Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer's disease
| Autor: | Martina Hrabinova, Pavol Kristian, Slavka Hamulakova, Maria Banasova, Ján Imrich, Kamil Kuca, Ladislav Janovec |
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| Rok vydání: | 2012 |
| Předmět: |
Molecular model
Aché Stereochemistry Protein Conformation Chemistry Techniques Synthetic Piperazines chemistry.chemical_compound Alzheimer Disease Drug Discovery medicine Humans Piperazine Butyrylcholinesterase Cholinesterase Pharmacology biology Chemistry Organic Chemistry General Medicine Acetylcholinesterase language.human_language Dissociation constant Molecular Docking Simulation Tacrine Drug Design biology.protein language Cholinesterase Inhibitors Selectivity medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 55 |
| ISSN: | 1768-3254 |
| Popis: | New tacrine derivatives 5a – d , 6a – d with piperazino-ethyl spacer linked with corresponding secondary amines and tacrine homodimer 8 were synthesized and tested as cholinesterase inhibitors on human acetylcholinesterase ( h AChE) and human plasmatic butyrylcholinesterase ( h BChE). In most cases the majority of synthesized derivatives exhibit a high AChE and BChE inhibitory activity with IC 50 values in the low-nanomolar range, being clearly more potent than the reference standard tacrine (9-amino-1,2,3,4-tetrahydroacridine, 1 ) and 7-MEOTA (7-methoxy-9-amino-1,2,3,4-tetrahydroacridine). Among them, inhibitors 8 and 5c , showed a strong inhibitory activity against h AChE, with an IC 50 value of 4.49 nM and 4.97, nM resp., and a high selectivity to h AChE. The compound 5d acted as the most potent inhibitor against h BChE with an IC 50 value of 33.7 nM and exhibited also a good selectivity towards h BChE. The dissociation constants K i of the selected inhibitors were compared with their IC 50 values. Molecular modeling studies were performed to predict the binding modes between individual derivatives and h AChE/ h BChE. |
| Databáze: | OpenAIRE |
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