Structure–activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors

Article abstract of DOI:10.1080/14756366.2017.1399885

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a–4c and 7a–7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure–activity relat

Full text of DOI:10.1080/14756366.2017.1399885

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Structure–activity relationship investigation
of benzamide and picolinamide derivatives
containing dimethylamine side chain as
acetylcholinesterase inhibitors
Xiao-hui Gao, Lin-bo Liu, Hao-ran Liu, Jing-jing Tang, Lu Kang, Hongnian Wu,
Peiwu Cui & Jianye Yan
To cite this article: Xiao-hui Gao, Lin-bo Liu, Hao-ran Liu, Jing-jing Tang, Lu Kang, Hongnian
Wu, Peiwu Cui & Jianye Yan (2018) Structure–activity relationship investigation of benzamide
and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase
inhibitors, Journal of Enzyme Inhibition and Medicinal Chemistry, 33:1, 110-114, DOI:
10.1080/14756366.2017.1399885
To link to this article: https://doi.org/10.1080/14756366.2017.1399885
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Date: 22 December 2017, At: 01:51

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2017
VOL. 33, NO. 1, 110–114
https://doi.org/10.1080/14756366.2017.1399885
SHORT COMMUNICATION
Structure–activity relationship investigation of benzamide and picolinamide
derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors
a
b
b
b
b
c
c
c
Xiao-hui Gao , Lin-bo Liu , Hao-ran Liu , Jing-jing Tang , Lu Kang , Hongnian Wu , Peiwu Cui and Jianye Yan
a
Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy,
b
Changsha Medical University, Changsha, China; College of Chemistry and Chemical Engineering, Hu’nan University, Changsha, China;
c
College of Pharmacy, Hu’nan University of Chinese Medicine, Changsha, China
ABSTRACT
ARTICLE HISTORY
A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a–4c and
Received 10 August 2017
Revised 27 October 2017
Accepted 28 October 2017
7
a–7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)
inhibitory activity in vitro. Structure–activity relationship investigation revealed that the substituted position
of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and
BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that
of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity
KEYWORDS
Cholinesterase inhibitors;
benzamide; picolinamide;
structure–activity relation-
ship; Alzheimer's disease
(IC50: 2.49 ± 0.19 lM) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic
study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking
study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.
1
7
Introduction
metabotropic glutamate receptor 5 antagonists , but few investi-
gations on the bioactivity of them in inhibiting AChE or BChE
Alzheimer’s disease (AD), as a chronic and progressive neurodege-
nerative disorder characterised by memory loss, language impair-
ment and intellectual ability degression, is one of most common
diseases in the elderly population . Although the precise aeti-
ology of AD is not elucidated enough, AChE inhibitors remain the
primary drugs for the therapy to increase acetylcholine level in
18
were reported . In order to study the possible inhibition profile
and mechanism of new synthesised compounds, enzyme kinetic
experiments and molecular docking studies were performed.
1
–3
Materials and methods
4
,5
brain to meliorate the symptom
.
In recent decades, many natural products or their derivatives Chemistry
were discovered as new potential remedy for the treatment of
All chemicals or reagents were of analytical reagent grade without
further purification. The purity of compounds was checked by
Shimadzu LC-20 A high-performance liquid chromatography. The
melting points were measured on a WRS-lA melting point
detector. Infrared spectra were obtained from Shimadzu Infinity-1
infrared spectrometer. H NMR spectra were obtained from a
3
Bruker 400 MHz NMR spectra instrument in CDCl with TMS as the
internal reference. Mass spectra were obtained from Finnigan LCQ
Advantage MAX by electrospray ionisation (ESI-MS).
6
–9
AD . Followed by these investigations, a series of natural prod-
ucts derivatives were synthesised and evaluated for AChE inhibi-
tory activity in our laboratory. Among them, Mannich base
derivatives of Flavokawain B with chalcone structure were found
1
0
better AChE inhibitory activity than other compounds .
Afterwards, a series of chalcone nitrogen-containing derivatives
1
1
1–13
were synthesised and revealed potent AChE inhibitory activity
.
