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Synthesis, Functionalization and Applications of Nitrogen-Containing Compounds

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 5156

Special Issue Editor


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Guest Editor
Department of Organic Chemistry and Technology, Cracow University of Technology, Warszawska 24, 31-155 Krakow, Poland
Interests: cycloaddition reactions; nitro compounds; heterocycles; reaction mechanisms; regio- and stereoselectivity; organic reactivity; DFT calculations; molecular electron density theory (MEDT)

Special Issue Information

Dear Colleagues,

Heterocyclic compounds are common in our life, and their chemistry is a constantly developing field of science that is attracting a growing number of scientists around the world. Heterocyclic compounds; containing one or more nitrogen atoms in the ring, such as pyrroles, pyrazoles, imidazoles, as well as structures containing another heteroatom, including isoxazoles, isothiazoles and others; deserve special attention. Nitrogen-containing heterocyclic compounds are widely used in medicine to produce many pharmaceuticals, due to their remarkable biological activity. These compounds are also commonly found within a variety of agrochemicals such as fungicides, insecticides, and herbicides.

This Special Issue will cover the most recent trends in the chemistry of nitrogen heterocyclic compounds. In particular, we invite researchers to publish their recent short laboratory notes and full papers regarding the synthesis of these compounds (including structural studies), their properties, biological activity, and potential application. We also welcome theoretical considerations based on the analysis of electron density applied to: synthetic aspects, reaction mechanisms, and structural analysis. Review articles by experts in the field will also be appreciated.

Dr. Karolina Kula
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • synthesis and transformation of heterocycles
  • structural chemistry
  • reaction mechanisms
  • stereochemistry
  • regiochemistry
  • quantum-chemical calculations
  • biological activity of heterocyclic compounds
  • green chemistry

Published Papers (7 papers)

