Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes

Article abstract of DOI:10.1016/j.ejmech.2016.10.042

Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1–38) were elucidated by IR,¹H NMR,¹³C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26–29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26–29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26–29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds.

Full text of DOI:10.1016/j.ejmech.2016.10.042

European Journal of Medicinal Chemistry 124 (2016) 1026e1040
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Synthesis of new donepezil analogues and investigation of their
effects on cholinesterase enzymes
a
,
b
c
€
a, b, *
Begüm Nurpelin Sa gꢀ lık , Sinem Ilgın , Yusuf Ozkay
a
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eski s¸ ehir, Turkey
Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eski s¸ ehir, Turkey
Department of Toxicology, Faculty of Pharmacy, Anadolu University, 26470 Eski s¸ ehir, Turkey
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2016
Received in revised form
Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alz-
heimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures
1
13
of the synthesized compounds (1e38) were elucidated by IR, H NMR, C NMR and HRMS spectroscopic
methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was
investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE)
enzyme. On the other hand, compounds 26e29 indicated important inhibitory activity on AChE enzyme.
Kinetic studies were performed in order to observe the effects of the most active compounds on
substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic
properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the
compounds. The compounds 26e29 were found to be nontoxic at their effective concentrations against
AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were per-
formed for the most active compounds 26e29 and interaction modes with enzyme active sites were
determined. Docking studies revealed that there is a strong interaction between the active sites of AChE
enzyme and analyzed compounds.
1
7 October 2016
Accepted 18 October 2016
Available online 19 October 2016
Keywords:
Alzheimer diseases
Acetylcholinesterase
Indanone
Piperazine
Docking
©
2016 Elsevier Masson SAS. All rights reserved.
1
. Introduction
memantine, and acetylcholinesterase (AChE) inhibitors, tacrine,
donepezil (DNP), rivastigmine and galantamine have been
approved by the European and United States regulatory authorities
[15,16]. Among these drugs, DNP is the most preferred AChE in-
hibitor because it gives the most positive response in AD treatment.
Furthermore, DNP has some advantages as blood-brain barrier
permeability, non-hepatotoxicity, the least side efficacy and usage
once-daily [17].
Alzheimer's disease (AD) is a progressive neurodegenerative
process, characterized by age-related loss of memory [1]. Language
disorders [2], visual deficiency [3], orientation disorders [4],
shortage of decision-making, management function [5] and mem-
ory impairment [6] are the primary symptoms of the disease. Its
etiology has not been enlightened yet. It is thought that accumu-
lation of
b
amyloid in the senile plaques [7], neurofibrillary tangle
Cholinergic hypothesis reveals that there is a loss in cholinergic
activity because of the decreased level of Ach, which is hydrolyzed
by cholinesterase enzymes in synaptic gap [18,19]. There are two
types of cholinesterase enzymes in the central nervous system
(CNS): AChE and butyrylcholinesterase (BChE) [20]. These two
isoenzymes are responsible for hydrolyzing ACh. Although AChE
has more hydrolytic activity than BChE, it is reported that BChE
plays a key role in the regulation of AChE activity [21]. Thus, AChE
inhibitors are preferred in the treatment of AD to keep up ACh
normal levels in the CNS and to eliminate the symptoms of disease.
According to the X-ray crystallographic structure of AChE (PDB
ID:4EY7), two main binding sites has been determined: the cata-
lytic anionic site (CAS) including Ser203, Glu334, His447, Trp86,
composed by hyperphosphorylation of tau protein [8], loss of
cholinergic activity in certain part of brain [9], cerebrovascular
disorders [10], oxidative stress [11], functional loss of neuron
and synapse [12] and absence of acetylcholine (ACh) [13] are
responsible for the pathophysiology of AD [14]. Although
numerous therapeutic approaches have been offered, only non-
competitive
N-methyl-D-aspartate
receptor
antagonist,
*
Corresponding author. Anadolu University, Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, 26470, Eski s¸ ehir, Turkey.
€
E-mail address: yozkay@anadolu.edu.tr (Y. Ozkay).
http://dx.doi.org/10.1016/j.ejmech.2016.10.042
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1027
Tyr130, Tyr133, Tyr337, Phe338 and the peripheral anionic site
PAS) consisting of Tyr72, Asp74, Tyr124, Tyr341, Trp286 [22e25]. It
has been reported that DNP interacts with both CAS and PAS and
thus it is situated in the gorge concordantly owing to the feature of
dual binding site (DBS) [26e28]. Analyses of binding modes of the
enhanced biological activity.
2. Result and discussion
2.1. Chemistry
(
DNP indicate that the benzyl moiety is in a p- p interaction with the
indole of Trp86 in the CAS. The formation of hydrogen bond be-
tween the oxygen atom of the carbonyl group in the 1-indanone
and the amino group of Phe338 is a very significant interaction in
The compounds 1e14 and 15e38 were synthesized as shown in
Scheme 1 and Scheme 2. Initially, 2-chloro-N-arylacetamide de-
rivatives were prepared via the acetylation reaction using chlor-
oacetyl chloride. In the second step, substitution reaction between
5,6-dimethoxy-2-[(piperidin-4-yl)-methyl]-2,3-dihydro-1H-
inden-1-one and 2-chloro-N-arylacetamide derivatives gave the
compounds 1e14. The reaction of 4-fluorobenzaldehyde and
appropriate secondary amine afforded 4-substitutedbenzaldehyde
derivatives, which were treated with corresponding 2,3-dihydro-
1H-inden-1-one to gain compounds 15e38 by Claisen-Schmidt
condensation.
terms of binding to the active site. The 1-indanone constitutes a
p-
p
interaction with the indole of Trp286 in the PAS region. The
piperidine has a position in the gorge to interact with Tyr337 and
Tyr341 by doing a hydrogen bond. It also set up a van der Waals
interaction with amino acids in both CAS and PAS [29e31].
As stated above, receptor-ligand interactions and mechanism of
molecular recognition of the DNP have been clarified well.
Observed data clearly indicate that both 1-indanone and piperidine
on the chemical structure of DNP are responsible for inhibition of
the AChE. Therefore, there are too many studies including anti-
cholinesterase activity evaluation of piperidine and/or 1-indanone
compounds [32e40]. There are also many reports about cholines-
terase inhibitory potential of novel compounds, including bio-
isosteric replacement of piperidine with another basic center like
piperazine, pyrrolidine etc. [41e47]. In the view of chemical
structure of DNP, it has been reported that new AChE inhibitor
candidates should bear a core ring system that interacts with PAS, a
The structure of the newly synthesized compounds was eluci-
1
13
dated by IR, H NMR, C NMR, HRMS spectroscopic methods
(Electronic Supporting Information) and elemental analysis.
2.2. Anticholinesterase activity assay
All synthesized compounds were assessed as the AChE and BChE
inhibitors by using in vitro modified Ellman's spectrophotometric
method [51]. The assay was performed in two steps. First of all, the
ꢀ
3
ꢀ4
ꢀ9
basic center that binds to CAS and a linker as eOe, CH
CONH(CH )n, etc. between the core ring system and basic center
48e50]. For example, a strong AChE inhibitor BYYT-25, containing
2
, CONH,
compounds 1e38 were tested at 10 and 10 M concentrations.
ꢀ5
2
Second step was performed by using 10 -10 M concentrations
of the selected compounds that indicate more than 50% inhibitory
activity at initial concentrations.
[
an indanone core ring, an oxygen linker and a 4-(pyrrolydin-1-yl-
methyl)phenyl basic center, has been synthesized as a result of
described chemical requirements [49].
Based on the pharmacological profile of DNP and the informa-
tion about its molecular interaction with AChE, in the present study,
a novel series of DNP analogues was synthesized (Fig. 1) to inves-
tigate their inhibitory potency against cholinesterase enzymes.
Thus, it is aimed to gain new cholinesterase inhibitors with
Table 1 presents the anticholinesterase activity of compounds
1e38 at initial concentrations. None of the compounds displayed
remarkable inhibitor activity on BChE enzyme. Even the most
effective compound 17 could show the inhibition of 19.23% against
ꢀ
3
BChE at 10 M concentration. It was noted that all synthesized
compounds showed more potent inhibition profile on AChE rather
than BChE. The compounds 1e14 displayed lower inhibition against
Fig. 1. Structures of donepezil and synthesized compounds 1e38.

1028
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
Scheme 1. Synthesis pathway of the compounds 1e14.
ꢀ
3
AChE when compare with the compounds 15e38. At 10 M con-
centration, the compounds 17, 20, 24e29 possessed inhibition
mixed-type. Competitive inhibitors possess the same intercept on
y-axis but there are diverse slopes and intercepts on x-axis be-
tween the two data sets. Non-competitive inhibition has plots with
the same intercept on x-axis but there are different slopes and
intercepts on y-axis. Mix-typed inhibition causes different in-
tercepts on both y- and x-axis as presented in Fig. 2. Therefore, this
pattern indicates that the mechanism of AChE inhibition of 29 is
mix-typed.
ꢀ
4
profile over 50%, whereas at 10 M concentration the compounds
2
2
6e29 indicated more than 50% activity. Thus, the compounds
ꢀ
5
ꢀ9
6e29 were evaluated in further concentrations (10 -10
M)
against AChE along with reference drugs DNP and tacrine (Table 2).
