Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives

Article abstract of DOI:10.1111/cbdd.12514

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3?3l) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration

Full text of DOI:10.1111/cbdd.12514

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Received Date : 17-Sep-2014
Revised Date : 30-Nov-2014
Accepted Date : 05-Jan-2015
Article type
: Research Article
Novel potent and selective acetylcholinesterase inhibitors as
potential drugs for the treatment of Alzheimer’s disease: Synthesis,
pharmacological evaluation, and molecular modeling of amino alkyl
substituted fluoro-chalcones derivatives
Hao-ran Liu1*, Chao Zhou1, Hao-qun Fan1, Jing-jing Tang1 Lin-bo Liu1 Xiao-hui Gao2, Qiu-an
Wang1 Wu-kun Liu1
1 College of chemistry and chemical engineering, Hu’nan University, Changsha, 410082,
China
2 College of pharmacy, Hu’nan University of Chinese Medicine, Changsha, 410208, China
*Corresponding author: Hao-ran Liu, pharmaliu@126.com
Abstract: A new series of fluoro-chalcones substituted amino alkyl derivatives
(3a~3l) were designed, synthesized, characterized and evaluated for the inhibitory
activity against acetylcholinesterase (AChE) and butylcholinesterase (BuChE). The
results showed that the alteration of fluorine atom position and amino alkyl groups
markedly influenced the activity and the selectivity of chalcone derivates in inhibiting
AChE and BuChE. Among them, compound 3l posses the most potent inhibitory
against AChE (IC50= 0.21 0.03 μmol/L), and the highest selectivity for AChE over
BuChE(IC50 (BuChE)/IC50 (AChE)=65.0). Molecular modeling and enzyme kinetic
study on compound 3l supported its dual AChE inhibitory profile, simultaneously
binding at the catalytic active and peripheral anionic site of the enzyme.
Keywords: Fluorine; Chalcone; Selectivity; AChE inhibitors; Molecular modeling
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
an 'Accepted Article', doi: 10.1111/cbdd.12514
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
In recent years, a lot of attention were thrown to natural products for the therapy
Alzheimer’s disease (AD) which was usually treated with
of
acetylcholinesterase(AChE) inhibitors (1-5). By screening AChE inhibitors in clinical
application, such as tacrine, donepezil, galanthamine and rivastigmine, we thought
that amino substituent was possibly important pharmacophore of them. Thereby, a
series chalcone derivates containing amino substituents were designed and
synthesized in our recent investigations(6,7). The previous results suggested that
dimethylamine, diethylamine, dipropylamine, pyrrolidine-containing chalcones had
more potent effects in inhibiting AChE compared with other nitrogen-containing
chalcones.
In order to develop chalcone derivates as AChE inhibitors in further, we
considered to introduce halogen atoms such as fluorine into nitrogen-containing
chalcones since fluorine seemed important to enhance bioactivities(8-10). So far
hundreds of fluorine-containing drugs had been applied in clinical practice, such as
antidepressant Fluoxetine，antibacterial Ofloxacin, anti-cancer agent 5-Fluorouracil,
and antilipemic agent Atorvastatin calcium, etc (Figure 1).
In the present study, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde and
4-fluorobenzaldehyde (1a-1c) were used for the synthesis of 4-hydroxy-fluoro
chalcones (2a-2c) and fluoro-chalcones substituted amino alkyl derivatives (3a-3l).
Followed by the synthesis of these compounds, biological activity evaluation, kinetic
assay and molecular modeling were conducted.
Materials and Method
Chemistry
1
Melting points were measured on a WRS-lA melting point detector. The H NMR
spectra were recorded on a spectrometer operating at 500 MHz. Mass spectra (MS)
were recorded on a ZAB-HS mass spectrometer using ESI (electrospray ionization)
model. Ultraviolet spectrum (UV) was determined by Shimadzu UV1800 UV-Vis
spectrophotometer. Infrared spectrum (IR) was obtained from Shimadzu Infinity-1
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
infrared spectrometer. The purity of the compounds was checked by Shimadzu
