Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.05.132

A series of 2-phenoxy-indan-1-one derivatives have been designed, synthesized, and tested as acetylcholinesterase inhibitors. The most potent compound exhibited high AChE inhibitory activity (IC₅₀ = 50 nM), and the molecular docking study indicated that it was nicely accommodated by AChE.

Full text of DOI:10.1016/j.bmcl.2005.05.132

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3834–3837
Design, synthesis, and evaluation of 2-phenoxy-indan-1-one
derivatives as acetylcholinesterase inhibitors
Rong Sheng,a Xiao Lin,a Jingya Li,b Yanke Jiang,c Zhicai Shangc and Yongzhou Hua,*
aZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hubin Campus, Hangzhou 310031,China
bThe National Center for Drug Screening, Shanghai 201203, China
cDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China
Received 7 May 2005; revised 30 May 2005; accepted 31 May 2005
Available online 1 July 2005
Abstract—A series of 2-phenoxy-indan-1-one derivatives have been designed, synthesized, and tested as acetylcholinesterase inhib-
itors. The most potent compound exhibited high AChE inhibitory activity (IC50 = 50 nM), and the molecular docking study indi-
cated that it was nicely accommodated by AChE.
Ó 2005 Elsevier Ltd. All rights reserved.
AlzheimerÕs disease (AD) is one of the most severe
health problems of the aged. Acetylcholinesterase
(AChE) inhibitors are the first and the most developed
group of drugs approved for AD symptomatic treat-
ment, such as tacrine, donepezil, rivastigmine, huper-
zine, and galanthamine. Among them, donepezil (1)
and rivastigmine (2) exhibit excellent effects in the early
to moderate stages of AD patients with few side effects.1
The crystallographic structure of donepezil–TcAChE
complex reveals that the dimethoxy-indanone and ben-
zylpiperidine moieties of donepezil interact with the
peripheral and central binding site of AChE separately.2
Rivastigmine was presumed as central site binding
inhibitor.3 Recently, it has been pointed out that AChE
may be involved in several noncatalytic actions4 such as
accelerating b-amyloid peptide deposition and promot-
ing the formation of b-amyloid fibril.5 It has been spec-
ulated that the peripheral binding site may be
responsible for this aggregation-promoting action of
AChE.6 Therefore, molecules that are able to interact
with both central and peripheral binding sites may pre-
vent the catalytic and noncatalytic actions of AChE.
Following this reasoning, 5,6-dimethoxy-indan-1-one
from donepezil and dialkyl-benzylamine from rivastig-
mine were chosen as the two pharmacophoric moieties
to interact with the two binding sites of AChE separate-
ly, and they were linked with oxygen. With the changing
of the position (para or meta) and the sort of aminoalkyl
group on the benzene ring, a series of 2-phenoxy-indan-
1-one derivatives 3a–x were designed, synthesized, and
tested for their AChE inhibitory activity (Fig. 1).
Target compounds 3a–x were synthesized as shown in
Scheme 1. Reaction of 3-(or 4-)(1-chloro-ethyl)anisole
4 with a secondary amine (dimethylamine, diethylamine,
pyrrolidine, and so on) provided 5a–l, followed by O-de-
methylation with 47% HBr to give phenols 6a–l.7 Other
phenols, 8a–l, could be prepared by reductive amination
of 3-(or 4-)hydroxyl benzaldehyde 7 with the corre-
sponding secondary amine and NaBH4.8 Reaction of
5,6-dimethoxy-indan-1-one 9 with CuBr2 in refluxing
ethyl acetate yielded 2-bromo-5,6-dimethoxy-indan-1-
one, 10. Finally, the final products 3a–x were achieved
by refluxing phenols 6a–l or 8a–l with 10 in acetone ni-
trile in the presence of K2CO3.
To determine AChE and BChE inhibitory activities,
compounds 3a–x were measured in vitro according to
the modified Ellman method using rat cortex homoge-
nate (AChE) and rat serum (BChE).9
As shown in Table 1, most of the compounds showed
high activity of AChE inhibition, while all the com-
pounds were almost inactive against BChE. The activity
of AChE inhibition was influenced by the position and
the sort of aminoalkyl group on benzene ring. In the tri-
al, the para-position substituted compounds (i.e., 3g, k,
o) were more potent than the meta-position substituted
compounds (i.e., 3e, i, m), and compounds having mor-
Keywords: 2-Phenoxy-indan-1-one derivatives; Synthesis; Acetylcho-
linesterase inhibitors.
*
Corresponding author. Tel.: +86 571 87217210; fax: +86 571
87217412; e-mail: huyz@zjuem.zju.edu.cn
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.132