The IC50 values on AChE were recorded as 0.2197 and 0.3715 M for
DNP and tacrine, respectively. This result confirms that DNP is more
potent inhibitor then tacrine against AChE. It was determined that
the compound 29 is the most active derivative in the series. The
compound 29 displayed 90.31% inhibition potency at a concentra-
tion of 10 M. IC50 values of the compounds 26, 27, 28 and 29 were
calculated as 6.382 M, 8.540 M, 6.056 M and 4.895 M,
respectively (Table 2). As a result of anticholinesterase activity, it
can be clearly declared that the compounds 26e29 are selective
AChE inhibitors.
m
2.4. Cytotoxicity test
ꢀ
3
New drug development is a long and arduous process, which
includes studies regarding chemistry, physical properties and bio-
logical evaluation. Biological evaluation covers pharmacology,
ADME and toxicology. Hence, the development of novel pharma-
ceuticals requires toxicity studies to be performed on candidate
drugs.
m
m
m
m
2
.3. Kinetic studies of enzyme inhibition
In the present study toxicity of the compounds 26e29 was
investigated by MTT assay, which is based on the reduction of
yellow MTT dye by metabolically active eukaryotic and prokaryotic
cells to form the purple formazan product. This assay is mainly
preferred to form a view about cell viability and to observe the
growth of cell culture [53,54]. MTT assay was carried out using
healthy NIH/3T3 mouse embryonic fibroblast cell lines (ATCC
CRL1658), which is recommended for cytotoxicity screening by ISO
The mechanism of AChE inhibition was investigated by enzyme
kinetic [52] using Ellman's spectrophotometric method [51]. The
linear Limeweaver-Burk graphics were used to estimate the type of
inhibition. Enzyme kinetic was analyzed by recording substrate-
velocity curves in absence and presence of the most potent com-
pound 29, which was prepared at IC50 (4.895
9.790 M) concentrations. In each case, the initial velocity mea-
surements were gained at different substrate (ATC) concentrations
ranging from 150 M to 0.2929 M.
mM) and 2 ꢁ IC50
(
m
(10993-5, 2009) [55]. Cytotoxicity test resulted with following IC50;
320 ± 22.10
mM (for compound 26), 230 ± 20.86
mM (for compound
m
m
27), 78 ± 19.47
mM (for compound 28), 78 ± 5.70
mM (for compound
The graphical analysis of steady-state inhibition data for the
compound 29 is shown in Fig. 2. The LineweavereBurk plot es-
tablishes the inhibition type; competitive, non-competitive or
29) (Table 3). IC50 of the compounds 26, 27, 28 and 29 against NIH/
3T3 is about 50, 27, 13 and 16 folds higher than IC50 against AChE
(Table 2). This finding enhances the importance of the compounds

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1029
Scheme 2. Synthesis pathway of the compounds 15e38.
2
6e29 as AChE inhibitors. It is easy to declare that the compounds
Molinspiration property program [57]. This program was coded to
give the data of Lipinski's rule, which evaluates the ADME prop-
erties of drug like compounds and is important for the optimization
of a biologically active compound. The rule requires that an orally
active drug has no more than one violation [58].
are nontoxic at their effective concentrations against AChE.
2.5. Theoretical calculation of ADME parameters
Poor pharmacokinetic is one of the important causes of costly
The theoretical calculations of ADME parameters (molecular
weight, log P, topological polar surface area (tPSA), number of
hydrogen donors, number of hydrogen acceptors, number of
rotatable bonds and volume) are presented in Table 4 along with
the violations of Lipinski's rule. According to these data only the
compound 5 does not abide to the rule with two violations. On the
other hand, all the other compounds (1e4, 6e38) follow Lipinski's
rule by causing no more than one violation. For the most active
late-stage failures in drug development. Pharmacokinetic profiles
of the new drug candidates should be evaluated as early as possible
in the drug development process. In recent years, combinatorial
chemistry has significantly increased the number of compounds for
which early data on absorption, distribution, metabolism and
excretion (ADME) are needed [56]. Hence, ADME properties of the
synthesized compounds (1e38) were calculated by online

1030
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
Table 1
Initial screening and inhibition percent of the compounds 1e38 against AChE and BChE at 10 3-10ꢀ4 M concentrations. Inhibitions rates, being higher than 50%, are presented
ꢀ
in bold numbers.
Comp.
AChE Inhibition %
BChE Inhibition %
Comp.
AChE Inhibition %
BChE Inhibition %
ꢀ
3
ꢀ4
ꢀ3
ꢀ4
ꢀ3
ꢀ4
ꢀ3
ꢀ4
10 M
10
M
10
M
10
M
10
M
10
M
10
M
10
M
1
2
3
4
5
6
7
8
9
4.62 ± 0.39
2.13 ± 0.41
5.82 ± 0.61
5.90 ± 0.30
3.72 ± 0.26
3.20 ± 0.19
1.24 ± 0.19
5.81 ± 0.21
2.74 ± 0.11
13.91 ± 0.82
8.67 ± 0.78
12.81 ± 0.45
7.33 ± 0.66
6.19 ± 0.43
17.87 ± 1.83
15.52 ± 1.28
54.66 ± 2.27
18.61 ± 1.73
6.59 ± 0.47
2.19 ± 0.13
1.43 ± 0.16
3.93 ± 0.39
4.65 ± 0.62
2.32 ± 0.42
2.48 ± 0.33
0.13 ± 0.23
2.15 ± 0.34
2.17 ± 0.45
2.49 ± 0.14
6.98 ± 0.49
0.41 ± 0.03
0.76 ± 0.02
1.34 ± 0.09
9.97 ± 0.93
14.00 ± 1.33
34.99 ± 2.65
9.23 ± 0.83
4.53 ± 0.23
5.23 ± 0.46
4.29 ± 0.70
5.33 ± 0.47
4.89 ± 0.38
6.21 ± 0.70
4.18 ± 0.38
3.77 ± 0.44
5.00 ± 0.68
5.89 ± 0.72
4.28 ± 0.27
4.75 ± 0.38
5.39 ± 0.44
4.88 ± 0.36
5.85 ± 0.22
12.88 ± 0.88
14.66 ± 1.56
19.23 ± 2.08
15.09 ± 1.39
5.05 ± 0.42
2.31 ± 0.19
2.08 ± 0.24
3.19 ± 0.56
3.10 ± 0.71
3.09 ± 0.09
1.13 ± 0.16
2.05 ± 0.63
2.58 ± 0.50
3.20 ± 0.59
1.33 ± 0.11
1.99 ± 0.23
2.77 ± 0.19
2.69 ± 0.21
1.29 ± 0.07
7.56 ± 0.69
9.63 ± 0.97
8.55 ± 0.92
8.77 ± 0.77
4.20 ± 0.56
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
86.87 ± 2.38
10.54 ± 0.75
2.30 ± 0.14
45.50 ± 1.95
70.62 ± 2.83
74.38 ± 2.18
89.14 ± 1.33
87.05 ± 1.52
88.05 ± 1.33
90.31 ± 1.20
6.88 ± 0.19
1.90 ± 0.11
4.76 ± 0.18
3.09 ± 0.10
5.88 ± 0.26
5.10 ± 0.34
12.15 ± 0.43
2.35 ± 0.17
3.31 ± 0.15
47.44 ± 1.63
8.09 ± 0.47
1.45 ± 0.08
1.85 ± 0.12
22.32 ± 1.14
29.67 ± 1.83
68.09 ± 1.12
74.94 ± 1.07
77.44 ± 1.21
70.09 ± 1.18
1.19 ± 0.06
0.62 ± 0.04
0.88 ± 0.03
2.72 ± 0.14
1.53 ± 0.09
2.09 ± 0.17
0.54 ± 0.03
0.42 ± 0.02
0.24 ± 0.07
16.88 ± 0.86
7.63 ± 0.19
3.45 ± 0.13
18.23 ± 1.09
15.23 ± 0.72
17.23 ± 1.21
16.98 ± 0.83
15.99 ± 0.77
16.15 ± 0.27
18.67 ± 0.77
5.20 ± 0.31
1.73 ± 0.12
3.22 ± 0.12
3.08 ± 0.21
5.70 ± 0.26
4.98 ± 0.22
10.28 ± 0.54
2.80 ± 0.19
3.76 ± 0.22
8.56 ± 0.42
5.91 ± 0.31
1.25 ± 0.07
7.55 ± 0.43
9.56 ± 0.34
10.55 ± 0.83
12.14 ± 0.66
11.27 ± 0.65
10.08 ± 0.63
13.95 ± 0.49
2.38 ± 0.23
1.06 ± 0.07
1.08 ± 0.09
1.25 ± 0.06
3.18 ± 0.31
2.77 ± 0.13
5.27 ± 0.28
1.65 ± 0.08
1.96 ± 0.16
10
11
12
13
14
15
16
17
18
19
Table 2
Inhibition percent and IC50
(m
M) of the compounds 26e29 against AChE at 10ꢀ3-10 M concentrations.
ꢀ9
Compound Concentrations
ꢀ
3
ꢀ4
ꢀ5
ꢀ6
ꢀ7
ꢀ8
ꢀ9
10
M
10
M
10
M
10
M
10
M
10
M
10
M
IC50 (mM)
2
2
2
2
6
7
8
9
89.14 ± 1.33
87.05 ± 1.52
88.05 ± 1.33
90.31 ± 1.20
99.37 ± 1.24
99.16 ± 1.36
68.09 ± 1.12
74.94 ± 1.07
77.44 ± 1.21
70.09 ± 1.18
98.63 ± 1.18
98.90 ± 1.19
56.31 ± 0.98
51.43 ± 1.00
60.53 ± 1.29
61.22 ± 0.88
93.82 ± 1.06
95.95 ± 1.22
10.81 ± 0.35
13.65 ± 0.39
13.44 ± 0.48
11.53 ± 0.32
90.67 ± 0.87
75.05 ± 0.96
7.50 ± 0.24
9.75 ± 0.28
12.25 ± 0.37
7.48 ± 0.29
37.90 ± 0.91
36.64 ± 0.67
7.42 ± 0.20
8.47 ± 0.22
9.91 ± 0.35
3.75 ± 0.12
30.18 ± 0.73
20.40 ± 0.53
5.76 ± 0.15
7.22 ± 0.16
9.11 ± 0.28
3.34 ± 0.11
10.85 ± 0.42
17.05 ± 0.39
6.382 ± 0.32
8.540 ± 0.56
6.056 ± 0.29
4.895 ± 0.14
0.2197 ± 0.06
0.3715 ± 0.05
Donepezil
Tacrine
ꢀ
1
Fig. 2. LineweavereBurk graphs of the compounds 29. Respective Vmax (abs/min) values for control, 4.895
7.96, 9.71 and 3.07.
m
mM and 9.790 mM lines: 0.88, 0.41 and 0.16. Respective K (mM) values:
2

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1031
Table 3
IC50 M) of compounds 26e29 on NH3T3 cells.
Information. According to poses, it is clearly understood that the
compounds bind to AChE enzyme in a similar position with DNP
due to the DBS. The compounds 26e29 mainly carry the lipophilic
benzene and 1-indanone ring systems, piperazine moiety as a polar
group and a basic dimethylaminoalkyl side chain. The docking
poses indicate that lipophilic groups interact with the PAS region,
whereas the polar and basic groups bind to the CAS region.
The compounds 26e29 bear methoxy or dimethoxy sub-
stituents at fifth and/or sixth position of 1-indanone. The oxygen
atom of the methoxy group is very significant in terms of polar
interactions. The docking poses reveals that the methoxy sub-
stituents interact with His287, Ser293, Gln291, Leu289 and Glu292
by formation of hydrogen bond. Besides, the compounds 26 and 29,
bearing dimethoxy substituents, shows more potent binding to the
active site owing to the more polar interactions. A hydrogen bond is
also established between 1-indanone carbonyl and the amino
group of Phe295 for the compounds 26 and 29, while the same
formation occurs with Arg296 for the compound 28.
