2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors: A study on the importance of modifications at the side chain on the activity

Article abstract of DOI:10.1016/j.bmc.2008.07.014

As a part of our project aimed at developing new agents of potential application in AD, a new series of 2-phenoxy-indan-1-one derivatives which possess alkylamine side chain were designed, synthesized, and evaluated for their inhibitory activity against AChE and BuChE. Most of the compounds were found to inhibit AChE in the nanomolar range. The optimum inhibitor 3g exhibited 34-fold increase in AChE inhibition than donepezil and displayed neuroprotective effect against H₂O₂-induced cell death.

Full text of DOI:10.1016/j.bmc.2008.07.014

Bioorganic & Medicinal Chemistry 16 (2008) 7646–7653
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors: A
study on the importance of modifications at the side chain on the activity
Yanhong Shen a,b, Rong Sheng a, Jing Zhang a, Qiaojun He a, Bo Yang a, Yongzhou Hu a,
*
a ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
b Department of Chemistry, Anyang Institute of Technology, Anyang 455000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of our project aimed at developing new agents of potential application in AD, a new series of 2-
phenoxy-indan-1-one derivatives which possess alkylamine side chain were designed, synthesized and
evaluated for their inhibitory activity against AChE and BuChE. Most of the compounds were found to
inhibit AChE in the nanomolar range. The optimum inhibitor 3g exhibited 34-fold increase in AChE inhi-
bition than donepezil and displayed neuroprotective effect against H2O2-induced cell death.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 May 2008
Revised 3 July 2008
Accepted 4 July 2008
Available online 10 July 2008
Keywords:
Acetylcholinesterase inhibitors
2-Phenoxy-indan-1-one derivatives
Alzheimer’s disease
Neuroprotective effect
1. Introduction
sons, the interest in AChE inhibitors has increased in the last few
years.
Alzheimer’s disease (AD), the most common cause of dementia
in elder, is a progressive neurodegenerative disorder characterized
by loss of memory and cognition. The so-called ‘cholinergic
hypothesis’ postulated that the cognitive decline experienced by
AD patients is due to an extensive loss of cholinergic neurons.1
To date, the enhancement of the central cholinergic function is
the mainly effective approach, by means of reversible acetylcholin-
esterase (AChE) inhibitors, such as tacrine, donepezil, galantamine,
and rivastigmine.2
Another theory about AD pathogenesis is ‘amyloid hypothesis’,
which states that the production and the deposition of b-amyloid
(Ab) in the form of fibrils lead to neuronal cell death and to the
clinical symptoms.3 Since AChE is able to promote the aggregation
of Ab into amyloid fibrils through the residues located in the
peripheral anionic site of the enzyme (PAS), AChE inhibitors able
to interact with PAS can prevent synthesis, deposition and aggrega-
tion of toxic Ab.4–6 The dual-binding inhibitors target simulta-
neously both the catalytic and the peripheral-binding sites not
only inhibited the hydrolysis of AChE toward ACh, but also pre-
vented proaggregating activity of AChE toward Ab. Furthermore,
some clinical studies showed that patients treated with cholines-
terase inhibitors did not show the widespread cortical atrophic
changes associated with AD, providing empirical evidence of neu-
roprotection by cholinesterase inhibitors.7–9 For these above rea-
In our previous work, we have designed and synthesized
some hybrids of donepezil and rivastigmine, by chosen 5,6-dime-
thoxy-indan-1-one and N,N-dialkyl-benzylamine as the two
pharmacophoric moieties.10 Among these compounds, compound
1 demonstrated the most potent AChE inhibitory activity. The
docking results showed that it could interact well with AChE
along the gorge. Nevertheless, near the bottom of the gorge,
the distance between the charged nitrogen of pyrrolidine in
compound 1 and the pyrrole ring of Trp84 is too long (4.7 Å)
to constitute close and efficient affinity. Thus we tried to make
some modifications in the linker between the benzene ring and
the tertiary amine and to study the effect of the changes on
the binding affinity and AChE inhibitory activity (Fig. 1).
Following this strategy, the length of the linker between the
benzene ring and the tertiary amine was increased up to 2–4 meth-
ylene units to identify the optimal distance (2a–m). On the other
hand, a carbonyl group was introduced within the linker chain
(3a–n), considering that it might have the chance to favorably
interact with some of the amino acid residues of the enzyme.
Moreover, the position of substituent on the benzene ring and
the nature of the tertiary amino groups were changed in order to
search for the correct orientation and the favorable tertiary amine
group. Twenty-seven target compounds were synthesized and
tested for their AChE inhibitory activities. To study further the bio-
logical profile of these compounds, their butyrylcholinesterase
(BuChE) inhibitory activity and the neuroprotective effect against
H2O2-induced cell death were also evaluated. Finally, to explore
* Corresponding author. Tel./fax: +86 571 88208460.
E-mail address: huyz@zju.edu.cn (Y. Hu).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.07.014

Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
7647
2-alkylamino-1-(4-hydroxyphenyl)ethanones 9a–d.15 Intermedi-
ates 9e–j could be readily prepared through Mannich reaction by
treatment of hydroxyacetophenones with paraformaldehyde and
secondary amines.16 Reaction of anisole with 4-chlorobutanoyl
chloride in the presence of AlCl3 provided 10, which reacted with
secondary amines to achieve 11, followed by O-demethylation
with 47% HBr in acetic acid to give intermediates 9k–n. Finally,
intermediates 6a–m and 9a–n were condensed with 2-bromo-
5,6-dimethoxy-indan-1-one 1217 in the presence of K2CO3 to give
the corresponding target products 2a–m and 3a–n, respectively.
O
O
H3CO
O
N
H3CO
H3CO
1
R1
R2
O
X N
H3CO
2a-m X=(CH2)n, n=2-4
3a-n X=CO(CH2)n, n=1-3
2.2. Biological activity and molecular modeling
R1
R2
N
N
=
N
The assay for AChE and BuChE inhibitory activity of synthesized
compounds was performed according to the modified method of
Ellman18,19 using rat cortex homogenate (AChE) and rat serum
(BuChE), with donepezil as the reference compound. The results
are reported in Table 1.
CH3
CH2CH3
CH2CH3
N
N
CH2CH3
Figure 1. Chemical structure of compound 1 and 2-phenoxy-indan-1-one deriva-
tives 2a–m and 3a–n.
From the IC50 values of compounds 2a–m, which possess 1–4
methylene units between the benzene ring and tertiary amino, it
appeared that variation of the chain length influenced AChE inhib-
itory activity obviously. In general, the compounds with a CH2CH2
(i.e. 2b and 2c) linker showed better inhibition than the molecules
with CH2CH2CH2 (i.e. 2g and 2k) or CH2CH2CH2CH2 (i.e. 2l and
2m) as the linker, which indicated that CH2CH2 as linker is favor-
able for the interaction between this series of compounds with
enzyme.
the possible binding conformation of synthesized compounds and
protein–ligand interaction mode, the docking study was performed
using the Flexidock program in SYBYL software.
2. Results and discussion
2.1. Chemistry
Compounds 3a–n, which possesses carbonyl group in the linker,
demonstrated similar or better inhibitory activity compared to
donepezil. Generally, the compounds with a COCH2CH2 linker
showed the most potent inhibitory activity in this series. Com-
pounds 3g11 and 3h possessed potent activity with IC50 of
0.78 nM and 1.85 nM, which were 34-fold and 14-fold more potent
than donepezil, respectively. When the linker was lengthened or
shortened, inhibition of AChE dropped.
