Vol. 15 No. 4(60) (2017)
Published:
2017-12-14
Original Researches
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Esters of 4-formylpyrazol-3-carboxylic acids
The scientific publications devoted to chemistry of the synthetically promising bifunctional derivatives of pyrazole – esters of 4-formylepyrazole-3-carbonic acids have been generalized and systematized. A special attention has been given to description of two main synthetic approaches: 1) processes of the conjugated formation of aldehyde and ester groups, on one hand, and the pyrazolic system, on the other; 2) synthetic strategies targeted on functionalization of the pyrazolic nucleus. It has been shown that the first approach is performed usually by the scheme [3+2] meaning in situ cyclojoining of the generated nitrilimines or esters of diazoacetic acid with formylacetylenes or their derivatives followed by cyclization with simultaneous formylation of hydrazones and semicarbazones of pyruvic acid by Wilsmaer-Haack reagent. The second approach deals with formylation of esters of pyrazole-3-carbonic acids according to Wilsmaer-Haack reaction. As seen from the analysis of chemical properties of esters of 4-formylpyrazole-3-carbonic acids, the aldehyde group is the most typical target of their chemical transformations. Such transformations are reactions with nitrogen-containing nucleophiles, alkenylation, oxidation, reduction and other multicomponent reactions that can be considered as usual approaches to structural functionalization of the pyrazolic nucleus. Cyclocondensations are also important in this context since these processes involve formyl, ester and other functional groups obtained from them. These substances appeared to be effective substrates for construction of some biologically active pyrazolo[4,3-d]pyrimidine and pyrazolo [3,4-d]pyridazynic systems.
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Synthesis of heteryl derivatives of 2,5-disubstituted 1,3,4-okasadiazole
At the present stage of development of organic chemistry there are a lot of basic synthetic approaches to synthesis of 1,3,4-oksadiazole derivatives with a wide spectrum of biological activity. The heterocyclic systems which contain 1,3,4-oksadiazole nucleus have a rich synthetic history and they are characterized by a wide range of methods of synthesis. In the review for the first time have been systematized and summarized literature sources for the chemistry of heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazole as important synthetic substrates and precursors for the design of biologically active substances. There have been considered the main approaches to synthesis of this series of compounds, which consist in the intramolecular dehydration of 1,2-diacylhydrazine, in the interaction of hydrazides of heterylcarbonic acids with carbonyl dichloride, orthoethers, carbon (IV) sulfide and in the formation of an oxadiazole nucleus based on functional acylthiosemicarbazide and hydrazone. A significant emphasis is concentrated on the cyclodehydration reaction of N,N’-diacylhydrazide using dehydrating agents, which are a powerful tool for constructing their synthetically and biologically attractive derivatives.
There have been analyzed in detail the methods for the preparation of acridone derivatives which contain the 1,3,4-oxadiazole fragment, have been delineated their preparative boundaries and has been revealed the biological potential. It is important to note that the processes of heteryl functionalization are new in the chemistry of 1,3,4-oxadiazole and they allow us to obtain new bioperspective hybrid structures. Analysis of literature data shows that the derivatives of 2,5-disubstituted 1,3,4-oxadiazole are considered as promising substances with antibacterial, fungicidal, anti-inflammatory, hypoglycemic, antimalarial activity. The search for biologically active substances in this series of compounds is expedient and has practical and theoretical significance. -
Synthesis of 1,2-benzoxathiine 2,2-dioxide derivatives using aliphatic aldehydes and assessment of their antimicrobial activity
Nowadays the problem of the antimicrobial resistance promotes the search of new chemical core-structures with the antimicrobial properties.
Aim. To study the interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with active methylene nitriles and aliphatic aldehydes and assess the antimicrobial activity of the compounds obtained.
Results and discussion. 1,2-Benzoxathiin-4(3H)-one 2,2-dioxide as a structural analog of 1,3-dicarbonyl compounds was used in the three-component interaction with aliphatic aldehydes and active methylene nitriles. In the case of malononitrile the target compounds were formed. When using ethyl cyanoacetate the only isolated product was triethylammonium salt that could be also obtained by the two-component reaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with aliphatic aldehydes. The study of the antimicrobial properties showed the higher activity of the compounds studied than in the reference drugs, especially against gram-positive strains.
Experimental part. The series of 2-amino-4-alkyl-4,6-dihydropyrano[3,2-c][2,1]benzoxathiin-3-carbonitrile 5,5-dioxides and triethylammonium 3-[1-(4-hydroxy-2,2-dioxido-1,2-benzoxathiin-3-yl)alkyl]-1,2-benzoxathiin-4-olate 2,2-dioxides was synthesized. The antimicrobial activity of the compounds obtained was determined by the agar “well” diffusion method.
Conclusions. It has been shown that 1,2-benzoxathiin-4(3H)-one 2,2-dioxide as a structural analog of 1H-2,1-benzothiazin-4-one 2,2-dioxide can be used in similar three- and two-component reactions, but its reactivity is less due to the replacement of the 1-N-R-group with an O-atom. The novel compounds obtained exceeded the antimicrobial activity of the reference drugs, and were more active against gram-positive bacteria in contrast to isosteric derivatives of 1H-2,1-benzothiazin-4-one 2,2-dioxide that were active against gram-negative strains and fungi. -
The inhibitory potential of calixarenes against nucleotide pyrophosphatase/phosphodiesterase 1
It has been previously shown that phosphonic acids covalently attached to the macrocyclic platform of calix[4]arenes are capable of inhibiting alkaline phosphatases. In this paper the effects of the upper-rim functionalized calix[4]arenes on the activity of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) have been examined.
