Синтез, дослідження 6-((5-фенетил-4-R-1,2,4-триазол-3-ілтіо)піридин-3-іл)-(алкіл, гетерил)метанімінів та їх похідних

In the pharmaceutical practice directly related to the search of biological active substances and their introduction into medicine or veterinary it is generally recognized that a successful choice of the research object is a prerequisite for a positive final outcome to create original effective and low-toxic drugs. At present, derivatives of 1,2,4-triazoles containing pyridine deserve special attention. That is why the synthesis and study of physicochemical properties of new compounds, which contain 1,2,4-triazole and pyridine rings, are important tasks of modern synthetic and pharmaceutical chemistry.Aim. To study the reactions associated with formation and transformation of 6-((5-phenethyl-4-R-1,2,4-triazole-3-ylthio)pyridine-3-yl)-(alkyl-, heteryl)methanimines and their recovery, study physicochemical properties of new compounds synthesized. Materials and methods. 6-((5-phenethyl-4-R-1,2,4-triazole-3-ylthio)pyridine-3-yl)-(alkyl-, heter-yl)methanimines were obtained by the mixture from 6-(5-phenethyl-4-R-1,2,4-triazole-3-ylthio)pyridine-3-amine and aldehydes. The synthesis was carried out in the acetic acid medium. The mixture was kept at room temperature for 6 h. 6-((5-phenethyl-4-R-1,2,4-triazole-3-ylthio)pyridine-3-yl)-(alkyl-, heteryl)methanimines were reduced in the 1,4-dioxane medium. As a reducing agent sodium borohydride was used. Results and discussion. As a result of synthetic transformations 17 new compounds have been obtained, the structure of the compounds synthesized has been confirmed by modern complex of physicochemical methods of analysis (IR-spectrophotometry, elemental analysis), and their individuality has been proven on an Agilent 1260 Infinity HPLC high-performance liquid chromatograph equipped with an Agilent 6120 mass spectrometer.Conclusions. The preparative method for the synthesis of 6-((5-phenethyl-4-R-1,2,4-triazole-3-ylthio)pyridine-3-yl)-(alkyl-, heteryl)methanimines and 6-(5-phenethyl-4-R-1,2,4-triazole-3-ylthio)-N-(alkyl-, heteryl)pyridine-3-amines has been developed.В фармацевтической практике, непосредственно связанной с поиском биологически активных веществ и их введением в медицину или ветеринарию, общепринято, что успешный выбор объекта исследования является предпосылкой для положительного конечного результата, для создания оригинальных эффективных и малотоксичных лекарств. На данный момент особого внимания заслуживают производные 1,2,4-триазолов, которые содержат пиридин. Именно поэтому синтез и изучение физико-химических свойств новых соединений, содержащих 1,2,4-триазольное и пиридиновое кольца, являются важной задачей современной синтетической и фармацевтической химии.Цель. Изучить реакцию образования 6-((5-фенетил-4-R-1,2,4-триазол-3-илтио)пиридин-3-ил)-(алкил, гетерил)метаниминов и их селективного восстановления, исследовать физические и химические свойства новых синтезированных соединений.Материалы и методы. Для получения 6-((5-фенетил-4-R-1,2,4-триазол-3-илтио)пиридин-3-ил)-(алкил-, гетерил)метаниминов использовали 6-(5-фенетил-4-R-1,2,4-триазол-3-илтио)пиридин-3-амины и альдегиды. Синтез проводился в среде кислоты уксусной. Смесь оставляли при комнатной температуре на 6 часов. 6-((5-Фенетил-4-R-1,2,4-триазол-3-илтио)пиридин-3-ил)-(алкил-, гетерил)метанимины были восстановлены в среде 1,4-диоксана. В качестве восстановителя был использован натрия боргидрид.Результаты и их обсуждение. В результате синтетических превращений получено 17 новых соединений, структуру синтезированных соединений подтверждено благодаря современному комплексу физико-химических методов анализа (ИК-спектрофотометрии, элементного анализа), а их индивидуальность подтверждена исследованием на высокопроизводительном жидком хроматографе Agilent 1260 Infinity HPLC, оборудованном масс-спектрометром Agilent 6120.Выводы. Разработан препаративный метод синтеза 6-((5-фенетил-4-R-1,2,4-триазол-3-илтио)пиридин-3-ил)-(алкил-, гетерил)метаниминов и 6-(5-фенетил-4-R-1,2,4-триазол-3-илтио)-N- (алкил-, гетерил)пиридин-3-аминов.У фармацевтичній практиці, яка безпосередньо пов’язана з пошуком біологічно активних речовин та їх введенням у медицину або ветеринарію, загальним є те, що успішний вибір об’єкта дослідження є необхідною умовою для позитивного кінцевого результату та для створення оригінальних ефективних та малотоксичних препаратів. На цьому етапі на особливу увагу заслуговують похідні 1,2,4-триазолів, що містять піридин. Саме тому синтез та вивчення фізико-хімічних властивостей нових сполук, що містять 1,2,4-триазольний та піридиновий фрагмент, є важливими завданнями сучасної синтетичної та фармацевтичної хімії.Мета. Вивчити реакцію утворення 6-((5-фенетил-4-R-1,2,4-триазол-3-ілтіо)піридин-3-іл)-(алкіл, гетерил)метанімінів та їх селективного відновлення, дослідити фізичні та хімічні властивості нових синтезованих сполук.Матеріали та методи. Для отримання 6-((5-фенетил-4-R-1,2,4-триазол-3-ілтіо)піридин-3-іл)-(алкіл-, гетерил)метанімінів використано 6-(5-фенетил-4R-1,2,4-триазол-3-ілтіо)піридин-3-аміни та альдегіди. Синтез проводився в середовищі кислоти оцтової. Суміш залишали при кімнатній температурі на 6 годин. 6-((5-Фенетил-4-R-1,2,4-триазол-3-ілтіо)піридин-3-іл)-(алкіл-, гетерил)метаніміни були відновлені в середовищі 1,4-діоксану. В якості відновника використано натрію боргідрид.Результати та їх обговорення. В результаті синтетичних перетворень отримано 17 нових сполук, структуру синтезованих сполук підтверджено завдяки сучасному комплексу фізико-хімічних методів аналізу (ІЧ-спектрофотометрії, елементного аналізу), а їх індивідуальність підтверджена дослідженням на високопродуктивному рідинному хроматографі Agilent 1260 Infinity HPLC, обладнаному мас-спектрометром Agilent 6120.Висновки. Розроблено препаративний метод синтезу 6-((5-фенетил-4-R-1,2,4-триазол-3-ілтіо)піридин-3-іл)-(алкіл-, гетерил)метанімінів і 6-(5-фенетил-4-R-1,2,4-триазол-3-ілтіо)-N-(алкіл-, гетерил)піридин-3-амінів