(m
IC50 (mM)
2
2
2
2
6
7
8
9
320 ± 22.10
230 ± 20.86
78 ± 19.47
78 ± 5.70
Table 4
Some physicochemical parameters of the compounds 1e38 used in prediction of
ADME profiles.
Comp.
MW
logP
tPSA
nON
nOHNH
Vol
nrotb
Vio
1
2
3
4
5
6
7
8
9
479.60
493.63
509.63
497.59
514.05
524.60
539.65
422.52
436.55
452.55
440.51
456.97
467.52
482.58
348.45
348.45
378.47
362.47
362.47
392.50
378.47
378.47
408.50
405.54
405.54
435.57
419.57
419.57
449.60
410.52
410.52
440.54
319.40
319.40
349.43
321.42
321.42
351.45
4.43
4.86
4.46
4.57
5.08
4.37
4.05
3.87
4.32
3.93
4.04
4.55
3.83
3.52
3.77
3.77
3.36
4.14
4.14
3.73
3.14
3.14
2.73
3.80
3.80
3.39
4.07
4.07
3.66
5.47
5.47
5.05
4.28
4.28
3.87
4.63
4.63
4.22
80.77
80.77
90.00
80.77
80.77
126.59
99.23
67.88
67.88
77.11
67.88
67.88
113.70
86.34
32.78
32.78
42.02
32.78
32.78
42.02
53.01
53.01
62.24
36.02
36.02
45.25
36.02
36.02
45.25
32.78
32.78
42.02
29.54
29.54
38.78
29.54
29.54
38.78
7
7
8
7
7
10
9
6
6
7
6
6
9
8
4
4
5
4
4
5
5
5
6
5
5
6
5
5
6
4
4
5
3
3
4
3
3
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
429.83
446.39
455.37
434.76
443.36
453.16
480.92
399.28
415.84
424.83
404.21
412.82
422.62
450.37
331.85
331.85
357.40
348.65
348.65
374.20
356.91
356.91
382.46
394.80
394.80
420.35
411.60
411.60
437.15
386.70
386.70
412.25
302.51
302.51
328.05
312.87
312.87
338.41
7
7
8
7
7
8
9
7
7
8
7
7
8
9
3
3
4
4
4
5
5
5
6
6
6
7
7
7
8
4
4
5
3
3
4
5
5
6
0
0
1
0
2
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
0
0
0
0
0
0
The other important factor of binding with the active site is
interaction between the 1,4-disubstituted phenyl of the compound
6, 28 and 29 and Tyr341. However, this interaction is observed
with Trp286 for the compound 27.
The formation of cation- interaction between the nitrogen
p-p
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
p
atom of the dimethylamino group and Trp86 provides an efficient
binding. Furthermore, for the compounds 26, 28 and 29, there is a
formation of hydrogen bond between nitrogen of dimethyamino
group and the carboxyl of Glu202. The piperazine ring system es-
tablishes van der Waals interaction with the amino acids in the
cavity, and therefore, it consolidates the binding with the active
region of the enzyme.
The compound 26 carries dimethylaminoethyl side chain at
fourth position of piperazine, whereas the compounds 27e29
include dimethylaminopropyl group at same position. Docking re-
sults reveal that extended carbon chain raises the van der Waals
interaction with the amino acids in the gorge and intensifies the
proper binding.
2.7. Structure-activity relationships
As a result of enzyme inhibition and docking studies, following
points about structure activity relationships of the synthesized
compounds may be recommended;
ꢂ In the compounds 1e14, substitution of piperidine with N-ary-
lacetamides causes a dramatic activity loss when compared
with DNP that carries benzyl at the same position.
ꢂ In the compounds 15e38, dimethoxy substitution of 1-indanone
at fifth and sixth positions enhances the activity when
compared with mono substitutions at the same positions.
ꢂ Para substitution of benzylidene fragment with a basic center as
piperazine, pyrrolidine or diethylamino is not enough to create
important activity.
MW: Molecular weight; log P: log octanol/water partition coefficient; tPSA: Total
Polar Surface Area; nON: number of Hydrogen acceptors; nOHNH: number of
Hydrogen donors; Vol: Molecular volume; nrotb: number of rotatable bonds; Vio:
Violation.
compounds 26e29, all calculated physicochemical parameters are
compatible with Lipinski's rule. Thus, it can be declared that the
compounds 26e29 may have a good pharmacokinetic profile,
which enhances their biological importance.
ꢂ Side chains as methyl, ethyl, hydroxyethyl and benzyl at fourth
position of piperazine do not increase the activity.
ꢂ On the other hand, the side chains as dimethylaminoethyl and
dimethylaminopropyl, which bear second basic center, at fourth
position of piperazine cause a significant activity.
2.6. Molecular docking
Docking studies were performed in order to gain more insight
ꢂ Dimethylaminopropyl substitution intensifies the activity more
into the binding mode of the compounds 26e29 and to evaluate the
effects of structural modifications on the inhibitory activity against
AChE enzyme. Studies were carried out by using the X-ray crystal
structure of Homo sapiens AChE (hAChE PDB ID:4EY7) obtained
from Protein Data Bank server (www.pdb.org).
than dimethylaminoetyl group.
3. Conclusion
Modifying the structure of existing drugs is an important
approach in the development of novel agents. Prompted from this
strategy, in the present study, 38 new DNP analogues were
The docking poses of the compounds 26e29, showing remark-
able activity in the series, are presented in Electronic Supporting

1032
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
evaluated as anticholinesterase agents. Pharmacological, toxico-
logical and ADME studies revealed the potency of the compounds
z): For C26
Elemental analyses: C26
H
29
N
3
O
4
S Calculated: 480.1952. Found: 480.1959.
S, Calculated (%): C, 65.11; H, 6.10;
29 3 4
H N O
2
6e29. The docking studies clearly explained the molecular in-
N, 8.76; S, 6.68. Found (%): C, 65.09; H, 6.11; N, 8.74; S, 6.66.
4.1.1.2.2. N-(6-Methylbenzo[d]thiazol-2-yl)-2-(4-((5,6-
dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)
teractions between the compounds and AChE. Consequently, all
these data may have an impact on medicinal chemists to synthesize
more potent compounds as inhibitors against AChE.
ꢃ
ꢀ1
acetamide (2). Yield: 87%. Mp: 205.5 C. IR (ATR) Vmax (cm ): 3273
N-H stretching), 1695 (indanone C¼O stretching), 1680 (amide
C¼O stretching), 1593-1429 (C¼C and C¼N stretchings), 1257 (C-N
(
4
. Experimental
1
stretching), 1029 (C-O stretching). H NMR (500 MHz) (DMSO-d
(ppm): 1.20e1.31 (3H, m, H ), 1.45 (1H, s, H þH ), 1.62e1.65
þH
1H, m, H ), 1.70e1.75 (2H, m, H ), 2.17e2.22 (2H, m, H þH ),
þH
2.42 (3H, s, -CH ), 2.64e2.68 (2H, m, H
), 2.88 (2H, t, J ¼ 11.65 Hz,
-CH -), 3.26 (2H, s, -CH -CO-), 3.35 (1H, s, H ), 3.80 (3H, s, C -OCH ),
3.87 (3H, s, C -OCH ), 7.07 (1H, s, H ), 7.10 (1H, s, H ), 7.26 (1H, dd,
J ¼ 1.30 Hz and J ¼ 8.25 Hz, H
00), 7.63 (1H, d, J ¼ 8.25 Hz, H 00), 7.77
(1H, d, J ¼ 1.30 Hz, H
00), 9.72 (1H, s, -NH-). C-APT NMR (125 MHz)
(DMSO-d (ppm): 21.44 (1C, -CH ), 31.83 (1C, C ), 33.05 (2C,
), 33.15 (1C, C ), 40.02 (1C, -CH -), 45.22 (1C, C ), 53.72 (2C,
), 56.08 (1C, C -OCH ), 56.40 (1C, C -OCH ), 61.20 (1C, -CH
), 108.67 (1C, C ), 120.62 (1C, C
00), 121.78 (1C,
00), 128.91 (1C, C7a), 131.10 (1C, C
), 149.93 (1C, C3a), 150.76 (1C, C
6
)
4.1. Chemistry
d
3
0
5
0
3
0
0
5
(
4
0
2
0
6
0
2
0
0
6
All reagents were purchased from commercial suppliers and
3
3
were used without further purification. Melting points (M.p.) were
determined on Mettler Toledo-MP90 Melting Point System and
were uncorrected. The TLC was performed on silica gel 60 F254
2
2
2
5
3
6
3
4
7
5
4
13
(
Merck) layer using petroleum ether: ethyl acetate (3:1 or 1:1 v/v)
7
as eluents. IR spectra were recorded on an IR Affinity-1S Infrared
spectrophotometer (Shimadzu, Tokyo, Japan). H NMR spectra were
recorded on a Bruker, UltraShield 500 MHz NMR and C NMR
spectra were recorded on a Bruker, UltraShield 100 MHz NMR
spectrometer (Bruker, USA) using DMSO-d
were expressed in parts per million (ppm) and tetramethylsilane
was used as an internal standard. Mass spectra were recorded on a
LCMS-IT-TOF (Shimadzu, Kyoto, Japan) by using ESI method.
Elemental analyses were performed on a Leco CHNS-932 analyzer
6
)
d
3
3
1
C
C
3
0
0
þC
5
6
0
0
4
0
2
2
13
2
þC
5
3
6
3
2
-
CO-), 104.46 (1C, C
4
7
4
6
. Chemical shifts (
d)
C
7
C
6
C
5
00), 127.91 (1C, C
00), 149.19 (1C, C
5
7
00
a
), 133.49 (1C,
), 155.71 (1C,
00
6
3
a
), 158.07 (1C, C
(ESI) (MþH) (m/z): For C27
2
00), 170.08 (1C, -NH-CO-), 207.06 (1C, C
S Calculated: 494.2108. Found:
S, Calculated (%): C,
1
). HRMS
þ
31 3 4
H N O
31 3 4
494.2109. Elemental analyses: C27H N O
(
USA).
65.70; H, 6.33; N, 8.51; S, 6.49. Found (%): C, 65.68; H, 6.31; N, 8.48;
S, 6.50.
