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The crystal and electronic structure of an isocyanuric acid derivative was studied by high-resolution single-crystal X-ray diffraction within the Hansen–Coppens multipole formalism. The observed deformation electron density shows signs of thermal smearing. The experimental picture meaningfully assigned to the consequences of unmodelled anharmonic atomic motion. Straightforward simultaneous refinement of all parameters, including Gram–Charlier coefficients, resulted in more significant distortion of apparent static electron density, even though the residual density became significantly flatter and more featureless. Further, the method of transferring multipole parameters from the model refined against theoretical structure factors as an initial guess was employed, followed by the subsequent block refinement of Gram–Charlier coefficients and the other parameters. This procedure allowed us to appropriately distinguish static electron density from the contaminant smearing effects of insufficiently accounted atomic motion. In particular, some covalent bonds and the weak π...π interaction between isocyanurate moieties were studied via the mutual penetration of atomic-like kinetic and electrostatic potential φ-basins with complementary atomic ρ-basins. Further, local electronic temperature was applied as an advanced descriptor for both covalent bonds and noncovalent interactions. Total probability density function (PDF) of nuclear displacement showed virtually no negative regions close to and around the atomic nuclei. The distribution of anharmonic PDF to a certain extent matched the residual electron density from the multipole model before anharmonic refinement. No signs of disordering of the sulfonyl group hidden in the modelled anharmonic motion were found in the PDF.

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-tri-O-acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP). Graphic abstract Electronic supplementary material The online version of this article (10.1007/s11030-020-10141-y) contains supplementary material, which is available to authorized users.

A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (τ = 1/k

Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5 mg/kg, i.p) and donepezil (0.75 mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.

One of the most important strategies for the treatment of spinal cord injury is searching for new and effective pharmacological neuroprotectors and regeneration stimulators. The derivatives of pyrimidine are universal stimulators of the regeneration of various tissues as they support the recovery of nervous structures. The protective effect of the cocrystal of 1,2-dihydro-4,6-dimethyl-1-(2-hydroxyethyl)-pyrimidinone-2 with para-aminobenzoic acid (compound conjugate III, CCIII) was explored on a rat model with a contusion spinal cord injury. Injection of CCIII significantly reduced the expression of tumor necrosis factor α (TNF-α), inhibited the synthesis of myeloperoxidase (MPO), matrix metalloproteinase 9 (MPP9), cyclooxygenase-2 (COX2), and macrophage marker CD68, and increased the level of superoxide dismutase 1 (SOD1). Additionally, the expression of caspase-7 markers in the damaged tissue decreased under the action of CCIII. Treatment with the CCIII maintained a population of Olig2-positive myelin-forming cells at 30 days post-injury. The detected therapeutic effect is comparable with that of riluzole.

A laboratory culture of Chlorella was used to evaluate the toxicity of L-ascorbate 1-(2-hydroxyethyl)- 4,6-dimethyl-1,2-dihydropyrimidine-2-one synthesized on the basis of the drug Xymedon. Acute toxic effect by inhibiting the growth of Chlorella vulgaris algae for the test substance in concentrations of 0.01 g/100 ml, 0.05 g/100 ml and 0.1 g/100 ml in comparison with the control group was not detected. According to the results of the experiments, there was no effect of the test substance on the synthesis of protein and amino acid fractions.

The effect of the L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one on blastema regeneration in Girardia tigrina planarians was investigated. It was established that the preparation has low toxicity towards planarians, which is evidenced by its CL50 values (lethal concentration). The results of the vital computer morphometry and flow cytofluorometry confirm that L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2- dihydropyrimidine-2-one induces regeneration at high concentrations only: 0.01 g/100 mL, 0.05 g/100 mL, and 0.1 mg/100 mL. Low concentrations of the preparation have no influence on blastema regeneration in planarians.

