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1.
Org Biomol Chem ; 22(26): 5419-5427, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38884371

RESUMO

Pyridines undergo a facile SNHAr phosphinylation with H-phosphinates under catalyst- and solvent-free conditions (50-55 °C) in the presence of benzoylphenylacetylene to afford 4-phosphinylpyridines in up to 68% yield. In this reaction, benzoylphenylacetylene activates the pyridine ring by the formation of a 1,3(4)-dipolar complex, deprotonates H-phosphinates to generate P-centered anions and finally acts as an oxidizer, being eliminated from an intermediate ion pair. Terminal electron-deficient acetylenes (methyl propiolate and benzoylacetylene) are inefficient as mediators in the above SNHAr process.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38310447

RESUMO

BACKGROUND: Nanocomposite glycerohydrogels based on biocompatible elementcontaining glycerolates are of practicular interest for biomedical applications. OBJECTIVE: Using two biocompatible precursors, silicon and iron glycerolates, a new bioactive nanocomposite silicon‒iron glycerolates hydrogel was obtained by sol-gel method. METHODS: The composition and structural features of the hydrogel were studied using a complex of modern analytical techniques, including TEM, XRD, and AES. On the example of experimental animals hemostatic activity of the hydrogel was studied, as well as primary toxicological studies were carried out. RESULTS: The composition of dispersed phase and dispersion medium of silicon‒iron glycerolates hydrogel was determined. The structural features of hydrogel were revealed and its structure model was proposed. It was shown that silcon-iron glycerolates hydrogel is nontoxic, and exhibits pronounced hemostatic activity. CONCLUSION: Silicon-iron glycerolates hydrogel is a potential hemostatic agent for topical application in medical and veterinary practice.

3.
J Org Chem ; 89(1): 463-473, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38092669

RESUMO

A straightforward cross-dehydrogenative coupling approach to incorporate alicyclic amino residues into the structure of model cyclic aldonitrones, 2H-imidazole oxides, is reported. The elaborated C(sp2)-H functionalization is achieved by employing cyclic amines in the presence of the I2-tert-butyl hydroperoxide (TBHP) reagent system. As a result, a series of 19 novel heterocyclic derivatives were obtained in yields of up to 97%. A mechanistic study involving electron paramagnetic resonance spectroscopic experiments allowed the radical nature of the reaction to be confirmed. In particular, the envisioned mechanistic rationale comprises N-iodination of a cyclic amine, followed by N-I bond homolysis of the resulting intermediate and subsequent amination of the nitrone moiety via the newly generated nitrogen-centered radical.

4.
Front Pharmacol ; 14: 1219980, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37654616

RESUMO

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of ß-amyloid (Aß42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 µM), consistent with docking results. Dihydroacridines inhibited Aß42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aß42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.

5.
Int J Mol Sci ; 24(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36769163

RESUMO

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.


Assuntos
Fármacos Anti-HIV , HIV-1 , Piranocumarinas , Cumarínicos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Antivirais/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV
6.
Chem Asian J ; 18(5): e202201306, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36662627

RESUMO

The C-N coupling of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones with 1-adamantanol/1-bromoadamantane leads to 1,2,4-triazolo[4,3-a]pyrimidinium-5-olates, which are represented as mesomeric betaines (MBs). The formation of MBs involves not only N-alkylation of heterocyclic framework but also the rearrangement leading to a change in the type of fusion between pyrimidine and 1,2,4-triazole fragments. The structures of the obtained products were confirmed by the X-ray analysis and measurements of 13 C-13 C (JCC ) coupling constants in the 1D 13 C NMR spectra of selectively 13 C-labeled samples. Treatment of the betaines with lithium bis(trimethylsilyl)amide (LiHMDS) gave anionic carbenes, which were detected by 13 C NMR spectroscopy and were trapped by reactions with phenyl isothiocyanate and sulfur. Density functional theory (DFT) and the quantum theory of atoms in molecules (QTAIM) analyses allowed for an insight into the electronic structure of the obtained betaines and N-heterocyclic carbene derivatives.

7.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677784

RESUMO

New Tb(III) and Eu(III) complexes based on aryl-2,2'-bipyridine ligands with a cyclic DO3A chelating unit appended in the alpha position of the bipyridine core were synthesized. The photophysical properties of these complexes were compared with those of complexes of ligands with identical aryl-2,2'-bipyridine chromophores, but with an acyclic DTTA residue as an additional chelating site in the alpha position of the bipyridine core. The nature of the polyaminocarboxylic acid fragments was found to have a significant influence on the luminescence. For some of the Eu(III) complexes, upon the transition from acyclic DTTA- to the cyclic DO3A-appended ligands, a noticeable increase in the intensity of Eu(III) luminescence was observed, with an increase in the quantum yield of up to 2.55 times. In contrast, for most of the Tb(III) complexes, a similar transition resulted in a noticeable decrease in the luminescence intensity of the Tb(III) cation.

