- Discovery of 4′-OH-flurbiprofen Mannich base derivatives as potential Alzheimer's disease treatment with multiple inhibitory activities
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A series of 4′-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibi
- Liu, Hongyan,Qiang, Xiaoming,Song, Qing,Li, Wei,He, Yuxi,Ye, Chanyuan,Tan, Zhenghuai,Deng, Yong
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- Design, synthesis and evaluation of 4′-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment
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A series of 4′-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1–42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1–42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
- Cao, Zhongcheng,Yang, Jie,Xu, Rui,Song, Qin,Zhang, Xiaoyu,Liu, Hongyan,Qiang, Xiaoming,Li, Yan,Tan, Zhenghuai,Deng, Yong
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- NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity
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To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
- Chen, Yao,Sun, Jianfei,Huang, Zhangjian,Liao, Hong,Peng, Sixun,Lehmann, Jochen,Zhang, Yihua
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supporting information
p. 3162 - 3165
(2013/06/27)
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- Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer's disease agents
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To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant Aβ inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Aβ inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation.
- Chen, Yao,Sun, Jianfei,Huang, Zhangjian,Liao, Hong,Peng, Sixun,Lehmann, Jochen,Zhang, Yihua
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p. 2462 - 2470
(2013/06/27)
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- Isoxazole derivatives
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An isoxazole derivative represented by the formula: or a pharmaceutically acceptable salt thereof useful as a therapeutic drug for auto-immune diseases and inflammatory diseases.
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