The synthesis of target compounds 2a–m and 3a–n was
achieved following a convergent pathway strategy summarized
in Scheme 1. Treatment of 4-hydroxyalkylphenol 4a–c with SOCl2
in CH2Cl2 at room temperature for 1.5 h resulted in 5a–c11,12
,
which were then treated with the secondary amines to afford
intermediates 6a–m.13
For the synthesis of intermediates 9a–n, different routes were
followed. Reaction of 4-hydroxyacetophenone with PyHBr3 led to
2-bromo-1-(4-hydroxyphenyl)ethanone 814, which was then cou-
pled with various secondary amines at low temperature to afford
Comparing series 3a–n with 2a–m, it appeared that the intro-
duction of carbonyl group in the linker resulted in an obvious
enhancement of AChE inhibitory activity. For example, compound
HO
HO
a
HO
R1
N
b
OH
n
Cl
n
n
R2
4a-c
5a-c
6a-m
d
O
O
O
c
R1
R2
Br
N
CH3
HO
HO
HO
7a-b
8
9a-d
e
O
R1
R2
N
HO
9e-j
H3CO
HO
H3CO
b
f
R1
R2
R1
N
R2
Cl
N
O
O
O
10
O
11
9k-n
O
H3CO
H3CO
H3CO
H3CO
g
6a-m
9a-n
R1
O
Br
+
X N
R2
12
2a-m, 3a-n
Scheme 1. Synthesis of 2a–m and 3a–n. Reagent and conditions: (a) SOCl2, CH2Cl2, Et3N; (b) CH3CN, Et3N, reflux 7 h for pyrrolidine or piperidine, CH3CN, Et3N, sealed tube,
100 °C, 5 h for diethylamine or methylethylamine; (c) PyHBr3, THF, rt; (d) second amine, NaHCO3, CH3CN, 0–5 °C, 0.5 h; (e) (CHO)n, EtOH, concd HCl, reflux 6 h for pyrrolidine
or piperidine, (CHO)n, EtOH, concd HCl, sealed tube 90 °C, 5 h for diethylamine or methylethylamine; (f) CH3COOH, 47% HBr, reflux,11 h; (g) K2CO3, CH3CN, reflux, 0.5–3 h.

7648
Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
Table 1
Cholinesterase inhibitory activity and selectivity of prepared compoundsa
O
H3CO
H3CO
O
R1
R2
X N
Compound
X
Substituted position
IC50 AChE (nm)
IC50 BuChE (nm)
Selectivity for AChEb
R1
R2
N
2a
2b
2c
2d
2e
2f
CH2CH2
para
para
para
para
meta
meta
meta
meta
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
Methylethylamino
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
50.2 1.6
37.3 2.3
42.1 0.6
51.6 2.1
1550 20
1770 130
2090 21
710 18
5114 320
30,450 200
16,580 400
22,030 180
7002 270
15,380 280
11,100 480
8645 350
101.9
816.3
393.8
426.9
4.52
8.69
5.31
12.2
2g
2h
Methylethylamino
2i
2g
2k
CH2CH2CH2
para
para
para
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
640 51
209 4.6
277 19
2794 310
2337 18
3986 46
4.36
11.2
14.4
2l
2m
CH2CH2CH2CH2
COCH2
para
para
Pyrrolidine-1-yl
Diethylamino
415 20
481 32
3224 40
3256 310
7.76
6.77
3a
3b
3c
3d
para
para
para
para
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
364 4.3
240 3.2
280 14
31.6 1.6
1663 20
1722 460
2428 350
588 60
4.57
7.2
8.7
Methylethylamino
18.6
3e
3f
3g
3h
3i
COCH2CH2
para
para
para
para
meta
meta
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
Methylethylamino
Pyrrolidine-1-yl
Diethylamino
17.3 2.8
4.16 0.13
0.78 0.12
1.85 0.32
832 20
3239 410
6039 70
1520 260
4509 200
11,110 450
1519 35
187.2
1451.6
1948.7
2437
13.35
0.64
3j
2370 240
3k
3l
3m
3n
COCH2CH2CH2
para
para
para
para
Piperidine-1-yl
Pyrrolidine-1-yl
Diethylamino
529 40
62 2.5
40.6 3.6
37.6 1.8
8973 720
2930 190
37,650 690
26,870 430
16.96
47.2
927.3
714.6
Methylethylamino
Donepezil
26.8 1.5
3260 180
121
a
Data are means standard deviation of three independent experiments.
Selectivity for AChE is defined as IC50 (BuChE)/IC50 (AChE).
b
3g with COCH2CH2 as the linker showed higher potency
(IC50 = 0.78 nM) than compound 2k with CH2CH2CH2 as the linker
(IC50 = 277 nM).
On the other hand, the structure and position of alkylamine side
chain on the benzene ring in the tested compounds had also effect
on the inhibitory activity. Compounds with diethylamino group or
methylethylamino group showed more potent inhibitory activity
(i.e. 3d, 3g, and 3h) than those with other alkylamino groups (i.e.
3a and 3i). The para-position substituted compounds (i.e. 3f and
3g) were more active than the meta-position substituted com-
pounds (i.e. 3i and 3j).
All of the compounds were less potent in inhibiting BuChE than
AChE. Especially, the most potent AChE inhibitors 3g and 3h were
1948-fold and 2437-fold more active inhibiting AChE than BuChE,
respectively, being much more selective than donepezil.
The neuroprotective effect against H2O2-induced cell death was
determined using MTT reduction assay in PC12 cell system and
donepezil was as reference compound20 (Fig. 2). H2O2 (400
lM)
Figure 2. Neuroprotective effect of compound 3g against H2O2-induced cell death
in P12 cell system.
caused a significant decrease in cell viability (about 20.4%), but
the pretreatment of cells with increasing concentrations of
donepezil and compound 3g inhibited H2O2-induced neurotoxicity
and increased the cell viability. Both compound 3g and donepezil
showed almost the same neuroprotective effects at the higher con-
centration (0.1 and 0.5 lM).
To explore the possible binding conformation and protein–li-
gand interaction mode, a molecular modeling study of the opti-
mum compound 3g was performed using the Tripos FlexiDock
program.21 The Flexidock simulation indicated that the obtained
20 best-scoring ligand–AChE complex models have very similar
3D structures. Thus, only the lowest energy ligand–AChE complex
model was selected for further analyses on the ligand–AChE
interaction.

Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
7649
and uncorrected. 1H NMR and 13C NMR spectra were recorded on
a Brucker Advance DMX 400 MHz spectrometer with TMS as the
internal standard. Proton Chemical shifts are expressed in parts
per million (ppm) and coupling constants in Hz. Infrared spectra
were recorded on a JASCO FT/IR-4100 spectrophotometer. Elemen-
tal analyses were performed on a Flash EA 1112 elemental ana-
lyzer. Analytical TLC was carried out on Merck 0.2 mm precoated
silica-gel (60 F-254) aluminum sheets, with visualization by irradi-
ation with a UV lamp. Chromatographic separations were per-
formed on silica-gel 60 (230–400 mesh).
2-Bromo-5,6-dimethoxy-indan-1-one 12 and key intermediates
6a–m and 9a–n were synthesized according to literature methods.
4.2. General procedure for the synthesis of 2a–m
Under N2 atmosphere, to a solution of 6a–m (0.32 mmol) and
K2CO3 (0.38 mmol) in dry CH3CN (3 mL) under reflux, was slowly
added
a solution of 2-bromo-5,6-dimethoxy-indan-1-one 12
(0.38 mmol) in CH3CN (3 mL). The mixture was refluxed for 2 h.
