Azolopyrimidine-Based Thioethers: Synthesis via Cross-Dehydrogenative C-S Coupling and In Silico Evaluation of Anti-SARS-CoV-2 Activity.

Azoloazine derivatives are known as promising small molecules that are potentially able to counteract a broad spectrum of RNA viruses including SARS-CoV-2. However, a pool of synthetic pathways to provide convenient structural modification of such compounds without de novo construction of the heterocyclic scaffold is rather limited so far. This work proposes an approach to the direct C(sp)-H functionalization of azolopyrimidine substrates with aromatic thiol residues, mediated by the iodine/persulfate reagent system.

Iodine-Catalyzed Radical C-H Amination of Nonaromatic Imidazole Oxides: Access to Cyclic α-Aminonitrones.

A straightforward cross-dehydrogenative coupling approach to incorporate alicyclic amino residues into the structure of model cyclic aldonitrones, 2-imidazole oxides, is reported. The elaborated C(sp)-H functionalization is achieved by employing cyclic amines in the presence of the I--butyl hydroperoxide (TBHP) reagent system. As a result, a series of 19 novel heterocyclic derivatives were obtained in yields of up to 97%.

Triazavirin-A Novel Effective Antiviral Drug.

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients.

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.

Development of Drugs with Direct Antiviral Action Based on Azaheterocyclic Systems.

This article discusses the results of studies carried out in recent years by a team of scientists from the Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, in cooperation with the First President of Russia Boris Yeltsin Ural Federal University, Ural State Medical University, Volgograd State Medical University, and other scientific and production organizations of the country to create triazavirin (riamilovir) and other direct etiotropic antiviral drugs based on azaheterocyclic derivatives.

2,7-Diazapyrenes: a brief review on synthetic strategies and application opportunities.

2,7-Diazapyrenes are promising azaaromatic scaffolds with a unique structural geometry and supramolecular properties. This core moiety and its derivatives with some -methyl cations like -methyl-2,7,-diazapyrenium, and ,'-dimethyl-2,7-diazapyrenium attract special attention due to their challenging photophysical properties, especially in the context of interactions with DNA and some of its mononucleotides. This review focuses on the analysis of the main synthetic approaches to 2,7-diazapyrene and its functional derivatives employing various strategies under different reaction conditions.

Design and Antioxidant Properties of Bifunctional 2-Imidazole-Derived Phenolic Compounds-A New Family of Effective Inhibitors for Oxidative Stress-Associated Destructive Processes.

The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2-imidazole-derived phenolic compounds affording the bifunctional 2-imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2-imidazole family of various architectures bearing both electron-donating and electron-withdrawing substituents in the aryl fragment along with the different arrangements of the hydroxy groups in the polyphenol moiety, namely derivatives of phloroglucinol, pyrogallol, hydroxyquinol, including previously unknown water-soluble molecules, were studied. The structural and antioxidant properties of these bifunctional 5-aryl-2-imidazoles were comprehensively studied.

Rapid and sensitive determination of nitrobenzene in solutions and commercial honey samples using a screen-printed electrode modified by 1,3-/1,4-diazines.

In this work, a screen-printed electrode (SPE) modified by 1,3/1,4-diazines was prepared for the rapid and sensitive determination of nitrobenzene (NB). The obtained results indicated enhanced cathodic currents of direct NB reduction into hydroxylaminophenol on the diazine-modified SPEs. The enhanced effect was most likely due to the combination of complexation and collisional processes of diazines towards nitroaromatic compounds and also the diazine-modified electrodes' increased electroconductivity.

Metal-Free C-H/C-H Coupling of 2-Imidazole 1-Oxides with Polyphenols toward Imidazole-Linked Polyphenolic Compounds.

The methodology of nucleophilic substitution of hydrogen (S) was successfully applied as a convenient synthetic tool to afford azaheterocyclic derivatives of phenols of various architectures. A series of 26 novel imidazole-linked polyphenolic compounds were first prepared in 72-95% yields through the direct metal-free C-H/C-H coupling of polyphenols with 2-imidazole 1-oxides. Comprehensive studies on the reaction condition optimization, scope, and limitations enabled the development of a straightforward method toward novel bifunctional derivatives bearing both phenolic and imidazole scaffolds of particular interest in the design of challenging molecules for versatile applications in medicinal chemistry and materials science.

Recent advances in the functionalization of polyfluoro(aza)aromatics C-C coupling strategies.

Polyfluoro(aza)aromatic compounds are of interest in various fields of practical applications, such as medicinal and agrochemistry, materials science and advanced technologies. The C-C coupling reactions are known to be a promising synthetic tool to create challenging fluorinated molecules of diverse architectures. In this review, we have summarized the recent advances in the functionalization of polyfluoro(aza)aromatics via both transition metal-catalyzed and metal-free C-C coupling reactions for the period from 2006 to the beginning of 2021.

