Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease.

Abstract

A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.

• Authors: Fei Mao, Jianheng Li, Hui Wei, Ling Huang, Xingshu Li
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 30 Issue 6 Pg. 995-1001 (Dec 2015) ISSN: 1475-6374 [Electronic] England
• PMID: 25792506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinesterase Inhibitors
• Propylamines
• propargylamine
• Tacrine
• Pargyline
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, enzymology, metabolism)
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (adverse effects, chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Hepatic Stellate Cells (cytology, drug effects)
• Humans
• Molecular Structure
• Pargyline (adverse effects, analogs & derivatives, chemistry, pharmacology)
• Propylamines (adverse effects, chemistry, pharmacology)
• Structure-Activity Relationship
• Tacrine (adverse effects, analogs & derivatives, chemistry, pharmacology)