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Synthesis of Heteroaromatic 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 2022) | Viewed by 47486

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Special Issue Editor


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Guest Editor
School of Science and Technology, Georgia Gwinnett College, 1000 University Center Lane, Lawrenceville, GA 30043, USA
Interests: heterocycle synthesis; organofluorine chemistry

Special Issue Information

Dear Colleagues,

Heteroaromatic molecules serve as critical components of pharmacophores and other industrially important materials. New approaches to the preparation of both single-ring and fused-ring heteroaromatic species have been the subject of intense exploration over the past decade.

In this context, synthetic organic chemistry plays a key role and constitutes a flexible tool by providing access to a wide variety of compound types, including azoles, furans, pyrroles, pyridines, pyrimidines, and quinolinoids, to name a few. Through the variation and selective positioning of functional groups within the heteroaromatic molecular architecture, it is possible to modulate the properties of these compounds, which can yield substantial medicinal and industrial value. Additionally, the application of environmentally responsible synthetic processes to the preparation of heteoraromatics has burgeoned over the last decade. To that end, original research articles and reviews regarding recent advancements in the design and synthesis of heteroaromatic compounds of interest, especially those which highlight application of green chemistry principles, are welcomed for inclusion in this Special Issue of Molecules.

Prof. Dr. Joseph Sloop
Guest Editor

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Keywords

  • heteroaromatics
  • regioselective synthesis
  • chemoselective synthesis
  • azoles
  • indoles
  • quinoline
  • pyridines
  • solvent-free reactions
  • green chemistry
  • cyclization
  • multicomponent reactions
  • photochemical synthetic methods

Published Papers (21 papers)

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Editorial

Jump to: Research, Review

4 pages, 198 KiB  
Editorial
Synthesis of Heteroaromatic Compounds
by Joseph Sloop
Molecules 2023, 28(8), 3563; https://doi.org/10.3390/molecules28083563 - 19 Apr 2023
Cited by 1 | Viewed by 1019
Abstract
The synthesis of heteroaromatic compounds has been the subject of intense investigation for well over a century [...] Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)