The aim of the study was to investigate the hepatoprotective properties of the conjugate of the xymedon drug substance with succinic acid (1a). The study presents an in vitro comparative evaluation of the cytotoxicity and cytoprotective properties of 1a and succinic acid on a cell line of normal human hepatocytes Chang Liver, and in vivo investigation of the ability of 1a to restore liver from the toxic damage caused by CCl4 in Wistar rats. It was shown that the cytotoxicity of 1a was 19.9 ± 0.8 mmol/L, and that of succinic acid was 14.1 ± 0.2 mmol/L. Against the background of d-galactosamine exposure, the cytoprotective effect of 1a was found to be superior to that of succinic acid. It was shown that 1a caused a significant reduction in necrotic and steatosis changes in the liver and restoration of biochemical markers of cytolysis, as well as bilirubin metabolism and synthetic liver function.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with &omega, (ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

Pyridines containing amine, amide, or hydrazide substituent were quaternized with (ω-haloalkyl)sulfonylacetamides, resulting in new pyridinium compounds that exhibited tuberculostatic activity against the strain H37Rv of Mycobacterium tuberculosis.

The main purpose of the work is to study pharmacological peculiar properties of effect of pyrimidine derivatives, salt-like conjugates of the pyrimidine-based drug Xymedon (I) with biogenic acids (succinic (II), l-ascorbic (III), para-aminobenzoic (IV), niacin (V), and l-methionine (VI)) as well as a compound (VII), in which the atom N of the pyrimidine ring is alkylated by the methyl group, on the liver, kidney, and pancreas in rats under toxic influence of carbon tetrachloride. The experiment has been carried out on 115 mature outbred white rats of both sexes at the prophylactic scheme. The compounds were studied in doses 1/300 of LD50. The research has studied the structural-morphological changes in the liver, kidneys, and pancreas, as well as biochemical markers: cytolysis (lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase), liver (total, direct, and indirect bilirubin, γ-glutamyl transpeptidase) kidney (urea, creatinine), and pancreas (amylase, lipase) functions. The study has shown that noncovalent conjugates of Xymedon with biogenic acids had a protective effect on the liver as well as on the kidneys and pancreas poisoned by carbon tetrachloride. The derivative with l-ascorbic acid, which had the most pronounced effect on structural-morphological changes in liver among other pyrimidine derivatives, has also proved to be effective in terms of the impact on the kidney and pancreatic cells. The derivative with p-aminobenzoic acid, along with improving the structural-morphological organization of kidneys, also results in reduced levels of creatinine and bilirubin in the blood.

Four new triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl nucleoside analogues were synthesized by coupling with 8-bromoctyl- or 10- bromdecyltriphenylphosphonium bromide and evaluated for the in vitro antibacterial activity against S. aureus, B. cereus, E. faecalis, two MRSA strains isolated from patients and resistant to fluoroquinolone antibiotic ciprofloxacin and β-lactam antibiotic amoxicillin, E. coli, antifungal activity against T. mentagrophytes C. albicans and cytotoxicity against human cancer cell lines M−HeLa, MCF-7, A549, HuTu-80, PC3, PANC-1 and normal cell line Wi-38. In these compounds a TPP cation was attached via an octyl or a decyl linker to the N 3 atom of the heterocycle moiety (thymine, 6-methyluracil, quinazoline-2,4-dione) which was bonded with 2′,3′,5′-tri- O - acetyl-greek beta- d -ribofuranose residue by the (1,2,3-triazol-4-il)methyl bridge. All synthesized compounds showed high antibacterial activity against S. aureus within the range of MIC values 1.2–4.3 greek muM, and three of them appeared to be bactericidal with respect to tis bacterium at MBC values 4.1–4.3 greek muM. Two lead compounds showed both high antibacterial activity against the MRSA strains resistant to Ciprofloxacin and Amoxicillin within the range of MIC values 1.0–4.3 greek muM and high cytotoxicity against human cancer cell lines HuTu-80 and MCF-7 within the range of IC50 values 6.4–10.2 greek muM. This is one of the few examples when phosphonium salts exhibited both antibacterial activity and cytotoxicity against human cancer cell lines. According to the results obtained the bactericidal effect of the lead compounds, unlike classical surfactants, was not caused by a violation of the integrity of the cytoplasmic membrane of bacteria and their cytotoxic activity is most likely associated both with the induction of apoptosis along the mitochondrial pathway and the arrest of the cell cycle in the G0/G1 phase.