4
4
.1.1. General procedure for the synthesis of the compounds
.1.1.1. 2-Chloro-N-arylacetamide derivatives. Chloroacetyl chloride
4.1.1.2.3. N-(6-Methoxybenzo[d]thiazol-2-yl)-2-(4-((5,6-
dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)
ꢃ
ꢀ1
(
33 mmol, 2.63 mL) was added dropwise with stirring to a mixture
acetamide (3). Yield: 92%. Mp: 175 C. IR (ATR) Vmax (cm ): 3275
(N-H stretching), 1697 (indanone C¼O stretching), 1681 (amide
of triethylamine (33 mmol, 4.63 mL) and 2-aminobenzothiazole or
aniline derivative (30 mmol) in THF (100 mL) at 0 C. After the
completion of dropping, the mixture was allowed to stir for 1 h. The
solvent was evaporated under reduced pressure. The residue was
washed with water to remove trimethylamine hydrochloride, dried
and recrystallized from EtOH [59,60].
ꢃ
C¼O stretching), 1602-1500 (C¼C and C¼N stretchings), 1259 (C-N
1
stretching), 1029 (C-O stretching). H NMR (500 MHz) (DMSO-d
6
)
d
(ppm): 1.21e1.31 (3H, m, H
(1H, m, H ), 1.70e1.75 (2H, m, H
2.64e2.69 (2H, m, H
), 3.27 (2H, s, -CH
OCH
J ¼ 8.80 Hz, H
J ¼ 2.55 Hz, H
00), 7.64 (1H, d, J ¼ 8.80 Hz, H
APT NMR (125 MHz) (DMSO-d (ppm): 31.84 (1C, C
), 39.86 (1C, -CH -), 45.22 (1C, C
-OCH ), 56.11 (1C, C ), 56.70 (1C, C
-CO-), 104.46 (1C, C ), 105.26 (1C, C
00), 108.68
), 115.38 (1C, C
00), 121.58 (1C, C 00), 128.91 (1C, C7a), 133.26
), 143.04 (1C, C ), 149.59 (1C, C3a), 155.72
00), 149.19 (1C, C
), 155.94 (1C, C
00), 169.93 (1C, -NH-CO-),
207.06 (1C, C
3
0
þH
5
0
), 1.45 (1H, s, H
þH ), 2.17e2.22 (2H, m, H
), 2.90 (2H, t, J ¼ 11.50 Hz, -CH -), 3.39 (1H, s,
-CO-), 3.80 (3H, s, C -OCH ), 3.84 (3H, s, C
-OCH
), 7.03 (1H, dd, J ¼ 2.60 Hz and
00), 7.07 (1H, s, H
), 7.10 (1H, s, H ), 7.57 (1H, d,
00), 9.76 (1H, s, -NH-). C-
), 33.16 (2C,
), 53.73 (2C,
3
0
þH
5
0
), 1.62e1.65
0
0
0
0
þH ),
0
6
4
2
6
2
3
2
2
H
2
5
3
00
-
6
4
.1.1.2. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)
methyl)piperidin-1-yl)-N-acetamide derivatives (1e14). A mixture
of 5,6-dimethoxy-2-(piperidin-4-yl-methyl)-2,3-dihydro-1H-
3
), 3.87 (3H, s, C
6
3
5
4
7
13
7
4
inden-1-one (1 mmol, 0.289 g) and 2-chloro-N-arylacetamide de-
rivatives (1 mmol) in acetone (10 mL) was stirred at 40 C for 12 h in
the presence of potassium carbonate (1 mmol, 0.138 g). The solvent
was evaporated. The residue was washed with water, dried and
crystallized from ethanol [61].
6
)
d
3
ꢃ
C
C
OCH
(1C, C
(1C, C
(1C, C
3
0
0
þC
5
6
0
0
), 33.82 (1C, C
), 56.08 (1C, C
4
0
2
2
þC
5
3
6
00-OCH
3
6
-
2
3
), 61.17 (1C, -CH
2
4
5
7
7
4
4
.1.1.2.1. N-(Benzo[d]thiazol-2-yl)-2-(4-((5,6-dimethoxy-1-oxo-
7
00
a
6
6
2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)acetamide (1).
3
00
a
5
), 156.64 (1C, C
2
ꢃ
ꢀ1
þ
Yield: 89%. Mp: 193.1 C. IR (ATR) Vmax (cm ): 3263 (N-H
1
). HRMS (ESI) (MþH) (m/z): For C27
31 3 5
H N O S
stretching), 1697 (indanone C¼O stretching), 1681 (amide C¼O
Calculated: 510.2057. Found: 510.2054. Elemental analyses:
27 31 3 5
C H N O S, Calculated (%): C, 63.63; H, 6.13; N, 8.25; S, 6.29.
stretching), 1593-1446 (C¼C and C¼N stretchings), 1265 (C-N
1
stretching), 1033 (C-O stretching). H NMR (500 MHz) (DMSO-d
6
)
Found (%): C, 63.61; H, 6.12; N, 8.24; S, 6.30.
d
(ppm): 1.22e1.30 (3H, m, H
1H, m, H ),1.72e1.75 (2H, m, H
.66e2.69 (2H, m, H
), 2.90 (2H, t, J ¼ 11,60 Hz, -CH
CO-), 3.34 (1H, s, H ), 3.80 (3H, s, C -OCH ), 3.88 (3H, s, C
), 7.07 (1H, s, H ), 7.10 (1H, s, H
), 7.32 (1H, t, J ¼ 7.20 Hz, H
.45 (1H, t, J ¼ 7.60 Hz, H
00), 7.75 (1H, d, J ¼ 7.95 Hz, H 00), 7.99 (1H, d,
J ¼ 7.95 Hz, H
00), 9.72 (1H, s, -NH-). C-APT NMR (125 MHz)
DMSO-d (ppm): 31.82 (1C, C ), 33.05 (2C, C ), 33.82 (1C,
þC
), 38.66 (1C, -CH -), 45.22 (1C, C ), 53.72 (2C, C ), 56.08 (1C,
þC
), 56.40 (1C, C -OCH ), 62.21 (1C, -CH -CO-), 104.46 (1C,
), 120.98 (1C, C
00), 122.18 (1C, C 00), 124.03 (1C,
00), 128.91 (1C, C7a), 131.95 (1C, C
), 148.96 (1C,
), 149.59 (1C, C ), 155.72 (1C, C
00), 170.24 (1C, -NH-CO-), 207.07 (1C, C
3
0
þH
5
0
), 1.47 (1H, s, H
), 2.18e2.22 (2H, m, H
-), 3.19 (2H, s,
3
0
þH
5
0
), 1.63e1.71
4.1.1.2.4. N-(6-Fluorobenzo[d]thiazol-2-yl)-2-(4-((5,6-dimethoxy-
1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)acetamide
(
2
4
0
2
0
þH
6
0
2
0
þH ),
0
6
ꢃ
ꢀ1
3
2
(4). Yield: 88%. Mp: 212.5 C. IR (ATR) Vmax (cm ): 3265 (N-H
stretching), 1701 (indanone C¼O stretching), 1676 (amide C¼O
-
CH
2
2
5
3
6
-
OCH
7
3
4
7
5
00),
stretching), 1604-1456 (C¼C and C¼N stretchings), 1199 (C-N
1
6
4
stretching), 1124 (C-O stretching). H NMR (500 MHz) (DMSO-d
6
)
13
0
þH
0
), 1.45 (1H, s, H
), 2.17e2.21 (2H, m, H
-), 3.22 (2H, s,
0
þH
0
), 1.65e1.66
7
d
(ppm): 1.20e1.28 (3H, m, H
(1H, m, H ), 1.70e1.75 (2H, m, H
2.64e2.68 (2H, m, H
), 2.89 (2H, t, J ¼ 11.55 Hz, -CH
-CH CO-), 3.39 (1H, s, H ), 3.79 (3H, s, C -OCH ), 3.87 (3H, s, C
OCH ), 7.06 (1H, s, H ), 7.09 (1H, s, H ), 7.27e7.32 (1H, m, H
7.74e7.77 (1H, m, H
00), 7.89e7.91 (1H, m, H 00), 9.75 (1H, s, -NH-).
C-APT NMR (125 MHz) (DMSO-d (ppm): 31.80 (1C, C ), 33.09
(2C, C ), 33.80 (1C, C ), 40.02 (1C, -CH -), 45.21 (1C, C ), 53.71
þC
3
5
3
5
(
6
)
d
3
3
0
5
0
4
0
2
0
þH
6
0
2
0
þH ),
0
6
C
C
C
C
C
C
4
5
4
6
0
2
2
2
0
6
0
3
2
-OCH
3
6
3
2
2
2
5
3
6
-
), 108.68 (1C, C
00), 126.59 (1C, C
3a), 149.19 (1C, C
7
4
7
3
4
7
7
00),
00
5
7
a
4
5
13
00
), 158.00 (1C,
)
d
6
3
a
5
6
3
þ
). HRMS (ESI) (MþH) (m/
3
0
5
0
4
0
2
2
2
1

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1033
(
-
(
(
C
(
4
6
2C, C
CH -CO-), 104.46 (1C, C
1C, C
00), 123.59 (1C, C 00), 128.91 (1C, C7a), 131.79 (1C, C
1C, C ), 149.19 (1C, C ), 149.59 (1C, C3a), 155.71 (1C,
00), 148.03 (1C, C
00), 170.31 (1C, -NH-CO-), 207.06 (1C, C
). HRMS
FS Calculated: 498.1857. Found:
FS, Calculated (%): C,
2.76; H, 5.67; N, 8.44; S, 6.44. Found (%): C, 62.75; H, 5.66; N, 8.42;
2
0
þC
6
0
), 56.08 (1C, C
5
-OCH
3
), 56.39 (1C, C
6
-OCH
3
), 61.14 (1C,
00), 122.12
), 133.15
OCH
3
), 3.83 (3H, s, C
), 7.30 (1H, s, H
C-APT NMR (125 MHz) (DMSO-d
(2C, C ), 33.15 (1C, C ), 39.68 (1C, -CH
þC
(2C, C ), 56.08 (1C, C -OCH ), 56.12 (1C, C
þC
), 56.46 (1C, C -OCH ), 61.12 (1C, -CH
), 104.26 (1C, C
00), 104.46 (1C, C
), 128.91 (1C, C7a), 142.47 (1C, C
), 149.42 (1C, C3a), 150.28 (1C, C
00), 169.61 (1C, -NH-CO-), 207.07 (1C, C
6
00-OCH
3
), 3.87 (3H, s, C
00), 7.55 (1H, s, H
(ppm): 31.85 (1C, C
-), 45.22 (1C, C
), 56.33 (1C,
-CO-), 104.03 (1C,
6
-OCH
00), 9.78 (1H, s, -NH-).