Research

Jump to: Editorial, Review

20 pages, 4430 KiB  
Article
4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABAA Receptor Subtype
by Letizia Crocetti, Gabriella Guerrini, Fabrizio Melani, Claudia Vergelli and Maria Paola Giovannoni
Molecules 2023, 28(7), 3054; https://doi.org/10.3390/molecules28073054 - 29 Mar 2023
Cited by 1 | Viewed by 1336
Abstract
The isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taking into account this evidence [...] Read more.
The isosteric replacement of the benzene with thiophene ring is a chemical modification widely applied in medicinal chemistry. Several drugs containing the thiophene ring are marketed for treating various pathologies (osteoporosis, peripheral artery disorder, psychosis, anxiety and convulsion). Taking into account this evidence and as a continuation of our study in the GABAA receptor modulators field, we designed and synthesized new compounds containing the thiophene ring with 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidine and pyrazolo[1,5-a]thieno[2,3-c] pyrimidine scaffold. Moreover, these cores, never reported in the literature, are isosteres of pyrazolo[1,5-a]quinazolines (PQ), previously published by us as GABAAR subtype ligands. We introduced in the new scaffold those functions and groups (esters, ketones, alpha/beta-thiophene) that in our PQ derivatives were responsible for the activity, and at the same time, we have extensively investigated the reactivity of the new nucleus regarding the alkylation, reduction, halogenation and hydrolyses. On the six final designed compounds (12cf, 22a,b) molecular docking and dynamic simulation studies have been performed. The analysis of dynamic simulation, applying our reported model ‘Proximity Frequencies’, collocates with high probability 12c, 22b, in the agonist class towards α1β2γ2-GABAAR. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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13 pages, 1336 KiB  
Article
The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones
by Viktoria V. Viktorova, Elena V. Steparuk, Dmitrii L. Obydennov and Vyacheslav Y. Sosnovskikh
Molecules 2023, 28(3), 1285; https://doi.org/10.3390/molecules28031285 - 28 Jan 2023
Cited by 3 | Viewed by 1403
Abstract
This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. [...] Read more.
This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. In the case of o-phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33–91%). Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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23 pages, 6254 KiB  
Article
Synthesis of Mono- and Polyazole Hybrids Based on Polyfluoroflavones
by Mariya A. Panova, Konstantin V. Shcherbakov, Ekaterina F. Zhilina, Yanina V. Burgart and Victor I. Saloutin
Molecules 2023, 28(2), 869; https://doi.org/10.3390/molecules28020869 - 15 Jan 2023
Cited by 2 | Viewed by 1444
Abstract
The possibility of functionalization of 2-(polyfluorophenyl)-4H-chromen-4-ones, with them having different numbers of fluorine atoms, with 1,2,4-triazole or imidazole under conditions of base-promoted nucleophilic aromatic substitution has been shown. A high selectivity of mono-substitution was found with the use of an [...] Read more.
The possibility of functionalization of 2-(polyfluorophenyl)-4H-chromen-4-ones, with them having different numbers of fluorine atoms, with 1,2,4-triazole or imidazole under conditions of base-promoted nucleophilic aromatic substitution has been shown. A high selectivity of mono-substitution was found with the use of an azole (1.5 equiv.)/NaOBut(1.5 equiv.)/MeCN system. The structural features of fluorinated mono(azolyl)-substituted flavones in crystals were established using XRD analysis. The ability of penta- and tetrafluoroflavones to form persubstituted products with triazole under azole (6 equiv.)/NaOBut(6 equiv.)/DMF conditions was found in contrast to similar transformations with imidazole. On the basis of mono(azolyl)-containing polyfluoroflavones in reactions with triazole and pyrazole, polynuclear hybrid compounds containing various azole fragments were obtained. For poly(pyrazolyl)-substituted flavones, green emission in the solid state under UV-irradiation was found, and for some derivatives, weak fungistatic activity was found. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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18 pages, 7001 KiB  
Article
Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase
by Tariq Z. Abolibda, Maher Fathalla, Basant Farag, Magdi E. A. Zaki and Sobhi M. Gomha
Molecules 2023, 28(2), 689; https://doi.org/10.3390/molecules28020689 - 10 Jan 2023
Cited by 21 | Viewed by 2258
Abstract
One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via [...] Read more.