The accurate X-ray diffraction experiment was performed on the crystal of 1,6-dimethyl-3-propargyl-2,4-pyrimidinedione at 100 K. The static electron density (ED) was obtained via multipole refinement against these data. The presence of low-intense but nonrandom positive residual density peaks revealed that the structure was complicated by the minor conformational static disorder. Further analysis of the number and positions of critical points (CPs) (3, +3) of Laplacian of ED ∇ 2 ρ ( r ) and the ratio of eigenvalues of its Hessian matrix unambiguously proved that the multipole-modeled ED of the main disorder component was contaminated by the second one. A method of visualizing the Laplacian minima as CP-ellipsoids with semiaxes inversely proportional to the eigenvalues of Hessian matrix of ∇ 2 ρ ( r ) was applied to evaluate the correctness of modeled ED. Extra Laplacian CPs (3, +3) were attributed to the incorrect multipole populations, while the elongated shape of the corresponding discoid CP-ellipsoids was mainly considered to be the effect of troublesome kappa-parameters. A number of different multipole models were constructed in order to minimize the undesirable effects of disorder on the multipole ED. The two-component multipole model showed that the heterocyclic moiety of the minor component with an occupancy of 2% underwent the 180° rotation about the N3–C7 bond axis. Furthermore, the partial transfer of multipole parameters from the model refined against theoretical structure factors was utilized on the most problematic atoms, which massively contributed to disorder treatment. This approach allowed us to restore the ED of the main component in the crystal environment, which quality was gauged by the quantum-topological analysis as well as by its conformity to the data obtained from ab initio periodic calculations. Attempts to speculate on reasons for the limited disordering observed were made: theoretical calculations suggest that moderate hydrogen bonds support the disordering in the structure, while multiple weak noncovalent contacts, e.g., pi interactions, may provide the restrictions on the 50:50 disorder.

Molecular docking and ab intio quantum mechanical calculations were used to assess the nucleophilic reactivity of conjugates of 6-methyluracil and imidazole-2-carbaldehyde oxime. Minimum energy profiles for oxime group rotation and proton transfer were calculated for isolated conjugate. Results indicated that proton transfer and activation are possible. Results suggests that the compound can be active itself, reacting with esters in a way, similar to enzymatic histidine-containing catalytic triad. Thus, this compound is of potential interest for direct scavenging organophosphorus inhibitors of cholinesterases and/or as co-reagent in cholinesterase-based pseudocatalytic bioscavengers.

Novel dicationic nucleolipid bearing piperidine head groups has been synthesized. Using various physico-chemical methods (tensiometry, conductometry, pH-metry, fluorescence spectroscopy, spectrophotometry) its aggregation behavior in aqueous solutions has been examined. It has been revealed, that replacement of ammonium head group by piperidine results in a decrease in aggregation thresholds (critical micelle concentration equals 1.1 mM), as well as affects morphological behavior dramatically. In particular, existence of aggregates with both hydrodynamic diameters of 2 nm and ∼100 nm depending on the amphiphile concentration has been demonstrated. Spectrophotometric analysis has revealed, that fabricated aggregates of nucleolipid exhibit high capability to increase the solubility of lipophilic azodye Orange OT in water. Using dynamic and electrophoretic light scattering techniques interaction of this nucleolipid with double-stranded DNA decamer has been performed. It has been shown, that nucleolipid binds with DNA decamer electrostatically (isoelectric point was found at Camphiphile / Coligonuceotide ∼ 0.5) and forms lipoplexes with hydrodynamic diameter in the range of 300−400 nm.