R. Sheng et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3834–3837
3835
Figure 1. Structures of donepezil 1, rivastigmine 2, and 2-phenoxy-indan-1-one derivatives 3a–x.
Scheme 1. Synthesis of 2-phenoxy-indan-1-one derivatives 3a–x.
pholine (i.e., 3q, r) and piperazine group (i.e., 3w, x)
showed less activity than those having other aminoalkyl
groups (i.e., 3a, b, g, h). We also found that the change
of R1 from H (i.e., 3a, c, m, o) to CH3 (i.e., 3b, d, n, p)
contributed little toward the AChE inhibitory activity.
functional groups: the phenyl and oxygen of indan-1-
one moiety, the phenyl of phenoxy group, and the pyr-
rolidine nitrogen. Near the bottom of the gorge, the
charged nitrogen of pyrrolidine makes a cation–p inter-
action with the pyrrole ring of Trp84, with the distance
˚
of 4.7 A. In the middle of the gorge, one face of the
phenyl ring of the phenoxy group displays classic paral-
The high AChE inhibitory activity of compound 3k
prompted us to perform molecular docking study to
understand the ligand–protein interactions in detail.
Compound 3k is a long chain molecule and we supposed
that its binding mode with AChE shares some of fea-
tures of donepezil–AChE complexes. Therefore, the
crystallographic structure of AChE–donepezil complex-
es was selected from PDB, and the Flexidock program
in SYBYL6.8 software was used for the docking study.
The most stable docking model was selected according
to the best scored conformation predicted by the Flexi-
dock scoring function.
lel p–p stacking with the phenyl ring of Tyr334, with the
˚
ring-to-ring distance being 4.83 A. At the top of the
gorge, the phenyl ring of indan-1-one stacks against
the indole of Trp279 through p–p interaction with the
˚
distance of 3.61 A, and the oxygen of indan-1-one
makes a hydrogen bond with the nitrogen of the
˚
Phe288; the distance is 3.17 A.
In summary, a series of 2-phenoxy-indan-1-one deriva-
tives were designed, synthesized, and evaluated as AChE
inhibitors.10 Structure–activity studies showed that the
AChE inhibitory activity of compounds was influenced
by the position and the type of the aminoalkyl group
on the benzene ring. The modeling study of the most
As seen in Figure 2, compound 3k interacts principally
along the active-site gorge of AChE through four major

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R. Sheng et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3834–3837
Table 1. Physical properties and ChE inhibition activity of 2-phenoxy-indan-1-one derivatives 3a–x
Compound
Structure
Position of aminoalkyl R1
group
Melting point (°C) IC50 for AChE (lM)a IC50 for BChE (lM)b
Donepezil
Rivastigmine
Huperzine A
0.016
1.82
0.053
1.10
0.82
0.21
0.15
2.28
1.36
0.10
0.22
2.66
1.96
0.050
0.14
3.18
3.58
0.15
0.13
7.6
0.35
56.2
207
3a
3b
3c
3d
3e
3f
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
H
96–98
CH3 92–94
288
1980
1370
190
H
CH3 107–109
112–114
H
CH3 94–96
98–100
199
251
3g
3h
3i
H
CH3 100–102
123–124
234
H
99–101
CH3 105–107
116–118
CH3 106–108
127–129
CH3 115–117
136–138
CH3 120–122
168–170
CH3 138–140
155–157
CH3 129–131
118–120
CH3 134–136
100–102
CH3 88–90
39.5
212
84.3
130
55.5
3j
3k
3l
H
3m
3n
3o
3p
3q
3r
3s
3t
H
158
262
176
219
247
384
346
209
252
347
393
H
H
14.6
22.1
1.30
H
3.14
6.41
3u
3v
3w
3x
H
17.6
H
1.42
2.98
a Assay performed by the modified Ellman method9 using rat cortex homogenate. Values are means of three different experiments.
b Assay performed using rat serum.
potent compound, 3k, indicated that it was nicely accom-
modated by AChE. Further studies on this series of deriv-
atives are in progress and will be reported in due course.
Acknowledgments
This work was supported by the Natural Science Foun-
dation of Zhejiang province of China (z303835).
References and notes
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Figure 2. Docking model of 3k within the AChE gorge.

R. Sheng et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3834–3837
3837
CDCl3) d: 7.23–7.27 (m, 3H), 6.98 (d, 2H, J = 8.0 Hz),
6.85 (s, 1H), 5.00 (dd, 1H,J = 7.8, and 3.6 Hz), 3.97 (s,
3H), 3.92 (s, 3H), 3.56–3.63 (m, 3H), 3.02 (dd, 1H,
J = 16.8 and 3.6 Hz), 2.49 (m, 4H), 1.78 (m, 4H); 13C
NMR (400 MHz, CDCl3) d: 200.1, 156.9, 156.4, 149.8,
146.19, 132.4, 130.0, 127.3, 115.3, 107.4, 104.7, 77.9, 59.9,
56.3, 56.1, 54.0, 34.0, 23.3; IR (KBr) m (cmÀ1): 3083, 2962,
1703, 1604, 1589, 1453, 1270, 820; EI-MS MS (m/z): 367
(M+), 297, 191 (100), 107; Anal. Calcd for C22H25NO4: C,
71.91; H, 6.86; N, 3.81. Found: C, 71.56; H, 6.79; N, 3.76.