design and use of carbene compounds are considered. Electronic indices have been shown to have some advantages over others for determining the nature (electron-donating and electron-withdrawing) of carbenes. -
The synthesis and antiviral activity of 1-(4-сhlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2а,4a-diazacyclopenta[cd]-azulene-2-carboxylic acid derivatives
Aim. To synthesize, prove the structural framework and study the antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid derivatives.
Results and discussion. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4adiazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide was determined in the Southern Research Institute (SRI, Birmingham, Alabama). The efficacy of this compound was expressed by EC50, IC50 and SI values determined in vitro within a range of concentrations of 0.1 – 100 μg/mL. The antiviral drug Ribavirin (Sigma) and the active substance of Amizon – 4-(N-benzyl)aminocarbonyl-1-methylpyridinium iodide were used as the reference drugs.
Experimental part. Condensation of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with α-amino-4-methylacetophenone hydrochloride led to 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine. By boiling the latter with α-bromo-4-chloroacetophenone in ethyl acetate 1-[2-(4-chlorophenyl)-2-oxoethyl]-3-(para-tolyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-1-ium bromide was isolated, which in aqueous alkali solution was converted into 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2а,4a-diazacyclopenta[cd]azulene. The latter while reacting with the corresponding aryliso(thio)cyanates in a dry benzene gave 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides. 1H NMR-spectra for the compounds synthesized were recorded on a Bruker VXR-300 spectrometer (Germany) with the operating frequency of 299.945 MHz, and also on a Bruker DRX300 (Germany) spectrometer with the operating frequency of 500.13 MHz, in DMSO-d6 using tetramethylsilane (TMS) as an internal standard. The melting points were measured using a RNMK 05 apparatus (VEB Analytik, Dresden).
Conclusions. The series of new 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides has been synthesized. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide has been studied in the Southern American Research Institute (SRI, Birmingham, Alabama), and the high level of the antiviral activity has been found against Flu A H1N1 California/07/2009 virus. -
Chemical transformations of new mono- and bis-derivatives of spiroindol-3,3’-pyrrolo[3,4-c]pyrrole based on bis-maleiminides and the study of the microbiological activity of the compounds synthesized
Aim. To synthesize new derivatives based on hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo-[3,4-c]pyrrole-2a,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trions) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H- spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2,2’,6’(1H,1’H,5’H)-trions by modifying the NH-group of the pyrrole moiety in position 4’ (alkylation, acylation, nitrosation) and study their microbiological activity.
Results and discussion. The possibility of further chemical modification of the derivatives of hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) has been developed on the example of ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrol-5’-methyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion), ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-isopropyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione), hexamethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-benzyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H-spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-methyl-2,2’,6’(1H,1’H,5’H)-trione by modification of the NH-group of the pyrrole fragment in position 4’ (nitrosation) or the NH-group of the indole fragment in position 1 (alkylation), or acylation at once in two positions. The structure of the compounds obtained has been reliably confirmed by instrumental methods. Data from the microbiological screening show a high biological effect of the compounds synthesized in relation to gram-positive (Staphylococcus aureus, Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris) and fungi (Candida albicans).
Experimental part. The synthesis of the initial and target compounds in classical preparative conditions was performed; instrumental methods for determining the structure of organic compounds, the agar diffusion method in the modification of wells were used.
Conclusions. The chemical modification of mono- and bis-derivatives of spiro-2-oxindole[3,3’]pyrrole has been performed: new functionalized nitroso derivatives have been synthesized, the alkylation reaction has been performed, and the reaction of acylation has been studied. It has been shown that the acylation occurs immediately in two positions – by the secondary amino group of the pyrrole and indole fragments, while the alkylation proceeds by the indole fragment. The structure of the compounds obtained has been proven. The antimicrobial effect of the compounds synthesized has been studied. -
Spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides: synthesis and the biological activity study
The development of medicines with several pharmacological activities, including the analgesic, anti-inflammatory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.
Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, and study the biological activity of the substances obtained.
Results and discussions. The target compounds were synthesized as a result of the interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, malononitrile and isatins. When using ethyl cyanoacetate the interaction appeared to be much more complicated and requires further research. The study of the biological activity has revealed the compounds with the analgesic properties and the antimicrobial effect against gram-positive strains.
Experimental part. Two new 2-amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]benzoxathiine-4,3’-indoline]-3-carbonitrile 5,5-dioxides were synthesized by the three-component reaction based on 1,2-benzoxathiin-4(3H)-one 2,2-dioxide. The anti-inflammatory activity was studied on the model of the carrageenan induced paw edema, and the analgesic activity was assessed on the model of the local inflammatory hyperalgesia. The study of the antimicrobial activity of the compounds obtained was performed by the agar well diffusion method.
Conclusions. New spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides have been synthesized. The compounds obtained have revealed high levels of the analgesic properties and the antimicrobial activity. The latter exceeds the activity of the reference drugs, and has appeared to be higher against grampositive bacteria.