LC-20A high performance liquid chromatograph. All reagents were reagent grade and
used directly as obtained commercially.
General method for synthesis of 4-hydroxy-fluochalcones (2a-2c)
4-hydroxyacetophenone (1.36 g, 0.01 mol) and fluo-benzaldehyde (0.01 mol) were
mixed in ethanol (20 mL) in a three-necked flask placed in an ice bath. Then sodium
hydroxide solution (10 mL, 10%) was added drop-wise into it with stirring for 30 min.
The mixing was continued for 24 h at room temperature. The mixture was kept in a
refrigerator overnight when it became quite thick. Then it was diluted with ice-cold
distilled water (30 mL), filtered, washed with cold water, dried in air and re-crystallized
from rectified methanol.
(E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (2a)
Light white powder solid (1.961 g, 81%); mp: 155-156 ; 1H NMR (500 MHz, DMSO):
δ=6.910-6.927 (m, 2H), 7.304-7.347 (m, 2H), 7.493-7.808 (m, 3H), 7.970 (d, J=16.0
Hz, 1H), 8.067-8.133 (m, 2H), 10.483 ppm (s, 1H); IR (KBr): ν=3147, 3026, 1651,
1608, 1573, 1440, 1342, 1286, 1219, 1167, 839, 761 cm-1; MS (ESI) m/z: 242 [M+H]+.
(E)-1-(3-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (2b)
Light white powder solid (2.008 g, 83%); mp: 142-143 ; 1H NMR (500 MHz, DMSO):
δ=6.905 (d, J=8.5 Hz, 2H), 7.254-7.498 (m, 2H), 7.514-7.847 (m, 3H), 7.984 (d,
J=15.5 Hz, 1H), 8.097 (d, J=8.5 Hz, 2H), 10.452 ppm (1H, s); IR (KBr): ν=3134, 3026,
1649, 1607, 1583, 1446, 1340, 1288, 1215, 1172, 839, 779 cm-1; MS (ESI) m/z: 242
[M+H]+.
(E)-1-(4-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (2c)
1
Bright yellow powder solid (2.057 g, 85%); mp: 192-193 ; H NMR (500 MHz,
DMSO): δ=6.898 (d, J=8.5 Hz, 2H), 7.280-7.316 (m, 2H), 7.680 (d, J=15.5 Hz, 1H),
7.885 (d, J=15.5 Hz, 1H), 7.941-7.969 (m, 2H), 8.076 (d, J=8.5 Hz, 2H), 10.424 ppm
(s,1H); IR (KBr): ν=3134, 3026, 1649, 1610, 1571, 1438, 1342, 1286, 1217, 1167, 823,
763 cm-1; MS (ESI) m/z: 242 [M+H]+.
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
General method for synthesis of 4-aminomethoxy- fluochalcones (3a-3l)
4-hydroxy-fluochalcones (0.242 g, 1 mmol) and potassium carbonate (0.414 g, 3
mmol) were mixed in acetone (25 mL) with continuous stirring at 56 in an oil bath
for 30 min, then 2-chloro-N-substituted ethanamine hydrochloride (2 mmol) and
sodium iodide (0.075 g, 0.5 mmol) were added into it. The mixture was refluxed
overnight，filtered and concentrated. The concentrate was extracted with CH2Cl2 (3 ×
30 mL). The CH2Cl2 phase was washed by saturated salt water (3 × 30 mL), dried
with sodium sulphate anhydrous, followed by concentrating in vacuum, then the
residue was purified with silica gel column chromatography (eluting with 60:1
dichloromethane/ methyl alcohol) to gain the product.
(E)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(2-fluorophenyl)prop-2-en-1-one
(3a)
Light yellow powder solids (234 mg, 75%); mp: 86-87 ℃; 1H NMR (500 MHz, CDCl3):
δ=2.417 (s, 6H), 2.844 (t, J=11.0 Hz, 2H), 4.195 (t, J=11.0 Hz, 2H), 6.994-7.023 (m,
2H), 7.111-7.151 (m, 1H), 7.179-7.211 (m, 1H), 7.352-7.675 (m, 3H), 7.888 (d, J=16.5,
1H), 8.023-8.046 ppm (m, 2H); IR (KBr): ν=2806, 2769, 1661, 1611, 1576, 1458,
1261, 1227, 1176, 1020, 760 cm-1; MS (ESI) m/z: 313 [M+H]+.
(E)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(3-fluorophenyl)prop-2-en-1-one
(3b)
1
White powder solids (250 mg, 80%); mp: 62-63 ℃; H NMR (500 MHz, CDCl3):
δ=2.791 (s, 6H), 3.306 (t, J=9.5 Hz, 2H), 4.507 (t, J=9.5 Hz, 2H), 7.010-7.028 (m, 2H),
7.094-7.134 (m, 1H), 7.336-7.422 (m, 3H), 7.518 (d, J=15.5 Hz, 1H), 7.753 (d, J=15.5
Hz, 1H), 8.029-8.058 ppm (m, 2H); IR (KBr): ν=2805, 2774, 1658, 1606, 1576, 1458,
1246, 1227, 1175, 1020, 730 cm-1; MS (ESI) m/z: 313 [M+H]+.
(E)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-fluorophenyl)prop-2-en-1-one
(3c)
1
White powder solids (244 mg, 78%); mp: 233-234 ℃; H NMR (500 MHz, CDCl3):
δ=2.385 (s, 6H), 2.803 (t, J=11.0 Hz, 2H), 4.176 (t, J=11.0 Hz, 2H), 7.000-7.018 (m,
2H), 7.092-7.127 (m, 2H), 7.475 (d, J=16.0 Hz, 1H), 7.621-7.650 (m, 2H), 7.766 (d,
J=15.5 Hz, 1H), 8.020-8.043 ppm (m, 2H); IR (KBr): ν=2805, 2774, 2359, 1658, 1595,
This article is protected by copyright. All rights reserved.