Non-natural nucleosides based on 1,2,4-triazolo[5,1-c][1,2,4]triazin-4(6H)- ones

Two regioselective methods for the synthesis of nucleosides in the series of 3-phenyl- and 3- ethoxycarbonyl-1,2,4-triazolo[5,1-c][1,2,4]triazin-4-ones were developed. The first route involves a Vorbrüggen glycosylation reaction. The second one is based on condensation of 1,2,4- triazolo[5,1-c][1,2, 4]triazin-4-one sodium salts with protected 1-bromo-sugar derivatives

Synthesis of acyclic nucleoside analogues by one-step Vorbrüggen glyco-sylation of 1,2,4-triazolo[1,5-a]pyrimidine-7-ones

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. The interaction 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 1Н, 13С, two-dimensional 1Н-13С NMR spectroscopy and X-ray analysis

Long-range 1H-15N J couplings providing a method for direct studies of the structure and azide-tetrazole equilibrium in a series of azido-1,2,4-triazines and azidopyrimidines

The selectively 15N labeled azido-1,2,4-triazine 2*A and azidopyrimidine 4*A were synthesized by treating hydrazinoazines with 15N-labeled nitrous acid. The synthesized compounds were studied by 1H, 13C, and 15N NMR spectroscopy in DMSO, TFA, and DMSO/TFA solutions, where the azide-tetrazole equilibrium could lead to the formation of two tetrazoles (T, T′) and one azide (A) isomer for each compound. The incorporation of the 15N label led to the appearance of long-range 1H-15N coupling constants (JHN), which can be measured easily by using amplitude-modulated 1D 1H spin-echo experiments with selective inversion of the 15N nuclei. The observed JHN patterns enable the unambiguous determination of the mode of fusion between the azole and azine rings in the two groups of tetrazole isomers (2*T′, 4*T′ and 2*T, 4*T), even for minor isoforms with a low concentration in solution. However, the azide isomers (2*A and 4*A) are characterized by the absence of detectable J HN coupling. The analysis of the JHN couplings in 15N-labeled compounds provides a simple and efficient method for direct NMR studies of the azide-tetrazole equilibrium in solution. © 2013 American Chemical Society

Spin-spin coupling constants 13C-15N and 1H-15N in the investigation of azido-tetrazole tautomerism in a series of 2-azidopyrimidines

A new method was developed for the investigation of an azido-tetrazole equilibrium based on using a complex analysis of 13C-15N and 1H-15N spin-spin coupling constants. The use of this approach became possible due to the selective inclusion of 15N isotopes into the structures of 2-azidopyrimidines and their cyclic analogs tetrazolo[1,5-a]pyrimidines. © 2013 Springer Science+Business Media New York

Incorporation o f stable isotopes 2H, 13C and 15N in the structure of azolo[5,1-c][l,2,4]triazines and azolo[1,5-a]pyrimidine as a tool for studying the chemical and biological transformations of nitrogenous heterocycles

It is shown that selective incorporation of stable isotopes allows one to expand standard capabilities of NMR spectroscopy and is an effective approach to the study of the structure and reactivity of organic compounds. Azidotetrazole equilibrium, Dimroth rearrangement, and adamantylation of azoloazines were examined using compounds labeled by stable isotopes.This work was financially supported by the Ministry o f Education and Science o f the Russian Federation (state contract in 2458)

THE STUDY OF ANAMNESTIC FACTORS AND THEIR ROLE IN ESTIMATION OF SHORT-TERM (IN-HOSPITAL) PROGNOSIS IN PATIENTS UNDERWENT BRAIN STROKE OR TRANSIENT ISCHEMIC ATTACK, BY THE DATA FROM LIS-2 REGISTRY

Aim. To assess the role of anamnestic factors in estimation of the shortest-term (in-hospital) prognosis in patients after stroke. Material and methods. We included all patients during the period 01.01.2009 to 31.12.2011 (n=960), who were diagnosed the stroke ot TIA inMHILyubertsyDistrictHospital№2.Results. Into the registry LIS-2 included 960 patients. During hospitalization 207 patients died, in-hospital mortality was 21,6%. Mortality increased with the age, and the age became an independent death risk factor in hospital (p=0,037). Hemoorhagic stroke increased the risk of death 6,95 times, and consciousness disorders — 2-5 times (depending on the level of disorder), CHF signs— by 3,14 times, and AF— 1,86 times. These values were evaluated as independent anamnestic risk factors of the in-hospital death.Conclusion. The data from LIS-2 registry demonstrates analogy with the data from other stroke registries in RF. In-hospital mortality in LIS-2 was 2-3 times higher comparing to the registries of other countries. Factors influenced in-hospital mortality were age, type of the stroke, level of consciousness at admission, CHF and cardiac rhythm disorders as AF

IMPACT OF ATRIAL FIBRILLATION ON THE NEAR AND LONG-TERM PROGNOSIS OF LIFE AFTER ACUTE MYOCARDIAL INFARCTION. THE DATA OF THE LIS-1 STUDY (LYUBERTSY MORTALITY STUDY OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTION)

Aim. To study the effect of atrial fibrillation (AF) that existed before the myocardial infarction (MI), on near and long-term mortality in patients with acute MI.Material and methods. The data of LIS register (Lyubertsy study on mortality rate in patients after MI), that included all patients hospitalized for acute MI (n=1133) during the period from 1 January 2005 to 31 December 2007, were used to solve the aim of the study.Results. AF was recorded in 88 patients (7.8%), and the frequency of AF significantly increased with age. 22 patients with a history of AF (25%) died in hospital, and mortality in this group of patients was significantly higher than this in the whole group of patients (15.2%; p=0.025). However, these differences were not statistically significant when adjusted for age and gender (OR=1.25; 95% CI 0.77-2.04; p=0.37). 66 people from 961 patients, who were discharged from the hospital, had the AF before acute MI. Relative risk of death in patients with AF in this group (adjusted for age and sex) was significantly higher than this in patients without AF (OR=1.91; 95% CI 1.18-3.11; p=0.005). Conclusion. AF diagnosed in patients with acute MI at admission did not influence significantly hospital mortality. However, pre-existing AF increases significantly the risk of death in patients survived acute period of MI

