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Recent Advances in the Use of Azoles in Medicinal Chemistry

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 10618

Special Issue Editor

Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia
Interests: organic chemistry; synthesis; fluorine; nitrogen; heterocycle; isocyanide; multicomponent reaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, about 200 million chemical compounds are known. Among this structural variety of substances, the majority are heterocycles. Heterocycles are often found in the structure of natural compounds, and their most important applications are drug design, medicinal chemistry, agrochemistry and the rapidly developing field of materials chemistry. This area of chemistry is truly limitless, since varying the size of the heterocycle, condensation with benzene rings or other heterocycles and the nature and number of heteroatoms and substituents allow the construction of a huge number of structures. Five-membered nitrogen heterocycles (azoles) are among the most important heterocycles.

In this respect, researchers in the field of the synthesis, application and transformation of five-membered azaheterocycles are invited to participate in this Special Issue of Molecules.

Dr. Valentine G. Nenajdenko
Guest Editor

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Keywords

  • heterocycle
  • azole
  • nitrogen
  • synthesis
  • application

Published Papers (8 papers)

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Research

21 pages, 2448 KiB  
Article
Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties
Molecules 2023, 28(12), 4822; https://doi.org/10.3390/molecules28124822 - 16 Jun 2023
Viewed by 742
Abstract
Modification of 5-aryl-4-trifluoroacetyltriazoles at the NH-moiety was investigated. Screening of the alkylation conditions revealed that using Na2CO3 as a base and DMF as a solvent of 2-substituted triazoles can be preferentially prepared in up to 86% yield. In the best [...] Read more.
Modification of 5-aryl-4-trifluoroacetyltriazoles at the NH-moiety was investigated. Screening of the alkylation conditions revealed that using Na2CO3 as a base and DMF as a solvent of 2-substituted triazoles can be preferentially prepared in up to 86% yield. In the best cases, the amount of minor 1-alkyl isomer was less than 6%. SNAr reaction of the 5-aryl-4-trifluoroacetyltriazoles with aryl halides having electron-withdrawing groups led to regiospecific formation of 2-aryltriazoles isolated in good-to-high yields. Chan–Lam reaction of the 5-aryl-4-trifluoroacetyltriazoles with boronic acids afforded 2-aryltriazoles as single isomers in up to 89% yield. The subsequent reaction of the prepared 2-aryltriazoles with primary and secondary amines gave a set of amides of 4-(2,5-diaryltriazolyl)carboxylic acid. The fluorescent properties of the prepared 2-substituted derivatives of triazoles were investigated to demonstrate their utility as new efficient luminophores having more than 60% quantum yields. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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19 pages, 5406 KiB  
Article
Isoxazolyl-Derived 1,4-Dihydroazolo[5,1-c][1,2,4]Triazines: Synthesis and Photochemical Properties
Molecules 2023, 28(7), 3192; https://doi.org/10.3390/molecules28073192 - 03 Apr 2023
Cited by 3 | Viewed by 1260
Abstract
New fluorescent dyes containing an assembled 1,4-dihydroazolo[5,1-c][1,2,4]triazine (DAT) core and an isoxazole ring were synthesized through a reaction between diazopyrazole or diazoimidazoles and isoxazolyl-derived enamines in mild conditions. The photophysical characteristics (maxima absorption and emission, Stokes shifts, fluorescent quantum yields, and [...] Read more.
New fluorescent dyes containing an assembled 1,4-dihydroazolo[5,1-c][1,2,4]triazine (DAT) core and an isoxazole ring were synthesized through a reaction between diazopyrazole or diazoimidazoles and isoxazolyl-derived enamines in mild conditions. The photophysical characteristics (maxima absorption and emission, Stokes shifts, fluorescent quantum yields, and fluorescence lifetimes) of the new fluorophores were obtained. The prepared DATs demonstrated emission maxima ranging within 433–487 nm, quantum yields within 6.1–33.3%, and a large Stokes shift. The photophysical characteristics of representative DAT examples were studied in ten different solvents. Specific (hydrogen bonds) and non-specific (dipole–dipole) intermolecular and intramolecular interactions were analyzed using XRD data and spectral experiments. Solvatochromism was analyzed using Lippert–Mataga and Dimroth–Reichardt plots, revealing the relationship between the DAT structure and the nature of solute–solvent interactions. The significant advantages of DATs are the fluorescence of their powders (QY up to 98.7%). DAT-NMe2 10 expressed bright aggregation-induced emission (AIE) behavior in DMSO and THF as the water content increased. The numerous possible variations of the structures of the heterocycles included in the DATs, as well as substituents, create excellent prospects for adjusting their photophysical and physicochemical properties. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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12 pages, 3109 KiB  
Article
One-Pot Synthesis, E-/Z-Equilibrium in Solution of 3-Hetarylaminomethylidenefuran-2(3H)-ones and the Way to Selective Synthesis of the E-Enamines
Molecules 2023, 28(3), 963; https://doi.org/10.3390/molecules28030963 - 18 Jan 2023
Cited by 1 | Viewed by 980
Abstract
We describe a method to synthesize a new class of hetarylaminomethylidene derivatives of furan-2(3H)-ones. The method uses 5-(4-chlorophenyl)furan-2(3H)-one, triethyl orthoformate, and heterocyclic amines with different ring sizes and heteroatoms under refluxing in absolute isopropyl alcohol. The obtained enamines exist [...] Read more.