-functionalization of calix[4]arene with 1,3,7-triazapyrene in the design of novel fluorophores with the dual target detection of Al and Fe cations.

A -functionalization strategy has successfully been applied to the synthesis of novel 1,3,7-triazapyrene derivatives of calixarenes. The key synthetic step in these transformations providing the direct C-C bond formation is nucleophilic substitution of hydrogen (S ) in 1,3,7-triazapyrene. General photophysical characteristics for these macrocyclic compounds, as well as features in emission properties upon addition of various metal cations have been elaborated.

C(sp)-H functionalization in non-aromatic azomethine-based heterocycles.

Direct C(sp2)-H functionalization of the endocyclic azomethine and aldonitrone moieties in non-aromatic azaheterocycles has established itself as a promising methodology over the last decade. Transition metal-catalyzed cross-coupling reactions, α-metalation-electrophile quenching protocols, and (metal-free) nucleophilic substitution of hydrogen reactions (SNH) are the major routes applied on cyclic imines and their derivatives. In this overview, we show the tangible progress made in this area during the period from 2008 to 2020.

Transition-Metal-Free C-H/C-Li Coupling of Nonaromatic 2-Imidazole 1-Oxides with Pentafluorophenyl Lithium in the Design of Novel Fluorophores with Intramolecular Charge Transfer Effect.

Methodology of nucleophilic substitution of hydrogen (S) was first applied for the direct modification of nonaromatic 2-imidazoles to afford novel polyfluoroarylated azaheterocycles. Scope, tolerance for these transition-metal-free C-H/C-Li coupling reactions, and photophysical properties for the novel 4-(perfluorophenyl)-5-aryl-2-imidazoles were comprehensively studied. In particular, some of the obtained perfluoroaryl-substituted 2-imidazoles were found to be of particular interest as promising push-pull fluorophore systems in the design of fluorometric sensor materials due to the effect of intramolecular charge transfer.

Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles.

The reaction of 6-chloro-1-methylpyrazin-2(1 H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1 H)-ones. This regioselective three-component reaction represents the first example of a tele-nucleophilic substitution of hydrogen (S) in which the anionic σ adduct is quenched by electrophiles (other than a proton) before elimination takes place. Quenching the reaction with iodine (I) or bromine (Br) provides an alternative reaction pathway, yielding a 3-functionalized 6-chloro-1-methylpyrazin-2(1 H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1 H)-one, respectively.

Transition metal-free oxidative and deoxygenative C-H/C-Li cross-couplings of 2-imidazole 1-oxides with carboranyl lithium as an efficient synthetic approach to azaheterocyclic carboranes.

The direct C-H functionalization methodology has first been applied to perform transition metal-free C-H/C-Li cross-couplings of 2-imidazole 1-oxides with carboranyllithium. This atom- and step-economical approach, based on one-pot reactions of nucleophilic substitution of hydrogen (S ) in non-aromatic azaheterocycles, affords novel imidazolyl-modified carboranes of two types (-oxides and their deoxygenative analogues), which are particularly of interest in the design of advanced materials.

Metal-free C-H functionalization of 2H-imidazole 1-oxides with pyrrolyl fragments in the design of novel azaheterocyclic ensembles.

The methodology of direct C(sp)-H functionalization has for the first time been applied as an efficient and advanced approach to carry out C-H/C-H coupling of 2H-imidazole 1-oxides and pyrroles. The atom-economical method used does not require either any auxiliary group in the starting substrates, or catalysis by transition metals. As a result, a number of novel 1H-pyrrol-2-yl-2H-imidazoles, that are particularly of interest in the design of bioactive molecules, have been prepared under mild conditions and in good to excellent yields.

Palladium(II)-catalyzed oxidative C-H/C-H coupling and eliminative S(N)(H) reactions in direct functionalization of imidazole oxides with indoles.

Two novel synthetic approaches to realize the direct C(sp(2))-H bond functionalization in cyclic nitrones are reported. Palladium(II)-catalyzed oxidative C-C coupling of 2,2-dialkyl-4-phenyl-2H-imidazole 1-oxides with indoles was shown to result in the formation of 5-indolyl-3-yl derivatives, while nucleophilic substitution of hydrogen (S(N)(H)) at C(5) of the same imidazole system was found to afford the corresponding deoxygenated compounds.

S(N)(H) approach in the synthesis of nitronyl nitroxides.

We show that the S(N)(H) approach opens up new possibilities in the synthesis of hetaryl-substituted nitronyl nitroxides. The reaction of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl lithium salt with pyridine-, pyrimidine-, pyrazine-, isoquinoline-, phthalazine-, quinoxaline-, and 1,2,4-triazine-N-oxides readily gives rise to the corresponding paramagnetic hetarenes. The reaction of this salt with quinoxaline-1,4-dioxide enabled the synthesis of the first nitronyl nitroxide biradical with two spin-labeled fragments in the vicinal positions of the heteroaromatic cycle; the persistent biradicals of this type were not known earlier.