Search

A series of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines has been synthesized through oxidation reaction of the corresponding 3,6-disubstituted 1,2,4,5-tetrazines bearing amidine fragments. It is shown that the heterocyclic systems obtained can be modified easily at C(3) position in the reactions with aliphatic alcohols and amines. Also, the reactivity of [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines towards CH-active compounds has been studied. The obtained triazolo[1,5-b]annulated 1,2,4,5-tetrazines proved to be active in micromolar concentrations in vitro against filamentous anthropophilic and zooanthropophilic dermatophyte fungi (Trichophyton, Microsporum and Epidermofiton), which cause skin and its appendages (hair, nails) diseases.

Abstract The development of highly facile synthetic procedures for the expedient synthesis of complex natural molecules is always in demand. As this aspect, the Diels–Alder reaction (DAR) has a versatile approach to the synthesis of complex natural compounds and highly regio-/stereoselcetive heterocyclic scaffolds. Additionally, α-pyrone and terpenoquinone are two versatile key intermediates that are prevalent in various bioactive natural compounds for instance, (±)-crinine, (±)-joubertinamine, (±)-pancratistatin, (−)-cyclozonarone, and 8-ephipuupehedione, etc. Hence, the current review summarizes the Diels–Alder reaction application of α-pyrone and terpenoquinone to the constructive synthesis of various natural products over the past two decades (2001–2021). Equally, it serves as a stencil for the invention and development of new synthetic strategies for high-complex molecular structured natural and heterocyclic molecules. Graphical Abstract

A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPPs) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of the ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (13g), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure–activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico.

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

Convenient methods for the synthesis of three monomers based on functionalized (bi)pyridines with using “1,2,4-triaizine” methodology have been developed.

An electron-deficient series of 1,2,4-triazines and quinazoline have been used for cross-dehydrogenative coupling with 1,3-dihydroxy and 1,3-dimethoxyxanthones to give stable nucleophilic addition products. The adducts and their subsequent oxidation products were obtained in good yields and the structures of the compounds were confirmed by 1H NMR spectroscopy. These results expand the scope of the methodology of nucleophilic substitution of hydrogen with the participation of xanthones with azines. Moreover, this methodology makes it possible to obtain new organic materials based on xanthones, which have a wide spectrum of biological activity.

A convenient synthetic approach to meso-substituted with 2,2’-bipyridine and 1-(pyridin-2-yl)isoquinoline residues calix[4]arenes is reported. This approach involves the reaction of generated in situ 2-lithio-calix[4]arene with 1,2,4-triazine precursor with the following aromatization of the obtained adduct, and the aza-Diels-Alder reaction of the 1,2,4-triazinyl-substituted calix[4]arene with 2,5-norbornadien or in-situ generated 1,2-dehydrobenzene. The UV/fluorescence response of thus obtained meso-pyridyl-substituted calix[4]arenes to metal cations is studied.

A convenient synthesis of 1,2,4-triazines bearing the moieties of (hetero)arylhydrazines at the position of C5 of the 1,2,4-triazine core is reported.

The composition of the reaction mixture after DTTA tert-butyl ester alkylation with 6'-halomethyl-5-phenyl-2,2'-bipyridines was studied. In addition to the target product, DTTA-appended 2,2’-bipyridine, the corresponding 6'-hydroxymethyl-substituted 2,2’-bipyridine and (5'-phenyl-[2,2'-bipyridin]-6-yl)methyl formate were isolated as by-products in some cases. Finally, an improved procedure for the DTTA tert-butyl ester alkylation with 6'-halomethyl-5-phenyl-2,2'-bipyridines by using Finkelstein reaction was developed.

In the present work we studied a modified Bischler-Möhlau reaction – synthesis of indoles from benzoin and aniline. Our proposed modification of this method differs from that described earlier in that the reaction is carried out at a lower temperature, which makes it possible to improve yields and reduce formation of tarry side products. In addition, unlike the previous contradictory works, which described the preparation of a single 4-hydroxy or 6-hydroxy isomer in condensation of m-aminophenol and benzoin, we obtained both 4-hydroxy and 6-hydroxy isomers.

An efficient synthetic approach towards 5-arylethynyl-1,2,4-triazines via direct C-H-functionalization of 5-H-1,2,4-triazines in reaction with lithium acetylenes is reported.

The aim of this literature review is to consider the range of different integral characteristics and indices, by which it can be possible to evaluate impaired hemodynamics and cerebrospinal fluid dynamics in the central nervous system according to radiation introscopy, including ultrasound and phase-contrast magnetic resonance imaging. Consideration is given to various volume-velocity and temporal parameters and the possibility of using the described characteristics to study joint blood and cerebrospinal fluid flows. Emphasis is laid on the analysis of the information provided by each of the indices and by the possibility of its clinical application. This expanded study of the interaction of fluids in the central nervous system will be able to give a better insight into the mechanisms involved in maintaining homeostasis in the brain.