Then, it was cooled to room temperature and the solvent was re-
moved under vacuum pressure. EtOAc (10 mL) and 2 N HCl
(10 mL) was added to the residue and the aqueous solution was
neutralized using 28% NH4OH and extracted with CH2Cl2 (3ꢀ
10 mL). The combined organic layer was washed successively with
water and brine, dried over anhydrous Na2SO4, evaporated in vac-
uum. The residue was purified by a silica-gel column chromatogra-
phy (PE/EtOAc/TEA = 100:100:1).
Figure 3. Interaction between ligand 3g and AChE.
As it can be seen in Figure 3, there are some important interac-
tions between ligand and AChE. The indanone ring occupies a posi-
tion at the peripheral site and remains stacked onto the aromatic
ring of Trp279 through a classical p–p stacking interaction, mean-
while, the carbonyl group of indanone moiety form a direct hydro-
4.2.1. 5,6-Dimethoxy-2-(4-(2-(piperidin-1-yl)ethyl)phenoxy)-
indan-1-one (2a)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(2-(piperidin-1-yl)ethyl)phenol (65.6 mg,
0.32 mmol) produced compound 2a (90.4 mg, 71.5%) as white solid
(mp 151–153 °C); MS (ESI): 396 (M+1+)+; 1HNMR (d, CDCl3): 7.25
(s, 1H, H-7), 7.13 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.96 (d, 2H, H-30,
H-50, J = 8.4 Hz), 6.85 (s, 1H, H-4), 5.00–5.02 (dd, 1H, H-2, J = 7.6,
4.4 Hz), 3.98 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.57–3.63 (dd, 1H,
H-3, J = 16.8, 7.6 Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 4.4 Hz),
2.80 (t, 2H, CH2CH2N, J = 6 Hz), 2.54–2.67 (m, 6H, PhCH2CH2, piper-
idine-CH2, H-200 and H-600), 1.66–1.69 (m, 4H, H-300, H-500), 1.49 (s,
gen-bond contact with OH group of Tyr121. Half up the gorge, the
phenyl ring can establish a p–p interaction with the aromatic ring
of Phe331. Noteworthy, the carbonyl group in the linker form the
direct hydrogen bonds with OH group in Ser200. As expected, pro-
tonated nitrogen of the ligand is able to reach the bottom of the
gorge and make a
Trp84, with a closer distance (4.1 Å) than the calculated distance
between the compound and AChE (4.7 Å). So, when the
p-cation interaction with the pyrrole ring of
1
COCH2CH2 linker was introduced into the ligand, the compound
3g assumed a slightly different orientation with respect to com-
pound 1. The carbonyl group in the linker formed a hydrogen bond
and charged nitrogen established more favorable interaction with
the AChE. And the subtle balance of different force makes the mol-
ecule bind well in the gorge and suggests the reason for its high
inhibitory potency of AChE.
2H, H-400); IR (KBr), (cmꢁ1): 3018, 2930, 1701, 1587, 1513, 1358,
m
1269, 1120, 920, 861, 827, 689. Anal. Calcd for C24H29NO4: C,
72.89; H, 7.39; N, 3.54. Found: C, 72.68; H, 7.34; N, 3.58.
4.2.2. 5,6-Dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-
indan-1-one (2b)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(2-(pyrrolidin-1-yl)ethyl)phenol (61.1 mg,
0.32 mmol) produced compound 2b (82.6 mg, 67.8%) as white solid
(mp 113–115 °C); MS (ESI): 382 (M+1+)+; 1HNMR (d, CDCl3): 7.27
(s, 1H, H-7), 7.18 (d, 2H, H-20, H-60, J = 8.4 Hz), 7.00 (d, 2H, H-30,
H-50, J = 8.4 Hz), 6.89 (s, 1H, H-4), 5.02–5.05 (dd, 1H, H-2, J = 7.6,
4.4 Hz), 4.01 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.60–3.66 (dd, 1H,
H-3, J = 16.8, 7.6 Hz), 3.06–3.11 (dd, 1H, H-3, J = 16.8, 4.4 Hz),
2.84 (t, 2H, CH2CH2N, J = 6 Hz), 2.74–2.78 (t, 2H, PhCH2CH2,
J = 6 Hz), 2.67 (m, 4H, pyrrolidine-CH2, H-200, H-600), 1.87 (m, 4H,
3. Conclusions
In summary, a number of 2-phenoxy-indan-1-one derivatives
were designed, synthesized and tested for their biological activity,
some of them exhibited more potent AChE inhibition activity and
selectivity than donepezil. The preliminary structure–activity rela-
tionships and molecular modeling study provided further insight
into interactions between the enzyme and its ligand. The neuro-
protective effect against H2O2-induced cell death was revealed
using MTT reduction assay. As a promising AChE inhibitor with
outstanding potential, in vivo studies for 3g is in progress.
H-300, H-500); IR (KBr),
m
(cmꢁ1): 3008, 2936, 2786, 1711, 1605,
1504, 1461, 1234, 1081, 1012, 824. Anal. Calcd for C23H27NO4: C,
72.42; H, 7.13; N, 3.67. Found: C, 72.27; H, 7.16; N, 3.60.
4. Experimental
4.1. Chemistry
4.2.3. 2-(4-(2-(Diethylamino)ethyl)phenoxy)-5,6-dimethoxy-
indan-1-one (2c)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(2-(diethylamino)ethyl)phenol (61.8 mg,
0.32 mmol) produced compound 2c (67.4 mg, 55.1%) as white solid
(mp 84–86 °C); MS (ESI): 384 (M+1+)+; 1HNMR (d, CDCl3): 7.24 (s,
Reagents and solvents were purchased from common commer-
cial suppliers and were used without further purification. Melting
points were obtained on a B-540 Buchi melting-point apparatus

7650
Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
1H, H-7), 7.12 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.96 (d, 2H, H-30, H-50,
J = 8.4 Hz), 6.85 (s, 1H, H-4), 4.99–5.03 (dd, 1H, H-2, J = 7.6, 4.4 Hz),
3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.57–3.63 (dd, 1H, H-3,
J = 16.8, 7.6 Hz), 3.04–3.09 (dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.72 (m,
4H, CH2CH2), 2.61 (q, 4H, NCH2CH3, J = 7.2 Hz), 1.06 (t, 6H,
NCH2CH3, J = 7.2 Hz); 13C NMR (400 MHz, CDCl3): 200.0, 156.4,
156.3, 149.8, 146.1, 133.4, 129.5, 127.3, 115.6, 107.4, 104.8, 78.0,
4.91–4.92 (dd, 1H, H-2, J = 7.6, 4.4 Hz), 3.85 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 3.46–3.52 (dd, 1H, H-3, J = 16.8, 7.6 Hz), 2.89–2.94
(dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.62 (m, 4H, PhCH2CH2N), 2.61 (q,
4H, NCH2CH3, J = 7.6 Hz), 1.06 (t, 6H, NCH2CH3, J = 7.6 Hz); IR
(KBr), m
(cmꢁ1): 3015, 2963, 2878, 2781, 1709, 1590, 1503, 1458,
1015, 862. Anal. Calcd for C23H29NO4: C, 72.04; H, 7.62; N, 3.65.
Found: C, 71.67; H, 7.56; N, 3.69.
56.2, 56.0, 54.7, 46.7, 33.7, 32.1, 11.4; IR (KBr),
2964, 2803, 1710, 1589, 1512, 1468, 1011, 829. Anal. Calcd for
23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C, 71.71; H, 7.69;
m
(cmꢁ1): 3075,
4.2.8. 2-(3-(2-(Ethyl(methyl)amino)ethyl)phenoxy)-5,6-
dimethoxy-indan-1-one (2h)
C
N, 3.68.
