LAPSE:2023.28287
Published Article
LAPSE:2023.28287
Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay
April 11, 2023
Abstract
The strategy of the nucleophilic substitution of hydrogen (SNH) was first applied for the metal-free C-H/C-H coupling reactions of 4H-imidazole 3-oxides with indoles. As a result, a series of novel bifunctional azaheterocyclic derivatives were obtained in yields up to 95%. In silico experiments on the molecular docking were performed to evaluate the binding possibility of the synthesized small azaheterocyclic molecules to the selected biotargets (BACE1, BChE, CK1δ, AChE) associated with the pathogenesis of neurodegenerative diseases. To assess the cytotoxicity for the synthesized compounds, a series of in vitro experiments were also carried out on healthy human embryo kidney cells (HEK-293). The leading compound bearing both 5-phenyl-4H-imidazole and 1-methyl-1H-indole moieties was defined as the prospective molecule possessing the lowest cytotoxicity (IC50 > 300 µM on HEK-293) and the highest binding energy in the protein−ligand complex (AChE, −13.57 kcal/mol). The developed compounds could be of particular interest in medicinal chemistry, particularly in the targeted design of small-molecule candidates for the treatment of neurodegenerative disorders.
The strategy of the nucleophilic substitution of hydrogen (SNH) was first applied for the metal-free C-H/C-H coupling reactions of 4H-imidazole 3-oxides with indoles. As a result, a series of novel bifunctional azaheterocyclic derivatives were obtained in yields up to 95%. In silico experiments on the molecular docking were performed to evaluate the binding possibility of the synthesized small azaheterocyclic molecules to the selected biotargets (BACE1, BChE, CK1δ, AChE) associated with the pathogenesis of neurodegenerative diseases. To assess the cytotoxicity for the synthesized compounds, a series of in vitro experiments were also carried out on healthy human embryo kidney cells (HEK-293). The leading compound bearing both 5-phenyl-4H-imidazole and 1-methyl-1H-indole moieties was defined as the prospective molecule possessing the lowest cytotoxicity (IC50 > 300 µM on HEK-293) and the highest binding energy in the protein−ligand complex (AChE, −13.57 kcal/mol). The developed compounds could be of particular interest in medicinal chemistry, particularly in the targeted design of small-molecule candidates for the treatment of neurodegenerative disorders.
Record ID
Keywords
azaheterocycles, C-H functionalization, imidazoles, in vitro cytotoxicity assay, indoles, molecular docking, neurodegenerative diseases, nucleophilic substitution of hydrogen, PASE
Subject
Suggested Citation
Nikiforov EA, Vaskina NF, Moseev TD, Varaksin MV, Butorin II, Melekhin VV, Tokhtueva MD, Mazhukin DG, Tikhonov AY, Charushin VN, Chupakhin ON. Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay. (2023). LAPSE:2023.28287
Author Affiliations
Nikiforov EA: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia [ORCID]
Vaskina NF: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Moseev TD: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia [ORCID]
Varaksin MV: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia [ORCID]
Butorin II: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Melekhin VV: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; Department of Medical Biology and Genetics, Ural State Medical University, 3 Repina Street, 620028 Ekaterinburg, Russia
Tokhtueva MD: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Mazhukin DG: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akad. Lavrentyev Avenue, 630090 Novosibirsk, Russia [ORCID]
Tikhonov AY: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akad. Lavrentyev Avenue, 630090 Novosibirsk, Russia [ORCID]
Charushin VN: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia [ORCID]
Chupakhin ON: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia
Vaskina NF: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Moseev TD: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia [ORCID]
Varaksin MV: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia [ORCID]
Butorin II: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Melekhin VV: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; Department of Medical Biology and Genetics, Ural State Medical University, 3 Repina Street, 620028 Ekaterinburg, Russia
Tokhtueva MD: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia
Mazhukin DG: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akad. Lavrentyev Avenue, 630090 Novosibirsk, Russia [ORCID]
Tikhonov AY: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akad. Lavrentyev Avenue, 630090 Novosibirsk, Russia [ORCID]
Charushin VN: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia [ORCID]
Chupakhin ON: Institute of Chemical Engineering, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia; I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620990 Ekaterinburg, Russia
Journal Name
Processes
Volume
11
Issue
3
First Page
846
Year
2023
Publication Date
2023-03-12
ISSN
2227-9717
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PII: pr11030846, Publication Type: Journal Article
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LAPSE:2023.28287
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https://doi.org/10.3390/pr11030846
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