), 33.08
), 53.73
3 4
), 7.07 (1H, s, H ),
2
4
), 108.53 (1C, C
7
), 120.04 (1C, C
4
7.10 (1H, s, H
7
4
7
13
00
)
d
7
5
7
a
6
3
0
0
0
6
5
6
3
5
4
2
2
00
), 158.74 (1C, C
0
0
00-OCH
3
a
2
1
2
6
5
3
5 3
þ
ESI) (MþH) (m/z): For C26
H
28
N
3
O
4
C
6
C
4
C
7
C
6
C
2
00-OCH
3
6
3
2
98.1862. Elemental analyses: C26
28
H N
3
O
4
4
7
00), 108.67 (1C, C
7
), 123.38 (1C,
00), 148.56 (1C,
6
00
00), 142.95 (1C, C
a
5
S, 6.43.
3
00
a
), 155.72 (1C, C
5
), 156.40 (1C,
þ
4
.1.1.2.5. N-(6-Chlorobenzo[d]thiazol-2-yl)-2-(4-((5,6-
dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)
acetamide (5). Yield: 84%. Mp: 171.7 C. IR (ATR) Vmax (cm ): 3292
N-H stretching), 1705 (indanone C¼O stretching), 1676 (amide
C¼O stretching), 1593-1444 (C¼C and C¼N stretchings), 1261 (C-N
1
). HRMS (ESI) (MþH) (m/
z): For C28
H N
33 3
O
6
S Calculated: 540.2163. Found: 540.2163.
S, Calculated (%): C, 62.32; H, 6.16;
ꢃ
ꢀ1
Elemental analyses: C28H N O
33 3 6
(
N, 7.79; S, 5.94. Found (%): C, 62.30; H, 6.17; N, 7.80; S, 5.93.
4.1.1.2.8. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-phenylacetamide (8). Yield: 92%. Mp:
1
stretching), 1033 (C-O stretching). H NMR (500 MHz) (DMSO-d
(ppm): 1.21e1.30 (3H, m, H ), 1.45 (1H, s, H ), 1.62e1.65
1H, m, H ),1.70e1.75 (2H, m, H ), 2.18e2.22 (2H, m, H þH ),
þH
.65e2.69 (2H, m, H -), 3.22 (2H, s,
), 2.90 (2H, t, J ¼ 11.70 Hz, -CH
CO-), 3.35 (1H, s, H ), 3.80 (3H, s, C -OCH ), 3.87 (3H, s, C
), 7.07 (1H, s, H ), 7.10 (1H, s, H
), 7.46 (1H, dd, J ¼ 2.20 Hz and
J ¼ 8.60 Hz, H
00), 7.74 (1H, d, J ¼ 8.60 Hz, H 00), 8.14 (1H, d,
J ¼ 2.15 Hz, H
00), 9.74 (1H, s, -NH-). C-APT NMR (125 MHz)
DMSO-d (ppm): 31.78 (1C, C ), 33.08 (2C, C ), 33.80 (1C,
þC
), 40.02 (1C, -CH -), 45.21 (1C, C ), 53.70 (2C, C ), 56.08 (1C,
þC
), 56.39 (1C, C -OCH ), 61.15 (1C, -CH -CO-),104.45 (1C, C ),
), 121.91 (1C, C
00), 122.18 (1C, C 00), 126.94 (1C, C
28.91 (1C, C7a), 131.33 (1C, C ), 133.66 (1C, C
00), 147.66 (1C, C
49.18 (1C, C ), 149.59 (1C, C3a), 155.71 (1C, C
70.43 (1C, -NH-CO-), 207.06 (1C, C
For
Elemental analyses: C26
6
)
ꢃ
ꢀ1
d
3
0
þH
5
0
3
0
þH
5
0
174.1 C. IR (ATR) Vmax (cm ): 3290 (N-H stretching), 1697 (inda-
(
2
-
4
0
2
0
6
0
2
0
6
0
none C¼O stretching), 1681 (amide C¼O stretching), 1589-1442
1
3
2
(C¼C and C¼N stretchings), 1037 (C-N stretching). H NMR
CH
2
2
5
3
6
-
(500 MHz) (DMSO-d
6
)
d
(ppm): 1.25e1.38 (3H, m, H
3
0
þH
5
0
), 1.46
þH ),
), 2.70 (2H, t,
CO-), 3.30e3.33 (1H, m, H ),
-OCH ), 7.08 (1H, s, H ), 7.10
00), 7.31e7.33 (2H, m, H 00), 7.64 (2H,
OCH
3
4
7
(1H, s, H
2.08e2.15 (2H, m, H
J ¼ 11.45 Hz, -CH -), 3.05 (2H, s, -CH
3.80 (3H, s, C -OCH ), 3.87 (3H, s, C
(1H, s, H ), 7.29 (1H, m, H
dd, J ¼ 2.40 Hz and J ¼ 8.60 Hz, H
NMR (125 MHz) (DMSO-d
3
0
þH
5
0
), 1.63e1.65 (1H, m, H
4
0
), 1.71e1.78 (2H, m, H
2
0
0
6
0
þH ), 2.50e2.51 (2H, m, H
0
5
4
2
6
3
13
7
2
2
2
(
C
C
1
1
6
)
d
3
3
0
5
0
5
3
6
3
4
0
0
0
00þH
4
5
2
2
2
6
7
4
3
5
13
-OCH
08.66 (1C, C
3
6
3
2
4
2
00þH
6
00), 9.66 (1H, s, -NH-). C-APT
(ppm): 33.03 (2C, C
00),
)
d
0
þC
-), 45.22 (1C, C
), 56.46 (1C, C -OCH ), 60.93 (1C, -CH
), 108.68 (1C, C ), 119.88 (2C, C
6
00), 123.84
0
), 33.14 (1C,
7
4
7
5
6
3
5
00
),
C
C
), 33.82 (1C, C
0
), 40.02 (1C, -CH
-OCH
), 53.94 (2C,
7
a
6
5
3
4
2
2
1
1
6
3
00
a
), 158.90 (1C, C
2
00),
2
0
þC ), 56.08 (1C, C
6
0
5
3
6
3
2
-
þ
). HRMS (ESI) (MþH) (m/z):
CO-), 104.46 (1C, C
(1C, C
00), 129.13 (2C, C
4
7
2
00þC
1
C
26
H
28
N
3
O
4
SCl Calculated: 514.1562. Found: 514.1562.
SCl, Calculated (%): C, 60.75; H,
.49; N, 8.17; S, 6.24. Found (%): C, 60.73; H, 5.48; N, 8.18; S, 6.25.
.1.1.2.6. N-(6-Nitrobenzo[d]thiazol-2-yl)-2-(4-((5,6-dimethoxy-
-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)acetamide
4
3
00þC
5
00), 128.91 (1C, C7a), 139.03 (1C, C 00),
1
28
H N
3
O
4
149.20 (1C, C3a), 155.65 (1C, C
6
), 155.72 (1C, C
5
), 168.70 (1C, -NH-
þ
5
CO-), 207.07 (1C, C
1
). HRMS (ESI) (MþH) (m/z): For C25
30 2 4
H N O
4
Calculated: 423.2278. Found: 423.2298. Elemental analyses:
25 30 2 4
C H N O , Calculated (%): C, 71.07; H, 7.16; N, 6.63. Found (%): C,
1
(
ꢃ
ꢀ1
6). Yield: 89%. Mp: 132.4 C. IR (ATR) Vmax (cm ): 3296 (N-H
71.05; H, 7.15; N, 6.62.
stretching), 1712 (indanone C¼O stretching), 1695 (amide C¼O
4.1.1.2.9. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(p-tolyl)acetamide (9). Yield: 86%. Mp:
stretching), 1506-1440 (C¼C and C¼N stretchings), 1126 (C-N
1
ꢃ
ꢀ1
stretching), 1037 (C-O stretching). H NMR (500 MHz) (DMSO-d
6
)
144.5 C. IR (ATR) Vmax (cm ): 3273 (N-H stretching), 1697
(indanone C¼O stretching), 1668 (amide C¼O stretching), 1589-
1498 (C¼C and C¼N stretchings), 1120 (C-N stretching), 810 (1,4-
d
(ppm): 1.25e1.31 (3H, m, H
1H, m, H ), 1.70e1.77 (2H, m, H
), 2.66e2.69 (2H, m, H
), 2.96 (2H, t, J ¼ 11.20 Hz, -CH
CO-), 3.46 (1H, s, H ), 3.80 (3H, s, C -OCH ), 3.87
), 7.07 (1H, s, H ), 7.10 (1H, s, H ), 7.87 (1H, d,
00), 8.28 (1H, dd, J ¼ 2.40 Hz and J ¼ 8.90 Hz, H 00), 9.03
00), 9.77 (1H, s, -NH-). C-APT NMR (125 MHz)
3
0
þH
5
0
), 1.48 (1H, s, H
þH ), 2.26e2.30 (2H, m,
-),
3
0
þH
5
0
), 1.64e1.67
(
H
3
4
0
2
0
0
6
1
0
þH
0
disubstitued benzene out of plane bending). H NMR (500 MHz)
2
6
3
2
.25 (2H, s, -CH
2
2
5
3
(DMSO-d
þH ), 1.62e1.65 (1H, m, H
2.09e2.16 (2H, m, H ), 2.26 (3H, s, -CH
þH
), 2.87 (2H, t, J ¼ 11.425 Hz, -CH -), 3.07 (2H, s, -CH
3.22e3.27 (1H, m, H ), 3.80 (3H, s, C -OCH ), 3.87 (3H, s, C -OCH
7.07 (1H, s, H ), 7.10e7.12 (3H, m, H
þH
00), 7.52 (2H, d,
J ¼ 8.35 Hz, H
(DMSO-d
33.14 (1C, C
56.08 (1C, C
104.46 (1C, C
6
)
d
(ppm): 1.24e1.36 (3H, m, H
), 1.71e1.75 (2H, m, H
), 2.65e2.69 (2H, m,
CO-),
),
3
0
þH
5
0
), 1.45 (1H, s,
(
3H, s, C -OCH
6
3
4
7
H
3
0
5
0
4
0
2
0
þH ),
0
6
J ¼ 8.95 Hz, H
4
5
2
0
6
0
3
13
(
(
C
C
C
1H, d, J ¼ 2.40 Hz, H
DMSO-d (ppm): 32.71 (1C, C
), 40.02 (1C, -CH -), 45.19 (1C, C
), 56.40 (1C, C -OCH ), 59.98 (1C, -CH
), 120.83 (1C, C
00), 122.16 (1C, C
7
H
3
2
2
)
d
3
), 33.84 (2C, C
), 53.60 (2C, C
3
0
þC
5
0
), 33.87 (1C,
), 56.08 (1C,
2
5
3
6
3
6
0
0
þC
0
00þH
4
5
4
2
2
2
6
4
7
3
5
13
-OCH
), 108.67 (1C, C
3
6
3
2
-CO-), 103.76 (1C,
00), 127.31 (1C, C
2
00þH
6
00), 9.56 (1H, s, -NH-). C-APT NMR (125 MHz)
00),
)
d
(ppm): 20.90 (-CH
), 31.76 (1C, C
-), 45.22 (1C, C
), 56.40 (1C, C -OCH
), 108.67 (1C, C ), 119.88 (2C, C
00), 128.90 (1C, C7a), 132.74 (1C, C
), 155.71 (1C, C
), 33.03 (2C, C
), 53.96 (2C, C
), 62.67 (1C, -CH
0
0
þC
þC
0
0
),
),
7
4
7
5
6
3
3
3
2
5
6
1
1
1
28.84 (1C, C7a), 131.48 (1C, C
49.36 (1C, C ), 149.63 (1C, C3a), 155.67 (1C, C
77.53 (1C, -NH-CO-), 207.58 (1C, C
For C26
analyses: C26
.11. Found (%): C, 59.51; H, 5.39; N, 10.66; S, 6.10.