New uncharged conjugates of 6-methyluracil derivatives with imidazole-2-aldoxime and 1,2,4-triazole-3-hydroxamic acid units were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. Using paraoxon (POX) as a model organophosphate, it was shown that 6-methyluracil derivatives linked with hydroxamic acid are able to reactivate POX-inhibited human acetylcholinesterase (AChE) in vitro. The reactivating efficacy of one compound (5b) is lower than that of pyridinium-2-aldoxime (2-PAM). Meanwhile, unlike 2-PAM, in vivo study showed that the lead compound 5b is able: (1) to reactivate POX-inhibited AChE in the brain; (2) to decrease death of neurons and, (3) to prevent memory impairment in rat model of POX-induced neurodegeneration.

A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with protected azido β- d -ribofuranose. The obtained compounds differ in both the nature of the pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the β- d -ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were evaluated for their cytotoxicity in vitro.

Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain.

Complexation of metal cations with acyclic and macrocyclic nucleobase derivatives containing uracil and 2-thiocytosine units linked by polymethylene spacers was studied. The investigated compounds have demonstrated high extraction selectivity for the Ag+ ion over a large number of competitive cations (Na+, Ca2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+). The structure and composition of Ag+ complexes have been investigated by a variety of physical-chemical methods. The crystal structures of three Ag+ complexes with 2-thiocytosine have been established by X-ray analysis. To refine the composition of the complexes formed in solution, the self-diffusion coefficients have been determined by NMR spectroscopy. For the estimation of the most reliable complex structures, the combined analysis of NMR data and DFT calculations was successfully applied. It was shown that the tendency of 2-thiocytosine moieties to form N1-nitrogen coordinated complexes and the presence of a polymethylene spacer between amine groups in the pyrimidinophanes provides the formation of Ag+ mediated duplex-type multi-component complexes.

Novel pyrimidinophanes possessing two o-nitrobenzylethyldialkylammonium heads bridging with different spacers were prepared. Pyrimidinophanes 2a, 2b and 3 are reversible inhibitors of cholinesterases. They show a very good selectivity for human acetylcholinesterase (AChE), with an inhibitory power 100–200 times higher than for human butyrylcholinesterase (BChE). Docking simulations indicate specific binding of pyrimidinophanes 2a and 4 onto the peripheral anionic site of AChE. Other compounds bind to the active center of AChE as well as to the peripheral anionic site. These compounds are dual binding site inhibitors. Pyrimidinophane 2b and its acyclic counterpart 1 were tested in the animal model of myasthenia gravis and may be considered as valuable candidates for the treatment of pathological muscle weakness syndromes.

Pyrimidinophanes are macrocycles consisting of pyrimidine moieties bridged to each other with alkyl spacers. Most of the known pyrimidinophanes originate from pyrimidinic nucleobase uracil and its 5(6)-substituted derivatives. Diverse macrocyclic compounds with pyrimidine moieties have appeared during the last two decades, and in this review the synthesis and properties of the pyrimidinophanes studied have been described.

Hepatoprotective properties of a new pyrimidine derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one, synthesized on the basis Xymedon, were assessed in white rats exposed to CCl4. The compound under study administered prior to exposure to CCl4 reduced the deviation of biochemical parameters from reference values and severity of structural and morphological changes in liver, when compared to the control. Hepatoprotective properties of the studied compound were more pronounced than those of Xymedon.

Replacement of terminal atoms of Br in 1,3-bis(bromopentyl)-5(6)-substituted uracils with 2-mercapto-5-methyl-1,3,4-thiadiazole, 2,5-dimercapto-1,3,4-thiadiazole, 2-mercaptoimidazole, and 2-mercaptobenzimidazoles resulted in a series of acyclic compounds and isomeric heterocyclophanes. Structures of macrocyclic regioisomers were unambiguously determined by NMR data. One of the regioisomers exhibits a hypochromic effect with respect to model compounds. The acyclic uracils obtained bridged with five-membered heterocycles are alkylated with methyliodide and methyl tosylate, and oxidated with m-CPBA, H2O2, and I2.