According to the general method, the reaction of 12 (103 mg,
0.38 mmol)
with
3-(2-(ethyl(methyl)amino)ethyl)phenol
4.2.4. 2-(4-(2-(Ethyl(methyl)amino)ethyl)phenoxy)-5,6-
dimethoxy-indan-1-one (2d)
(57.3 mg, 0.32 mmol) produced compound 2 h (67.0 mg, 56.7%)
as oil. MS (ESI): 370 (M+1+)+; 1HNMR (d, CDCl3): 7.19–7.23 (m,
2H, H-7, H-50), 6.84–6.91 (m, 4H, H-4, H-20, H-40, H-60), 5.00–5.03
(dd, 1H, H-2, J = 7.6, 4.4 Hz), 3.96 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 3.58–3.64 (dd, 1H, H-3, J = 16.8, 7.6 Hz), 3.01–3.06 (dd,
1H, H-3, J = 16.8, 4.4 Hz), 2.75 (t, 2H, CH2CH2N, J = 6 Hz), 2.60 (t,
2H, CH2CH2N, J = 6 Hz), 2.46 (q, 2H, NCH2CH3, J = 7.6 Hz), 2.30(s,
According to the general method, the reaction of 12 (103 mg,
0.38 mmol)
with
4-(2-(ethyl(methyl)amino)ethyl)phenol
(57.3 mg, 0.32 mmol) produced compound 2d (92.1 mg, 78.3%) as
whitesolid(mp75–77 °C);MS(ESI): 370(M+1+)+; 1HNMR(d, CDCl3):
7.24 (s, 1H, H-7), 7.14 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.97 (d, 2H, H-30,
H-50, J = 8.4 Hz), 6.86 (s, 1H, H-4), 5.00–5.03 (dd, 1H, H-2, J = 7.6,
4.4 Hz), 3.98 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.57–3.63 (dd, 1H,
H-3, J = 16.8, 7.6 Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.79
(t, 2H, CH2CH2N, J = 6 Hz), 2.65 (t, 2H, CH2CH2N, J = 6 Hz), 2.57–
2.62 (q, 2H, NCH2CH3, J = 7.6 Hz), 2.37 (s, 3H), 1.12 (t, 3H, NCH2CH3,
3H, NCH3), 1.07 (t, 3H, NCH2CH3, J = 7.6 Hz); IR (KBr),
m
(cmꢁ1):
2967, 2873, 2781, 1709, 1589, 1501, 1459, 1012, 862, 782. Anal.
Calcd for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.46;
H, 7.48; N, 3.83.
J = 7.6 Hz); IR (KBr),
m
(cmꢁ1): 3010, 2967, 2840, 2803, 1702, 1606,
4.2.9. 5,6-Dimethoxy-2-(4-(3-(piperidin-1-yl)propyl)phenoxy)-
indan-1-one (2i)
1509, 1469, 1011, 861. Anal. Calcd for C22H27NO4: C, 71.52; H,
7.37; N, 3.79. Found: C, 71.57; H, 7.40; N, 3.68.
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(3-(piperidin-1-yl)propyl)phenol (70.1 mg,
0.32 mmol) produced compound 2i (82.4 mg, 63.0%) as white solid
(mp 110–112 °C);MS (ESI): 410 (M+1+)+; 1HNMR (d, CDCl3): 7.23 (s,
1H, H-7), 7.09 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.94 (d, 2H, H-30, H-50,
J = 8.4 Hz), 6.84 (s, 1H, H-4), 4.98–5.00 (dd, 1H, H-2, J = 7.6,
4.4 Hz),3.96 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.55–3.61 (dd, 1H,
H-3, J = 16.8, 7.6 Hz), 3.02–3.07 (dd, 1H, H-3, J = 16.8, 4.4 Hz),
2.55 (t, 2H, PhCH2CH2, J = 6Hz), 2.32–2.39 (m, 6H, piperidine-CH2,
H-200, H-600, CH2CH2CH2N), 1.79–1.83 (m, 2H, PhCH2CH2CH2N),
1.57–1.62 (m, 4H, H-300, H-500), 1.43 (s, 2H, H-400); IR (KBr),
4.2.5. 5,6-Dimethoxy-2-(3-(2-(piperidin-1-yl)ethyl)phenoxy)-
indan-1-one (2e)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(2-(piperidin-1-yl)ethyl)phenol (65.6 mg,
0.32 mmol) produced compound 2e (89.7 mg, 71.3%) as white solid
(mp 112–114 °C); MS (ESI): 396 (M+1+)+; 1HNMR (d, CDCl3): 7.20–
7.25 (m, 2H, H-7, H-50), 6.85–6.92 (m, 4H, H-4, H-20, H-40, H-60),
5.02–5.05 (dd, 1H, H-2, J = 7.6, 4.4 Hz), 3.98 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 3.60–3.65 (dd, 1H, H-3, J = 16.8, 7.6 Hz), 3.04–3.09
(dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.81 (t, 2H, PhCH2CH2N), 2.59 (t,
2H, PhCH2CH2N), 2.515–2.521 (m, 4H, piperidine-CH2, H-200and
H-600), 1.63–1.68 (m, H-300, H-500), 1.47–1.48 (m, 2H, H-400); IR
m
(cmꢁ1): 3005, 2935, 2830, 1710, 1605, 1512, 1452, 1010, 838.
Anal. Calcd for C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C,
73.45; H, 7.69; N, 3.47.
(KBr), m
(cmꢁ1): 3015, 2956, 2872, 2780, 1705, 1586, 1503, 1450,
1012, 862. Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54.
Found: C, 72.63; H, 7.41; N, 3.60.
4.2.10. 5,6-Dimethoxy-2-(4-(3-(pyrrolidin-1-yl)propyl)phenoxy)-
indan-1-one (2j)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(3-(pyrrolidin-1-yl)propyl)phenol (65.6 mg,
0.32 mmol) produced compound 2j (74.6 mg, 59.0%) as white solid
(mp 98–100 °C); MS (ESI): 396 (M+1+)+; 1HNMR (d, CDCl3): 7.24 (s,
1H, H-7), 7.11 (d, 2H, H-20, H-60, J = 8.4Hz), 6.95 (d, 2H, H-30, H-50,
J = 8.4Hz), 6.85(s, 1H, H-4), 4.99–5.02 (dd, 1H, H-2, J = 7.6, 4.4Hz),
3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.56–3.62 (dd, 1H, H-3,
J = 16.8, 7.6 Hz), 3.04–3.09 (dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.59 (t,
2H, J = 6 Hz, PhCH2CH2), 2.45–2.51 (m, 6H, pyrrolidine-CH2, H-200,
4.2.6. 5,6-Dimethoxy-2-(3-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-
indan-1-one (2f)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(2-(pyrrolidin-1-yl)ethyl)phenol (61.1 mg,
0.32 mmol) produced compound 2f (84.5 mg, 69.3%) as oil; MS
(ESI): 382 (M+1+)+; 1HNMR (d, CDCl3): 7.20–7.24 (m, 2H, H-7, H-
50), 6.86–6.93 (m, 4H, H-4, H-20, H-40, H-60), 5.02–5.05 (dd, 1H, H-
2, J = 7.6, 4.4 Hz), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.60–
3.66 (dd, 1H, H-3, J = 16.8, 7.6 Hz), 3.01–3.06 (dd, 1H, H-3,
J = 16.8, 4.4 Hz), 2.88–2.90 (m, 4H, PhCH2CH2N), 2.807 (m, 4H, pyr-
rolidine-CH2, H-200, H-600), 1.89–1.90 (m, 4H, pyrrolidine-CH2, H-300,
H-600,
PhCH2CH2CH2N); IR (KBr),
CH2CH2CH2N),
1.78–1.87
(m,
6H,
H-300,
H-400,
m
(cmꢁ1): 3008, 2934, 2803, 1710,
1605, 1503, 1456, 1010, 838, 774. Anal. Calcd for C24H29NO4: C,
72.89; H, 7.39; N, 3.54. Found: C, 72.56; H, 7.45; N, 3.50.