.1.1.2.7. N-(5,6-Dimethoxybenzo[d]thiazol-2-yl)-2-(4-((5,6-
dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)piperidin-1-yl)
7
00
a
), 133.42 (1C, C
6
00), 148.61 (1C, C
5
),
00),
4
0
), 39.68 (1C, -CH
-OCH
2
2
00
), 156.28 (1C, C
). HRMS (ESI) (MþH) (m/z):
-CO-),
6
3
a
2
5
3
6
3
2
þ
00þC
00), 129.49 (2C,
00), 136.52 (1C, C 00), 149.19
1 4
1
4
7
2
6
28
H N
4
O
H
6
S Calculated: 525.1802. Found: 525.1806. Elemental
S, Calculated (%): C, 59.53; H, 5.38; N, 10.68; S,
C
3
00þC
5
28
N
4
O
6
(1C, C3a), 159.59 (1C, C
6
5
), 168.77 (1C, -NH-CO-),
). HRMS (ESI) (MþH) (m/z): For C26 Calcu-
32 2 4
lated: 437.2435. Found: 437.2454. Elemental analyses: C26H N O ,
þ
6
207.07 (1C, C
1
32 2 4
H N O
4
Calculated (%): C, 71.53; H, 7.39; N, 6.42. Found (%): C, 71.51; H, 7.38;
N, 6.40.
ꢃ
ꢀ1
acetamide (7). Yield: 82%. Mp: 136.5 C. IR (ATR) Vmax (cm ): 3263
N-H stretching), 1695 (indanone C¼O stretching), 1683 (amide
C¼O stretching), 1539-1435 (C¼C and C¼N stretchings), 1201 (C-N
(
4.1.1.2.10. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(p-methoxyphenyl)acetamide
Yield: 89%. Mp: 138.2 C. IR (ATR) Vmax (cm ): 3278 (N-H
(10).
1
ꢃ
ꢀ1
stretching), 1159 (C-O stretching). H NMR (500 MHz) (DMSO-d
(ppm): 1.20e1.30 (3H, m, H ), 1.45 (1H, s, H ), 1.62e1.65
1H, m, H ), 1.70e1.77 (2H, m, H ), 2.17e2.21 (2H, m, H þH ),
þH
.65e2.69 (2H, m, H -), 3.18 (2H, s,
), 2.89 (2H, t, J ¼ 11.60 Hz, -CH
CO-), 3.31 (1H, s, H ), 3.80 (3H, s, C -OCH ), 3.81 (3H, s, C
6
)
d
3
0
þH
5
0
3
0
þH
5
0
stretching), 1697 (indanone C¼O stretching), 1674 (amide C¼O
(
2
4
0
2
0
6
0
2
0
6
0
stretching), 1591-1498 (C¼C and C¼N stretchings), 1236 (C-N
1
3
2
stretching), 1122 (C-N stretching). H NMR (500 MHz) (DMSO-d
6
)
-
CH
2
2
5
3
5
00
-
d
(ppm): 1.24e1.39 (3H, m, H
3
0
þH
5
0
), 1.45 (1H, s, H
3
0
þH
5
0
), 1.63e1.65

1034
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
(
1H, m, H
4
0
), 1.71e1.76 (2H, m, H
.65e2.69 (2H, m, H ), 2.89 (2H, s, -CH
.22e3.25 (1H, m, H ), 3.73 (3H, s, C
.87 (3H, s, C -OCH
), 6.88 (2H, d, J ¼ 2.15 Hz, H
), 7.10 (1H, s, H
), 7.54 (2H, d, J ¼ 2.67 Hz, H
NH-). C-APT NMR (125 MHz) (DMSO-d
2
0
þH
6
0
), 2.17e2.18 (2H, m, H
-), 3.10 (2H, s, -CH
), 3.80 (3H, s, C -OCH
00), 7.06 (1H, s,
00), 9.56 (1H, s,
2
0
þH
CO-),
),
6
0
),
stretching), 852 (1,4-disubstitued benzene out of plane bending).
1
2
3
3
H
-
C
C
6
C
1
1
3
2
2
H NMR (500 MHz) (DMSO-d
1.46 (1H, s, H ), 1.62e1.65 (1H, m, H
þH
þH ), 2.14e2.18 (2H, m, H þH ), 2.66e2.69 (2H, m, H
(2H, t, J ¼ 11.50 Hz, -CH -), 3.18 (2H, s, -CH CO-), 3.22e3.27 (1H, m,
), 3.80 (3H, s, C -OCH ), 3.87 (3H, s, C -OCH ), 7.06 (1H, s, H ),
7.10 (1H, s, H
00), 8.23 (2H, d,
J ¼ 2.375 Hz, H
(DMSO-d
6
)
d
(ppm): 1.25e1.31 (3H, m, H
), 1.71e1.76 (2H, m,
), 2.88
3
0
þH
5
0
),
00-OCH
0
0
0
4
2
4
3
5
3
3
5
00þH
H
0
0
0
0
6
3
3
5
2
6
2
6
3
00þH
4
7
2
6
2
2
13
6
)
d
(ppm): 33.05 (2C,
H
2
5
3
6
3
4
0
þC
), 53.93 (2C, C
-CO-), 104.46 (1C, C
0
), 33.13 (1C, C
), 33.14 (1C, C
), 56.08 (1C, C
0
), 40.02 (1C, -CH
-OCH ), 56.40 (1C, C
), 108.67 (1C, C ), 114.26 (2C,
00), 128.90 (1C, C7a), 132.18 (1C, C
), 155.72 (1C, C
00), 155.83 (1C, C
). HRMS (ESI) (MþH) (m/z):
Calculated: 453.2384. Found: 453.2389. Elemental
, Calculated (%): C, 69.01; H, 7.13; N, 6.19.
Found (%): C, 69.00; H, 7.11; N, 6.18.
.1.1.2.11. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(p-fluorophenyl)acetamide (11).
-), 45.21 (1C,
), 7.93 (2H, d, J ¼ 2.45 Hz, H
00þH
3
5
3
4
2
7
2
6
13
0
þC
0
-OCH ),
00þH
00), 10.30 (1H, s, -NH-). C-APT NMR (125 MHz)
2
2
6
5
3
6
3
3
5
2.15 (1C, -CH
2
4
7
6
)
d
(ppm): 31.67 (2C, C
3
0
þC
), 53.88 (2C, C
), 62.73 (1C, -CH
5
0
), 33.13 (1C, C
3
), 33.82 (1C,
), 56.08 (1C,
-CO-), 104.45 (1C,
00þC
00), 121.50 (2C, C
00þC
00),
C
4
C
5
C
4
0
), 40.02 (1C, -CH
-OCH ), 56.40 (1C, C
), 108.67 (1C, C ), 119.60 (2C, C
-), 45.21 (1C, C
0
þC
0
3
5
2
6
1
2
2
2
6
49.19 (1C, C3a), 149.60 (1C, C
6
4
5
),
3
6
-OCH
3
2
þ
68.90 (1C, -NH-CO-), 207.06 (1C, C
For C26
analyses: C26
1
7
2
00þC
6
00), 125.53 (2C, C
3
00þC
5
00),
H
32
N
2
O
5
128.90 (1C, C7a), 142.78 (1C, C
4 1
00), 145.30 (1C, C 00), 149.19 (1C, C3a),
H
32
N
2
O
5
149.59 (1C, C
6
), 155.72 (1C, C
5
), 168.70 (1C, -NH-CO-), 207.06 (1C,
Calculated:
þ
C
1
). HRMS (ESI) (MþH) (m/z): For C25
29 3 6
H N O
4
29 3 6
468.2129. Found: 468.2131. Elemental analyses: C25H N O ,
Calculated (%): C, 64.23; H, 6.25; N, 8.99. Found (%): C, 64.22; H,
6.24; N, 8.98.
ꢃ
ꢀ1
Yield: 91%. Mp: 155.8 C. IR (ATR) Vmax (cm ): 3309 (N-H
stretching), 1703 (indanone C¼O stretching), 1689 (amide C¼O
stretching), 1525-1498 (C¼C and C¼N stretchings), 1222 (C-N
4.1.1.2.14. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(3,4-dimethoxyphenyl)acetamide (14).
