Design, synthesis and evaluation of novel 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer's disease.
A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Aβ) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Aβ1-42 aggregation with inhibition ratio of 33.8% at 25 μM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD.
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Shixian
S
Liao
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Hui
H
Deng
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Shengbin
S
Huang
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Jingyuan
J
Yang
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Siqian
S
Wang
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Baodi
B
Yin
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Tieli
T
Zheng
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Dafeng
D
Zhang
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
Jinsong
J
Liu
School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325027, China.
Guohui
G
Gao
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: dentmajianfeng@163.com.
Jianfeng
J
Ma
School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: dzn84@163.com.
Zhennan
Z
Deng
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004593:Electrophorus; D018397:Equidae; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D047309:Flavones; C000603600:N-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-2-(4-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)phenoxy)acetamide; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Alzheimer’s disease; Antioxidant; Aβ(1–42) aggregation inhibition; Cholinesterase inhibitors; Hybrids; Neuroprotectant