8.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36498864

RESUMO

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. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug.


Assuntos
COVID-19 , Encefalite Transmitida por Carrapatos , Influenza Humana , Animais , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Azóis
9.
Molecules ; 27(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36557999

RESUMO

This paper reports the synthesis of four types of annulated pyranoindole congeners: pyrano[3,2-f]indole, pyrano[2,3-g]indole, pyrano[2,3-f]indole, and pyrano[2,3-e]indole and photophysical studies in this series. The synthesis of pyrano[3,2-f], [2,3-g], and [2,3-e]indoles involve a tandem of Bischler-Möhlau reaction of 3-aminophenol with benzoin to form 6-hydroxy- or 4-hydroxyindole followed by Pechmann condensation of these hydroxyindoles with ß-ketoesters. Pyrano[2,3-f]indoles were synthesized through the Nenitzescu reaction of p-benzoquinone and ethyl aminocrotonates and subsequent Pechmann condensation of the obtained 5-hydroxyindole derivatives. Among the pyranoindoles studied, the most promising were pyrano[3,2-f] and [2,3-g]indoles. These compounds were characterized by moderate to high quantum yields (30-89%) and a large (9000-15,000 cm-1) Stokes shift. More detailed photophysical studies were carried out for a series of the most promising derivatives of pyrano[3,2-f] and [2,3-g]indoles to demonstrate their positive solvatochromism, and the data collected was analyzed using Lippert-Mataga equation. Quantum chemical calculations were performed to deepen the knowledge of the absorption and emission properties of pyrano[3,2-f] and [2,3-g]indoles as well as to explain their unusual geometries and electronic structures.


Assuntos
Corantes , Indóis , Fenômenos Químicos , Indóis/química
10.
Molecules ; 27(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36558082

RESUMO

The risk of progression of most sporadic neurodegenerative diseases, including Alzheimer's disease, increases with age. Traditionally, this is associated with a decrease in the efficiency of cell protection systems, in particular, molecular chaperones. Thus, the development of small molecules able to induce the synthesis of chaperones is a promising therapeutic approach to prevent neural diseases associated with ageing. Here, we describe a new compound IA-50, belonging to the class of indolylazines and featured by a low size of topological polar surface area, the property related to substances with potentially high membrane-penetrating activity. We also estimated the absorption, distribution, metabolism and excretion characteristics of IA-50 and found the substance to fit the effective drug criteria. The new compound was found to induce the synthesis and accumulation of Hsp70 in normal and aged neurons and in the hippocampi of young and old mice. The transgenic model of Alzheimer's disease, based on 5xFAD mice, confirmed that the injection of IA-50 prevented the formation of ß-amyloid aggregates, loss of hippocampal neurons and the development of memory impairment. These data indicate that this novel substance may induce the expression of chaperones in neural cells and brain tissues, suggesting its possible application in the therapy of ageing-associated disorders.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Envelhecimento/metabolismo , Chaperonas Moleculares/metabolismo , Camundongos Transgênicos , Modelos Animais de Doenças
11.
Molecules ; 27(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36431885

RESUMO

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.


Assuntos
Azidas , Cobre , Cobre/química , Catálise , Azidas/química , Triazóis/química , Alcinos/química
12.
Molecules ; 27(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36296472

RESUMO

A series of new α-(N-biphenyl)-substituted 2,2'-bipyridines were obtained through the combination of the ipso-nucleophilic aromatic substitution of the C5-cyano group, aza-Diels-Alder and Suzuki cross-coupling reactions, starting from 5-cyano-1,2,4-triazines. For the obtained compounds, photophysical and fluorosolvatochromic properties were studied. Fluorophores 3l and 3b demonstrated unexpected AIEE activity, while 3a and 3h showed promising nitroexplosive detection abilities.


Assuntos
2,2'-Dipiridil , Corantes Fluorescentes , Compostos de Bifenilo , Ionóforos , Triazinas
13.
Molecules ; 27(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36296698

RESUMO

A different type of MnO2-induced oxidative cyclization of dihydrotriazines has been developed. These dihydrotriazines are considered as a "formal" Schiff's base. This method provided easy access to naphthofuro-fused triazine via the C-C/C-O oxidative coupling reaction. The reaction sequence comprised the nucleophilic addition of 2-naphthol or phenol to 1,2,4-triazine, followed by oxidative cyclization. The scope and limitations of this novel coupling reaction have been investigated. Further application of the synthesized compound has been demonstrated by synthesizing carbazole-substituted benzofuro-fused triazines. The scalability of the reaction was demonstrated at a 40 mmol load. The mechanistic study strongly suggests that this reaction proceeds through the formation of an O-coordinated manganese complex.