H-500); IR (KBr), (cmꢁ1): 3018, 2959, 2876, 2780, 1707, 1588, 1501,
m
1455, 1012, 862, 782. Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13;
N, 3.67. Found: C, 72.19; H, 7.17; N, 3.73.
4.2.11. 2-(4-(3-(Diethylamino)propyl)phenoxy)-5,6-dimethoxy-
indan-1-one (2k)
4.2.7. 2-(3-(2-(Diethylamino)ethyl)phenoxy)-5,6-dimethoxy-
indan-1-one (2g)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(3-(diethylamino)propyl)phenol (66.2 mg,
0.32 mmol) produced compound 2k (72.9 mg, 57.4%) as white solid
(mp 88–90 °C); MS (ESI): 398 (M+1+)+; 1HNMR (d, CDCl3): 7.24 (s,
1H, H-7), 7.11 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.95 (d, 2H, H-30, H-
50, J = 8.4 Hz), 6.85 (s, 1H, H-4), 4.99–5.01 (dd, 1H, H-2, J = 7.6,
4.4 Hz), 3.97 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.56–3.62 (dd, 1H,
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(2-(diethylamino)ethyl)phenol (61.8 mg,
0.32 mmol) produced compound 2 g (78.4 mg, 64%) as white solid
(mp 59–63 °C); MS (ESI): 384 (M+1+)+; 1HNMR (d, CDCl3): 7.09–
7.15 (m, 2H, H-7, H-50), 6.75–6.80 (m, 4H, H-4, H-20, H-40, H-60),

Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
7651
H-3, J = 16.8, 7.6 Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.45
(m, 4H, PhCH2CH2CH2, PhCH2CH2CH2), 2.59 (q, 4H, NCH2CH3), 1.73–
1.78 (m, 2H, PhCH2CH2CH2N, J = 7.6 Hz), 0.99 (t, 6H, J = 7.6 Hz,
CH3); 13C NMR (400 MHz, CDCl3): 200.1, 156.3, 156.0, 149.8,
146.1, 135.1, 129.1, 127.2, 115.4, 107.3, 104.7, 77.9, 56.2, 56.0,
5.11–5.13 (dd, 1H, H-2, J = 7.2, 3.6 Hz), 3.99 (s, 3H, OCH3), 3.93
(s, 3H, OCH3), 3.73 (s, 2H, COCH2N), 3.63–3.69 (dd, 1H, H-3,
J = 16.8, 7.2 Hz), 3.06–3.11 (dd, 1H, H-3, J = 16.8, 3.6 Hz), 2.53–
2.57 (m, 4H, pyperidine-CH2, H-200, H-600), 1.62–1.67 (m, 4H, H-
300, H-500), 1.46–1.47 (m, 2H, H-400); IR (KBr),
m
(cmꢁ1): 2935,
52.0, 46.6, 33.7, 32.7, 28.2, 11.2; IR (KBr),
2801, 1707, 1606, 1503, 1451, 1011, 838. Anal. Calcd for
24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.58; H, 7.90;
m
(cmꢁ1): 3067, 2968,
2849, 1711, 1677, 1597, 1502, 1467, 1011, 837, 753. Anal. Calcd
for C24H27NO5: C, 70.40; H, 6.65; N, 3.42. Found: C, 70.09; H,
6.53; N, 3.46.
C
N, 3.59.
4.3.2. 5,6-Dimethoxy-2-(4-(2-(pyrrolidin-1-yl)acetyl)phenoxy)-
indan-1-one (3b)
4.2.12. 5,6-Dimethoxy-2-(4-(4-(pyrrolidin-1-yl)butyl)phenoxy)-
indan-1-one (2l)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)etha-
none (65.6 mg, 0.32 mmol) produced compound 3b (80.9 mg,
64.2%) as white solid (mp 62–64 °C); MS (ESI): 396 (M+1+)+;
1HNMR (d, CDCl3): 7.98 (d, 2H, H-30, H-50, J = 9.2 Hz), 7.23 (s, 1H,
H-7), 7.06 (d, 2H, H-20, H-60, J = 9.2 Hz), 6.87 (s, 1H, H-4), 5.11–
5.13 (dd, 1H, H-2, J = 7.2, 3.6 Hz), 3.99 (s, 2H, COCH2N), 3.98 (s,
3H, OCH3), 3.92 (s, 3H, OCH3), 3.63–3.68 (dd, 1H, H-3, J = 16.8,
7.2 Hz), 3.05–3.10 (dd, 1H, H-3, J = 16.8, 3.6 Hz), 2.70–2.75 (m,
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(4-(pyrrolidin-1-yl)butyl)phenol (70.1 mg,
0.32 mmol) produced compound 2l (81.1 mg, 62%) as white solid
(mp 106–108 °C); MS (ESI): 410 (M+1+)+; 1HNMR (d, CDCl3): 7.24
(s, 1H, H-7), 7.09 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.95 (d, 2H, H-30,
H-50, J = 8.4 Hz), 6.86 (s, 1H, H-4), 4.99–5.01 (dd, 1H, H-2, J = 7.6,
4.4 Hz), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.57–3.62 (dd, 1H,
H-3, J = 16.8, 7.6 Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 4.4 Hz),
2.72 (m, 4H, pyrrolidine-CH2, H-200, H-600), 2.58–2.63 (m, 4H,
PhCH2CH2CH2CH2N), 1.86–1.90 (m, 4H, PhCH2CH2CH2CH2N),
4H, NCH2CH2), 1.84–1.90 (m, 4H, NCH2CH2); IR (KBr),
m
(cmꢁ1):
2928, 1715, 1673, 1598, 1501, 1465, 1009, 835, 751. Anal. Calcd
for C23H25NO5: C, 69.86; H, 6.37; N, 3.54. Found: C, 69.47; H,
6.42; N, 3.55.
1.64–1.66 (m, 4H, H-300, H-400); IR (KBr),
m
(cmꢁ1): 2934, 2790,
1709, 1598, 1504, 1463, 1013, 826. Anal. Calcd for C25H31NO4: C,
73.32; H, 7.63; N, 3.42. Found: C, 72.96; H, 7.76; N, 3.48.