One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a–e, 10a–c and 12a–c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (−9.900 and −9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 μM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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21 pages, 4666 KiB  
Article
2-(2-(Dimethylamino)vinyl)-4H-pyran-4-ones as Novel and Convenient Building-Blocks for the Synthesis of Conjugated 4-Pyrone Derivatives
by Dmitrii L. Obydennov, Diana I. Nigamatova, Alexander S. Shirinkin, Oleg E. Melnikov, Vladislav V. Fedin, Sergey A. Usachev, Alena E. Simbirtseva, Mikhail Y. Kornev and Vyacheslav Y. Sosnovskikh
Molecules 2022, 27(24), 8996; https://doi.org/10.3390/molecules27248996 - 16 Dec 2022
Cited by 2 | Viewed by 1753
Abstract
A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring [...] Read more.
A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%). Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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12 pages, 1084 KiB  
Article
Design, Synthesis and Fungicidal Activity of N-(thiophen-2-yl) Nicotinamide Derivatives
by Hongfei Wu, Xingxing Lu, Jingbo Xu, Xiaoming Zhang, Zhinian Li, Xinling Yang and Yun Ling
Molecules 2022, 27(24), 8700; https://doi.org/10.3390/molecules27248700 - 8 Dec 2022
Cited by 4 | Viewed by 1317
Abstract
Based on the modification of natural products and the active substructure splicing method, a series of new N-(thiophen-2-yl) nicotinamide derivatives were designed and synthesized by splicing the nitrogen-containing heterocycle natural molecule nicotinic acid and the sulfur-containing heterocycle thiophene. The structures of the [...] Read more.
Based on the modification of natural products and the active substructure splicing method, a series of new N-(thiophen-2-yl) nicotinamide derivatives were designed and synthesized by splicing the nitrogen-containing heterocycle natural molecule nicotinic acid and the sulfur-containing heterocycle thiophene. The structures of the target compounds were identified through 1H NMR, 13C NMR and HRMS spectra. The in vivo bioassay results of all the compounds against cucumber downy mildew (CDM, Pseudoperonospora cubensis (Berk.et Curt.) Rostov.) in a greenhouse indicated that compounds 4a (EC50 = 4.69 mg/L) and 4f (EC50 = 1.96 mg/L) exhibited excellent fungicidal activities which were higher than both diflumetorim (EC50 = 21.44 mg/L) and flumorph (EC50 = 7.55 mg/L). The bioassay results of the field trial against CDM demonstrated that the 10% EC formulation of compound 4f displayed excellent efficacies (70% and 79% control efficacies, respectively, each at 100 mg/L and 200 mg/L) which were superior to those of the two commercial fungicides flumorph (56% control efficacy at 200 mg/L) and mancozeb (76% control efficacy at 1000 mg/L). N-(thiophen-2-yl) nicotinamide derivatives are significant lead compounds that can be used for further structural optimization, and compound 4f is also a promising fungicide candidate against CDM that can be used for further development. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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23 pages, 5550 KiB  
Article
4-(Aryl)-Benzo[4,5]imidazo[1,2-a]pyrimidine-3-Carbonitrile-Based Fluorophores: Povarov Reaction-Based Synthesis, Photophysical Studies, and DFT Calculations
by Victor V. Fedotov, Maria I. Valieva, Olga S. Taniya, Semen V. Aminov, Mikhail A. Kharitonov, Alexander S. Novikov, Dmitry S. Kopchuk, Pavel A. Slepukhin, Grigory V. Zyryanov, Evgeny N. Ulomsky, Vladimir L. Rusinov and Valery N. Charushin
Molecules 2022, 27(22), 8029; https://doi.org/10.3390/molecules27228029 - 19 Nov 2022
Cited by 5 | Viewed by 2029
Abstract
A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels–Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-a [...] Read more.
A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels–Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-a]pyrimidines took place. The structures of all the obtained compounds were confirmed based on the data from 1H- and 13C-NMR spectroscopy, IR spectroscopy, and elemental analysis. For all the obtained compounds, their photophysical properties were studied. In all the cases, a positive emission solvatochromism with Stokes shifts from 120 to 180 nm was recorded. Aggregation-Induced Emission (AIE) has been illustrated for compound 6c using different water fractions (fw) in THF. The compounds 6c and 6f demonstrated changes in emission maxima or/and intensities after mechanical stimulation. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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12 pages, 1672 KiB  
Communication
Synthesis of 2,5-Dialkyl-1,3,4-oxadiazoles Bearing Carboxymethylamino Groups
by Marcin Łuczyński, Kornelia Kubiesa and Agnieszka Kudelko
