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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Ma Qianwen, Zhipei Sang, Wang Huijuan, Wenmin Liu, Wang Keren, Han Xue, Huifang Wang, Yu Lintao, and Ye Mengyao
- Subjects
0301 basic medicine ,Monoamine Oxidase Inhibitors ,Molecular model ,Cell Survival ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Phthalimides ,01 natural sciences ,Biochemistry ,Phthalimide ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Alzheimer Disease ,Cell Line, Tumor ,Drug Discovery ,Cholinesterases ,Humans ,Amines ,Cytotoxicity ,Monoamine Oxidase ,Molecular Biology ,Cholinesterase ,Binding Sites ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Active site ,In vitro ,Protein Structure, Tertiary ,0104 chemical sciences ,Molecular Docking Simulation ,Kinetics ,030104 developmental biology ,Blood-Brain Barrier ,Drug Design ,biology.protein ,Lipinski's rule of five ,Molecular Medicine ,Cholinesterase Inhibitors ,Monoamine oxidase B - 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 ( hu AChE, hu BuChE, and hu MAO-B with IC 50 values of 1.2 μM, 3.8 μM 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.
- Published
- 2017