The experimental study of the prophylactic efficacy of Triazaverin against the experimental form of the influenza virus A (H5N1) on albino mice intranasally infected with the influenza virus A/Chicken/Kurgan/Russia/02/05 vs. the reference drugs Tamiflu®, Remantadin and Arbidol® showed that in doses of 1 to 100 mg/kg it was efficient in the animal protection from death. The drug was also efficient in the urgent prophylaxis. Triazaverin effectively inhibited the influenza A virus multiplication in the lungs of the albino mice.

Abstract Artificial intelligence (AI) is undergoing a revolution thanks to the breakthroughs of machine learning algorithms in computer vision, speech recognition, natural language processing and generative modelling. Recent works on publicly available pharmaceutical data showed that AI methods are highly promising for Drug Target prediction. However, the quality of public data might be different than that of industry data due to different labs reporting measurements, different measurement techniques, fewer samples and less diverse and specialized assays. As part of a European funded project (ExCAPE), that brought together expertise from pharmaceutical industry, machine learning, and high-performance computing, we investigated how well machine learning models obtained from public data can be transferred to internal pharmaceutical industry data. Our results show that machine learning models trained on public data can indeed maintain their predictive power to a large degree when applied to industry data. Moreover, we observed that deep learning derived machine learning models outperformed comparable models, which were trained by other machine learning algorithms, when applied to internal pharmaceutical company datasets. To our knowledge, this is the first large-scale study evaluating the potential of machine learning and especially deep learning directly at the level of industry-scale settings and moreover investigating the transferability of publicly learned target prediction models towards industrial bioactivity prediction pipelines.

In the present work, we report a convenient synthesis of 5- and 7-substituted-4-phenyl coumarins. In contrast to previous results obtained with 4-alkylcoumarins, nicotinoylation of 5,7-dihydroxy-4-phenylcoumarin with nicotinoyl benzotriazole or nicotinoyl azide selectively provides 5-O protected ester. The combination of the nicotinoylation reaction followed by tosylation-denicotinoylation yields 5-hydroxy-7-tosyloxy-coumarin derivative, which may be useful in the synthesis of inophyllum, a tetracyclic HIV reverse transcriptase inhibitor, as well as its analogues.

Directed formation of the structure of the culture of living cells is the most important task of tissue engineering. New materials for 3D scaffolds of living tissue are critical for the mass adoption of regenerative medicine protocols. In this manuscript, we demonstrate the results of the molecular structure study of collagen from Dosidicus gigas and reveal the possibility of obtaining a thin membrane material. The collagen membrane is characterized by high flexibility and plasticity as well as mechanical strength. The technology of obtaining collagen scaffolds, as well as the results of studies of its mechanical properties, surface morphology, protein composition, and the process of cell proliferation on its surface, are shown in the given manuscript. The investigation of living tissue culture grown on the surface of a collagen scaffold by X-ray tomography on a synchrotron source made it possible to remodel the structure of the extracellular matrix. It was found that the scaffolds obtained from squid collagen are characterized by a high degree of fibril ordering and high surface roughness and provide efficient directed growth of the cell culture. The resulting material provides the formation of the extracellular matrix and is characterized by a short time to living tissue sorption.

The study of polymers’ rheological properties is of paramount importance both for the problems of their industrial production as well as for their practical application. Two polymers used for embolization of arteriovenous malformations (AVMs) are studied in this work: Onyx-18® and Squid-12®. Viscosity curve tests and computational fluid dynamics (CFD) were used to uncover viscosity law as a function of shear rate as well as behavior of the polymers in catheter or pathological tissue models. The property of thermal activation of viscosity was demonstrated, namely, the law of dependence of viscosity on temperature in the range from 20 °C to 37 °C was established. A zone of viscosity nonmonotonicity was identified, and a physical interpretation of the dependence of the embolic polymers’ viscosity on the shear rate was given on the basis of Cisco’s model. The obtained empirical constants will be useful for researchers based on the CFD of AVMs. A description of the process of temperature activation of the embolic polymers’ viscosity is important for understanding the mechanics of the embolization process by practicing surgeons as well as for producing new prospective embolic agents.

This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.

The article proposes a method of market structure report indicators analysis within the framework of the paradigm "Structure-Behaviour-Effectiveness" with the application of PAEI code within the life cycle of market subjects for sustainable development. PAEI codes by stages of the subject's development are considered, the correspondence of the code to the indicators of the market structure report is determined. As a result, a set of key indicators of the market structure report is developed in accordance with the phases of the life cycle of its subject as a tool to improve subject-orientated market analysis in the world sustainable development.