КОМП’ЮТЕРНЕ ПРОГНОЗУВАННЯ ГОСТРОЇ ТОКСИЧНОСТІ ПОХІДНИХ 5-ФЕНЕТИЛ-4-R-3-ТІО(АМІНО)-1,2,4-ТРІАЗОЛУ ЗАВДЯКИ GUSAR-ONLINE ПРОГНОЗУ

An important step in the development of a new drug is the prediction of its toxicity by computer screening using the program GUSAR-online. The purpose of this work is an online prediction of acute toxicity among new derivatives of 5-phenethyl-4-R-3-thio(amino) 1,2,4-triazoles. Computer prediction of acute toxicity of 5-phenethyl-4-R-3-thio(amino)- 1,2,4-triazole derivatives was performed according to the structural formulas of the compounds in the online version of the GUSAR-online program.GUSAR-online prediction for 5-phenethyl-4-R-3-thio(amino)-1,2,4- triazole derivatives was performed during the research. It was found that the average lethal dose of LD50 is from 56.1 to 2396.0 mg / kg. Based on this, all compounds are low-toxic and virtually non-toxic substances.An important step in the development of a new drug is the prediction of its toxicity by computer screening using the program GUSAR-online. The purpose of this work is an online prediction of acute toxicity among new derivatives of 5-phenethyl-4-R-3-thio(amino) 1,2,4-triazoles. Computer prediction of acute toxicity of 5-phenethyl-4-R-3-thio(amino)- 1,2,4-triazole derivatives was performed according to the structural formulas of the compounds in the online version of the GUSAR-online program.GUSAR-online prediction for 5-phenethyl-4-R-3-thio(amino)-1,2,4- triazole derivatives was performed during the research. It was found that the average lethal dose of LD50 is from 56.1 to 2396.0 mg / kg. Based on this, all compounds are low-toxic and virtually non-toxic substances

Ethno-didactic specifics of training chinese students in the russian language: the experience of russian universities

The paper systematizes and generalizes the ethno-oriented experience of teaching Russian as a foreign language in the education systems of Russia and China. The number of foreign subjects wishing to study for a degree in Russia is now increasing; it is almost the same as it was before the perestroika times. The majority of foreign students come from China. In order to make the training effective, ethnic and cultural specifics should be taken into consideration in teaching Russian as a foreign languag

Elastic constants of borocarbides. New approach to acoustic Measurement technique

A new version of the phase method of determining the sound velocity is proposed and implemented. It utilizes the ``Nonius'' measurement technique and can give acceptable accuracy (~1%) in samples of submillimeter size. Measurements of the sound velocity are made in single-crystal samples of the borocarbides RNi2B2C (R = Y,Lu,Ho). The elastic constants and the Debye temperature are calculated.Comment: 5 figures, 2 table

On the analyticity and Gevrey class regularity up to the boundary for the Euler Equations

We consider the Euler equations in a three-dimensional Gevrey-class bounded domain. Using Lagrangian coordinates we obtain the Gevrey-class persistence of the solution, up to the boundary, with an explicit estimate on the rate of decay of the Gevrey-class regularity radius

Long-term results of antiviral therapy in patients with chronic hepatitis C with sustained virologic response