All results suggested that two aromatic rings with a spacer were
possible privilege structures for the design of AChE inhibitors.
Here, we intent to explore whether the a,b-unsaturated car-
bonyl group linked two benzene rings in chalcone structure can
be replaced by other structural units? And the substituted position
General procedure for the synthesis of 3a–3c
of nitrogen-containing side chain can influence the inhibition Benzoyl chloride (compound 2) was synthesised from benzamide
activity against AChE? Thus, a series of benzamide and picolina- (compound 1, 5 mmol) with excess oxalyl chloride (2.55 ml,
mide derivatives were designed, synthesised and evaluated the 30 mmol) in CH Cl (40 ml) containing N,N-dimethylformamide
2 2
biological activity of inhibiting AChE (Figure 1). These derivatives (DMF) as a catalytist. The mixture was refluxed for about 2 h until
are similar to chalcone derivatives in our previous investigations. the disappearance of the benzoyl acid monitoring by TLC, and then,
In fact, recently, a lot of benzamide and picolinamide derivatives the mixture was cooled to room temperature. The redundant oxalyl
1
4
were investigated as anticancer agents , DNA minor groove chloride was evaporated under vacuum. The crude benzoyl chloride
1
5
16
binders , 11 b-hydroxysteroid dehydrogenase inhibitos
or was used in the following reaction without further purification.
CONTACT Hao-ran Liu
26.com College of Pharmacy, Hu’nan University of Chinese Medicine, Changsha, China
Supplemental data for this article can be accessed here.
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
pharmaliu@126.com
College of Chemistry and Chemical Engineering, Hu’nan University, Changsha, China; Jianye Yan yanjianye201@
1
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri-
bution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
111
The benzoyl chloride was dissolved in acetonitrile (20 ml) and (2-aminophenol, 3- aminophenol and 4-aminophenol) (5.5 mmol,
then para-aminophenol, meta-aminophenol or ortho-aminophenol 1.1 equiv) were added to the reaction solution, respectively. The
dissolving in toluene (1 ml, 11 mmol) was drop-wise added to the reaction mixture was stirred at room temperature for 10–12 h
until compound 5a, 5b or 5c disappeared. Then, the reaction
mixture was filtered and the toluene was evaporated under
reduced pressure. The residue was dissolved in 10% NaOH and
filtered, and then, 15% HCl was added to adjust pH of the solu-
tion to 3–4, followed by the production of precipitation. The
desired products phenylcinnamide (compounds 6a–6i) were
gained from the solution by filtration with a good yield of
acetonitrile solution in an ice bath, respectively. The mixture was
refluxed for 6–10 h until benzoyl chloride disappeared. After the
solvent was removed under reduced pressure, the crude product
was added into 30% sodium hydroxide solution and filtered, 10%
HCl was applied to adjust pH of the solution to 3–4, followed by
the production of the precipitation. Then light grey solid com-
pound 3a, 3b and 3c were gained with yield of 80–90%.
70 ꢀ 75%.
General method for synthesis of 4a–4c
General procedure for the synthesis of 7a–7i
Compound 4a–4c was synthesised from compound 3a–3c
Compounds 7a–7i were synthesised from compound 6a–6i
(0.3208 g, 1.5 mmol) and 2-dimethylaminoethyl chloride hydro-
(
(
1.5 mmol) and 2-dimethylaminoethyl chloride hydrochloride
4.5 mmol) with the general procedure and purified using silica-gel
chloride (0.6729 g, 4.5 mmol) and purified using silica-gel column
chromatography with methanol/dichloromethane (1:5 5 ꢀ 70, v/v)
as elution.
Spectrum data of compounds 4a–4c for the characterisation
are outlined in Supplement data.
column chromatography with methanol/dichloromethane as elu-
tion to gain the desired products.
Spectrum data of compounds 7a–7i for the characterisation are
outlined in Supplement data.
