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Bioorg Chem. 2015 Dec;63:58-63. doi: 10.1016/j.bioorg.2015.09.009. Epub 2015 Sep 30.

Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives.

Author information

1
Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
2
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
3
Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan; Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
4
Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
5
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.

Abstract

Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.

KEYWORDS:

Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Coumarin; Homology models; Molecular docking; Thioureas

PMID:
26440714
DOI:
10.1016/j.bioorg.2015.09.009
[Indexed for MEDLINE]

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