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Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

Abstract Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.
PMID
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Authors

Mayor MeshTerms
Keywords

Cholinesterase inhibitor

cinnamic acid

multi-target ligand

tacrine hybrid

Journal Title journal of enzyme inhibition and medicinal chemistry
Publication Year Start




PMID- 29278947
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20180105
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 33
IP  - 1
DP  - 2018 Dec
TI  - Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as
      cholinesterase inhibitors against Alzheimer's disease.
PG  - 290-302
LID - 10.1080/14756366.2017.1412314 [doi]
AB  - Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic
      strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI 
      with multi-target effect is still of great importance. Herein, we report the
      synthesis, structure-activity relationship study and biological evaluation of a
      series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are
      evaluated for their in vitro cholinesterase inhibitory activities. The
      representatives which show potent activity on cholinesterase, are evaluated for
      the amyloid beta-protein self-aggregation inhibition and in vivo assays. The
      optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 +/- 1.2, 16.5 +/- 1.7,
      and 15.3 +/- 1.8 nM, respectively) show good performance in ameliorating the
      scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity
      evaluation. These compounds deserve further evaluation for the development of new
      therapeutic agents against AD.
FAU - Chen, Yao
AU  - Chen Y
AD  - a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
AD  - b Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources
      Industrialization , Nanjing University of Chinese Medicine , Nanjing , China.
AD  - c State Key Laboratory Cultivation Base for TCM Quality and Efficacy , Nanjing
      University of Chinese Medicine , Nanjing , China.
FAU - Zhu, Jie
AU  - Zhu J
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
FAU - Mo, Jun
AU  - Mo J
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
FAU - Yang, Hongyu
AU  - Yang H
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
FAU - Jiang, Xueyang
AU  - Jiang X
AD  - e Key Laboratory of Biomedical Functional Materials, School of Science , China
      Pharmaceutical University , Nanjing , China.
FAU - Lin, Hongzhi
AU  - Lin H
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
FAU - Gu, Kai
AU  - Gu K
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
FAU - Pei, Yuqiong
AU  - Pei Y
AD  - a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
FAU - Wu, Liang
AU  - Wu L
AD  - a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
FAU - Tan, Renxiang
AU  - Tan R
AD  - e Key Laboratory of Biomedical Functional Materials, School of Science , China
      Pharmaceutical University , Nanjing , China.
FAU - Hou, Jing
AU  - Hou J
AD  - c State Key Laboratory Cultivation Base for TCM Quality and Efficacy , Nanjing
      University of Chinese Medicine , Nanjing , China.
FAU - Chen, Jingyi
AU  - Chen J
AD  - f School of Nursing , Nanjing University of Chinese Medicine , Nanjing , China.
FAU - Lv, Yang
AU  - Lv Y
AD  - a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
FAU - Bian, Yaoyao
AU  - Bian Y
AD  - f School of Nursing , Nanjing University of Chinese Medicine , Nanjing , China.
FAU - Sun, Haopeng
AU  - Sun H
AD  - d Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing ,
      China.
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Cinnamates)
RN  - 0 (Protein Aggregates)
RN  - 4VX7YNB537 (Tacrine)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - EC 3.1.1.8 (Butyrylcholinesterase)
RN  - U14A832J8D (cinnamic acid)
SB  - IM
MH  - Acetylcholinesterase/metabolism
MH  - Alzheimer Disease/*drug therapy/metabolism
MH  - Amyloid beta-Peptides/antagonists & inhibitors/metabolism
MH  - Animals
MH  - Butyrylcholinesterase/metabolism
MH  - Cholinesterase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Cinnamates/chemistry/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Electrophorus
MH  - Horses
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Protein Aggregates/drug effects
MH  - Structure-Activity Relationship
MH  - Tacrine/chemistry/*pharmacology
OTO - NOTNLM
OT  - Cholinesterase inhibitor
OT  - cinnamic acid
OT  - multi-target ligand
OT  - tacrine hybrid
EDAT- 2017/12/28 06:00
MHDA- 2018/01/06 06:00
CRDT- 2017/12/28 06:00
PHST- 2017/12/28 06:00 [entrez]
PHST- 2017/12/28 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
AID - 10.1080/14756366.2017.1412314 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2018 Dec;33(1):290-302. doi:
      10.1080/14756366.2017.1412314.