A. E. Nikolaev

Macrocyclic and acyclic 1,3-bis[5-(trialkylammonio)pentyl]-5(6)-substituted uracil dibromides: synthesis, antimicrobial properties, and the structure—activity relationship

A series of acyclic onium uracil derivatives was synthesized, including 1,3-bis[5-(alkyldiethylammonio)pentyl]-5(6)-substituted uracil dibromides and isostructural macrocyclic compounds (isomeric cis- and trans-pyrimidinophanes bearing onium groups in the decamethylene chains). The compounds were found to exhibit considerable bacteriostatic and fungistatic activity. The onium uracil derivatives were found to make a specific contribution to the antimicrobial action: the bacteriostatic and fungistatic activities of the compounds are determined by their topology, the nature of a substituent at atom C(5) of the uracil ring and a substituent in the onium group. The mechanism of antimicrobial action and cytotoxicity of uracil onium derivatives were studied.

Tunable biomimetic systems based on a novel amphiphilic pyrimidinophane and a helper nonionic surfactant

Tunable nanosystems based on a novel water insoluble pyrimidinic amphiphile are designed. pH dependent aggregates composed of protonated pyrimidinophane 1 are formed at pH<4, which undergo reversible transition to precipitate at neutral and basic conditions. The approach assuming the application of a helper nonionic surfactant Triton-X-100 (TX-100) is used in this work. Different models of a self-assembly were found depending on the molar ratio of components and solution pH. In the equimolar 1-TX-100 solution, mixed assemblies contributed by aggregated molecules of both TX-100 and cationic form of 1 are formed in acidic conditions. Upon alkalization, deprotonated pyrimidinophane molecules shift toward the micellar core. The assemblies undergo reversible precipitation after 4-5h, while the excess of TX-100 leads to the formation of highly stable mixed aggregates. The acidification-alkalization cycles followed by the aggregation/precipitation and the re-charging of aggregates can be multiply repeated. Surprisingly, stable mixed aggregates are also formed under the excess of pyrimidinophane in both the acidic and alkaline conditions, but at a certain component ratio. They are characterized by the highest micellization degree among all the systems studied. The low concentration threshold of these assemblies in alkali solution is probably due to their nonionic character.

Synthesis of pyrimidinocyclophanes having a bridging nitrogen atom

Reactions of 1,3-bis(ω-bromoalkyl)-substituted uracils, quinazoline-2,4-dione, and 5-methyl-1,3,5-triazine-2,4,6-trione and 1,3-bis(m-bromomethylbenzyl)-5-bromouracil with amines (aliphatic amines, benzylamines, naphthylmethanamine, and anisidine) gave a series of macrocyclic compounds having one pyrimidine or triazine fragment and an azapolymethylene bridge connecting the N1 and N3 atoms of the heteroring. The bridging nitrogen atom in some macrocyclic compounds was subjected to quaternization with methyl p-toluenesulfonate.

Synthesis and antimicrobial activity of pyrimidinophanes containing a uracil moiety and a bridging sulfur atom

Pyrimidinophanes containing one 5(6)-alkylsubstituted uracil moiety and a 10-or 12-methylene bridge including a sulfur atom were synthesized. The bridging S atoms of the macrocycles were converted to sulfonium groups by interaction with para-toluenesulfonate methyl or nonyl esters. The resulting amphiphilic pyrimidinophanes were tested for bacteriostatic and fungistatic activity against Gram-positive and Gram-negative bacteria and fungi. Amphiphilic pyrimidinophanes with 5-decyl-6-methyluracil moieties had high levels of bacteriostatic activity against Gram-positive bacteria. The minimum inhibitory concentration of the macrocycle containing a methyl group in the sulfonium grouping against Staphylococcus aureus was 0.75 !g/ml. These data are of value in seeking new highly effective antimicrobial agents.

Reactions of Pyrimidinophanes and Their Acyclic Analogs with Electron-Deficient Substrates

Acyclic and macrocyclic compounds having different numbers of pyrimidine fragments and nitrogen atoms in the polymethylene bridges or in substituents at the pyrimidine rings reacted with 2,3,5,6-tetrachloro-1,4-benzoquinone and 1,4-benzoquinone according to the charge transfer scheme to give products with an ionic structure. The reaction was accompanied by protonation of nitrogen atoms in the polymethylene bridges or in substiuents at the pyrimidine rings and reduction of 2,3,5,6-tetrachloro-1,4-benzoquinone or 1,4-benzoquinone to 2,3,5,6-tetrachlorobenzene-1,4-diol or benzene-1,4-diol, respectively. The isolated products are dielectrics.

