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Abstract Six compounds of the 5(7)-alkylamino-6-nitroazolopyrimidine and 8-alkylazolo[5,1-b]purine series were selected based on the structural analysis of A1 adenosine receptor inhibitors and the role of this biological target in the modulation of intraocular pressure, an important factor in the pathogenesis of glaucoma. These heterocycles were shown to exhibit a weak affinity towards the A1 adenosine receptor on an in vitro model of the adenosine-dependent change of the chronotropic effect on isolated atria of white mice. On the other hand, thiadiazolo[3,2-a]pyrimidines and triazolo[5,1-b]purine displayed an in vivo hypotensive effect in rats. The leading compound, 5-methyl-8-(hydroxyethyl)triazolo[5,1-b]purine) (0.2% solution), caused a 34% reduction of ophthalmotonus in 3 h without an adverse resorptive effect. In addition, using the MTT-test it was shown on the human HepG2 cell line that the heterocycles affecting the intraocular pressure were by one to two orders of magnitude less cytotoxic than the reference doxorubicin.

Received: 19.04.2021. Revised: 30.04.2021. Accepted: 18.05.2021. Available online: 20.05.2021. Two ethyleneglycol esters of 1-pyrene carboxylic acid were studied as chemosensors for the fluorescence “turn-off” detection of two nitro-containing analytes, such as antiviral drug Riamilovir (Triazavirin ®) and herbicidal agent dinitro-ortho-cresol (DNOC). In both cases the dramatic fluorescence quenching was observed with quenching constants as high as 3·104 M-1 and limits of detection (LOD) as low as 100 ppb. This work was supported by the Russian Foundation for Basic Research (Project № 19-33-90155).

In the present work, we report the structural analogs of the antiviral drug Triazavirin. We carry out a study of nucleophilic substitution reaction of the nitro group in azolo[5,1-c][1,2,4]triazines with various aromatic amines and a hydrazine derivative. © 2020 Author(s). The work was supported by the Russian Foundation for Basic Research (project № 19-33-90086).

New analogues of acyclovir have been prepared by reacting 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 1а-i and (2-acetoxyethoxy)methyl acetate 2 in the presence of trimethylsilyl trifluoromethanesulfonate as a catalyst. Thei nteraction between the compounds 1а-е and 2 has led to a mixture of N3 and N4 isomers. In contrast, the reaction of compounds 1g-i and 2 proceeded selectively to form N3 isomers. In the case of compounds 1a-c the predominant product is the one with the acyclic moiety in azine ring (N4 isomer). Interaction between 1d-f and 2 has led to mixtures comprising mainly N3 isomer. It has been found that the ratio of glycosylation products 1 and 2 are thermodynamically controlled. The structure of the obtained compounds has been proved by 1 Н, 13 С, two-dimensional 1 Н- 13 С NMR spectroscopy and X-ray analysis.

Triazolo[5,1-b]purines are rare structural analogues of natural nucleosides and nucleobases purine series. At the same time, prominent representatives of azolopurines exhibit a broad spectrum of antiviral effect, activity against of rheumatoid arthritis, psoriasis, Alzheimer's, Parkinson's and etc. Despite the practical value azolo[5,1-b]purines extremely sparingly represented in the chemical literature, due to the complexity of their synthesis. We suggest a convenient way to synthesize triazolopurines with aminotriazolo[1,5-a]pyrimidines (2) as available starting compounds obtained in good yield by reduction of nitro derivatives (1)., Триазоло[5,1-b]пурины являются малораспространенными структурными аналогами природных нуклеозидов и нуклеиновых оснований пуринового ряда. В то же время известные представители азолопуринов проявляют широкий спектр противовирусного действия, активность в отношении ревматоидного артрита, псориаза, болезней Альцгеймера, Паркинсона и проч. Несмотря на практическую ценность, азоло[5,1-b]пурины чрезвычайно скупо представлены в химической литературе, что обусловлено сложностью их синтеза. Нами предложен удобный путь к синтезу триазолопуринов с участием аминотриазоло[1,5-a]пиримидинов (2) в качестве доступных исходных соединений, получаемых с хорошими выходами восстановлением нитропроизводных (1).

We describe the synthesis of 2-azido-5-nitropyrimidine and its azido-tetrazole tautomerism in various solvents and in the crystalline state. It was established that on interacting with N-nucleophiles the attack occurred at the C-2 carbon atom. The O- and S-nucleophiles attacked C-4 position of pyrimidine ring, resulting in tetrazole ring closure.

The comparative study of the therapeutic efficacy of Triazavirin against experimental Forest-Spring encephalitis on albino mice vs. the active drug Ribavirin® showed that in high doses (200-400 mg/kg) Triazavirin moderately protected the infected animals. A significant increase of the animal lifespan in the test groups (from 4.1 to 4.8 days) and a statistically (p ≤ 0.05) valid decrease of the virus accumulation in the target organ (the brain) were observed.

