Journal
MEDCHEMCOMM
Volume 8, Issue 7, Pages 1459-1467Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7md00199a
Keywords
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Funding
- National Natural Science Foundation of China [81573313]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT_15R63]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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A series of homoisoflavonoid derivatives was designed, synthesized and evaluated as potential multifunctional anti-Alzheimer's agents for their inhibitory activity on cholinesterase and monoamine oxidase. Among them, compound 16 showed moderate acetylcholinesterase (AChE) inhibitory activity (eeAChE IC50 = 0.89 +/- 0.02 mu M; hAChE IC50 = 0.657 +/- 0.002 mu M) and significant monoamine oxidase B (MAO-B) inhibitory activity (hMAO-B IC50 = 0.0372 +/- 0.0002 mu M). Kinetic analysis of AChE, MAO-B inhibition and molecular modeling studies revealed that compound 16 is a dual binding site inhibitor of AChE and noncompetitive inhibitor of MAO-B. Furthermore, 16 could penetrate through the blood-brain barrier (BBB) in vitro. Most importantly, oral administration of 16 demonstrated no marked signs of acute toxicity and it could significantly reverse scopolamine-induced memory impairment in mice. These results suggested that compound 16 is a promising multifunctional drug candidate with potential effect for the treatment of Alzheimer's disease.
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