We describe a method to synthesize a new class of hetarylaminomethylidene derivatives of furan-2(3H)-ones. The method uses 5-(4-chlorophenyl)furan-2(3H)-one, triethyl orthoformate, and heterocyclic amines with different ring sizes and heteroatoms under refluxing in absolute isopropyl alcohol. The obtained enamines exist in an equilibrium of E- and Z-isomers, whose configurations relative to the double exocyclic C=C bond were confirmed with a set of NMR spectroscopy data. The E-/Z-equilibrium of the synthesized compounds is affected by the configuration of the intermediate, the volume of its substituents, the site of enolate attack, the presence of intramolecular interactions of amino components, the time of the transformation, the order of mixing of the initial reagents, and the use of polar solvents in the NMR experiment. The advantages of the method are that the reaction time is short, the product yield is high, and product purification is easy. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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12 pages, 1680 KiB  
Communication
Biologically Oriented Hybrids of Indole and Hydantoin Derivatives
Molecules 2023, 28(2), 602; https://doi.org/10.3390/molecules28020602 - 06 Jan 2023
Cited by 8 | Viewed by 1186
Abstract
Indoles and hydantoins are important heterocycles scaffolds which present in numerous bioactive compounds which possess various biological activities. Moreover, they are essential building blocks in organic synthesis, particularly for the preparation of important hybrid molecules. The series of hybrid compounds containing indoles and [...] Read more.
Indoles and hydantoins are important heterocycles scaffolds which present in numerous bioactive compounds which possess various biological activities. Moreover, they are essential building blocks in organic synthesis, particularly for the preparation of important hybrid molecules. The series of hybrid compounds containing indoles and imidazolidin-2-one moiety with direct C–C bond were synthesized using an amidoalkylation one-pot reaction. All compounds were investigated as a growth regulator for germination, growth and development of wheat seeds (Triticum aestivum L). Their effect on drought resistance at very low concentrations (4 × 10−5 M) was evaluated. The study highlighted identified the leading compounds, 3a and 3e, with higher growth-regulating activity than the indole-auxin analogues. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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19 pages, 3145 KiB  
Article
Synthesis, Fungicidal Activity and Plant Protective Properties of 1,2,3-Thiadiazole and Isothiazole-Based N-acyl-N-arylalaninates
Molecules 2023, 28(1), 419; https://doi.org/10.3390/molecules28010419 - 03 Jan 2023
Cited by 2 | Viewed by 1329
Abstract
The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of N-acyl-N-arylalanines was developed and [...] Read more.
The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of N-acyl-N-arylalanines was developed and synthesized, in which 1,2,3-thiadiazol-5-ylcarbonyl or 3,4-dichloroisothiazol-5-ylcarbonyl (fragments from synthetic plant resistance activators tiadinil and isotianil, respectively) and a fragment of N-arylalanine, the toxophoric group of acylalanine fungicides. Several new synthesized compounds have shown moderate antifungal activity against fungi in vitro, such as B. cinerea, R. solani and S. sclerotiorum. In vivo tests against A. brassicicola showed that compound 1d was 92% effective at a concentration of 200 µg/mL, similar to level of tiadinil, a known inducer of systemic resistance. Thus, 1d could be considered a new candidate fungicide for further detailed study. The present results will advance research and influence the search for more promising fungicides for disease control in agriculture. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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23 pages, 6091 KiB  
Article
Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine Derivatives: Synthesis, Anti-Viral In Vitro Study and Target Validation Activity
Molecules 2022, 27(22), 7940; https://doi.org/10.3390/molecules27227940 - 16 Nov 2022
Cited by 4 | Viewed by 1215
Abstract
This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro [...] Read more.
This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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11 pages, 5404 KiB  
Article
Diastereoselective Synthesis of Highly Functionalized Proline Derivatives
Molecules 2022, 27(20), 6898; https://doi.org/10.3390/molecules27206898 - 14 Oct 2022
Cited by 1 | Viewed by 1184
Abstract
An efficient way to access highly functionalized proline derivatives was developed based on a Cu(I)-catalyzed reaction between CF3-substituted allenynes and tosylazide, which involved a cascade of [3 + 2]-cycloaddition/ketenimine and a rearrangement/Alder-ene cyclization to afford the new proline framework with a [...] Read more.
An efficient way to access highly functionalized proline derivatives was developed based on a Cu(I)-catalyzed reaction between CF3-substituted allenynes and tosylazide, which involved a cascade of [3 + 2]-cycloaddition/ketenimine and a rearrangement/Alder-ene cyclization to afford the new proline framework with a high diastereoselectivity. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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13 pages, 1175 KiB  
Article
Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes
Molecules 2022, 27(12), 3860; https://doi.org/10.3390/molecules27123860 - 16 Jun 2022
Cited by 6 | Viewed by 2050
Abstract
The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray [...] Read more.
The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray crystallography. Mechanistic study demonstrated the crucial role of hydroxy(aryl)iodonium tosylate as a precatalyst, which is generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid in the presence of a catalytic amount of p-toluenesulfonic acid. Full article
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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