1
stretching), 1124 (C-O stretching), 827 (1,4-disubstitued benzene
Yield: 87%. Oil. H NMR (500 MHz) (DMSO-d
6
)
d
(ppm): 1.24e1.33
), 1.62e1.65 (1H, m, H ),
), 2.11e2.16 (2H, m, H ), 2.66e2.69
þH
), 2.87 (2H, t, J ¼ 11.40 Hz, -CH -), 3.06 (2H, s, -CH CO-),
3.21e3.27 (1H, m, H ), 3.72 (3H, s, C -OCH ), 3.74 (3H, s, C ),
3.78 (3H, s, C ), 3.87 (3H, s, C -OCH ), 6.88 (1H, d,
J ¼ 8.70 Hz, H ), 7.09 (1H, s, H ), 7.17 (1H, dd,
00), 7.06 (1H, s, H
J ¼ 2.30 Hz and J ¼ 8.70 Hz, H
00), 7.34 (1H, d, J ¼ 2.30 Hz, H 00), 9.50
(1H, s, -NH-). C-APT NMR (125 MHz) (DMSO-d (ppm): 31.72
(2C, C ), 33.12 (1C, C ), 33.86 (1C, C ), 40.02 (1C, -CH -), 45.22
þC
(1C, C ), 54.00 (2C, C ), 55.94 (1C, C ), 55.97 (1C, C
þC
OCH ), 56.08 (1C, C -OCH ), 56.46 (1C, C ), 62.17 (1C, -CH
CO-), 104.45 (1C, C ), 105.22 (1C, C
00), 108.67 (1C, C
00), 128.91 (1C, C7a), 132.73 (1C, C 00), 145.43 (1C,
00), 149.19 (1C, C3a), 149.59 (1C, C
1
out of plane bending). H NMR (500 MHz) (DMSO-d
6
)
d
(ppm):
), 1.62e1.64 (1H, m,
), 2.09e2.16 (2H, m, H ),
þH
), 2.87 (2H, t, J ¼ 11.45 Hz, -CH -), 3.09 (2H, s,
CO-), 3.21e3.27 (1H, m, H ), 3.80 (3H, s, C -OCH ), 3.87 (3H, s,
-OCH ), 7.06 (1H, s, H ), 7.10 (1H, s, H ), 7.13e7.16 (2H, m,
00), 7.66e7.68 (2H, m, H
(3H, m, H
1.71e1.76 (2H, m, H
(2H, m, H
3
0
þH
5
0
), 1.46 (1H, s, H
3
0
þH
5
0
0
4
1
H
2
-
C
H
.24e1.33 (3H, m, H
), 1.71e1.75 (2H, m, H
.65e2.68 (2H, m, H
CH
3
0
þH
5
0
), 1.45 (1H, s, H
3
0
þH
5
0
2
0
þH
6
0
2
0
0
6
0
0
þH
0
0
0
4
2
6
2
6
3
2
2
00-OCH
3
2
2
5
3
3 3
00-OCH
2
2
5
3
4
3
6
3
6
3
4
7
5
4
7
1
3
00þH
00þH
00), 9.73 (1H, s, -NH-). C-APT
þC ), 33.14 (1C,
-), 45.22 (1C, C ), 53.96 (2C,
), 56.40 (1C, C -OCH ), 62.67 (1C, -CH
), 108.67 (1C, C ), 115.63 (2C, C
00), 128.91 (1C, C7a), 135.48 (1C, C
3
5
2
6
6
2
13
NMR (125 MHz) (DMSO-d
), 33.85 (1C, C
6
)
d
(ppm): 32.98 (2C, C
3
0
5
0
6
) d
C
C
3
4
0
), 40.02 (1C, -CH
-OCH
2
2
3
0
5
0
3
4
0
2
0
þC ), 56.08 (1C, C
0
-
0
0
00-OCH
00
-
-
2
6
5
3
6
3
2
2
2
6
3
3
4
CO-), 104.45 (1C, C
4
7
3
00þC
5
00), 121.76
00), 149.19 (1C, C3a),
00),168.99 (1C, -NH-CO-
3
5
3
6
-OCH
3
2
(
2C, C
2
00þC
6
1
4
2
7
), 111.84 (1C,
1
)
49.59 (1C, C
6
),155.72 (1C, C
5
),159.51 (1C, C
). HRMS (ESI) (MþH) (m/z): For C25
4
C
5
C
4
C
5
00), 112.54 (1C, C
00), 149.05 (1C, C
), 168.60 (1C, -NH-CO-), 207.08 (1C, C
6
1
þ
, 207.07 (1C, C
1
H
29
N
2
O
4
F
3
6
), 155.72 (1C,
þ
Calculated: 441.2184. Found: 441.2190. Elemental analyses:
1
). HRMS (ESI) (MþH) (m/
C
6
H
25 29
N
2
O
4
F, Calculated (%): C, 68.16; H, 6.64; N, 6.36. Found (%): C,
8.15; H, 6.62; N, 6.35.
.1.1.2.12. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(p-chlorophenyl)acetamide (12).
z): For
27 34
C H N
2
O
6
Calculated: 483.2490. Found: 483.2497.
34 2 6
Elemental analyses: C27H N O , Calculated (%): C, 67.20; H, 7.10; N,
4
5.81. Found (%): C, 67.21; H, 7.09; N, 5.80.
ꢃ
ꢀ1
Yield: 90%. Mp: 156.6 C. IR (ATR) Vmax (cm ): 3309 (N-H
stretching), 1714 (indanone C¼O stretching), 1691 (amide C¼O
stretching), 1587-1490 (C¼C and C¼N stretchings), 1091 (C-N
4.1.1.3. 4-Substitued benzaldehyde derivatives. A mixture of 4-
fluorobenzaldehyde (30 mmol, 3.21 mL) and appropriate second-
ary amine derivative (60 mmol) in dimethylformamide (DMF)
(10 mL) was refluxed for 48 h in the presence of potassium car-
bonate (30 mmol, 4.14 g). The raw product was precipitated by
pouring into ice water. The residue was filtered, washed with water,
dried and recrystallized from EtOH [62].
stretching), 825 (1,4-disubstitued benzene out of plane bending).
1
H NMR (500 MHz) (DMSO-d
.46 (1H, s, H ), 1.62e1.65 (1H, m, H
þH
þH ), 2.09e2.15 (2H, m, H þH ), 2.65e2.69 (2H, m, H
2H, s, -CH -), 3.11 (2H, s, -CH CO-), 3.22e3.25 (1H, m, H ), 3.80 (3H,
s, C -OCH ), 3.87 (3H, s, C -OCH ), 7.06 (1H, s, H ), 7.10 (1H, s, H ),
.36 (2H, d, J ¼ 8.85 Hz, H
00), 7.69 (2H, d, J ¼ 8.90 Hz, H
6
)
d
(ppm): 1.24e1.35 (3H, m, H
), 1.71e1.75 (2H, m,
), 2.87
3
0
þH
5
0
),
1
H
(
3
0
5
0
0
4
0
0
0
0
2
6
2
6
3
2
2
2
5
3
6
3
4
7
00),
4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-
7
3
00þH
5
2
00þH
6
substituedbenzilidene)-2,3-dihydro-1H-inden-1-one
derivatives
9
3
4
C
.82 (1H, s, -NH-). 13C-APT NMR (125 MHz) (DMSO-d
6
)
d
(ppm):
(15e38). A mixture of appropriate indan-1-one derivative
(2 mmol), benzaldehyde derivative (2 mmol) and potassium hy-
droxide (2 mmol, 0.112 g) in methanol (10 mL) was stirred at room
temperature for 48 h. The resulting colored solid was filtered, dried
and crystallized from EtOH [63].
3.03 (2C, C
5.21 (1C, C
-OCH ), 61.12 (1C, -CH
21.51 (2C, C
1C, C
1C, C
m/z): For C25
3
0
þC
), 53.92 (2C, C
-CO-), 104.46 (1C, C
5
0
), 33.14 (1C, C
3
), 33.82 (1C, C
4
0
), 40.02 (1C, -CH
-OCH ), 56.40 (1C,
), 108.68 (1C, C ),
00), 127.41 (1C, C7a), 128.91
5
2
-),
0
þC
0
), 56.08 (1C, C
2
2
6
5
3
6
3
2
4
7
1
2
00þC
6
00), 129.00 (2C, C
3
00þC
(
(
(
4
00), 138.03 (1C, C
1
00), 149.19 (1C, C3a), 149.60 (1C, C
6
), 155.72
). HRMS (ESI) (MþH)
4.1.1.4.1. 2-(4-(4-Methylpiperazin-1-yl)benzylidene)-5-methoxy-
þ
ꢃ
5
), 169.62 (1C, -NH-CO-), 207.05 (1C, C
1
2,3-dihydro-1H-inden-1-one (15). Yield: 90%. Mp: 184.7 C. IR (ATR)
V
ꢀ1
H
29
N
2
O
4
CI Calculated: 457.1889. Found: 457.1887.
CI, Calculated (%): C, 65.71; H, 6.40;
N, 6.13. Found (%): C, 65.70; H, 6.41; N, 6.12.
.1.1.2.13. 2-(4-((5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-
yl)methyl)piperidin-1-yl)-N-(p-nitrophenyl)acetamide (13).
max (cm ): 1678 (C¼O stretching), 1597-1487 (C¼C stretching),
29 2 4
Elemental analyses: C25H N O
1222 (C-N stretching), 1103 (C-O stretching), 810 (1,4-disubstitued
1
6
benzene out of plane bending). H NMR (500 MHz) (DMSO-d )
4
d
(ppm): 2.23 (3H, s, -N-CH
3
), 2.44e2.46 (4H, m, H
00), 3.89 (3H, s, -OCH
þH ), 7.19 (1H, s, H
þH ), 7.70 (1H, d, J ¼ 8.50 Hz, H
APT NMR (125 MHz) (DMSO-d (ppm): 32.62 (1C, C ), 46.21 (1C,
3
00þH
5
00),
3.29e3.33 (4H, m, H
7.01e7.04 (3H, m, H
7.62 (2H, d, J ¼ 8.85 Hz, H
2
00þH
6
3 3
), 4.01 (2H, s, H ),
ꢃ
ꢀ1
Yield: 93%. Mp: 182.8 C. IR (ATR) Vmax (cm ): 3255 (N-H
stretching), 1712 (indanone C¼O stretching), 1695 (amide C¼O
stretching), 1598-1492 (C¼C and C¼N stretchings), 1109 (C-N
3
0
þH
5
0
6
4
), 7.38 (1H, s, ¼CH-),
13
0
0
7
). C-
2
6
6
)
d
3

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1035
-
N-CH
OCH ), 110.65 (1C, C
1C, C ), 125.56 (1C, C
1C, ¼CH-), 132.67 (2C, C
65.01 (1C, C ), 193.35 (1C, C
3
), 47.33 (2C, C
3
00þC
5
00), 54.83 (2C, C
þC
2
00þC
6
00), 56.22 (1C, C
), 125.12
), 132.57
5
-
4.1.1.4.5. 2-(4-(4-Ethylpiperazin-1-yl)benzylidene)-6-methoxy-
ꢃ
0
0
), 115.63 (1C, C
2,3-dihydro-1H-inden-1-one (19). Yield: 88%. Mp: 179.4 C. IR (ATR)
3
6
), 114.95 (2C, C
3
5
4
ꢀ1
(
(
1
1
0
7
), 131.53 (1C, C7a), 131.86 (1C, C
4
0
V
max (cm ): 1681 (C¼O stretching), 1597-1489 (C¼C stretching),
0
þC
0
), 151.98 (1C, C
). HRMS (ESI) (MþH) (m/z): For
), 152.97 (1C, C3a),
1238 (C-N stretching), 1103 (C-O stretching), 812 (1,4-disubstitued
2
6
2
þ
1
5
1
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
-CH ), 2.37e2.39 (6H, m, -N-
00), 3.84 (3H, s, -OCH
), 3.31e3.34 (4H, m,
), 7.04 (2H, d, J ¼ 8.80 Hz, H þH ), 7.23
), 7.28 (1H, dd, J ¼ 2.50 Hz and J ¼ 8.25 Hz, H ),
), 7.64 (2H, d,
). C-APT NMR (125 MHz) (DMSO-d (ppm):
00), 51.84
), 105.97
), 127.85
6
)
C
H N
22 24 2
O
2
Calculated: 349.1911. Found: 349.1911. Elemental ana-
, Calculated (%): C, 75.83; H, 6.94; N, 8.04. Found
%): C, 75.82; H, 6.93; N, 8.05.