4.3.3. 2-(4-(2-(Diethylamino)acetyl)phenoxy)-5,6-dimethoxy-
indan-1-one (3c)
4.2.13. 2-(4-(4-(Diethylamino)butyl)phenoxy)-5,6-dimethoxy-
indan-1-one (2m)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 2-(diethylamino)-1-(4-hydroxyphenyl)ethanone
(66.2 mg, 0.32 mmol) produced compound 3c (74.2 mg, 58.4%) as
white solid (mp 118–120 °C); MS (ESI): 398 (M+1+)+; 1H NMR (d,
CDCl3): 8.03 (d, 2H, H-30, H-50, J = 8.8 Hz), 7.22 (s, 1H, H-7), 7.06
(d, 2H, H-20, H-60, J = 8.8 Hz), 6.88 (s, 1H, H-4), 5.12–5.15 (dd, 1H,
H-2, J = 7.2, 3.6 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.89
(s, 2H, COCH2N), 3.63–3.68 (dd, 1H, H-3, J = 16.8, 7.2 Hz), 3.04–
3.09 (dd, 1H, H-3, J = 16.8, 3.6 Hz), 2.68 (q, 4H, NCH2CH3,
J = 6.8 Hz), 1.07 (t, 6H, NCH2CH3, J = 6.8 Hz); 13C NMR (400 MHz,
CDCl3): 199.2, 196.6, 161.8, 156.6, 150.0, 146.0, 130.5, 129.9,
127.1, 115.1, 107.4, 104.8, 77.6, 59.3, 56.3, 56.1, 47.7, 33.6, 11.7;
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(4-(diethylamino)butyl)phenol (70.7 mg,
0.32 mmol) produced compound 2m (77.6 mg, 59%) as oil. MS
(ESI): 412 (M+1+)+; 1HNMR (d, CDCl3): 7.25 (s, 1H, H-7), 7.09 (d,
2H, H-20, H-60, J = 8.4 Hz), 6.95 (d, 2H, H-30, H-50, J = 8.4 Hz), 6.86
(s, 1H, H-4), 5.00–5.02 (dd, 1H, H-2, J = 7.6, 4.4 Hz), 3.98 (s, 3H,
OCH3), 3.93 (s, 3H, OCH3), 3.58–3.63 (dd, 1H, H-3, J = 16.8,
7.6 Hz), 3.04–3.09 (dd, 1H, H-3, J = 16.8, 4.4 Hz), 2.70–2.75 (m,
4H, NCH2CH3), 2.61–2.63 (m, 4H, PhCH2CH2CH2CH2N), 1.62–1.63
(m, 4H, PhCH2CH2CH2CH2N, J = 7.2 Hz), 1.13–1.17 (m, 6H, NCH2CH3,
J = 7.2 Hz); 13C NMR (400 MHz, CDCl3): 200.1, 156.3, 156.0, 149.8,
146.1, 135.2, 129.1, 127.2, 115.4, 107.3, 104.7, 77.9, 56.2, 56.0,
IR (KBr), m
(cmꢁ1): 3058, 2836, 1702, 1678, 1605, 1500, 827. Anal.
Calcd for C23H27NO5: C, 69.50; H, 6.85; N, 3.52. Found: C, 69.26;
H, 6.81; N, 3.59.
52.2, 46.5, 34.6, 33.7, 29.3, 25.4, 10.7; IR (KBr),
2862, 1707, 1604, 1506, 1468, 1011, 837. Anal. Calcd for
25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C, 72.83; H, 8.05; N,
m
(cmꢁ1): 2930,
C
3.58.
4.3.4. 2-(4-(2-(Ethyl(methyl)amino)acetyl)phenoxy)-5,6-
dimethoxy-indan-1-one (3d)
4.3. General procedure for the synthesis of 3a–n
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 2-(ethyl(methyl)amino)-1-(4-hydroxyphenyl)
ethanone (61.8 mg, 0.32 mmol) produced compound 3d (77.8 mg,
63.5%) as white solid (mp 87–89 °C); MS (ESI): 384 (M+1+)+; 1H
NMR (d, CDCl3): 8.00 (d, 2H, H-30, H-50, J = 8.8 Hz), 7.21 (s, 1H, H-
7), 7.05 (d, 2H, H-20, H-60, J = 8.8Hz), 6.86 (s, 1H, H-4), 5.10–5.12
(dd, 1H, H-2, J = 7.2, 3.6Hz), 3.97 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 3.77 (s, 2H, COCH2N), 3.61–3.67 (dd, 1H, H-3, J = 16.8,
7.2Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 3.6Hz), 2.56–2.61 (q, 2H,
NCH2CH3, J = 7.2Hz), 2.34 (s, 3H, NCH3), 1.09 (t, 3H, NCH2CH3,
Under N2 atmosphere, to a solution of 9a–n (0.32 mmol) and
K2CO3 (0.38 mmol) in dry CH3CN (3 mL), was slowly added a solu-
tion of 2-bromo-5,6-dimethoxy-indan-1-one 12 (0.38 mmol) in
CH3CN (3 mL). The mixture was refluxed for 0.5 h. Then, it was
cooled to room temperature and the solvent was removed under
vacuum pressure. The resulting residue was dissolved in methy-
lene chloride (20 mL), washed successively with water and brine,
dried over anhydrous Na2SO4 and evaporated to dryness, yielding
syrup that was purified by silica-gel column chromatography(PE/
EtOAc/TEA 100: 100: 1).
J = 7.2Hz); IR (KBr), m
(cmꢁ1): 3072, 2966, 2935, 2836, 1700, 1675,
1601, 1502, 1011, 829. Anal. Calcd for C22H25NO5: C, 68.91; H,
6.57; N, 3.65. Found: C, 68.75; H, 6.66; N, 3.69.
4.3.1. 5,6-Dimethoxy-2-(4-(2-(piperidin-1-yl)acetyl)phenoxy)-
indan-1-one (3a)
4.3.5. 5,6-Dimethoxy-2-(4-(3-(piperidin-1-yl)propanoyl)phenoxy)-
indan-1-one (3e)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-2-(piperidin-1-yl)etha-
none (70.1 mg, 0.32 mmol) produced compound 3a(94.2 mg,
72.1%) as white solid (mp 58–60 °C); MS (ESI): 410 (M+1+)+;
1HNMR (d, CDCl3): 8.03 (d, 2H, H-30, H-50, J = 8.8 Hz), 7.24 (s,
1H, H-7), 7.06 (d, 2H, H-20, H-60, J = 8.8 Hz), 6.88 (s, 1H, H-4),
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-3-(piperidin-1-yl)propan-
1-one (74.6 mg, 0.32 mmol) produced compound 3e (89.6 mg,
66.2%) as white solid (mp 96–98 °C); MS (ESI): 424 (M+1+)+; 1H
NMR (d, CDCl3): 7.97 (d, 2H, H-30, H50, J = 8Hz), 7.24 (s, 1H, H-7),

7652
Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
7.08 (d, 2H, H-20, H-60, J = 8 Hz), 6.88 (s, 1H, H-4), 5.12–5.15 (dd,
1H, H-2, J = 7.6, 4.4 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
3.64–3.70 (dd, 1H, H-3, J = 16.8, 7.6 Hz), 3.15 (t, 2H, COCH2CH2N),
3.06–3.11 (dd, 1H, H-3, J = 16.8, 3.2 Hz), 2.78 (t, 2H, COCH2CH2N),
2.46 (m, 4H, piperidine-CH2, H-200, H-600), 1.58–1.63 (m, 4H, H-300,
53%) as white solid (mp 76–78 °C); MS (ESI): 410 (M+1+)+; 1H
NMR (d, CDCl3): 7.60–7.63 (m, 2H, H-7, H-20), 7.38 (t, 1H, H-50,
J = 8.4 Hz), 7.24–7.28 (m, 2H, H-40, H-60), 6.86 (s, 1H, H-4), 5.08–
5.11 (dd, 1H, H-2, J = 6.8, 3.6 Hz), 3.98 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 3.64–3.70 (dd, 1H, H-3, J = 16.8, 6.8 Hz), 3.21 (t, 2H,
COCH2CH2N, 7.6 Hz), 3.03–3.08 (dd, 1H, H-3, J = 16.8, 3.6 Hz),
2.92 (t, 2H, COCH2CH2N, 7.6 Hz), 2.60 (m, 4H, pyrrolidine-CH2, H-
H-500), 1.45–1.46 (m, 2H, H-400); IR (KBr),
1711, 1676, 1598, 1502, 1467, 1011, 840, 753. Anal. Calcd for
25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C, 70.76; H, 6.83; N,
m
(cmꢁ1): 2934, 2840,
C
3.51.