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Research

25 pages, 1813 KiB  
Article
Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin
by Ulan Kemelbekov, Vitaly Volynkin, Symbat Zhumakova, Kulpan Orynbassarova, Marina Papezhuk and Valentina Yu
Molecules 2024, 29(5), 1098; https://doi.org/10.3390/molecules29051098 - 29 Feb 2024
Viewed by 444
Abstract
Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative [...] Read more.
Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative analysis of the results of pharmacological studies on models of the conduction and terminal anesthesia, as well as acute toxicity studies of the inclusion complex of 1-methyl-4-ethynyl-4-hydroxypiperidine (MEP) with β-cyclodextrin, was carried out. A virtual screening and comparative analysis of pharmacological activity were also performed on a number of the prepared piperidine derivatives and their host–guest complexes of β-cyclodextrin to identify the structure–activity relationship. Various programs were used to study biological activity in silico. For comparative analysis of chemical and pharmacological properties, data from previous works were used. For some piperidine derivatives, new dosage forms were prepared as beta-cyclodextrin host–guest complexes. Some compounds were recognized as promising local anesthetics. Pharmacological studies have shown that KFCD-7 is more active than reference drugs in terms of local anesthetic activity and acute toxicity but is less active than host–guest complexes, based on other piperidines. This fact is in good agreement with the predicted results of biological activity. Full article
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15 pages, 1729 KiB  
Article
Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide
by Maxim D. Gotsko, Ivan V. Saliy, Igor A. Ushakov, Lyubov N. Sobenina and Boris A. Trofimov
Molecules 2024, 29(4), 885; https://doi.org/10.3390/molecules29040885 - 17 Feb 2024
Viewed by 560
Abstract
An efficient method for the synthesis of pharmaceutically prospective but still rare functionalized 2,3′-bipyrroles (in up to 80% yield) by the cycloaddition of easily available acylethynylpyrroles with tosylmethylisocyanide (TosMIC) has been developed. The reaction proceeds under reflux (1 h) in the KOH/THF system. [...] Read more.
An efficient method for the synthesis of pharmaceutically prospective but still rare functionalized 2,3′-bipyrroles (in up to 80% yield) by the cycloaddition of easily available acylethynylpyrroles with tosylmethylisocyanide (TosMIC) has been developed. The reaction proceeds under reflux (1 h) in the KOH/THF system. In the t-BuONa/THF system, TosMIC acts in two directions: along with 2,3′-bipyrroles, the unexpected formation of pyrrolo[1,2-c]imidazoles is also observed (products ratio~1:1). Full article
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23 pages, 6246 KiB  
Article
(1E,3E)-1,4-Dinitro-1,3-butadiene—Synthesis, Spectral Characteristics and Computational Study Based on MEDT, ADME and PASS Simulation
by Mikołaj Sadowski, Beata Synkiewicz-Musialska and Karolina Kula
Molecules 2024, 29(2), 542; https://doi.org/10.3390/molecules29020542 - 22 Jan 2024
Viewed by 788
Abstract
The chemistry of conjugated nitrodienes is becoming increasingly popular. These molecules are successfully applied in cycloaddition to synthesize six-membered rings in Diels-Alder reactions. Nitrodienes can be also applied to obtain bis-compounds in [3+2] cycloaddition. Moreover, the presence of a nitro group in the [...] Read more.
The chemistry of conjugated nitrodienes is becoming increasingly popular. These molecules are successfully applied in cycloaddition to synthesize six-membered rings in Diels-Alder reactions. Nitrodienes can be also applied to obtain bis-compounds in [3+2] cycloaddition. Moreover, the presence of a nitro group in the structure provides a possibility of further modification of the products. The simplest symmetrical representative of conjugated nitrodienes is (1E,3E)-1,4-dinitro-1,3-butadiene. Although the first mentions of the compound date back to the early 1950s, the compound has not yet been examined thoroughly enough. Therefore, in this article, a comprehensive study of (1E,3E)-1,4-dinitro-1,3-butadiene has been described. For this purpose, an experimental study including the synthesis process as well as an evaluation of the spectral characteristics has been conducted. So as to better understand the properties of this compound, a computational study of reactivity indices based on MEDT and also an assessment of pharmacokinetics and biological activity according to ADME and PASS methodologies have been made. On this basis, some future application trends of (1E,3E)-1,4-dinitro-1,3-butadiene have been proposed. Full article
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12 pages, 3658 KiB  
Article
Novichok Nerve Agents as Inhibitors of Acetylcholinesterase—In Silico Study of Their Non-Covalent Binding Affinity
by Rafal Madaj, Bartłomiej Gostyński, Arkadiusz Chworos and Marek Cypryk
Molecules 2024, 29(2), 338; https://doi.org/10.3390/molecules29020338 - 09 Jan 2024
Viewed by 839
Abstract
In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized–Born surface area (MM/GBSA) were applied to assess quantitatively differences between the [...] Read more.
