A. S. Mikhailov

Antimicrobial activity of pyrimidinophanes with thiocytosine and uracil moieties.

Reactions of pyrimidinophanes with two 6-methylthiocytosine and one 5(6)-alkyluracil moieties bridged with each other by polymethylene spacers with methyl or nonyl p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonate and trifluorosulfonate afforded amphiphilic macrocyclic bis-p-toluene-, methane- and trifluorosulfonates. Despite the presence of several reaction centers in the initial pyrimidinophane molecules, protonation and methylation occurred only at the N(1) atom (with quaternization) of the 6-methylthiocytosine moieties. The bacteriostatic and fungistatic activity of the products was estimated. Macrocyclic tosylates exhibit a remarkable selectivity towards Staphylococcus aureus, with MIC values comparable with a reference drug. Bacteriostatic activity of the amphiphilic pyrimidinophanes depends on the size of the macrocycles, and the highest activity corresponds to definite lengths of polymethylene bridges. Besides, the antimicrobial activity of the screened pyrimidine derivatives depends on their topology. While macrocyclic tosylates are more active against bacteria than against fungi, acyclic tosylate with the same structural fragments shows a dramatical decrease of MIC towards mold and yeast with respect to the corresponding macrocycle. It is found that macrocyclic and acyclic tosylates in high dilutions decrease the extracellular lipase activity.

Novel bolaamphiphilic pyrimidinophane as building block for design of nanosized supramolecular systems with concentration-dependent structural behavior.

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.

6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

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 Alzheimers disease, and to significantly decrease the number and area of β‐amyloid peptide plaques in the brain.

Amphiphilic macrocycles bearing biofragment: Molecular design as factor controlling self-assembly

Two novel macrocyclic 6-methyluracilic amphiphiles (uracilophanes) with four (UP1) and two (UP2) uracil moieties and ammonium groups have been synthesized. Tetracationic multi-uracilophane is composed of two macrocyclic units bridged each other with an external methylene spacer, while in the cryptand-like dicationic uracilophane pyrimidinic moieties are connected with an internal methylene spacer. This internal spacer provided a conformational rigidity to the macrocycle. The self-assembly of the uracilophanes is studied and compared with a reference dicationic uracilophane (UP3) with no spacer fragment. Compounds UP1 and UP3 are capable of aggregating, which is characterized by the analogous critical micelle concentration of 1mM, although the former has four decyl tails versus two decyl tails in UP3 molecule. NMR self-diffusion, fluorimetry and DLS techniques revealed that bimodal size distribution occurs in the UP1 solution, with small (≤2nm) and large (ca. 30-50 nm) aggregates contributed. Unexpectedly, the cryptand-like uracilophane UP2 with the same hydrophobicity as UP3 does not form aggregates. The balance of the geometry and energetic factors was analyzed and compared with those contributing to the aggregation of the reference compound UP3. It was established that it is the geometry that controls the packing of the cryptand-like uracilophanes upon aggregation, while hydrophobic effect plays a minor role. In contrast, both factors control the aggregation of oligomeric macrocycle, with energetic factor prevailing. These findings are of importance for (i) the understanding the diverse structural behavior of bioamphiphiles that have very similar chemical structure, but different conformations; and (ii) the design of amphiphiles with controlled model of self-assembly. Supramolecular systems studied can be recommended for biotechnological applications.

Synthesis and antimicrobial activity of pyrimidinophanes with two uracil units and bridging nitrogen atoms

A series of pyrimidinophanes containing two uracil units and nitrogen atoms in bridging polymethylene chains –(CH2)nN(Et)(CH2)m– (n, m = 5, 6) have been synthesized. The uracil moieties are represented by 6-methyl-, 5-decyl-6-methyl-, and 5-fluorouracils. Quaternization of the bridging N atom with ethylbromide or n-decylbromide yielded amphiphilic pyrimidinophanes, which were evaluated for their antibacterial and antifungal activity in terms of minimal inhibiting concentration (MIC) against Gram-positive and Gram-negative bacteria and fungi. It has been found that MICs of the amphiphilic pyrimidinophanes decrease with increasing lipophilicity of the alkyl substituents at the bridging N atoms and with increasing polymethylene N(pyr)–N chain length (in some cases MIC against Staphylococcus aureus is below 1 ìg/mL). The MICs increase dramatically upon introduction of lipophilic n-decyl substituents at C(5) atoms of the uracil moiety. The results can be used in the search for new highly effective antimicrobial agents.

Synthesis of pyrimidinophanes containing nitrogen atoms in polymethylene bridges

The reactions of 1,3-bis(ω-bromobutyl- or -pentyl)-6-methyluracil with 1,3-bis(ω-ethylaminobutyl- or -pentyl)-6-methyluracil afforded pyrimidinophanes containing N atoms in bridging polymethylene chains. Individual geometric isomers of pyrimidinophanes were isolated. The structure of one of these isomers was established by X-ray diffraction analysis. Quaternization of the bridging N atoms with o-nitrobenzyl bromide gave rise to water-soluble pyrimidinophanes.

Synthesis, IR Spectra, and Steric Structure of Macrocycles Derived from Pyrimidine Compounds

A new macrocycle including pyrimidine fragments, 12,23,36-trimethyl-24,40-dioxo-15,33-dithia-2,9,13,22,26,35,38,39-octaazatetracyclo[32.3.1.110,14.122,26]tetraconta-1(38),10(39),11,13,23,34,36-heptaene, was synthesized. According to the data of IR and UV spectroscopy and HF/6-31G** quantum-chemical calculations, macrocyclic compounds of this series in crystal exist in the amino form, one NH group of which is likely to be involved in intramolecular hydrogen bond, and the other, in intermolacular hydrogen bond. The strength of the latter depends on the macroring size. In solution, the above structures are supplemented by conformers containing both intramolecularly H-bonded and free amino groups, predominantly with trans structure of the HÄNÄCÍN fragment. The imino form of the aminopyrimidine moieties is hardly probable.

Copper(II) bromide complexes with acyclic and cyclic pyrimidine-containing phane ligands

Complexes of copper(II) bromide with cyclic and isostructural acyclic phane ligands containing derivatives of pyrimidine nucleobases (cytosine and uracil) were synthesized and characterized. In two cyclic pyrimidinophanes used, the macrocycles included two 6-methylthiocytosine and one 6-methyluracil units linked by polymethylene chains (L3) and two 6-methyluracil units linked by N-containing bridges (L5). Ligand L3 and its isostructural acyclic analogs are coordinated by the Cu2+ ion through the same donor sites (the ring N atoms of the thiocytosine units). The coordination polyhedra of the Cu atom in complexes with cyclic and acyclic ligands are different. Ligand L5 and its isostructural acyclic analog also form copper(II) complexes with different coordination polyhedra involving different donor sites. The acyclic ligand is coordinated by the Cu2+ ion via the bridging N atom, while cyclic ligand L5, via the uracil CO groups (the bridging N atoms become protonated). The resulting complexes are dielectrics.

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.

Reverse Micellar Catalysis of Phosphorylation of Pyrimidinophanes

The reaction of pyrimidinophanes with 4-nitrophenyl bis(chloromethyl)phosphinate in reverse micellar solutions of cetyltrimethylammonium bromide, polyethylene glycol 600 monolaurate, and their mixture was studied by spectrophotometry in chloroform. The catalytic activity of the micelles was found to depend on the macrocycle size and concentration and relative content of surfactants in the solution.