Prophylactic efficacy of Triazavirin against experimental Forest-Spring encephalitis was studied on albino mice. vs. the active drug Ribavirin. A significant increase of the animal lifespan in the test groups (from 4 to 5 days) and a statistically (por = 0.05) valid decrease of the virus accumulation level in the target organ (the brain) were observed.

Melt and fluid inclusions were investigated in six quartz phenocryst samples from the igneous rocks of the extrusive (ignimbrites and rhyolites) and subvolcanic (granite porphyries) facies of the Lashkerek Depression in the Kurama mining district, Middle Tien Shan. The method of inclusion homogenization was used, and glasses from more than 40 inclusions were analyzed on electron and ion microprobes. The chemical characteristics of these inclusions are typical of silicic magmatic melts. The average composition is the following (wt %): 72.4 SiO2, 0.06 TiO2, 13.3 Al2O3, 0.95 FeO, 0.03 MnO, 0.01 MgO, 0.46 CaO, 3.33 Na2O, 5.16K2O, 0.32 F, and 0.21 Cl. Potassium strongly prevails over sodium in all of the inclusions (K2O/Na2O averages 1.60). The average total of components in melt inclusions from five samples is 95.3 wt %, which indicates a possible average water content in the melt of no less than 3–4 wt %. Water contents of 2.0 wt % and 6.6 wt % were determined in melt inclusions from two samples using an ion microprobe. The analyses of ore elements in the melt inclusions revealed high contents of Sn (up to 970 ppm), Th (19–62 ppm, 47 ppm on average), and U (9–26 ppm, 18 ppm on average), but very low Eu contents (0.01 ppm). Melt inclusions of two different compositions were detected in quartz from a granite porphyry sample: silicate and chloride, the latter being more abundant. In addition to Na and K chlorides, the salt inclusions usually contain one or several anisotropic crystals and an opaque phase. The homogenization temperatures of the salt inclusions are rather high, from 680 to 820°C. In addition to silicate inclusions with homogenization temperatures of 820–850°C, a primary fluid inclusion of aqueous solution with a concentration of 3.7 wt % NaCl eq. and a very high density of 0.93 g/cm3 was found in quartz from the ignimbrite. High fluid pressure values of 6.5–8.3 kbar were calculated for the temperature of quartz formation. These estimates are comparable with values obtained by us previously for other regions of the world: 2.6–4.3 kbar for Italy, 3.7 kbar for Mongolia, 3.3–8.7 kbar for central Slovakia, and 3.3–9.6 kbar for eastern Slovakia. Unusual melt inclusions were investigated in quartz from another ignimbrite sample. In addition to a gas phase and transparent glass, they contain spherical Feoxide globules (81.2 wt % FeO) with high content of SiO2 (9.9 wt %). The globules were dissolved in the silicate melt within a narrow temperature range of 1050–1100°C, and the complete homogenization of the inclusions was observed at temperatures of 1140°C or higher. The combined analysis of the results of the investigation of these inclusions allowed us to conclude that immiscible liquids were formed in the high-temperature silicic magma with the separation of iron oxide-dominated droplets.

Skarns at the Dal’negorsk boron deposit belong to the infiltration type. In their outer contact zone (bounded by limestone and consisting of wollastonite + hedenbergite), rhythmically banded textures developed, with alternating wollastonite and hedenbergite bands. The petrological study and modeling of the process that produced them led us to propose a mechanism for the genesis of such textures. They are thought to form as a consequence of a dissipative structure in the infiltrating solution and its interaction with the rock. The dissipative structure itself resulted from the instability of the equilibrium state of the skarn-solution system and the development of pervasive spatial oscillations in the redox potential of the solution. The progressive development of the banded texture was associated with a change in the dissipative structure because of the existence of feedback (mutual influence) between the structure of the solution and the texture of the rock. The rhythms generated thereby are of several orders (as follows from their thicknesses and the distances between them), which is an indication of a large-scale invariance of the developing texture. The simulation of the process involved the analysis of a system of kinetic equations, the stability of the equilibrium, and the conditions of the stability of spatial oscillations in the concentrations of major components in the solution. A necessary condition of the stability of the dissipative structure is a low velocity of fluid filtration, which should be no higher than a critical value, with the latter controlled by kinetic parameters of the system. The proposed model can be modified and adapted for rhythmically banded skarns of other composition and for banded hydrothermal mineralized veins with the aim of constraining the petrogenetic conditions and elucidating the role of banded textures as precipitators of ore and minor components of the solution.