Aim of investigation. To estimate frequency of late relapses and clinical outcomes in patients with chronic hepatitis C (CHC) with sustained virologic response (SVO) achievement at antiviral therapy (AVT).Material and methods. Overall 208 patients with CHC, including 12 at the stage of liver cirrhosis (LC), who achieved SVO were investigated. Mean duration of the follow-up was 56,1±35,4 months. Standard clinical and laboratory investigation and evaluation of RNA HCV was carried out. In 114 patients RNA HCV and DNA HBV in blood serum and peripheral mononuclear blood cells were studied by polymerase chain reaction (PCR) with fluorescent hybridization detection in «real time» mode (sensitivity of 10 IU/ml for HCV and 5 IU/ml for HBV).Results. In 3 (1,5%) patients late (i.e. over 6 months after AVT) relapses of HCV-infection were observed. Application of ultraresponsive PCR method allowed to reveal relapse half a year prior to its clinical and laboratory manifestation in 2 cases. No data on latent HCVinfection was obtained not in a single case, including patients with relapse of cryoglobulinemia syndrome. A principal cause of elevation of alanine transaminase activity was non-alcoholic steatohepatitis. In one LC patient development of esophageal varicose veins was detected. There were no cases of decompensation of LC, hepatocellular carcinoma and death due to liver disease.Conclusion. At patients who have achieved SVO as a result of AVT, late relapses of HCV-infection are rare and in the majority no disease progression was found. Relapses of cryoglobulinemia syndrome were observed, but data on presence of latent HCV-infection were not received. Highly sensitive PCR methods are rational for assessment of SVO

Mapping of Mycobacterium tuberculosis Complex Genetic Diversity Profiles in Tanzania and Other African Countries

The aim of this study was to assess and characterize Mycobacterium tuberculosis complex (MTBC) genotypic diversity in Tanzania, as well as in neighbouring East and other several African countries. We used spoligotyping to identify a total of 293 M. tuberculosis clinical isolates (one isolate per patient) collected in the Bunda, Dar es Salaam, Ngorongoro and Serengeti areas in Tanzania. The results were compared with results in the SITVIT2 international database of the Pasteur Institute of Guadeloupe. Genotyping and phylogeographical analyses highlighted the predominance of the CAS, T, EAI, and LAM MTBC lineages in Tanzania. The three most frequent Spoligotype International Types (SITs) were: SIT21/CAS1-Kili (n = 76; 25.94%), SIT59/LAM11-ZWE (n = 22; 7.51%), and SIT126/EAI5 tentatively reclassified as EAI3-TZA (n = 18; 6.14%). Furthermore, three SITs were newly created in this study (SIT4056/EAI5 n = 2, SIT4057/T1 n = 1, and SIT4058/EAI5 n = 1). We noted that the East-African-Indian (EAI) lineage was more predominant in Bunda, the Manu lineage was more common among strains isolated in Ngorongoro, and the Central-Asian (CAS) lineage was more predominant in Dar es Salaam (p-value<0.0001). No statistically significant differences were noted when comparing HIV status of patients vs. major lineages (p-value = 0.103). However, when grouping lineages as Principal Genetic Groups (PGG), we noticed that PGG2/3 group (Haarlem, LAM, S, T, and X) was more associated with HIV-positive patients as compared to PGG1 group (Beijing, CAS, EAI, and Manu) (p-value = 0.03). This study provided mapping of MTBC genetic diversity in Tanzania (containing information on isolates from different cities) and neighbouring East African and other several African countries highlighting differences as regards to MTBC genotypic distribution between Tanzania and other African countries. This work also allowed underlining of spoligotyping patterns tentatively grouped within the newly designated EAI3-TZA lineage (remarkable by absence of spacers 2 and 3, and represented by SIT126) which seems to be specific to Tanzania. However, further genotyping information would be needed to confirm this specificity

Ultrafast dissociation features in RIXS spectra of the water molecule

In this combined theoretical and experimental study we report on an analysis of the resonant inelastic X ray scattering RIXS spectra of gas phase water via the lowest dissociative core excited state 1s amp; 8722;1O4a11 amp; 12297;. We focus on the spectral feature near the dissociation limit of the electronic ground state. We show that the narrow atomic like peak consists of the overlapping contribution from the RIXS channels back to the ground state and to the first valence excited state 1b amp; 8722;114a11 amp; 12297; of the molecule. The spectral feature has signatures of ultrafast dissociation UFD in the core excited state, as we show by means of ab initio calculations and time dependent nuclear wave packet simulations. We show that the electronically elastic RIXS channel gives substantial contribution to the atomic like resonance due to the strong bond length dependence of the magnitude and orientation of the transition dipole moment. By studying the RIXS for an excitation energy scan over the core excited state resonance, we can understand and single out the molecular and atomic like contributions in the decay to the lowest valence excited state. Our study is complemented by a theoretical discussion of RIXS in the case of isotopically substituted water HDO and D2O where the nuclear dynamics is significantly affected by the heavier fragments mas