1. Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease.
- Author
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Sang Z, Wang K, Wang H, Yu L, Wang H, Ma Q, Ye M, Han X, and Liu W
- Subjects
- Alzheimer Disease drug therapy, Amines pharmacology, Amines therapeutic use, Binding Sites, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Cell Line, Tumor, Cell Survival drug effects, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors therapeutic use, Cholinesterases chemistry, Cholinesterases metabolism, Humans, Inhibitory Concentration 50, Kinetics, Molecular Docking Simulation, Monoamine Oxidase chemistry, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Monoamine Oxidase Inhibitors therapeutic use, Phthalimides chemical synthesis, Phthalimides pharmacology, Phthalimides therapeutic use, Protein Structure, Tertiary, Structure-Activity Relationship, Amines chemistry, Cholinesterase Inhibitors chemical synthesis, Drug Design, Monoamine Oxidase Inhibitors chemical synthesis, Phthalimides chemistry
- Abstract
A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC
50 values of 1.2μM, 3.8μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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