Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase

Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17,...

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Published in:European journal of medicinal chemistry 2009-06, Vol.44 (6), p.2523-2532
Main Authors: Tang, Huang, Wei, Yong-Biao, Zhang, Chi, Ning, Fang-Xian, Qiao, Wei, Huang, Shi-Liang, Ma, Lin, Huang, Zhi-Shu, Gu, Lian-Quan
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Acetylcholinesterase inhibitors
Alkaloids - chemical synthesis
Alkaloids - chemistry
Alkaloids - pharmacology
Animals
Aporphines - chemical synthesis
Aporphines - chemistry
Aporphines - pharmacology
Biological and medical sciences
Butyrylcholinesterase - metabolism
Butyrylcholinesterase inhibitors
Computer Simulation
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Medical sciences
Miscellaneous
Models, Chemical
Models, Molecular
Molecular Structure
Oxoaporphine derivatives
Oxoisoaporphine derivatives
Pharmacology. Drug treatments
Reproducibility of Results
Stereoisomerism
Synthesis
Torpedo - metabolism
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Summary:Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765–3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids ( 5a– j, 4-carboxylic amide-7-oxo-7 H-dibenzo[ de, g]quinoline, Ar-CONH(CH 2) nNR) and their quaternary methiodide salts ( 6a– h, Ar-CONH(CH 2) nN +(CH 3)RI −) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2–3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme. [Display omitted]
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2009.01.021