Stereodirected synthesis of alkaloid-like quinolizidine systems

New stereoselective methods for the chemical modification of cytisine based on T-reactions are reported. A reaction of cytisine with 2-chloro-5-nitrobenzaldehyde and followed condensation with 1,3-dimethylbarbituric acid affords N-(5-nitro-2-{1,3-dimethylperhydropyrimidine-2,4,6-trione-5-methynyl})cytisine, which undergoes a cyclization with the tetrahydropyridine ring closure. The cyclization proceeds via two competing routes yielding 5,5-spirobarbituric acid derivatives with 11,19-diaza-pentacyclo[11.7.1.02,11.05,10.014,19]henicosane and 11,15-diazapentacyclo-[11.7.1.02,11.05,10.015,20]henicosane skeletons. The cyclization reaction in solutions afford either 24.25-trans and 15,16-trans isomers or trans and cis isomer mixtures, depending on the specific solvent. Meanwhile, 24,25-cis and 15,16-cis isomers are formed stereoselectively under heterogeneous conditions in water suspensions. Trans-5,5-spirobarbiturates under similar conditions undergo isomerization into more stable cis-analogs by the configuration inversion at the C7 atom. The synthesized 5,5-spirobarbituric acid derivatives were successfully converted into alkaloid-like quinolizidine systems (1R,2R,3R,13S)-7-nitro-18-oxo-11,19-diazapentacyclo[11.7.1.02,11.05,10.014,19]henicosa-5(10),6,8,14,16-pentaene-3-carboxylic acid and (1R,2S,3S,13S)-nitro-16-oxo-11,15-diazapentacyclo[11,7,1.02,11,05,10,015,20]henicosa-5,7,9,17,19-pentaene-3-carboxylic acid and their derivatives via the spiropyrimidine moiety removal by the stereoselective hydrolysis. The molecular and crystal structures of the target substances were elucidated by X-ray crystallography and NMR. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Reactivity in 7-benzyl-2,7-naphthyridine derivatives: Nucleophilic substitutions, rearrangements, heterocyclizations and related reactions

Background and Objective: Continuing our studies in the field of a new rearrangement in the 2,7- naphthyridine series, the synthesis and rearrangement of mono- 2 and di-amino derivatives 3 of 2,7- naphthyridine was carried out. Taking into account the wide range of pharmacological activities of pyrazole derivatives the synthesis of some 3-amino-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridines 8 and of pyrazolo[3,4-c]-2,7-naphthyridine 12 was described. Methods: Compounds 2 were reacted with amines furnishing the relevant rearrangement products 4. Starting from the 7-benzyl-3-chloro-1-hydrazino-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 6 and 5-hydrazino- 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-2,7-naphthyridin-1-amine 12 the 7-benzyl-3-chloro-1-(3,5-dimethyl-1Hpyrazol- 1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 and 3,5-dimethyl-1H-pyrazol-1-yl-9,11- dimethylpyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13 were synthesized, via the Knorr synthesis of pyrazoles. Results: The syntheses of 2-benzyl-6,8-diamino-3,4-dihydro-2,7-naphthyridin-1(2H)ones 4 deriving from the rearrangement of compounds 2 and/or 3 were performed. By reaction with benzylamine compound 2a or 3g gave the unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7- naphthyridin-1-amine 5: in fact, the rearrangement was followed by condensation between the C-1 carbonyl group of the 2,7-naphthyridine ring and the benzylamine. Starting from the 7-benzyl-3-chloro-1-(3,5-dimethyl- 1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 the relevant 3-amino-7-benzyl-1-(3,5- dimethyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitriles 8 were obtained. In harsh experimental conditions the nucleophilic substitution of the 1-pyrazolyl residue took place with formation of 7- benzyl-1,3-bis[(2-hydroxypropyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 10. Moreover compound 7 reacted with hydrazine hydrate giving the pyrazolo[3,4-c]-2,7-naphthyridine 12, which, in turn furnished a new tetra-heterocyclic system: 3-benzyl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-9,11-dimethyl-1,2,3,4- tetrahydropyrimido[1',2': 1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13. Conclusion: Replacement of methyl group on piperidine ring of 2,7-naphthyridine system with the benzyl one led to new results. Reaction of compound 2a or 3g with benzylamine brought to an unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine 5. The reactivity of 7-benzyl-3-chloro-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridine 7 with nucleophiles was investigated observing the unexpected substitution of the 1-pyrazolyl residue

Антибиотикорезистентность культур Enterococcus spp., выделенных от промышленной птицы в 2013–2016 гг. в хозяйствах Российской Федерации, и детекция у них генов резистентности к ванкомицину