General procedure for the synthesis of 6a–6i
AChE and BChE inhibition assay
Hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide (DCC)
was added into an anhydrous toluene solution (15 ml) containing
compound 5a, 5b or 5c (5 mmol, 1.0 equiv) at 0 C, and the
AChE/BChE activity assays were carried out by Ellman method
with slight modification . Each compound was dissolved in
19
ꢁ
Tween 80 and diluted with water to various concentrations imme-
diately before use. The assay solution which contained 40 lL
AChE/BChE, 100 lL acetylthiocholine iodide/S-butyrylthiocholine
iodide, 2.76 ml Na HPO /NaH PO buffer (pH 8.0, 0.1 M), and
mixture was stirred for 45 min. Then, a series of aminophenol
2
4
2
4
1
00 lL tested compound solution with different concentrations
ꢁ
were incubated at 30 C for 25 min. Then, the reaction was termi-
nated with 100 lL 20% sodium dodecylsulphate (SDS), then 100 lL
0
1
0 mM 5, 5 -Dithiobis-(2-nitrobenzamide) (DTNB) as chromogenic
agent was added into the mixture. The absorbance of each assay
mixture was measured at 412 nm by UV spectroscopy, which
showed a linear relationship with the activity of AChE/BChE. The
IC50 values were calculated by Bliss method and expressed as
Mean ± SD of the replicates.
Figure 1. Comparison of chalcone derivatives and amide derivatives with dietha-
nolamine side chain.
ꢁ
Scheme 1. Synthesis of benzamide derivatives. Reagents and conditions: (i) (COCl)
2
, DCM, reflux;(ii) aminophenol, TEA, acetonitrile, 60 C; (iii) (CH
)
3 2
2 2 2 2 3
N(CH ) Cl , K CO ,
NaI, acetone, reflux.
3 2 2 2 2 2 3
Scheme 2. Synthesis of picolinamide amide derivatives. Reagents and conditions: (iv) aminophenol, DCC, HOBT, toluene, RT; (v) (CH ) N(CH ) Cl , K CO , NaI, acetone,
reflux.

1
12
X. GAO ET AL.
Table 1. Cholinesterase inhibitory activity and log p values of benzamide and picolinamide derivatives.
a
IC50 (lM) ± SD
b
c
Compound
Structure
AChE
BChE
Selectivity
7.84
Log p
1
7
8.22 ± 1.16
142.94 ± 5.56
1.12
O
O
O
O
N
N
4a
N
H
5.79 ± 4.13
20.91 ± 1.61
17.96 ± 1.00
0.276
1.18
1.23
4
4
b
c
N
H
>500
<0.0359
O
N
H
O
N
2
.49 ± 0.19
247.50 ± 7.54
99.4
1.26
O
O
O
O
N
N
7
a
N
H
N
N
3
8.45 ± 2.19
48.55 ± 2.23
44.58 ± 1.16
1.26
1.31
1.37
7
b
c
N
H
>500
<0.0892
O
7
N
H
N
O
N
5
.76 ± 0.41
246.51 ± 1.85
42.80
1.33
O
O
O
O
N
N
7
d
N
H
N
N
1
7
3.25 ± 1.73
5.79 ± 0.84
22.15 ± 1.01
33.41 ± 1.37
1.67
1.37
1.42
7
e
f
N
H
0.441
O
7
N
H
O
N
N
4
.68 ± 0.30
114.36 ± 7.73
24.4
1.14
O
O
O
N
7
g
N
H
N
7
2.98 ± 3.03
35.91 ± 0.94
27.43 ± 2.31
0.492
1.37
1.18
N
7
h
i
N
H
O
N
>500
<0.0549
O
7
N
H
N
O
N
Rivastigmine
10.5 ± 0.86
0.26 ± 0.08
0.0247
–
a
IC50 values of compounds represent the concentration that caused 50% enzyme activity loss.
b
Selectivity for AChE is defined as IC50 (BChE)/IC50 (AChE).
c
The partition coefficients of in the octanol/buffer solution at pH 7.4 were determined by the classical shake-flask method.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
113
Kinetic studies
derivatives against AChE was ranked by the following order: Para-
substituted dimethylamine > meta-substituted dimethylami-
Kinetic characterisation of AChE/BChE was performed by
modified method previous reported . Compound 7a was pre-
incubated with the enzyme at 30 C, then 100 mL acetylthiocholine
iodide including five concentrations was added into the assay mix-
ture and kinetic characterisation was conducted spectrometrically
at 412 nm. Additionally, the parallel control experiment was made
without compound 7a in the mixture.