Assuntos
Bases de Schiff , Triazinas , Ciclização , Manganês , Compostos de Manganês , Óxidos , Carbazóis , Fenóis , Estresse Oxidativo
14.
RSC Adv ; 12(15): 9323-9341, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35424878

RESUMO

2,7-Diazapyrenes are promising azaaromatic scaffolds with a unique structural geometry and supramolecular properties. This core moiety and its derivatives with some N-methyl cations like N-methyl-2,7,-diazapyrenium, and N,N'-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. The opportunities of applications of 2,7-diazapyrenes, including their remarkable photophysical and supramolecular properties, DNA-bindings, in sensors, molecular electronics, supramolecular systems, and related areas are also highlighted.

15.
RSC Adv ; 12(7): 4042-4046, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35425460

RESUMO

Iron(ii) and iron(iii) salts of strong acids form iron glycerolates on heating at 180 °C with glycerol in the presence of an equivalent amount of alkali. Individual iron(iii) glycerolate was obtained for the first time. When Fe3O4 magnetic nanoparticles were heated with glycerol, an iron(iii) glycerolate shell was formed on their surface.

16.
Nat Prod Bioprospect ; 12(1): 12, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35357593

RESUMO

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.

17.
Beilstein J Org Chem ; 18: 243-250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35330779

RESUMO

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.

18.
J Fluoresc ; 32(1): 125-133, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34618285

RESUMO

A convenient synthetic approach to asymmetrically functionalized 1,3-di(2-pyridyl)benzenes starting from 3-(3-bromophenyl)-1,2,4-triazines using sequential aza-Diels-Alder reactions and Stille cross-coupling is reported. Photophysical properties of the obtained compounds are studied.

19.
Spectrochim Acta A Mol Biomol Spectrosc ; 267(Pt 2): 120499, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34749256

RESUMO

A series of coumarin-pyridine-based push-pull fluorophores were prepared starting from 1,2,4-triazines by using direct C-H functionalization (SNH-reaction)-Diels-Alder-retro Diels-Alder domino reaction sequence. This efficient synthetic strategy allowed to obtain a series of 19 coumarin-pyridine fluorophores. Their photophysical properties were studied. While pyridine-substituted derivatives of 4-alkylcoumarins may be considered as alternative to coumarin dyes characterized by emission maxima mainly in a visible region with wavelengths of 402-415 nm, absorption in the UV range at 210-307 nm, and good photoluminescence quantum yields of 6-19%, all the derivatives of 4-phenylcoumarin did not exhibit any noticeable fluorescence. More detailed photophysical studies were carried out for two the most representative derivatives of 4-alkyl-coumarin-pyridines to demonstrate their positive solvatochromism, and the collected data were analyzed by using Lippert-Mataga equation, as well as Kosower and Dimroth/Reichardt scales. The obtained results demonstrate that the combining two chromophore systems, such as 2,5-diarylpyridine and coumarin ones, is promising in terms of improving the photophysical properties of the new coumarin-pyridine hybrid compounds.


Assuntos
Cumarínicos , Corantes Fluorescentes , Fluorescência , Piridinas
20.
ChemMedChem ; 17(3): e202100577, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-34783161

RESUMO

A series of new 5-aryl-2,2'-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)<0.8-27 µM). Their antifungal action was found can be realized via binding Fe(III) ions. Tol-bipy suppressed growth of Gram-positive bacteria S. aureus, S. aureus MRSA and their monospecies biofilms (MIC 6-16 µM). Using molecular docking, the anti-staphylococcal action mechanism based on the inhibition of S. aureus DNA gyrase GyrB was proposed for the lead compounds. Among metal complexes, Cu(II) and Mn(II) complexes based on tetrafluorosalicylic acid and Tol-bipy or Ph-bipy had the high antifungal activity (MIC<0.24-32 µM). Mn(SalF4 -2H)2 (Tol-bipy)2 ] suppressed the growth of seven Candida strains at MIC 12-24 µM. [Cu(Sal-2H)(Ph-bipy)] and [Cu(SalF3 -2H)(Ph-bipy)2 ] showed the promising anti-gonorrhoeae activity (MIC 4.2-5.2 µM). (Cu(SalFn -2H)(Tol-bipy)2 ], [Cu(SalF4 -2H)(Ph-bipy)2 ] and [Cu(SalF3 -2H)(Ph-bipy)2 ]) were found active against the bacteria of S. aureus, S. aureus MRSA and their biofilms (MIC 2.4-41.4 µM). The most active compounds were tested for toxicity in vitro against human embryonic kidney (HEK-293) cells and in vivo experiments with CD-1 mice.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Metais Pesados/farmacologia , Simulação de Acoplamento Molecular , Salicilatos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Células HEK293 , Humanos , Metais Pesados/química , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neisseria gonorrhoeae/efeitos dos fármacos , Salicilatos/química , Relação Estrutura-Atividade
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