Rationale: Enterococci are the leading cause of a number of nosocomial and community-acquired human diseases. In the last decade, these pathogens are becoming resistant to antibacterials, including vancomycin. Multidrug-resistant enterococci have been also isolated from agricultural animals in many countries worldwide, which raises concern of scientists because of possible horizontal transfer of resistance genes. Aim: To assess antibacterial sensitivity of Enterococcus spp. isolates collected from the poultry in the Russian Federation from 2013 to 2016, and to identify vancomycin-resistance genes in their genomes. Materials and methods: Eighty-seven enterococci isolates belonging to E.  faecalis (n = 47, 54%), E.  faecium (n = 25, 28.7%) and other species (n = 15, 17.2%) were collected from clinical samples of 297 heads of poultry (liver, lungs, heart, spleen, contents of the nasal and sinus cavities) from 17  poultry farms of the Northwest, Central, Volga, Ural and Southern Federal districts of the Russian Federation. Sensitivity of enterococci to antibacterials was determined by disk-diffusion and broth microdilution methods. Vancomycin resistance genes van was detected by polymerase chain reaction with specific primers. Results: Most enterococci isolates were resistant to erythromycin (74/87, 85.1%), gentamicin (70/87, 80.5%), ceftriaxone (61/87, 70.1%), ciprofloxacin (56/87, 64.4%), tetracycline (57/87, 65.5%), and rifampicin (48/87, 55.2%), fewer ones to trimethoprim (38/87, 43.7%), ampicillin (28/87, 32.2%), linezolid (15/87, 17.2%) and chloramphenicol (5/87, 5.7%). The vanC type genes (vanC1 and vanC2/3) were identified in 10  isolates. Vancomycin minimal inhibitory concentrations for these isolates were 2 to 8  mg/L. E. faecium with vanC1 gene was isolated from poultry probably for the first time ever. Conclusion: Commercial poultry in the Russian poultry farms is an important reservoir and source of antibiotic-resistant enterococci populations, including enterococci carrying vanC1 and vanC2/3 vancomycin resistance genes. Актуальность. Энтерококки – ведущая причина ряда внутрибольничных и  внебольничных заболеваний человека. В  последнее десятилетие эти патогены приобретают устойчивость к  антибактериальным препаратам, в  том числе к  ванкомицину. Энтерококки с  множественной лекарственной устойчивостью выделяются также от сельскохозяйственных животных во многих странах мира, что вызывает настороженность ученых из-за возможного горизонтального переноса генетических детерминант резистентности. Цель  – определить чувствительность к  антибактериальным препаратам изолятов Enterococcus spp., выделенных от промышленной птицы в  Российской Федерации в  2013–2016  гг., детектировать в  их геномах гены устойчивости к  ванкомицину. Материал и  методы. Восемьдесят семь изолятов энтерококков, принадлежащих к  E.  faecalis (n = 47, 54%), E.  faecium (n = 25, 28,7%) и  другим видам (n = 15, 17,2%), выделены из клинических образцов 297  голов промышленной птицы (печень, легкие, сердце, селезенка, содержимое пазух носовых синусов) из 17  птицеводческих хозяйств Северо-Западного, Центрального, Приволжского, Уральского и  Южного федеральных округов Российской Федерации. Чувствительность энтерококков к антимикробным препаратам определяли диско-диффузионным методом и  методом микроразведений в  бульоне. Гены устойчивости к  ванкомицину (van) выявляли методом полимеразной цепной реакции со специфичными праймерами. Результаты. Большинство изолятов энтерококков были устойчивы к  эритромицину (74  из 87, 85,1%), гентамицину (70 из 87, 80,5%), цефтриаксону (61 из 87, 70,1%), ципрофлоксацину (56 из 87, 64,4%), тетрациклину (57 из 87, 65,5%) и рифампицину (48 из 87, 55,2%), а также к триметоприму (38 из 87, 43,7%), ампициллину (28 из 87, 32,2%), линезолиду (15  из 87, 17,2%) и  хлорамфениколу (5 из 87, 5,7%). У 10 изолятов были обнаружены гены типа vanC (vanC1 и vanC2/3). Минимальные подавляющие концентрации ванкомицина для этих изолятов составили 2–8 мг/л. Выделение от птицы и  идентификация изолята E.  faecium с  геном vanC1, по всей вероятности, является первым в  мировой практике. Заключение. Промышленная птица птицефабрик Российской Федерации – важный резервуар и источник антибиотикорезистентных популяций энтерококков, в том числе энтерококков с генами ванкомицинрезистентности vanC1 и vanC2/3.

Radiation environment in high-altitude Antarctic plateau:recent measurements and model studies

Abstract Polar regions are the most exposed to secondary particles and radiation produced by primary cosmic rays in the atmosphere, because naturally they are with marginal geomagnetic shielding. In addition, the secondary particle flux contributing to the complex radiation field is enhanced at high-mountain altitudes compared to sea level because of the reduced atmospheric attenuation. At present, there are very few systematic experimental measurements of environmental dose at high southern latitudes, specifically at high-altitude region. Here, we report a campaign of measurements with different devices, that is passive and Liulin-type dosimeters, of the radiation background at high-mountain Antarctic station Vostok (3488 m above sea level, 78° 27′ S; 106° 50′ E). We compare the measurements with a Monte Carlo-based model for the propagation of the cosmic rays through the atmosphere and assessment of the radiation field in the atmosphere. We employed the model to estimate the radiation dose at Vostok station during the ground-level enhancement at 28 October 2021. As in previous studies by other teams, we show that the annual dose equivalent at high-altitude Antarctic facilities can significantly exceed the limit of 1 mSv established for the general population by the ICRP