200, H-500), 1.81 (m, 4H, H-300, H-400); IR (KBr),
2800, 1706, 1690, 1589, 1501, 1456, 1012, 753. Anal. Calcd for
24H27NO5: C, 70.40; H, 6.65; N, 3.42. Found: C, 70.23; H, 6.78; N,
m
(cmꢁ1): 2960,
C
4.3.6. 5,6-Dimethoxy-2-(4-(3-(pyrrolidin-1-yl)propanoyl)phenoxy)-
indan-1-one (3f)
3.45.
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-3-(pyrrolidin-1-yl)propan-
1-one (70.1 mg, 0.32 mmol) produced compound 3f (86.4 mg,
66.0%) as white solid (mp 76–78 °C); MS (ESI): 410 (M+1+)+; 1H
NMR (d, CDCl3): 7.97 (d, 2 H, H-30, H-50, J = 8 Hz), 7.24 (s, 1H, H-
7), 7.08 (d, 2H, H-20, H-60, J = 8Hz), 6.88 (s, 1H, H-4), 5.13–5.15
(dd, 1H, H-2, J = 7.6, 4.4Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 3.64–3.70 (dd, 1H, H-3, J = 16.8, 7.6Hz), 3.25 (t, 2H,
COCH2CH2N), 3.06–3.11 (dd, 1H, H-3, J = 16.8, 3.2 Hz), 2.99 (t, 2H,
COCH2CH2N), 2.69 (m, 4H, pyrrolidine-CH2, H-200, H-500), 1.86 (m,
4.3.10. 2-(3-(3-(Diethylamino)propanoyl)phenoxy)-5,6-
dimethoxy-indan-1-one (3j)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(diethylamino)-1-(3-hydroxyphenyl)propan-
1-one (70.7 mg, 0.32 mmol) produced compound 3j (61.8 mg,
47.3%) as white solid (mp 101–103 °C); MS (ESI): 412 (M+1+)+;
1H NMR (d, CDCl3): 7.60–7.64 (m, 2H, H-7, H-20), 7.38 (t, 1H, H-
50, J = 8.4 Hz), 7.25–7.29 (m, 2H, H-40, H-60), 6.87 (s, 1H, H-4),
5.09–5.12 (dd, 1H, H-2, J = 6.8, 3.6 Hz), 3.99 (s, 3H, OCH3), 3.93 (s,
3H, OCH3), 3.65–3.71 (dd, 1H, H-3, J = 16.8, 6.8 Hz), 3.14–3.18 (t,
2H, COCH2CH2N, J = 6.8 Hz), 3.04–3.09 (dd, 1H, H-3, J = 16.8,
3.6 Hz), 2.94 (t, 2H, COCH2CH2N, 7.6 Hz), 2.58 (q, 4H, NCH2CH3,
4H, H-300, H-400); IR (KBr), (cmꢁ1): 2961, 2835, 1709, 1674, 1598,
m
1502, 1461, 1011, 842. Anal. Calcd for C24H27NO5: C, 70.40; H,
6.65; N, 3.42. Found: C, 70.07; H, 6.80; N, 3.48.
J = 7.2 Hz), 1.05 (t, 6H, NCH2CH3, J = 7.2 Hz); IR (KBr),
2958, 2803, 1705, 1688, 1589, 1506, 1458, 753. Anal. Calcd for
24H29NO5: C, 70.05; H, 7.10; N, 3.40. Found: C, 70.17; H, 7.16; N,
m
(cmꢁ1):
4.3.7. 2-(4-(3-(Diethylamino)propanoyl)phenoxy)-5,6-
C
dimethoxy-indan-1-one (3g)
3.26.
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(diethylamino)-1-(4-hydroxyphenyl)propan-
1-one (70.7 mg, 0.32 mmol) produced compound 3g (76.3 mg,
58.0%) as white solid (mp 94–96 °C); MS (ESI): 412 (M+1+)+; 1H
NMR (d, CDCl3): 7.96 (d, 2H, H-30, H-50, J = 8.8 Hz), 7.24 (s, 1H, H-
7), 7.08 (d, 2H, H-20, H-60, J = 8.4 Hz), 6.88 (s, 1H, H-4), 5.12–5.15
(dd, 1H, H-2, J = 7.2, 3.6 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 3.63–3.69 (dd, 1H, H-3, J = 16.8, 7.2 Hz), 3.12 (t, 2H,
COCH2CH2N), 3.06–3.11 (dd, 1H, H-3, J = 16.8, 3.6 Hz), 2.94 (t, 2H,
COCH2CH2N), 2.60–2.65 (q, 4H, NCH2CH3, J = 6.8 Hz), 1.06–1.10 (t,
4.3.11. 5,6-Dimethoxy-2-(4-(4-(piperidin-1-yl)butanoyl)phenoxy)-
indan-1-one (3k)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-4-(piperidin-1-yl)butan-1-
one (79.0 mg, 0.32 mmol) produced compound 3k (83.4 mg,
59.7%) as white solid (mp 52–54 °C); MS (ESI): 438 (M+1+)+; 1H
NMR (d, CDCl3): 7.95 (d, 2H, H-30, H-50, J = 9.2 Hz), 7.24 (s, 1H, H-
7), 7.06 (d, 2H, H-20, H-60, J = 9.2 Hz), 6.87 (s, 1H, H-4), 5.11–5.14
(dd, 1H, H-2, J = 7.6, 3.6 Hz), 3.98 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 3.62–3.68 (dd, 1H, H-3, J = 17.2, 7.6 Hz), 3.05–3.10 (dd,
1H, H-3, J = 16.8, 3.6 Hz), 2.96 (t, 2H, COCH2CH2CH2N), 2.43–2.47
(m, 6H, piperidine-CH2, H-200, H-600, COCH2CH2CH2N), 1.96–2.04
(m, 2H, CH2CH2CH2), 1.59–1.65 (m, 4H, H-300, H-500), 1.44–1.46(m,
2H, H-400); 13C NMR (400 MHz, CDCl3): 199.2, 198.5, 161.7, 156.6,
150.0, 146.0, 130.8, 130.2, 127.2, 115.1, 107.4, 104.8, 77.6, 58.2,
6H, NCH2CH3, J = 6.8 Hz); IR (KBr),
m
(cmꢁ1): 2967, 2933, 2835,
1709, 1673, 1598, 1503, 1464, 1009, 839; 13C NMR (400 MHz,
CDCl3): 199.1, 197.5, 161.8, 156.5, 149.9, 146.0, 130.5, 130.2,
127.0, 115.1, 107.3, 104.7, 77.5, 56.2, 56.0, 47.5, 46.6, 35.2, 33.5,
10.9; Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N, 3.40. Found:
C, 69.78; H, 7.19; N, 3.29.
56.3, 56.1, 54.2, 36.0, 33.6, 25.3, 24.0, 21.2; IR (KBr),
m
(cmꢁ1):
4.3.8. 2-(4-(3-(Ethyl(methyl)amino)propanoyl)phenoxy)-5,6-
dimethoxy-indan-1-one (3h)
3010, 2933, 2840, 1711, 1675, 1597, 1502, 1467, 1012, 835. Anal.
Calcd for C26H31NO5: C, 71.47; H, 7.14; N, 3.20. Found: C, 71.27;
H, 7.19; N, 3.28.