Molecules 2022, 27(22), 7687; https://doi.org/10.3390/molecules27227687 - 9 Nov 2022
Cited by 2 | Viewed by 1504
Abstract
A series of new symmetrical 2,5-dialkyl-1,3,4-oxadiazoles containing substituted alkyl groups at the terminal positions with substituents, such as bromine, isopropyloxycarbonylmethylamino, and carboxymethylamino, were successfully synthesized. The developed multistep method employed commercially available acid chlorides differing in alkyl chain length and terminal substituent, hydrazine [...] Read more.
A series of new symmetrical 2,5-dialkyl-1,3,4-oxadiazoles containing substituted alkyl groups at the terminal positions with substituents, such as bromine, isopropyloxycarbonylmethylamino, and carboxymethylamino, were successfully synthesized. The developed multistep method employed commercially available acid chlorides differing in alkyl chain length and terminal substituent, hydrazine hydrate, and phosphorus oxychloride. The intermediate bromine-containing 2,5-dialkyl-1,3,4-oxadiazoles were easily substituted with diisopropyl iminodiacetate, followed by hydrolysis in aqueous methanol solution giving the corresponding 1,3,4-oxadiazoles bearing carboxymethylamino substituents. The structure of all products was confirmed by conventional spectroscopic methods including 1H NMR, 13C NMR, and HRMS. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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20 pages, 6181 KiB  
Article
Synthesis, Molecular Docking Study, and Cytotoxicity Evaluation of Some Novel 1,3,4-Thiadiazole as Well as 1,3-Thiazole Derivatives Bearing a Pyridine Moiety
by Amr S. Abouzied, Jehan Y. Al-Humaidi, Abdulrahman S Bazaid, Husam Qanash, Naif K. Binsaleh, Abdulwahab Alamri, Sheikh Muhammad Ibrahim and Sobhi M. Gomha
Molecules 2022, 27(19), 6368; https://doi.org/10.3390/molecules27196368 - 27 Sep 2022
Cited by 21 | Viewed by 2074
Abstract
Pyridine, 1,3,4-thiadiazole, and 1,3-thiazole derivatives have various biological activities, such as antimicrobial, analgesic, anticonvulsant, and antitubercular, as well as other anticipated biological properties, including anticancer activity. The starting 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-phenylthiourea (2) was prepared and reacted with various hydrazonoyl halides 3a [...] Read more.
Pyridine, 1,3,4-thiadiazole, and 1,3-thiazole derivatives have various biological activities, such as antimicrobial, analgesic, anticonvulsant, and antitubercular, as well as other anticipated biological properties, including anticancer activity. The starting 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-phenylthiourea (2) was prepared and reacted with various hydrazonoyl halides 3ah, α-haloketones 5ad, 3-chloropentane-2,4-dione 7a and ethyl 2-chloro-3-oxobutanoate 7b, which afforded the 3-aryl-5-substituted 1,3,4-thiadiazoles 4ah, 3-phenyl-4-arylthiazoles 6ad and the 4-methyl-3- phenyl-5-substituted thiazoles 8a,b, respectively. The structures of the synthesized products were confirmed by spectral data. All of the compounds also showed remarkable anticancer activity against the cell line of human colon carcinoma (HTC-116) as well as hepatocellular carcinoma (HepG-2) compared with the Harmine as a reference under in vitro condition. 1,3,4-Thiadiazole 4h was found to be most promising and an excellent performer against both cancer cell lines (IC50 = 2.03 ± 0.72 and 2.17 ± 0.83 µM, respectively), better than the reference drug (IC50 = 2.40 ± 0.12 and 2.54 ± 0.82 µM, respectively). In order to check the binding modes of the above thiadiazole derivatives, molecular docking studies were performed that established a binding site with EGFR TK. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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16 pages, 3081 KiB  
Article
Furan-Containing Chiral Spiro-Fused Polycyclic Aromatic Compounds: Synthesis and Photophysical Properties
by Koji Nakano, Ko Takase and Keiichi Noguchi
Molecules 2022, 27(16), 5103; https://doi.org/10.3390/molecules27165103 - 11 Aug 2022
Cited by 3 | Viewed by 1666
Abstract
Spiro-fused polycyclic aromatic compounds (PACs) have received growing interest as rigid chiral scaffolds. However, furan-containing spiro-fused PACs have been quite limited. Here, we design spiro[indeno[1,2-b][1]benzofuran-10,10′-indeno[1,2-b][1]benzothiophene] as a new family of spiro-fused PACs that contains a furan unit. The compound [...] Read more.
