Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay
2023
Egor A. Nikiforov | Nailya F. Vaskina | Timofey D. Moseev | Mikhail V. Varaksin | Ilya I. Butorin | Vsevolod V. Melekhin | Maria D. Tokhtueva | Dmitrii G. Mazhukin | Alexsei Y. Tikhonov | Valery N. Charushin | Oleg N. Chupakhin
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, CK1&delta:, 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 µ:M on HEK-293) and the highest binding energy in the protein&ndash:ligand complex (AChE, &minus: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.
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