a
ne > ortho-substituted dimethylamine. However, interestingly, the
inhibitory potency of almost compounds against BChE was ranked
by the order: ortho-substituted dimethylamine > meta-substituted
dimethylamine > para-substituted dimethylamine. Among them,
compound 7a with IC50 values of 2.49 ± 0.19 mM, showed more
potent than Rivastigmine (IC50 ¼ 10.54 ± 0.26 mM) In addition com-
pound 7a revealed the highest selectivity for AChE (Ratio: 99.40).
Log p values of new synthesised compounds were ranged from
2
0
ꢁ
1
.12 to 1.42, which indicated that all the compounds are possible
Molecular docking
2
4
sufficiently lipophilic to pass the blood brain barrier (BBB) in vivo .
Compound 7a was selected for kinetic studies. The linear
Molecular modelling was performed by Molecular Operating
Environment (MOE) software package. The X-ray crystallographic Lineweaver–Burk equation of the Michaelis–Menten was applied
2
1
structures of AChE (PDB code: 1EVE) and BChE (PDB code: to evaluate the inhibition profile. The analysis of the steady-state
2
2
1
P0I) were gained from protein data bank. 3 D structure of com- inhibition data of compound 7a was shown in Supplement data:
pound 7a was established, and docked into the active site of the Table 2. According to the analysis, Km but not Vmax increased with
protein after energy being minimised. The dock scoring in MOE the increasing concentration of compound 7a, which presented a
software was done by ASE scoring function.
i
mixed-type inhibition. The competitive inhibition constant (K ) and
the non-competitive constant (K ) are 4.69 lM and 3.28 lM,
i’
respectively.
Log p measurement
Molecular docking was conducted for compound to study the
possible inhibition mode with AChE or BChE. 3 D structure of com-
pound 7a was established by virtue of the builder interface of
MOE program and docked into the active site of the protein after
Octanol–water partition coefficients of compounds 4a–4c, 7a~7i
2
3
were measured by the shake flask method described previously .
The aqueous phase was replaced by phosphate buffer solution (PBS,
pH ¼ 7.4). The assay mixture containing tested compounds was
ꢃ1
energy being minimised (For AChE, ꢃ22.7507 kcal.mol ; For BChE,
ꢃ1
ꢁ
ꢃ16.6987 kcal.mol ). As shown in Supplement data, compound
shaken at 37 C over night and then centrifuged at 2000 rpm for
7a
exhibited multiple points binding modes with AChE
2
0 min, followed by the analysis with HPLC. A C18 column
150 nm ꢂ 4.6 mm, 5 lm) was used with the mobile phase of metha-
nol-0.1% triethylamine (TEA) (85:15, v/v) at a flow rate of
(Supplement data: Figure 2 (A,B)). The binding points of compound
(
7a with AChE were Trp84(3.92 Å), Trp279(4.12 Å) and Tyr334(3.
ꢃ1
ꢁ
89 Å) (Supplement data: Table 3), while the binding points with
BChE was Tyr252(4.43 Å) (Supplement data: Figure 2(A,B); Table 3).
For both of them, the conformation of the side chain conformed
to the shape of the mid-gorge, but compound 7a could not com-
bine with Trp82 in BChE, which was an important amino acid in
catalysis domain. The results above were possible to partial
explain its potent and selective inhibition for AChE.
1
.0 ml.min
and the detection wavelength of 283 nm at 32 C.
Experiments were conducted in triplicate and log p values were
calculated.