Spiro-fused polycyclic aromatic compounds (PACs) have received growing interest as rigid chiral scaffolds. However, furan-containing spiro-fused PACs have been quite limited. Here, we design spiro[indeno[1,2-b][1]benzofuran-10,10′-indeno[1,2-b][1]benzothiophene] as a new family of spiro-fused PACs that contains a furan unit. The compound was successfully synthesized in enantiopure form and also transformed to its S,S-dioxide derivative and the pyrrole-containing analog via aromatic metamorphosis. The absorption and emission properties of the obtained furan-containing chiral spiro-fused PACs are apparently different from those of their thiophene analogs that have been reported, owing to the increased electron-richness of furan compared to thiophene. All of the furan-containing chiral spiro-fused PACs were found to be circularly polarized luminescent materials. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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16 pages, 2116 KiB  
Article
Synthesis and Luminescent Properties of s-Tetrazine Derivatives Conjugated with the 4H-1,2,4-Triazole Ring
by Anna Maj, Agnieszka Kudelko and Marcin Świątkowski
Molecules 2022, 27(11), 3642; https://doi.org/10.3390/molecules27113642 - 6 Jun 2022
Cited by 3 | Viewed by 1946
Abstract
New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied [...] Read more.
New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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11 pages, 7990 KiB  
Article
Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors
by Jing Wu, Bo Feng, Li-Xin Gao, Chun Zhang, Jia Li, Da-Jun Xiang, Yi Zang and Wen-Long Wang
Molecules 2022, 27(10), 3359; https://doi.org/10.3390/molecules27103359 - 23 May 2022
Cited by 3 | Viewed by 2095
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CLpro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H [...] Read more.
The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CLpro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CLpro. Among them, the representative compound 7a displayed inhibitory activity with an IC50 of 1.28 ± 0.17 μM against SARS-CoV-2 3CLpro. Molecular docking of 7a against 3CLpro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CLpro. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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16 pages, 4451 KiB  
Article
General Method of Synthesis of 5-(Het)arylamino-1,2,3-triazoles via Buchwald–Hartwig Reaction of 5-Amino- or 5-Halo-1,2,3-triazoles
by Pavel S. Gribanov, Anna N. Philippova, Maxim A. Topchiy, Lidiya I. Minaeva, Andrey F. Asachenko and Sergey N. Osipov
Molecules 2022, 27(6), 1999; https://doi.org/10.3390/molecules27061999 - 20 Mar 2022
Cited by 4 | Viewed by 2700
Abstract
An efficient access to the novel 5-(het)arylamino-1,2,3-triazole derivatives has been developed. The method is based on Buchwald–Hartwig cross-coupling reaction of 5-Amino or 5-Halo-1,2,3-triazoles with (het)aryl halides and amines, respectively. As result, it was found that palladium complex [(THP-Dipp)Pd(cinn)Cl] bearing expanded-ring N-heterocyclic carbene [...] Read more.
An efficient access to the novel 5-(het)arylamino-1,2,3-triazole derivatives has been developed. The method is based on Buchwald–Hartwig cross-coupling reaction of 5-Amino or 5-Halo-1,2,3-triazoles with (het)aryl halides and amines, respectively. As result, it was found that palladium complex [(THP-Dipp)Pd(cinn)Cl] bearing expanded-ring N-heterocyclic carbene ligand is the most active catalyst for the process to afford the target molecules in high yields. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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31 pages, 2477 KiB  
Article
Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazole Derivatives via C-H Bond Functionalization of Disulfide Intermediates
by Luis G. Ardón-Muñoz and Jeanne L. Bolliger
Molecules 2022, 27(5), 1464; https://doi.org/10.3390/molecules27051464 - 22 Feb 2022
Cited by 10 | Viewed by 2278
Abstract
Many nitrogen- and sulfur-containing heterocyclic compounds exhibit biological activity. Among these heterocycles are benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles for which two main synthetic approaches exist. Here we report a new synthetic protocol that allows the preparation of these tricyclic compounds via the oxidation of a [...] Read more.
Many nitrogen- and sulfur-containing heterocyclic compounds exhibit biological activity. Among these heterocycles are benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles for which two main synthetic approaches exist. Here we report a new synthetic protocol that allows the preparation of these tricyclic compounds via the oxidation of a mercaptophenyl moiety to its corresponding disulfide. Subsequent C-H bond functionalization is thought to enable an intramolecular ring closure, thus forming the desired benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. This method combines a high functional group tolerance with short reaction times and good to excellent yields. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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Review