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 3-(ethyl(methyl)amino)-1-(4-hydroxyphenyl)
propan-1-one (66.2 mg, 0.32 mmol) produced compound 3h
(62.2 mg, 49.2%) as oil; MS (ESI): 398 (M+1+)+; 1H NMR (d, CDCl3):
7.96 (d, 2H, H-30, H50, J = 8.8 Hz), 7.24 (s, 1H, H-7), 7.08 (d, 2H, H-20,
H-60, J = 8.8 Hz), 6.88 (s, 1H, H-4), 5.12–5.15 (dd, 1H, H-2, J = 7.2,
4.0 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.64–3.70 (dd, 1H,
H-3, J = 16.8, 7.2 Hz), 3.12 (t, 2H, COCH2CH2N), 3.06–3.11 (dd, 1H,
H-3, J = 16.8, 3.6 Hz), 2.82 (t, 2H, COCH2CH2N), 2.47–2.52 (q, 2H,
NCH2CH2, J = 7.2 Hz), 2.90 (s, 3H, NCH3), 1.07 (t, 3H, NCH2CH3,
4.3.12. 5,6-Dimethoxy-2-(4-(4-(pyrrolidin-1-yl)butanoyl)phenoxy)-
indan-1-one (3l)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(4-hydroxyphenyl)-4-(pyrrolidin-1-yl)butan-
1-one (74.5 mg, 0.32 mmol) produced compound 3l (52.0 mg,
38.4%) as white solid (mp 71–73 °C); MS (ESI): 424 (M+1+)+;
1H NMR (d, CDCl3): 7.96 (d, 2H, H-30, H-500, J = 8 Hz), 7.24 (s,
1H, H-7), 7.08 (d, 2H, H-20, H-60, J = 8 Hz), 6.88 (s, 1H, H-4),
5.12–5.15 (dd, 1H, H-2, J = 7.6, 4.4 Hz), 3.99 (s, 3H, OCH3),
3.93 (s, 3H, OCH3), 3.63–3.69 (dd, 1H, H-3, J = 16.8, 7.6 Hz),
3.11–3.14 (t, 2H, COCH2CH2CH2N), 3.06–3.11 (dd, 1H, H-3,
J = 16.8, 3.2 Hz), 2.97–2.99 (m, 4H, pyrrolidine-CH2, H-200, H-
500), 2.88 (t, 2H, COCH2CH2CH2N), 2.12–2.19 (m, 2H, CH2CH2CH2),
J = 7.2 Hz); IR (KBr),
m
(cmꢁ1): 2968, 2838, 2790, 1711, 1672,
1598, 1502, 1467, 1011, 840, 753. Anal. Calcd for C23H27NO5: C,
69.50; H, 6.85; N, 3.52. Found: C, 69.36; H, 6.81; N, 3.46.
4.3.9. 5,6-Dimethoxy-2-(3-(3-(pyrrolidin-1-yl)propanoyl)phenoxy)-
indan-1-one (3i)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 1-(3-hydroxyphenyl)-3-(pyrrolidin-1-yl)propan-
1-one (70.1 mg, 0.32 mmol) produced compound 3i (69.4 mg,
1.98–2.01 (m, 4H, NCH2CH2, H-300, H-400); IR (KBr),
3071, 2940, 1714, 1603, 1504, 1010, 834, 770. Anal. Calcd for
25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C, 70.73; H,
7.04; N, 3.17.
m
(cmꢁ1):
C

Y. Shen et al. / Bioorg. Med. Chem. 16 (2008) 7646–7653
7653
4.3.13. 2-(4-(4-(Diethylamino)butanoyl)phenoxy)-5,6-
dimethoxy-indan-1-one (3m)
and plates were assayed 12 h later. Twenty microliters of stock
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
(MTT, Sigma) solution was added to each well (0.25 mg/mL) for an-
other 4 h incubation. Afterwards, DMSO was added to each well
and optical density (OD) was read at 570 nm by Thermo Multiskan
Spectrum (Thermo Electron Corporation). The viability of un-
treated control cells was defined as 100%.22,23
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(diethylamino)-1-(4-hydroxyphenyl)butan-1-
one (74.5 mg, 0.32 mmol) produced compound 3m (63.9 mg,
47.2%) as oil; MS (ESI): 426 (M+1+)+; 1H NMR (d, CDCl3): 7.96 (d,
2H, H-30, H-50, J = 8.8 Hz), 7.24 (s, 1H, H-7), 7.08 (d, 2H, H-20, H-
60, J = 9.2 Hz), 6.88 (s, 1H, H-4), 5.12–5.14 (dd, 1H, H-2, J = 6.8,
3.6 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.63–3.69 (dd, 1H,
H-3, J = 16.8, 7.2 Hz), 3.06–3.12 (dd, 1H, H-3, J = 16.8, 3.6 Hz),
3.00–3.03 (t, 2H, COCH2CH2CH2N), 2.63–2.72 (m, 6H, NCH2CH2,
COCH2CH2CH2N), 1.96–2.00 (m, 2H, CH2CH2CH2), 1.10–1.14 (q,
4.4.3. Molecular modeling of compound 3g
Molecular modeling studies were performed using a flexible
docking method with the Tripos FlexiDock program. The X-ray
crystal structure of Torpedo californica AChE complexed with
donepezil (PDB file identificator 1EVE)24 was retrieved from the
Protein Data Bank (PDB). 0A CB2-binding pocket was defined to cov-
er all residues within 4 ÅA of the ligand in the initial AChE–ligand
complex. All of the single bonds of residue side chains inside the
defined AChE-binding pocket were regarded as rotatable or flexible
bonds, and the ligand was allowed to rotate on all single bonds and
move flexibly within the tentative-binding pocket. The atomic
charges were recalculated using the Kollman all-atom approach
for the protein and the Gasteiger–Hückel approach for the ligand.
The binding interaction energy was calculated to include van der
Waals, electrostatic, and torsional energy terms defined in the Tri-
pos force field. The structure optimization was performed for
200,000 generations using a genetic algorithm and the 20 best-
scoring ligand–protein complexes were kept for further analyses.
6H, NCH2CH3, J = 7.2 Hz); IR (KBr),
m
(cmꢁ1): 2967, 2935, 1711,
1676, 1598, 1502, 1467, 1012, 835. Anal. Calcd for C25H31NO5: C,
70.57; H, 7.34; N, 3.29. Found: C, 69.83; H, 7.32; N, 3.16.
4.3.14. 2-(4-(4-(Ethyl(methyl)amino)butanoyl)phenoxy)-5,6-
dimethoxy-indan-1-one (3n)
According to the general method, the reaction of 12 (103 mg,
0.38 mmol) with 4-(ethyl(methyl)amino)-1-(4-hydroxyphenyl)
butan-1-one (70.7 mg, 0.32 mmol) produced compound 3n
(48.2 mg, 36.7%) as oil; MS (ESI): 412 (M+1+)+; 1H NMR (d, CDCl3):
7.96 (d, 2H, H-30, H-50, J = 8.8 Hz), 7.24 (s, 1H, H-7), 7.08 (d, 2H, H-
20, H-60, J = 9.2 Hz), 6.88 (s, 1H, H-4), 5.12–5.14 (dd, 1H, H-2, J = 6.8,
3.6 Hz), 3.99 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.63–3.69 (dd, 1H,
H-3, J = 16.8, 7.2 Hz), 3.12–3.16 (t, 2H, COCH2CH2CH2N), 3.06–
3.11 (dd, 1H, H-3, J = 16.8, 3.6 Hz), 2.82–2.86 (t, 2H,
COCH2CH2CH2N), 2.47–2.52 (q, 2H, NCH2CH3, J = 7.2 Hz), 2.29 (s,
3H, NCH3), 1.96–2.00 (m, 2H, CH2CH2CH2),1.07 (t, 3H, NCH2CH3,
Acknowledgment
J = 7.2 Hz); IR (KBr),
m
(cmꢁ1): 3015, 2941, 1710, 1676, 1598,
This work was supported by the National Natural Science Foun-
dation of China (30572239).
1504, 1465, 1011, 838. Anal. Calcd for C24H29NO5: C, 70.05; H,
7.10; N, 3.40. Found: C, 69.76; H, 7.13; N, 3.26.
References
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lM)
l