TY - JOUR

T1 - Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay

AU - Nikiforov, Egor A.

AU - Vaskina, Nailya F.

AU - Moseev, Timofey D.

AU - Varaksin, Mikhail V.

AU - Butorin, Ilya I.

AU - Melekhin, Vsevolod V.

AU - Tokhtueva, Maria D.

AU - Mazhukin, Dmitrii G.

AU - Tikhonov, Alexsei Y.

AU - Charushin, Valery N.

AU - Chupakhin, Oleg N.

N1 - The chemical design, synthesis and characterization of indolyl-derived 4H-imidazoles and in vitro studies were supported by the Russian Science Foundation (Project # 20-73-10077). The in silico studies were supported by the Ministry of Science and Higher Education of the Russian Federation (Ref. # 075-15-2022-1118, dated 29 June 2022). The synthesis of starting 4H-imidazole N-oxide substrates was supported by the Ministry of Science and Higher Education of the Russian Federation (Project # 14.W03.31.0034).

PY - 2023

Y1 - 2023

N2 - The strategy of the nucleophilic substitution of hydrogen (S-N(H)) 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 mu M 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.

AB - The strategy of the nucleophilic substitution of hydrogen (S-N(H)) 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 mu M 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.

UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=tsmetrics&SrcApp=tsm_test&DestApp=WOS_CPL&DestLinkType=FullRecord&KeyUT=000958762900001

UR - http://www.scopus.com/inward/record.url?partnerID=8YFLogxK&scp=85151628875

U2 - 10.3390/pr11030846

DO - 10.3390/pr11030846

M3 - Article

VL - 11

JO - Processes

JF - Processes

SN - 2227-9717

IS - 3

M1 - 846

ER -