Results and discussion
Chemistry
The synthetic routes of benzamide derivatives (compound 4a–4c)
and picolinamide derivatives (compound 7a–7i) are outlined in
Conclusions
Schemes 1 and 2. First, benzamide or picolinamide reacted with a In summary, a new series of benzamide and policnamide deriva-
series of amines (p-aminophenol, m-aminophenol, o-aminophenol) tives were designed, synthesised and evaluated for their effects on
in the presence of oxalyl chloride and TEA in dichloromethane to AChE and BChE. SAR investigation showed that all compounds
gain compounds 3a–3c, respectively. Then chloroethyldimethyl- with Para-substituted dimethylamine side chain had more potent
inhibition activity and selectivity against AChE compared with
Meta- or Ortho-substituted ones. In addition, the inhibition
potency against AChE of picolinamide derivatives was more potent
than that of benzamide derivatives. Based on these results earlier,
it seems that an important rule is discovered and possibly applied
in the future: we can alter the substituted position of nitrogen-
containing side chain to gain selective and/or potent AChE inhibi-
tors conveniently, which can be helpful for the development of
potential AChE inhibitors for the treatment of AD.
amine in acetone was applied to generate compounds 4a–4c in
the presence of K CO and NaI. The final products were purified
2
3
1
by silica gel chromatography and characterised by H NMR, IR and
MS. The synthesis pathway of these two series compounds had a
little difference. Benzamide can react easily with oxalyl chloride
and gain benzoyl chloride with an excellent yield, but no perfect
products gained to synthesise picolinamide amides from picolina-
mide using this method, so another pathway was used to gener-
ate picolinamide amides with DCC, HOBT as catalysts.
Disclosure statement
Structure–effect relationship of new synthesised compounds on
the inhibition against AChE and BChE
The authors confirm that this article content has no conflict of
interest.
The half maximal inhibitory concentration (IC50 values) of new syn-
thesised compounds for AChE and BChE as well as the selectivity for
AChE were summarised in Table 1. It indicated that the alteration of
substituted position of dimethylamine significantly influenced the
activity and the selectivity of compounds. Among them, the inhibi-
tory potency and selectivity of benzamide and picolinamide amide
Funding
The present study was financial supported by “Natural science
foundation of Hu’nan province” (No. 2017JJ2050).

1
14
X. GAO ET AL.
References
13. Liu HR, Fan HQ, Gao XH, et al. Design, synthesis and
preliminary structure–activity relationship investigation of
nitrogen-containing chalcone derivatives as acetylcholin-
esterase and butyrylcholinesterase inhibitors: a further study
based on Flavokawain B Mannich base derivatives. J Enzyme
Inhib Med Chem 2015;17:1–10.
1
.
Kenichi O, Naoya O, Kengo I, et al. Effects of imaging modal-
ities, brain atlases and feature selection on prediction of
Alzheimer's disease. J Neurosci Methods 2015;256:168–83.
Anand R, Gill KD, Mahdi AA, et al. Therapeutics of
2
.
Alzheimer’s
Neuropharmacology 2014;76:27–50.
disease:
past,
present
and
future.
1
4. Mahdavi M, Mohseni Lavi M, Yekta R, et al. Evaluation of the
cytotoxic, apoptosis inducing activity and molecular docking
of spiroquinazolinone benzamide derivatives in MCF-7 breast
cancer cells. Chem Biol Interact 2016;260:232–42.
3
4
.
.
Klafki H, Staufenbiel M, Kornhuber J, et al. Therapeutic
approaches to Alzheimer’s disease. Brain 2006; 129:2840–55.
_
Gul c¸ in I, Abbasova M, Taslimi P, et al. Synthesis and biological
1
1
5. Khan GS, Pilkington LI, Barker D. Synthesis and biological
activity of benzamide DNA minor groove binders. Bioorg
Med Chem Lett 2016;26:804–8.
6. Ryu JH, Kim S, Han HY, et al. Synthesis and biological evalu-
ation of picolinamides as potent inhibitors of 11b-hydroxys-
teroid dehydrogenase type 1 (11b-HSD1). Bioorg Med Chem
Lett 2015;25:695–700.
evaluation of aminomethyl and alkoxymethyl derivatives as
carbonic anhydrase, acetylcholinesterase and butyrylcholines-
terase inhibitors. J Enzyme Inhib Med Chem 2017;32:1174–82.