Self-organization of oligomeric amphiphiles with pyrimidine moieties: The role of the structural factor

Supramolecular systems based on tetracationic pyrimidine-containing surfactants of acyclic and macrocyclic structures with varying nature of the spacer were studied. The critical micelle concentrations (CMC) and the hydrodynamic diameter of aggregates were determined, and the packing of molecules in the surface layer was analyzed. Insignificant differences in the CMC with variation in the nature of the spacer and in the transition from acyclic to macrocyclic surfactants suggest elimination of the structural factor in the self-organization of the investigated compounds. The molecular packing is shown to change greatly in the transition from monomeric pyrimidinophane to oligomeric tetracationic amphiphiles.

New amphiphilic multiheterocycle: Micelle-forming properties and effect on the reactivity of phosphorus acid esters

Supramolecular systems based on a novel tetracationic amphiphilic multiheterocycle have been studied by tensiometry, conductometry, pH-metry, spectrophotometry, and dynamic and electrophoretic light scattering. The critical micelle concentration of the system has been determined (0.4 mM), and the possibility of open and closed association models realization has been demonstrated. A high solubilizing ability of the aggregates toward hydrophobic guest species has been revealed. Micellar catalysts based on the new multiheterocycle have shown substrate specificity in the hydrolysis of phosphonates possessing different hydrophobicities.

Trimerization of Nitriles in the Synthesis of Multipyrimidinophanes

Multimacrocycles, i.e., compounds in which several macrorings are covalently linked by intermolecular bridges, are promising subjects for studies due to their potential unique aggregation and complexing properties. Multicalixarenes [1], multicyclodextrins [2, 3], multiporphyrins [4–6], and combinations of different covalently linked macrocycles [7, 8] have been synthesized and are extensively studied. In the present communication we describe the synthesis of macrocyclic compounds containing uracil fragments, pyrimidinophanes, and a new method for their covalent binding with each other to obtain a multimacroring, multipyrimidinophane. At present, multipyrimidinophanes are known, in which two “monomeric” pyrimidinophane units are linked through intermolecular paraand meta-phenylenedimaleimide [9], 4,4′-diphenol [10], and methylene [11] bridges. We now report on the synthesis of multipyrimidinophane consisting of three macrocyclic units attached to the carbon atoms of 1,3,5-triazine ring via trimerization of CN groups to 1,3,5-triazine structure. Successful cyclotrimerization of nitriles to 1,3,5-triazines requires quite severe conditions (high temperature and pressure) [12]. Cyanamide derivatives undergo cyclotrimerization more readily than nitriles [13–15]. For example, dialkylcyanamides react with trifluoromethanesulfonic anhydride under mild conditions to give the corresponding 1,3,5-triazines in almost quantitative yield [16, 17]. Both sterically hindered cyanamides and those containing various heteroatoms (N, O, S) in the substituents can be involved in this reaction. By reaction of 1,3-bis(5-bromopentyl)-6-methyluracil (I) with disodium cyanamide in acetonitrile we obtained 22% of pyrimidinophane II containing a cyanamide fragment in the decamethylene linker (Scheme 1). The H NMR spectrum of II was typical of other pyrimidinophanes consisting of one uracil fragment and 10 methylene group in the bridge; namely, protons in the methylene groups on the uracil nitrogen atoms (CH2 and CH2) were magnetically nonequivalent [18], and they resonated as four multiplets in the region δ 4.45–3.62 ppm. Pyrimidinophane II was treated with trifluoromethanesulfonic anhydride in methylene chloride. The reaction was accompanied by heat evolution, and the product was assigned the structure of multipyrimidinophane III formed as a result of trimerization of the ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 1096–1098.

1,3-dipolar cycloaddition reactions in the series of N-alkynyl-substituted uracils

Reactions of 1-(ω-bromoalkyl)-3,6-dimethyluracils and 1,3-bis(ω-bromoalkyl)-6-methyluracils with sodium azide gave the corresponding mono- and bis-azides. 1,3-Dipolar cycloaddition of the latter with prop-2-yn-1-ol, hex-1-yne, and dec-1-yne in the presence of copper(I) ions afforded acyclic and macrocyclic uracil derivatives containing 1,4-disubstituted 1,2,3-triazole fragments, which were subjected to quaternization with propyl iodide and methyl p-toluenesulfonate at the 1,2,3-triazole nitrogen atom.