Aim. To assess the inhibitory potential of calix[4]arene, thiacalix[4]arene and sulfonylcalix[4]arene derivatives against NPP1.
Results and discussion. It has been found that calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene tetrakismethylphosphonic acids inhibit NPP1 with the IC50 values in the micromolar range. The derivatives of sulfonylcalix[4]arene demonstrated the selectivity of inhibition of NPP1 over alkaline phosphatases. In addition, sulfonylcalix[4]arene tetrakismethylphosphonic acid was able to inhibit the nucleotide pyrophosphatase/phosphodiesterase activity of the human serum. The possible mechanism of the inhibition has been discussed.
Experimental part. The activity of NPP1 was monitored by spectrophotometry measuring the rate of hydrolysis of bis-p-nitrophenyl phosphate. The phosphodiesterase activity of the human serum was assessed in the presence of p-nitrophenyl ester of thymidine-5-monophosphate as a substrate. The homology model of the human NPP1 was generated based on the crystal structure of the murine enzyme. The molecular docking was performed using AutoDock 4.2.
Conclusions. The results obtained have shown the ability of sulfonylcalix[4]arene derivatives to inhibit the activity of NPP1 in vitro, including the nucleotide pyrophosphatase/phosphodiesterase activity in the human blood serum. -
Synthesis and the activity assessment of adamantylcontaining thiazolium inhibitors of butyrylcholinesterase
Cholinesterase inhibitors can be used for treatment of neuropsychiatric symptoms and functional impairments in neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases.
Aim. To synthesize and assess the inhibitory activity of adamantyl-containing 5-substituted N-benzyl and N-phenacylthiazolium salts against butyrylcholinesterase and acetylcholinesterase.
Results and discussion. The synthesis of 3-aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts included preparation of 5-acyloxyethyl thiazole derivatives by the reaction of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole with the corresponding adamantoyl- or adamantylacetyl chlorides. The derivatives of 5-acyloxyethyl thiazole were quaternized in the reaction with benzyl or phenacyl halides. The studies in vitro have shown that the compounds synthesized inhibit butyrylcholinesterase with IC50 values in the micromolar range. Some of them exhibited selectivity over acetylcholinesterase. The molecular docking was performed for understanding the mechanisms of the enzyme-inhibitor complex formation.
Experimental part. The synthesis of the intermediate and target compounds was carried out by the classical methods. The structures of compounds were proven by NMR 1H-spectroscopy and elemental analysis. The methods of enzymatic kinetics were used for determination of the inhibitory effects of the compounds synthesized. Calculations by molecular docking were carried out using Autodock 4.2 program.
Conclusions. 3-Aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts with adamantylcontaining substituents in position 5 can selectively inhibit butyrylcholinesterase compared to their effect on acetylcholinesterase. -
Synthesis and the antimicrobial activity of hexamethylene-Nmaleinimidospiroindole- 3,3’-pyrrolo[3,4-c]pyrrole derivatives
Aim. To synthesize a series of hexamethylene-N-maleinimidospiroindole-3,3’-pyrrolo[3,4-c]pyrrole derivatives, study the antimicrobial activity of the compounds synthesized and compare their antimicrobial activity with the antimicrobial activity of the bis-analogs previously synthesized.
Materials and methods. The methods of organic synthesis, instrumental methods for determination of the molecular structure of organic compounds, agar well diffusion method were used.
Experimental part. The interaction of isatins with a-amino acids and 1,6-bismaleinimidohexane in the equimolar ratio led to formation of 1′-(hexamethylene-N-maleinimido)-2a′,5a′-dihydro-1′H-spiroindol-3,3′-pyrrolo[3,4-c] pyrrol-2,2′,6′(1H,3′H,5′H)-trion derivatives. The structure of the compounds synthesized was reliably proven by the instrumental methods. Data of the microbiological screening showed a high level of the antimicrobial activity against Staphylococcus aureus and Candida albicans fungi.
Conclusions. It has been determined that the three-component condensation reaction of isatins with α-amino acids and 1,6-bismaleinimidohexane in the equimolar ratio is an efficient synthetic method of 1′-(hexamethylene-N-maleinimido)-2a′,5a′-dihydro-1′H-spiroindol-3,3′-pyrrolo[3,4-c]pyrrol-2,2′,6′(1H,3′H,5′H)-trion derivatives, which reveal a high level of the antimicrobial activity against Staphylococcus aureus and Candida albicans fungi. 1’-(Hexamethylene-N-maleiimido)-5’-methyl-2a’,5a’-dihydro-1’H-spiroindol-3,3’-pyrrolo[3,4-c]pyrrol-2,2’,6’(1H,3’H,5’H)-trione has shown the highest antimicrobial activity among derivatives of hexamethylene-Nmaleinimidospiroindol- 3,3’-pyrrolo[3,4-c]pyrrols.
