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- Volume 25, Issue 14, 2021
Current Organic Chemistry - Volume 25, Issue 14, 2021
Volume 25, Issue 14, 2021
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Peptidomimetics and Peptide-Based Blockbuster Drugs
Authors: Jianlin Han, Hiroyuki Konno, Tatsunori Sato, Kunisuke Izawa and Vadim A. SoloshonokAmino acids (AAs) play an important role in the modern health industry. The aim of this article was to assess that AAs’ residues are frequently found in the structures of smallmolecule modern pharmaceuticals, while peptidomimetics and peptide-based drugs are entirely derived from AAs. Currently, AAs serve as key structural features in numerous successful pharmaceuticals, so-called blockbuster drugs. In this work, we provide a detailed profile of 5 peptidomimetics and 4 peptide drugs. For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.
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The Photochemical Isomerisation of Hexatomic Heterocyclic Compounds
More LessThe photochemical isomerisation of hexatomic heterocyclic compounds has been discussed. The attention was focused on the mono- and dinitrogen hexatomic heterocycles. To justify the photochemical isomerisation of pyridines, Dewar isomers, azaprismane, and azaprefulvene derivatives have been proposed. The photoisomerisation of pyridinium salts requires a ring reduction with the formation of arizines. Pyridinium ylides gave photoisomerisation reaction through the formation of the corresponding azirines, while pyridinium N-oxide was required to react for the formation of the corresponding oxaziridines. The photochemical isomerisation of pyrazine derivatives, Dewar isomers, diazaprismane, and benzvalene intermediates has been proposed to justify the observed reactivity. Finally, in the case of pyridazine and pyrimidine derivatives, Dewar isomers were used to explain the obtained reaction products. In the discussion of the results, the presence of different mechanistic hypotheses has been evidenced.
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Amide-Directed Reactions of Small Carbocycles
Authors: Pavel M. Yamanushkin, Marina Rubina and Michael RubinThe topic of this review is the amide-directed functionalization of strained carbocycles - specifically, unsaturated or saturated three- and four-membered rings. The following approaches are discussed: a) directed carbometallation and hydrometallation of cyclopropenes catalyzed by transition metals; b) directed metal-templated nucleophilic addition reactions; c) directed C-H functionalization, including transition metal-catalyzed C-H-activation reactions; and d) directed radical additions.
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A Study of the Regiochemistry in the Synthesis of Pyrano[3,4-c]pyridines
Aims: Biological studies have shown that some condensed derivatives of pyrano[3,4- c]pyridines 6 exhibited pronounced biological activity. Considering these results, the principal aim of this work is to study the regiochemistry of the synthesis of pyrano[3,4-c]pyridines 6, to optimize the reaction conditions and thus to increase the previously observed low yields of pyrano[ 3,4-c]pyridines. Background: Within this research line, some of us, several years ago, developed a method for the preparation of 6-oxopyrano[3,4-c]pyridines 6 starting from 2,2-dimethyltetrahydro-4Hpyran- 4-one 1. In these studies, we separated and identified only the most expected reaction products 6-oxopyrano[3,4-c]pyridines 6. On the basis of this datum, we suggested that the enamines 2 and 3, reacting with acyl chlorides, were not acylated at C-3 and that 5-acylpyran-4- ones 4 were the only products of the reaction. We have justified this result by considering the steric effects exerted by the two methyl groups present in the pyran ring. Moreover, we did not identify the products at the second reaction center: that is, the isomeric compounds 7 and this result was justified considering the different reactivity of aliphatic and cyclic ketone groups. Objectives: The main objectives of this work were: • implementation of the reaction of 2,2-dimethyltetrahydro-4H-pyran-4-one 1 with morpholine; • acylation of the obtained enamines 2 and 3 with acyl chlorides under Stork conditions; • synthesis of pyranopyridines 6-8 based on β-diketones: 3-acylpyran-4-ones 4 and 5-acylpyran-4-ones 5; • confirmation of the structure of the obtained compounds. Methods: For the synthesis of pyrano[3,4-c]pyridines known methods were used. Thus, the reaction of starting 2,2- dimethyltetrahydro-4H-pyran-4-one 1 with morpholine in benzene led to the formation of isomeric enamines 2 and 3. After, they were acylated with acyl chlorides under Stork conditions with formation of two β -diketones: 3- acylpyran-4-ones 4 and 5-acylpyran-4-ones 5. Finally, in order to obtain the aimed pyrano[3,4-c]pyridines 6, the obtained β-dicarbonyl compounds 4 and 5 (as a mixture of isomers) were reacted with 2-cyanoacetamide in ethanol in the presence of diethylamine, according to the Knoevenagel condensation. The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physico-chemical methods (NMR, IR, Xray structural and elemental analysis) and, in the instance of compounds 7, also by an alternative synthesis. Results: Starting from the 2,2-dimethyltetrahydro-4H-pyran-4-one 1 a series of new and already known 6- oxopyrano[3,4-c]pyridines 6 were synthesized. As a result of the study of the regiochemistry in the synthesis of pyrano[3,4-c]pyridines, of the four possible isomer pyranopyridines 6-9, we have succeeded in identifying three of them (6-8). Thus, isomer pyranopyridines 7 and 8 were identified in the mixture with the main compounds 6. Moreover, isomeric pyrano[3,4-c]pyridines 8 were detected when alkyl groups are present in the starting compounds 4 and 5, while isomeric pyrano[4,3-b]pyridines 7 were detected in the case of the presence of aromatic groups. Unfortunately, we have not been able to isolate compounds 7 and 8 in the pure state from the reaction mixtures. At now, we have not been able to detect and identify isomeric pyrano[4,3-b]pyridines 9. On the whole, we have been able to better the effectiveness of the synthesis of pyrano[3,4-c]pyridines 6, increasing their yields by ≈ 5-15%. Conclusion: As a result of our investigation, we have found that the acylation reaction of enamines 2 and 3 and the cyclization reaction of β-diketones 4 and 5 are not regioselective. Therefore, we can state that enamines 2 and 3 can be acylated at both C-3 and C-5 with the formation of a mixture of 3-acylpyran-4-ones 4 and of 5-acylpyran-4-ones 5. Their condensation with 2-cyanoacetamide led to the formation of mixtures of regioisomeric pyranopyridines 6- 8. In conclusion, as a result of our present research, we can say that we have been able to increase the effectiveness of the synthesis of pyranopyridines, largely improving our previous results. Other: Now, we are working to look for the fourth isomeric pyrano[4,3-b]pyridines 9 by using the most modern and fine methods. Moreover, we hope that we shall be able to separate the mixtures of pyranopyridines 6-8: any way they can be used for further syntheses as they are.