INFLUENCE OF PATIENTS’ PREHOSPITAL ATTENDANCE AT OUTPATIENT CLINICS ON LONG-TERM OUTCOMES OF ACUTE CORONARY SYNDROME: LIS-3 STUDY

Aim. To assess influence of patients’ prehospital attendance at outpatient clinics on long-term outcomes of acute coronary syndrome (ACS).Material and methods. Patients (n=397) hospitalized with ACS (01.11.2013-31.07.2015) were included. 19.4% of patients died in hospital (77/397).-According to their rate of attendance at outpatient clinics all survived patients (n=320) were divided into 3 groups: committed to visiting outpatient-clinics (n=139), partially committed (n=103) and not committed (n=78). Follow-up period was 14-35 months (88.44% follow-up rate). During-follow-up period 12.5% of patients died (40/320). All-cause mortality and recurrent cardiovascular diseases (nonfatal myocardial infarction and stroke,-unstable angina) were defined as the primary endpoint. Prognostic significance of separate factors and their combinations were assessed by their influence on the primary endpoint.Results. Clinical severity of course of the disease was assessed regarding all factors that had influence on the primary endpoint. By their degree of influence on the primary endpoint each factor was given a certain score. According to the sum of all scores patients were divided into 2 groups: patients with less (n=205) and more (n=78) severe clinical course of the disease. Risk of development of primary endpoint was higher in patients with more severe clinical course of the disease (relative risk 3.997; 95% confidence interval 2.199-7.267; p <0.0001) regardless of patients’ attendance at outpatient-clinics (p>0.05).Conclusion. Patients’ prehospital attendance at outpatient clinics did not affect long-term outcomes of acute coronary syndrome. Patients with more-severe clinical course of the disease were more likely to develop adverse outcomes during the follow-up regardless of their prehospital attendance at outpatient clinics

Antiviral drug Triazavirin, selectively labeled with 2H, 13C, and 15N stable isotopes. Synthesis and properties

[Figure not available: see fulltext.] Isotope-labeled antiviral drug Triazavirin containing 2H, 13C, and 15N atoms in its structure has been synthesized. 13C2H3I and KS13CN served as donors of 13C isotopes. The use of 13С-MeI containing 2H atoms made it possible to additionally incorporate deuterium labels into the structure of the compound. The 15N atoms were incorporated using 15N-enriched sodium nitrite, aminoguanidine carbonate, and ethyl nitroacetate. The resulting 2H3,13C2,15N3-Triazavirin was characterized by NMR spectroscopy. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.This work was supported by the Russian Foundation for Basic Research (grant 20-03-00842) and the Ministry of Science and Higher Education of the Russian Federation (project No. FEUZ-2020-0058 (N687.42B.223/20))

Pulmonary Vascular Thrombosis in COVID-19: Clinical and Morphological Parallels

Aim. We aimed to study the histological and thrombotic changes in lung vessels in patients who died with COVID-19, to access the correlation between anticoagulation therapy (ACT) and thrombotic events (TE), treatment results, clinical and laboratory patients' characteristics.Material and Methods. We retrospectively analyzed treatment results of patients hospitalized with COVID-19 and lung vessel samples of the deceased patients. Dynamic changes and highest levels of D-dimer and fibrinogen were studied in its correlation with the disease severity according to SOFA score, computer tomographic (CT) results, lung, renal and hepatic dysfunction. The association between different doses of ACT and treatment results, laboratory indicators and thrombotic events was accessed. The histological lung vessels examination was performed using Martius Scarlet Blue (MSB)staining.Results. 313 patients were included in the study (61 patients died). The median age of hospitalized patients was 60 years (IQR 51-66 years). The frequency of the intravitallyconfirmed TE was 4,8%. The strong statistical association was revealed between D-dimer level and 3-4 points SOFA score, patients' mortality, oxygen support requirement, CT3-CT4 pneumonia, glomerular filtration rate and TE. There was no mortality in patients with D-dimer normal references, but in cases with three times elevation reached 13%, 48,5% - in cases with 3-6 times elevation and 64,6% - in cases with more than 6 times elevation. The strong statistical association was registered between fibrinogen and SOFA score, CT 3-4 pneumonia, patients' mortality. D-dimer and fibrinogen levels demonstrated weak correlation. There was no statistical correlation between prophylactic, intermediate and therapeutic ACT and D-dimer and fibrinogen levels, CT results, patients' mortality. MSBstaining was used in 36 deceased patients tissue samples. 1394 lung vessels were analyzed. Lung vessels thrombi persisted in samples of all 36 patients (100%). Vessels with the diameter 3,5-30 mm were thrombosed in 7%, with the diameter 0,034-0,84 mm - in 48%, with the diameter 0,85-3,4 mm - in 45%. The frequency of thrombi persisted 06 hours, 6-12 hours, 12-18hours, 18-24 hours and more than 24 hours was12%, 14%, 62%, 5% and 7% respectively.Conclusion. Thrombi of different ages from fresh to organized were observed in one third of lung vessels in all deceased patients. Lung vessels thrombosis plays an important role in pathogenesis and thanatogenesis of COVID-19. The D-dimer level correlates with lung, renal dysfunction, patients' mortality and doesn't show any correlation with ACT and can be accepted as a criterion of lung vessel thrombotic progression