Jump to: Editorial, Research

27 pages, 11253 KiB  
Review
Advances in the Synthesis of Heteroaromatic Hybrid Chalcones
by Ajay Mallia and Joseph Sloop
Molecules 2023, 28(7), 3201; https://doi.org/10.3390/molecules28073201 - 4 Apr 2023
Cited by 4 | Viewed by 2840
Abstract
Chalcones continue to occupy a venerated status as scaffolds for the construction of a variety of heterocyclic molecules with medicinal and industrial properties. Syntheses of hybrid chalcones featuring heteroaromatic components, especially those methods utilizing green chemistry principles, are important additions to the preparative [...] Read more.
Chalcones continue to occupy a venerated status as scaffolds for the construction of a variety of heterocyclic molecules with medicinal and industrial properties. Syntheses of hybrid chalcones featuring heteroaromatic components, especially those methods utilizing green chemistry principles, are important additions to the preparative methodologies for this valuable class of molecules. This review outlines the advances made in the last few decades toward the incorporation of heteroaromatic components in the construction of hybrid chalcones and highlights examples of environmentally responsible processes employed in their preparation. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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33 pages, 14780 KiB  
Review
The Synthesis and Biological Applications of the 1,2,3-Dithiazole Scaffold
by Andreas S. Kalogirou, Hans J. Oh and Christopher R. M. Asquith
Molecules 2023, 28(7), 3193; https://doi.org/10.3390/molecules28073193 - 3 Apr 2023
Cited by 4 | Viewed by 2031
Abstract
The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, [...] Read more.
The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, antibacterial, anticancer agent, antiviral, antifibrotic, and is a melanin and Arabidopsis gibberellin 2-oxidase inhibitor. These structure activity relationships are discussed in detail, along with insights and future directions. The review also highlights selected synthetic strategies developed towards the 1,2,3-dithiazole scaffold, how these are integrated to accessibility of chemical space, and to the prism of current and future biological activities. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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29 pages, 9995 KiB  
Review
Application of Olefin Metathesis in the Synthesis of Carbo- and Heteroaromatic Compounds—Recent Advances
by Szymon Rogalski and Cezary Pietraszuk
Molecules 2023, 28(4), 1680; https://doi.org/10.3390/molecules28041680 - 9 Feb 2023
Cited by 3 | Viewed by 2241
Abstract
The olefin metathesis reaction has found numerous applications in organic synthesis. This is due to a number of advantages, such as the tolerance of most functional groups and sterically demanding olefins. This article reviews recent advances in the application of the metathesis reaction, [...] Read more.
The olefin metathesis reaction has found numerous applications in organic synthesis. This is due to a number of advantages, such as the tolerance of most functional groups and sterically demanding olefins. This article reviews recent advances in the application of the metathesis reaction, particularly the metathetic cyclization of dienes and enynes, in synthesis protocols leading to (hetero)aromatic compounds. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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25 pages, 10590 KiB  
Review
Heteroaromatic Diazirines Are Essential Building Blocks for Material and Medicinal Chemistry
by Yuta Murai and Makoto Hashimoto
Molecules 2023, 28(3), 1408; https://doi.org/10.3390/molecules28031408 - 1 Feb 2023
Cited by 3 | Viewed by 2859
Abstract
In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as [...] Read more.
In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as ligand–receptor, nucleic acid–protein, lipid–protein, and protein–protein interactions. In particular, use of TPD has increased in recent materials science to create novel electric and polymer devices with comparative ease and reduced costs. Therefore, a combination of heteroaromatics and (3-trifluoromethyl)diazirine is a promising option for creating better materials and elucidating the unknown mechanisms of action of bioactive heteroaromatic compounds. In this review, a comprehensive synthesis of (3-trifluoromethyl)diazirine-substituted heteroaromatics is described. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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28 pages, 7882 KiB  
Review
Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines
by Gavin R. Hoffman and Allen M. Schoffstall
Molecules 2022, 27(15), 4681; https://doi.org/10.3390/molecules27154681 - 22 Jul 2022
Cited by 7 | Viewed by 2878
Abstract
Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several [...] Read more.
Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-a]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABAA modulating activity) as fluorescent probes and as structural units of polymers. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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25 pages, 13682 KiB  
Review
Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents
by Tuyen N. Tran and Maged Henary
Molecules 2022, 27(9), 2700; https://doi.org/10.3390/molecules27092700 - 22 Apr 2022
Cited by 24 | Viewed by 5149
Abstract
Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug [...] Read more.
Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses. Full article
(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)
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