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Synthesis, Docking and Antimicrobials Evaluation of Novel Pyrazolotriazines as RNA Polymerase Inhibitors
Authors: Amira Abdallah, Galal Elgemeie and Ebtsam AhmedAims: Producing novel pyrazolotriazines such as pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[5,1-c][1,2,4]triazine derivatives and evaluate their biological activity as antimicrobial agents followed by the Minimum Inhibitory Concentration (MIC) for the most active compounds. Moreover, study the molecular docking and the RNA polymerase inhibitory activity. Background: Pyrazolotriazine derivatives considered one of the most important heterocyclic compounds due to their broad biological activities. Due to the similarity with the purines and thioguanines, the pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[5,1-c][1,2,4]triazine compounds were used as antimetabolic agents. Moreover, many approved drugs contain pyrazolo[1,5- a][1,3,5]triazine ring systems such as (1882L04 and SB-H02), which confirmed the pharmaceutical applications. The key precursor 5-aminopyrazoles 3 which were firstly synthesized by our research group, were used to prepare the novel pyrazolotriazine derivatives. Objective: This study aimed to synthesize novel bioactive pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[5,1- c][1,2,4]triazine derivatives as antimicrobial agents. Also, the Minimum Inhibitory Concentration (MIC) for the most potent compounds was evaluated. On the other hand, the molecular docking study and the RNA polymerase inhibitory activity were measured. Methods: In this work, the 5-aminopyrazoles 3 were used to synthesize 4-amino-7-(arylamino)pyrazolo[1,5- a][1,3,5]triazine-8-carboxamides 7a-c, 4-amino-7-(arylamino)-2-thioxo-1,2-dihydropyrazolo[1,5-a][1,3,5]-triazine- 8-carboxamides 10a-c and 4-amino-3-cyano-7-(aryllamino)pyrazolo[5,1-c][1,2,4]triazine-8-carboxamides 12ac. The newly resultant compounds were evaluated as antibacterial agents by using (Gram-positive bacteria) such as [Staphylococcus aureus and Streptococcus mutans], and (Gram-negative bacteria) such as [Escherichia coli, Pseudomonas aeruginosa, and Klebsiella]. Moreover, the new compounds were evaluated as antifungal agents by using Candids Albicans fungal strain. Also, the Minimum Inhibitory Concentration (MIC) for the most potent compounds was measured. For all the synthesized compounds, the molecular docking studies were recorded and the RNA polymerase inhibitory activity was measured for the high docking score compounds. Results: The results revealed that most of the prepared compounds such as 7b, 10b, 10c, 12a, 12b, and 12c showed moderate activity towards some of the used strains. The MIC evaluations were recorded for the most active tested compounds 7b, 10b, 10c, 12a and 12c. On the other hand, the most potent and the high docking score compounds (10c, 12a and 12c), were measured in vitro to inhibit RNA polymerase enzyme. Conclusion: A number of novel bioactive pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[5,1-c][1,2,4]triazine derivatives were synthesized. All the resultant compounds were screened for their antimicrobials activity and the MIC test was measured for the most potent compounds. In addition, the in vitro to inhibit RNA polymerase enzyme was evaluated for the most active high docking score compounds. Other: Most of the heterocyclic ring systems have remarkable activities in all fields, especially in pharmaceutical applications.
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Volumes & issues
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Volume 29 (2025)
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Volume 28 (2024)
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Volume 27 (2023)
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Volume 26 (2022)
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Volume 25 (2021)
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Volume 24 (2020)
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Volume 23 (2019)
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Volume 22 (2018)
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Volume 21 (2017)
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Volume 20 (2016)
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Volume 19 (2015)
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Volume 18 (2014)
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Volume 17 (2013)
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Volume 16 (2012)
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Volume 15 (2011)
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Volume 14 (2010)
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Volume 13 (2009)
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Volume 12 (2008)
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Volume 11 (2007)
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Volume 10 (2006)
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Volume 9 (2005)
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Volume 8 (2004)
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Volume 7 (2003)
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Volume 6 (2002)
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Volume 5 (2001)
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Volume 4 (2000)