The Lena gold district is situated in the fold-and-shear belt of the southern framework of the Siberian Platform. The gold deposits are hosted in the Riphean-Vendian Khomolkho and Aunakit formations, revealing the strict control of ore mineralization by folding and shearing. The microstructure of metasomatically altered ore-bearing carbonaceous sedimentary rocks at the Sukhoi Log, Golets Vysochaishy, and Verninsky deposits (the latter includes the Pervenets vein zone) testifies to parallelism in the development of shearing, foliation, and ore-forming metasomatism. The local pressure gradients are marked by removal of silica from pressured zones into opened cleavage fractures and pockets. Two metasomatic stages are recognized: (1) early sodic metasomatism, which is characterized by the assemblage of magnesian siderite and paragonite, and (2) late potassic metasomatism, with formation of muscovite in association with sideroplesite and ankerite. The rocks altered at the early stage are distinguished by elevated Ni, Cr, and probably PGE contents. The second stage, close in age to the emplacement of Hercynian granitic plutons, was accompanied by the gain of chalcophile metals and deposition of the bulk of gold. In mineral composition, the metasomatic rocks are close to beresites, but the alteration differed in somewhat elevated alkalinity, so that microveinlets of albite and potassium feldspar occur in the ore zone together with muscovite. The ratio of modal muscovite to paragonite contents in orebodies is substantially higher than in the surrounding metasomatized rocks. This ratio directly depends on the degree of rock permeability and the intensity of the flow of ore-forming solutions. Carbonaceous matter (CM) in the ore zone underwent reworking and redeposition. CM is graphitized to a lesser extent than in the rocks affected by regional metamorphism. The spatial distribution of CM containing nitro and amino groups indicates more oxidizing conditions in the zone of ore deposition than at a distance from this zone. The temperature of metasomatic processes estimated from the muscovite, muscovite-paragonite, and chlorite mineral thermometers and fluid inclusions in quartz was 300–350°C at a pressure of about 1 kbar. The S, O, and C isotopic compositions of ore-forming fluids that pertain to the second stage of metasomatism (δ34S= +8.5‰, δ18O = +10‰, and δ13C= −11 to −18‰) indicate their crustal origin. The generally similar conditions and products of the ore-forming metasomatic process at the giant Sukhoi Log deposit and at the small Golets Vysochaishy deposit are combined with some differences. The formation of the described deposits was related to the deep convection of fluids along shear zones followed by more local flows of postmagmatic solutions derived from the emplaced granitic magma.

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-methylthio-6-nitro-1,2,4-triazolo[5,1-ñ]-1,2,4-triazine-7(4Í)-ide (3S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-7H-pyrido[1,2,3-d,e]-1,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration.

The acidity and basicity constants of isomeric phenyl(aryl)-1,2,4-triazin-3- and -5-ones in aqueous solution were determined by spectrophotometry: pK a = 7.3–6.2; pK BH+= 0.1 to –2.2. 1,2,4-Triazin-3-ones are weaker bases than the corresponding 1,2,4-triazin-5-ones. According to the AM1 calculations, the most thermodynamically favorable tautomer in the gas phase is the oxo form: namely, 2H-tautomers of the neutral bases and 2,4-H,H +-tautomers of the conjugate acids.

The efficacy of Triazavirin against the tick-borne encephalitis virus was estimated in the sensitive cell culture vs. the active drug Ribavirin. In a concentration of 128 mcg/ml Triazavirin was shown active in inhibition of the tick-borne encephalitis virus reproduction (strain Sofiin) by accumulation in the SKEV cell culture.

3-R-6-Phenyl-1,2,4-triazine 4-oxides react with cyclic β-diketones (dimethylbarbituric acid, dimedone, and indan) in both acidic (substrate activation) and basic conditions (nucleophile activation) with formation of σH-adducts, intermediates in the nucleophilic substitution of hydrogen (SN H) in 3-R-5-Nu-4-hydroxy-6-phenyl-4,5-dihydro-1,2,4-triazines. Oxidative aromatisation of these intermediates or auto-aromatisation of acylated (benzoyl chloride) at the NOH σ-adducts with elimination of benzoic acid gave the corresponding substituted 1,2,4-triazine 4-oxides or 1,2,4-triazines.

A new dynamic model of infiltration metasomatic zonation is discussed. The model describes the formation and evolution of metasomatic zoning patterns in terms of travelling fronts and waves. Travelling fronts cause the formation of well known vectoral zonation. All replacement reactions in this zonation are localized immediately around fronts (zone boundaries), and inside individual zones the chemical equilibrium is attained. Such a condition corresponds to the “local equilibrium model” and no regular oscillations occur. Travelling waves can stimulate stable spatial chemical oscillations and appearance of the dissipative structure in the solution flow, if redox reactions such as Fe2+ ↔ Fe3++ e – in solution occur. Corresponding to the evolution of the dissipative structure, the rhythmical banding in the metasomatic rocks is formed. Thus the proposed model describes the single approach as vectoral as periodic (rhythmically banded) zoning patterns.