The ability of simple uracils to afford bis(uracil-5-yl)methanes upon reaction with paraformaldehyde is well documented. This reaction has been used in the preparation of pyrimidinophanes. The extension of the scope of this reaction to the synthesis of multipyrimidinophanes has been reported. Starting with isomeric pyrimidinophane containing 6-methyluracil and 5-methyluracil (thymine) moieties, linearly arranged multimacrocycles were prepared. A completely unexpected result was that the reactions of isomeric pyrimidinophanes containing 6-methyluracil moieties with paraformaldehyde produced only cyclic-arranged macrocycles, in particular, cryptand-like pyrimidinophanes and multipyrimidinophanes with a cyclic topology.

A new macrocyclic bolaamphiphile with thiocytosine fragments in the molecule (B1) has been synthesized and advanced as perspective platform for the design of soft supramolecular systems. Strong concentration-dependent structural behavior is observed in the water-DMF (20% vol) solution of B1 as revealed by methods of tensiometry, conductometry, dynamic light scattering, and atomic force microscopy. Two breakpoints are observed in the surface tension isotherms. The first one, around 0.002 M, is identified as a critical micelle concentration (cmc), whereas the second critical concentration of 0.01 M is a turning point between the two models of the association involved. Large aggregates of ca. 200 nm are mostly formed beyond the cmc, whereas small micelle-like aggregates exist above 0.01 M. The growth of aggregates between these critical points occurs, resulting in a gel-like behavior. An unusual decrease in the solution pH with concentration takes place, which is assumed to originate from the steric hindrance around the B1 head groups. Because of controllable structural behavior, B1 is assumed to be a candidate for the development of biomimetic catalysts, nanocontainers, drug and gene carriers, etc.

The conformational structure of macrocycles obtained from two thiopyrimidine and uracil nucleic acids linked by polymethylene spacers is determined by the length of the spacers, intramolecular NH bonding, pH and solvent. In CDCl3, NH–O C hydrogen bonding can impact the overall stabilization of the folded conformation, however spatial preorganization to such hydrogen bonding is a prerequisite. Protonation leads to disruption of intramolecular hydrogen bonds, destabilization of the folded conformation and to strong counterion assisted self-aggregation of macrocyles which can be destroyed in polar solvents.

Cyclization of 1,3-bis(ω-bromoalkyl)-5-bromouracil with p-methoxybenzylamine or sodium sulfide led to a series of pyrimidinophanes containing heteroatoms in bridges. An unusual behaviour of the 5-bromouracil ring, namely its contraction into hydantoin units during the cyclization reactions with p-methoxybenzylamine was observed. Sodium sulfide does not affect the 5-bromouracil ring, and no transformation products were observed in the synthesis of pyrimidinophanes with sulfur bridges. A possible reaction mechanism is given.

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.

The structure of a series of macrocyclic compounds consisting of a pyrimidine or 1,3,5-triazine ring and an aza-or thiapolymethylene bridge connecting the N1 and N3 atoms of the heteroring is discussed. Some macroheterocycles undergo methylation at the sulfur atom by the action of methyl p-toluenesulfonate. The length of the polymethylene bridge determines conformation of the macroring. Compounds with a shorter bridge both in crystal and in solution are characterized by closely located structural fragments, while extension of the polymethylene chain gives rise to an unfolded structure. Conformational changes in solution are promoted by protonation of the bridging nitrogen atom, and deprotonation restores the initial structure of the macroring. The basicity of the bridging nitrogen atom depends on the geometric parameters of the macroring.