Akıncıo gꢀ lu A, Kocaman E, Akıncıo gꢀ lu H, et al. The synthesis
of novel sulfamides derived from b-benzylphenethylamines
as acetylcholinesterase, butyrylcholinesterase and carbonic
anhydrase enzymes inhibitors. Bioorg Chem 2017;74:238–50.
Jiang YY, Gao HW, Turdu G. Traditional Chinese medicinal
herbs as potential AChE inhibitors for anti-Alzheimer's dis-
ease: a review. Bioorg Chem 2017;75:50–61.
Bayrak C, Taslimi P, G u€ l c¸ in I, et al. The first synthesis of 4-
phenylbutenone derivative bromophenols including natural
products and their inhibition profiles for carbonic anhydrase,
acetylcholinesterase and butyrylcholinesterase enzymes.
Bioorg Chem 2017;72:359–66.
5
.
1
1
7. Vu HN, Kim JY, Hassan AHE, et al. Synthesis and biological
evaluation of picolinamides and thiazole-2-carboxamides as
mGluR5 (metabotropic glutamate receptor 5) antagonists.
Bioorg Med Chem Lett 2016;26:140–4.
8. Peng DY, Sun Q, Zhu XL, et al. Design, synthesis, and bioe-
valuation of benzamides: novel acetylcholinesterase inhibi-
tors with multi-functions on butylcholinesterase, Ab
aggregation, and b-secretase. Bioorg Med Chem 2012;20:
6
7
.
.
6739–50.
8
.
.
Yang X, Qiang XM, Li Y, et al. Pyridoxine-resveratrol hybrids
Mannich base derivatives as novel dual inhibitors of AChE
and MAO-B with antioxidant and metal-chelating properties
for the treatment of Alzheimer’s disease. Bioorg Chem
1
9. Alpan AS, Parlar S, Carlino L, et al. Synthesis, biological activ-
ity and molecular modeling studies on 1H-benzimidazole
derivatives as acetylcholinesterase inhibitors. Bioorg Med
Chem 2013;21:4928–37.
2017;71:305–14.
2
2
2
0. Skrzypek A, Matysiak J, Niewiadomy A, et al. Synthesis and
biological evaluation of 1,3,4-thiadiazole analogues as novel
AChE and BuChE inhibitors. Eur J Med Chem 2013;62:311–9.
1. Bozkurt B, Coban G, Kaya GI, et al. Alkaloid profiling, anti-
cholinesterase activity and molecular modeling study of
Galanthus elwesii. S Afr J Bot 2017;113:119–27.
2. Aouani I, Sellami B, Lahbib K, et al. Efficient synthesis of
novel dialkyl-3-cyanopropylphosphate derivatives and evalu-
ation of their anticholinesterase activity. Bioorg Chem
2017;72:301–7.
9
Tommonaro G, Garc ꢁı a-Font N, Vitale RM, et al. Avarol deriva-
tives as competitive AChE inhibitors, non hepatotoxic and
neuroprotective agents for Alzheimer’s disease. Eur J Med
Chem 2016;122:326–38.
1
1
1
0. Liu HR, Huang XQ, Lou DH, et al. Synthesis and acetylcholin-
esterase inhibitory activity of Mannich base derivatives flavo-
kawain B. Bioorg Med Chem Lett 2014;24:4749–53.
1. Liu HR, Liu XJ, Fan HQ, et al. Design, synthesis and pharma-
cological evaluation of chalcone derivatives as acetylcholin-
esterase inhibitors. Bioorg Med Chem 2014;22:6124–33.
2. Liu HR, Zhou C, Fan HQ, et al. Novel potent and selective 23. Yu H, Li WM, Kan KKW, et al. The physicochemical properties
acetylcholinesterase inhibitors as potential drugs for the
treatment of Alzheimer’s disease: synthesis, pharmacological
evaluation, and molecular modeling of amino-alkyl-substi-
and the in vivo AChE inhibition of two potential anti-
Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.
J Pharm Biomed Anal 2008;46:75–81.
tuted fluoro-chalcones derivatives. Chem Biol Drug Des 24. Glave WR, Hansch CJ. Relationship between lipophilic char-
015;86:517–22. acter and anesthetic activity. J Pharm Sci 1972;61:589–91.
2