R. Kh. Giniyatullin

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.

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.

Regulation of the rate of hydrolysis of phosphorus acid esters in organized systems based on amphiphilic pyrimidinophanes

The aggregation and catalytic activity of supramolecular systems based on new macrocyclic dimeric surfactants (pyrimidinophanes) was studied both in the absence and in the presence of polyethyleneimine (PEI). It was found that the critical micelle concentrations measured by tensiometry were independent of the structure of surfactants. The morphology of aggregates was responsible for various characters of the catalytic effects of pyrimidinophanes in the hydrolysis of phosphonic acid esters. A less hydrophobic pyrimidinophane exhibited a typical effect of cationic surfactants to accelerate the reaction both in the absence and in the presence of PEI. Unlike cationic micelles, a heminal-type pyrimidinophane exhibited an anomalous behavior: it had no effect on the rates of hydrolysis of the substrates and did not inhibit the hydrolysis. Upon the addition of lanthanum ions, the catalytic activity of dimeric surfactants increased. The overall catalytic effect due to the action of supramolecular systems based on pyrimidinophanes, PEI, and lanthanum ions can increase the rates of hydrolysis of the substrates by three orders of magnitude, as compared with that of alkaline hydrolysis.

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.

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.

Amphiphilic pyrimidinophane, a new dimeric surfactant: Synthesis, aggregation, and catalytic activity

Abstract Tensiometry, conductometry, dynamic light scattering, and potentiometry are used to study the aggregation of a new amphiphilic alkylated pyrimidinophane (APP) in aqueous solutions in the presence of polyethylen-imine. The new geminal surfactant is shown to possess high micellization ability (CMC = 0.00001 M) due to the presence of an additional alkyl radical in the pyrimidine fragment. APP aggregates are characterized by a low degree of counterion binding (lower than 50%). Spectrophotometry is employed to investigate the catalytic activities of individual surfactant solutions and solutions of APP—polyethylenimine binary mixtures with respect to the hydrolysis of phosphonic acid esters. The effect of APP on phosphonate hydrolysis is typical of cationic surfactants. The higher acceleration is observed for the hydrolysis of a more hydrophobic phophonate.

Reactivity of Phosphorus Esters in Supramolecular Systems Based on Surfactants Containing an Uracil Residue and Polyethylenimine

The reactivity of phosphorus esters with different hydrophobicities was studied in aqueous solutions of cationic surfactants containing an uracil residue, as well as in binary systems based on polyethylenimine. Pronounced substrate specificity was revealed in all supramolecular systems examined; in particular, acceleration of the hydrolysis of more hydrophobic substrate and inhibition of the reaction with less hydrophobic analog were observed. Aggregation in the examined systems was confirmed by tensiometric and conductometric measurements. The aggregation threshold considerably decreased in going from monocationic amphiphile to more hydrophobic dicationic analog due to the presence in the latter of two additional alkyl radicals.