In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized–Born surface area (MM/GBSA) were applied to assess quantitatively differences between the binding energies of acetylcholine (ACh; the natural agonist of AChE) and neurotoxic, synthetic correlatives (so-called “Novichoks”, and selected compounds from the G- and V-series). Several additional quantitative descriptors like root-mean-square fluctuation (RMSF) and the solvent accessible surface area (SASA) were briefly discussed to give—to the best of our knowledge—the first quantitative in silico description of AChE—Novichok non-covalent binding process and thus facilitate the search for an efficient and effective treatment for Novichok intoxication and in a broader sense—intoxication with other warfare nerve agents as well. Full article
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19 pages, 1163 KiB  
Article
Development of Self-Assembling bis-1,4-Dihydropyridines: Detailed Studies of Bromination of Four Methyl Groups and Bromine Nucleophilic Substitution
by Martins Kaukulis, Martins Rucins, Davis Lacis, Aiva Plotniece and Arkadij Sobolev
Molecules 2024, 29(1), 161; https://doi.org/10.3390/molecules29010161 - 27 Dec 2023
Viewed by 720
Abstract
One of the most important steps in the synthesis of 1,4-dihydropyridine (1,4-DHP) amphiphiles is the bromination of methyl groups in positions 2 and 6 of the entire ring. However, up to now, only N-bromosuccinimide was mainly used for bromination 1,4-DHPs. In this work, [...] Read more.
One of the most important steps in the synthesis of 1,4-dihydropyridine (1,4-DHP) amphiphiles is the bromination of methyl groups in positions 2 and 6 of the entire ring. However, up to now, only N-bromosuccinimide was mainly used for bromination 1,4-DHPs. In this work, the synthesis of bis-1,4-DHP derivatives with ethyl and dodecyl ester groups attached to 1,4-DHP ring at positions 3 and 5 was performed by Hantzsch synthesis. The experimental studies were carried out to find out the best conditions and the agent for the tetra bromination of bis-1,4-DHP methyl groups at positions 2 and 6. Four different brominating agents were screened. The use of pyridinium bromide–perbromide in ethyl acetate was found to be optimal for the bromination of methyl groups. The bromination reaction was followed by the synthesis of cationic pyridine moiety containing amphiphilic bis-1,4-DHP derivatives. By nucleophilic substitution of bromine with various substituted pyridines, 12 new amphiphilic bis-1,4-DHP derivatives were obtained. Evaluation of self-assembling properties of tetracationic bis-1,4-dihydropyridine derivatives by dynamic light scattering (DLS) measurements was also performed. Full article
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20 pages, 2205 KiB  
Article
Synthesis of Trifluoromethylated Pyrimido[1,2-b]indazole Derivatives through the Cyclocondensation of 3-Aminoindazoles with Ketoester and Their Functionalization via Suzuki-Miyaura Cross-Coupling and SNAr Reactions
by Sakina Tellal, Badr Jismy, Djamila Hikem-Oukacha and Mohamed Abarbri
Molecules 2024, 29(1), 44; https://doi.org/10.3390/molecules29010044 - 20 Dec 2023
Viewed by 562
Abstract
A new series of trifluoromethylated pyrimido[1,2-b]indazol-4(1H)-one derivatives was synthesized with good to excellent yields through a simple condensation of 3-aminoindazole derivatives with ethyl 4,4,4-trifluoro 3-oxobutanoate. The functionalization of the corresponding chlorinated fused tricyclic scaffolds via Suzuki-Miyaura and aromatic nucleophilic [...] Read more.
A new series of trifluoromethylated pyrimido[1,2-b]indazol-4(1H)-one derivatives was synthesized with good to excellent yields through a simple condensation of 3-aminoindazole derivatives with ethyl 4,4,4-trifluoro 3-oxobutanoate. The functionalization of the corresponding chlorinated fused tricyclic scaffolds via Suzuki-Miyaura and aromatic nucleophilic substitution reactions led to the synthesis of highly diverse trifluoromethylated pyrimido[1,2-b]indazole derivatives with good yields. Full article
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24 pages, 6872 KiB  
Article
On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions between Aryl Azides and Ethyl Propiolate
by Ewa Dresler, Przemysław Woliński, Aneta Wróblewska and Radomir Jasiński
Molecules 2023, 28(24), 8152; https://doi.org/10.3390/molecules28248152 - 18 Dec 2023
Cited by 2 | Viewed by 571
Abstract
The molecular mechanism of the [3+2] cycloaddition reactions between aryl azides and ethyl propiolate was evaluated in the framework of the Molecular Electron Density Theory. It was found that independently of the nature of the substituent within the azide molecule, the cycloaddition process [...] Read more.
The molecular mechanism of the [3+2] cycloaddition reactions between aryl azides and ethyl propiolate was evaluated in the framework of the Molecular Electron Density Theory. It was found that independently of the nature of the substituent within the azide molecule, the cycloaddition process is realized via a polar but single-step mechanism. All attempts of localization as postulated earlier by Abu-Orabi and coworkers’ zwitterionic intermediates were not successful. At the same time, the formation of zwitterions with an “extended” conformation is possible on parallel reaction paths. The ELF analysis shows that the studied cycloaddition reaction leading to the 1,4-triazole proceeds by a two-stage one-step mechanism. It also revealed that both zwitterions are created by the donation of the nitrogen atom’s nonbonding electron densities to carbon atoms of ethyl propiolate. Full article
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