New amphiphilic pyrimidinic macrocycles (APMs) with two (APM-1) and three (APM-2) decyl tails have been synthesized by quaternization of the bridged N. Complex examination of the APM-based systems with the help of tensiometry, conductometry, dynamic light scattering, and UV and NMR spectroscopy provides evidence for their aggregation. Calculations based on surface tension isotherms and on packing parameter considerations make it possible to assume a lamellar packing of macrocycles when aggregating. Marked differences in the aggregation behavior of APM-1 and APM-2 have been found. The additives of polyethylenimine (PEI) exert little influence on the critical micelle concentration (cmc) of APM-1, while in the APM-2/PEI systems there occurs a pronounced decrease in the cmc and also a ca. 2-fold decrease in the surface area per molecule. The APM-based assemblies are explored as nanoreactors for the hydrolysis of O-alkyl O-p-nitrophenyl (chloromethyl)phosphonates (alkyl = ethyl, hexyl). The kinetic study reveals a minor rate effect of the APM-1-based systems. In the APM-2-based systems an acceleration of the hydrolysis of both phosphonates occurs as compared to the uncatalyzed process. Within the APM-2 --APM-2/PEI --APM-2/PEI/La(III) series, due to the cooperative contributions of the supramolecular, polymer, and homogeneous catalysis, an increase in the catalytic effect is observed from 30 times to 3 orders of magnitude as compared to that of the basic hydrolysis of the substrates.

A series of acyclic compounds with two 3,6-dimethyluracil or 3-methyluracil units attached to a a thymine or isocyanurate fragment by polymethylene or xylylene spacers are investigated. Ring-closure reactions with paraformaldehyde in aqueous HCl in the presence of copper(I) chloride afforded pyrimidinophanes which can be considered macrocyclic counterparts of the acyclic triuracils. By X-ray diffraction data the structures of the macrocycles in the solid state are characterised by a close arrangement of the uracil units, but there are no π-π contacts between them. On the contrary, significant hypochromism of the macrocyclic triuracils compared with their acyclic counterparts indicates stacking between the thymine and 3,6-dimethyluracil units in chloroform and H2O solutions. The conformational behaviour of the acyclic and macrocyclic compounds in solution has been determined by NMR, UV and computational methods. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Intra-and intermolecular interactions in acyclic compounds containing nucleotide base (uracil and thymine) derivatives and their macrocyclic analogs (pyrimidinophanes) were studied by IR, UV, luminescence, and NMR spectroscopy. Molecules of these compounds include one or two N3-methylsubstituted or N3-unsubstituted uracil fragment or two adenine fragments linked through a hexamethylene spacer to an uracil, 5,5′-methylenediuracil or diphenylmethane fragment. The examined compounds almost all are characterized by π-π interactions and intramolecular hydrogen bonding between the terminal uracil or adenine fragments. Intramolecular association constants were determined and factors affecting them were discussed. Complex formation of acyclic and macrocyclic ligands with adenine and thymine derivatives was studied. The low values of the association constants were interpreted in terms of a competition between intra-and intermolecular bonding and very labile ligand structure.

Compounds consisting of two or three uracil fragments were synthesized by reaction of methyl-substituted uracil sodium salts with 1-(6-bromohexyl)-3,6-dimethyluracil or 1,6-dibromohexane. Treatment of these compounds with paraformaldehyde gave the corresponding pyrimidinophanes and acyclic compounds in which the uracil fragments are linked through methylene bridges. Uracil derivatives having no substituent on N3 were synthesized by reactions of silylated uracils with 1,3-bis(6-bromohexyl)uracil or 4,4′-(6-bromohexyloxy)diphenylmethane. The acyclic compound was converted into pyrimidinophane containing uracil fragments with N3H groups. A trinucleotide analog including uracil and two adenine fragments was synthesized from 1,3-bis(6-bromohexyl)uracil.

The reactions of 1,3-bis(5-bromopentyl)-5-methyl-or 1,3-bis(5-bromopentyl)-6-methyl-uracil with benzylamine afforded pyrimidinophanes containing the nitrogen atom in the polymethylene bridge. Single-crystal X-ray diffraction study and NMR and UV spectroscopic study in solution demonstrated that the phenyl and uracil fragments in the macrocycles are in spatial proximity. Unlike the known macrocycles containing the pyrimidine ring, the pyrimidinophanes under study are conformationally rigid.

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.

The reactions of disodium salts of N,N"-bis(2-mercapto-6-methylpyrimidin-4-yl)alkylenediamines with 1,3-bis(ω-bromoalkyl)-6-methyluracils afforded a series of macrocyclic compounds containing three pyrimidine fragments with different numbers of methylene groups in linking bridges.