A. D. Voloshina

Alkylated 1,4-diazabicyclo[2.2.2]octanes: self-association, catalytic properties, and biological activity

Aggregation of 1-hexadecyl-4-aza-1-azoniabicyclo[2.2.2]octane bromide in the presence of diethyl 4-nitrophenyl phosphate was studied using 1H NMR spectroscopy. The quantitative characteristics of the aggregation were determined. The data obtained were used to explain the catalytic effect of micelles on the hydrolysis of the phosphate. It was found that the aggregation properties and biological activity of alkylated mono- and dicationic 1,4-diazabicyclo-[2.2.2]octanes are correlated.

Self-assembling systems based on quaternized derivatives of 1,4-diazabicyclo[2.2.2]octane in nutrient broth as antimicrobial agents and carriers for hydrophobic drugs.

Aggregation properties of mono (mono-CS) and dicationic (di-CS) surfactants, namely quaternised derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO), have been evaluated in water and in nutrient broths of different pH, i.e. in Hottinger broth (рН=7.2) and Sabouraud dextrose broth (рН=5.6). Aggregation capacity of surfactants was shown to be responsible for the solubilization properties of a complex composed of a hydrophobic probe (Sudan I) and a selected drug (quercetin), contributing to the antimicrobial activity of this surfactant system. The effect of N-methyl-d-glucamine (NmDg) additive on the antimicrobial activity of mono-CS, and its aggregation and solubilization parameters, has also been evaluated. A substantial decrease in critical micelle concentration (CMC) of cationic surfactants in nutrient broths (up to 60 times) has been reported. Twofold dilution of monocationic surfactant by NmDg slightly changed the CMC of surfactant; however, it provided a remarkable increase in solubilization capacity (∼by 4 times) and decrease in its toxicity. The data anticipate the potential use of DABCO quaternized derivatives as innovative non-toxic delivery systems for hydrophobic drugs.

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.

Antimicrobial activity of imidazo[1,5-a]quinoxaline derivatives with pyridinium moiety

3-Phenyl(methyl)-5-alkyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-ones (2a-f) and their N-alkyl-pyridinium salts (3a-o), including 1,n-bis{3-(3-phenylimidazo[1,5-a]quinoxalin-4(5H)-on-1-yl)pyridinium}alkane dibromides (4a-d, 5, 6) have been synthesized. It has been established that the antimicrobial properties of imidazo[1,5-a]quinoxaline derivatives are connected with the presence of various alkyl substituents in the position 1 of the pyridine ring and in the position 5 of the imidazo[1,5-a]quinoxaline system. Chlorides and iodides are more active towards bacteria than fungi. Compounds 3d, 3e, 3m and 3n showed an effective bacteriostatic activity. Compound showed not only well defined bacteriostatic activities but also good fungistatic activities, with the MIC values comparable with the reference drugs. Toxicity of more effective (imidazo[1,5-a]quinoxalin-4-on-1-yl)-1-pyridinium halides was examined in mice.

Development of synthetic approaches to macrocyclic glycoterpenoids on the basis of glucuronic acid and diterpenoid isosteviol

An approach has been developed to the synthesis of macrocyclic glycoterpenoids containing diterpenoid isosteviol and glucuronic acid fragments. Selective screening revealed compounds exhibiting antitubercular activity against H37RV, M. Avium, and M. Terrae strains at a level comparable to the known antitubercular drugs isoniazid, ofloxacin, and pyrazinamide. The compound possessing the highest antitubercular activity is non-cytotoxic toward human erythrocytes.

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.

Aggregation behavior, anticorrosion effect, and antimicrobial activity of alkylmethylmorpholinium bromides

Quaternary ammonium derivatives containing a morpholinium moiety in the head group and exhibiting micelle-forming activity have been synthesized and characterized. These compounds exhibit poly-functional properties: they efficiently inhibit hydrogen sulfide and combined (H2S and CO2) corrosion of steel, are characterized by strong bactericidal activity against sulfate-reducing bacteria, and possess pronounced bacteriostatic and fungistatic effects.

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 and antifungal activity of derivatives of the diterpenoid isosteviol and the glycoside steviolbioside containing onium nitrogen atoms

Previously unknown derivatives of the diterpenoid isosteviol and the glycoside steviobioside containing onium nitrogen atoms were synthesized. The antimicrobial and antifungal activities of these compounds were studied.

Synthesis and antibacterial and antifungal properties of some phosphorus-containing 1,2-dihydroxynaphthalenes

A series of phosphorus-containing 1,2-dihydroxynaphthalenes have been obtained via the reaction of 1,2-naphthoquinone derivatives with tri(n-butyl)- or triphenylphosphine followed by treatment of the intermediate phosphobetaines with various acids. The antimicrobial activity of the synthesized compounds has been studied and the structure—activity relationship established, which gives grounds for the search for new biologically active compounds in this direction.