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Chromone and donepezil hybrids as new multipotent cholinesterase and monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease
A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). In vitro studies showed that the great majority of these compounds exhibited pot...
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Published in: | MedChemComm 2020-02, Vol.11 (2), p.225-233 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD).
In vitro
studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for
h
MAO-B. In particular, compound
5c
presented the most balanced potential for ChE inhibition (BuChE: IC
50
= 5.24 μM; AChE: IC
50
= 0.37 μM) and
h
MAO-B selectivity (IC
50
= 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that
5c
was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound
5c
could penetrate the blood-brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound
5c
might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.
Good permeability to cross the blood-brain barrier; low toxicity to PC12 cells. |
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ISSN: | 2632-8682 2040-2503 2632-8682 2040-2511 |
DOI: | 10.1039/c9md00441f |