.1.1.4.2. 2-(4-(4-Methylpiperazin-1-yl)benzylidene)-6-methoxy-
,3-dihydro-1H-inden-1-one (16). Yield: 87%. Mp: 198.7 C. IR (ATR)
d
(ppm): 1.04 (3H, t, J ¼ 7.15 Hz, -N-CH
2
3
lyses: C22
(
H N
24 2
O
2
CH
H
2
-CH
3
þ H
3
00þH
5
3
00þH
00), 3.97 (2H, s, H
0
0
5
2
6
3
3
4
(1H, d, J ¼ 2.45 Hz, H
5
7
ꢃ
2
V
1
7.46 (1H, s, ¼CH-), 7.58 (1H, d, J ¼ 8.35 Hz, H
4
ꢀ1
13
max (cm ): 1683 (C¼O stretching), 1597-1489 (C¼C stretching),
J ¼ 8.80 Hz, H
12.42 (1C, -N-CH
(1C, -N-CH -CH ), 52.06 (2C, C
(1C, C ), 114.85 (2C, C
þC
(1C, C ), 132.03 (1C, C
139.70 (1C, C
197.96 (1C, C
2
0
þH
6
0
6
) d
240 (C-N stretching), 1103 (C-O stretching), 813 (1,4-disubstitued
2
-CH
3
), 31.85 (1C, C
3
), 47.36 (2C, C
3
00þC
5
1
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
(ppm): 2.23 (3H, s, -N-CH
6
)
00),
),
2
3
2
00þC
6
00), 55.96 (1C, C
), 123.54 (1C, C
6
-OCH
3
d
3
), 2.44e2.46 (4H, m, H
00), 3.84 (3H, s, -OCH
þH ), 7.23 (1H, d, J ¼ 2.40 Hz, H
), 7.46 (1H, s, ¼CH-), 7.58 (1H,
3
00þH
5
7
3
0
5
0
5
), 124.95 (1C, C
1
0
3
7
(
.30e3.33 (4H, m, H
2
00þH
6
3
), 3.97 (2H, s, H
3
4
4
0
), 132.95 (2C, C
2
0
þC ), 133.54 (1C, ¼CH-),
6
0
.04 (2H, d, J ¼ 8.90 Hz, H
3
0
5
0
5
), 7.27
2
), 142.60 (1C, C3a), 152.19 (1C, C7a), 159.62 (1C, C
6
),
þ
1H, dd, J ¼ 2.50 Hz and J ¼ 8.30 Hz, H
7
1
). HRMS (ESI) (MþH) (m/z): For C23
26 2 2
H N O Calcu-
13
d, J ¼ 8.50 Hz, H
4
), 7.64 (2H, d, J ¼ 8.90 Hz, H
2
0
þH
6
0
). C-APT NMR
),
26 2 2
lated: 363.2067. Found: 363.2067. Elemental analyses: C23H N O ,
(
125 MHz) (DMSO-d
6
)
d
(ppm): 31.86 (1C, C
3
), 46.21 (1C, -N-CH
3
Calculated (%): C, 76.21; H, 7.23; N, 7.73. Found (%): C, 76.22; H, 7.24;
N, 7.71.
4
(
(
1
1
7.25 (2C, C
1C, C
1C, C
39.56 (1C, C
93.35 (1C, C
3
00þC
5
00), 54.82 (2C, C
2
00þC
6
00), 55.96 (1C, C
6
-OCH
3
0
), 105.97
), 127.86
7
), 114.89 (2C, C
3
0
þC
5
0
), 123.18 (1C, C
5
), 124.91 (1C, C
1
4.1.1.4.6. 2-(4-(4-Ethylpiperazin-1-yl)benzylidene)-5,6-
dimethoxy-2,3-dihydro-1H-inden-1-one (20). Yield: 84%. Mp:
), 132.05 (1C, C
4
0
), 132.26 (1C, ¼CH-), 132.56 (2C, C
2
0
þC
6
0
),
),
4
ꢃ
ꢀ1
2
), 142.61 (1C, C3a), 152.15 (1C, C7a), 159.59 (1C, C
6
138.5 C. IR (ATR) Vmax (cm ): 1681 (C¼O stretching), 1600-1498
þ
1
). HRMS (ESI) (MþH) (m/z): For C22
H N
24 2
O
2
Calcu-
(C¼C stretching), 1211 (C-N stretching), 1118 (C-O stretching), 813
1
lated: 349.1911. Found: 349.1909. Elemental analyses: C22
Calculated (%): C, 75.83; H, 6.94; N, 8.04. Found (%): C, 75.81; H,
.95; N, 8.03.
.1.1.4.3. 2-(4-(4-Methylpiperazin-1-yl)benzylidene)-5,6-
dimethoxy-2,3-dihydro-1H-inden-1-one (17). Yield: 88%. Mp:
24
H N
2
O
2
,
(1,4-disubstitued benzene out of plane bending).
H NMR
(500 MHz) (DMSO-d
6
)
d
(ppm): 1.04 (3H, t, J ¼ 3.70 Hz, -N-CH
2
-
6
CH ), 2.35e2.39 (6H, m, -N-CH
3
2
-CH
3
þH
3
00þH
5
00), 3.27e3.29 (4H, m,
-OCH ), 3.92 (2H, s,
þH ),
). C-APT NMR
-CH ), 32.21 (1C,
-CH ), 52.06 (2C,
-OCH ), 104.98 (1C, C
), 125.18 (1C, C ), 130.94 (1C, C
), 132.56 (2C, C
þC
3a), 149.70 (1C, C7a), 153.69 (1C, C ), 155.33 (1C, C ), 192.24 (1C, C
HRMS (ESI) (MþH) (m/z): For C24 Calculated: 393.2173.
Found: 393.2170. Elemental analyses: C24 , Calculated (%):
4
H
H
2
3
00þH
6
00), 3.83 (3H, s, C
), 7.01e7.02 (2H, m, H
5
-OCH
3
), 3.90 (3H, s, C
6
3
0
0
5
4
þ¼CH-), 7.20 (2H, d, J ¼ 4.25 Hz, H
3
ꢃ
ꢀ1
13
1
95.6 C. IR (ATR) Vmax (cm ): 1680 (C¼O stretching), 1585-1498
7.35 (1H, s, H
(125 MHz) (DMSO-d
), 47.45 (2C, C
7
), 7.59 (2H, d, J ¼ 8.85 Hz, H
(ppm): 12.42 (1C, -N-CH
00), 51.52 (1C, -N-CH
), 56.41 (1C, C
þC
2
0
þH
6
0
(
(
(
C¼C stretching), 1120 (C-N stretching), 1091 (C-O stretching), 815
6
)
d
2
3
1
1,4-disubstitued benzene out of plane bending).
500 MHz) (DMSO-d (ppm): 2.23 (3H, s, -N-CH ), 2.44e2.46 (4H,
00), 3.84 (3H, s, C
-OCH ),
H
NMR
C
C
3
3
00þC
5
2
3
)
d
3
2
00þC
6
00), 56.11 (1C, C
5
-OCH
3
6
3
7
),
),
6
m, H
3
H
3
00þH
5
00), 3.28e3.30 (4H, m, H
2
00þH
6
5
3
108.58 (1C, C
4
), 114.92 (2C, C
3
0
5
0
1
0
4
0
.91 (3H, s, C
6
-OCH
3
), 3.94 (2H, s, H
3
), 7.03 (2H, d, J ¼ 8.80 Hz,
131.91 (1C, ¼CH-), 132.28 (1C, C
2
2
0
6
0
), 144.96 (1C,
).
0
þH
0
), 7.21 (1H, s, ¼CH-), 7.22 (1H, s, H
), 7.35 (1H, s, H
), 7.61
C
3
5
4
7
6
5
1
13
þ
(
d
2H, d, J ¼ 8.80 Hz, H
2
0
þH
), 46.22 (1C, -N-CH
00), 56.13 (1C, C
-OCH ), 56.42 (1C, C
), 114.98 (2C, C
þC
6
0
). C-APT NMR (125 MHz) (DMSO-d
6
)
00),
),
),
28 2 3
H N O
(ppm): 32.22 (1C, C
3
3
), 47.34 (2C, C
3
00þC
5
28 2 3
H N O
5
1
1
C
4.84 (2C, C
2
00þC
6
5
3
6
-OCH
3
0
C, 73.44; H, 7.19; N, 7.14. Found (%): C, 73.43; H, 7.20; N, 7.13.
05.00 (1C, C
7
), 108.61 (1C, C
4
3
0
5
0
), 125.19 (1C, C
1
4.1.1.4.7. 2-(4-(4-(2-Hydroxyethyl)piperazin-1-yl)benzylidene)-5-
30.94 (1C, C
4
0
), 132.12 (1C, ¼CH-), 132.34 (1C, C
2
), 132.58 (2C,
methoxy-2,3-dihydro-1H-inden-1-one
(21). Yield: 91%. Mp:
ꢃ
ꢀ1
0
þC
0
), 144.99 (1C, C3a), 149.71 (1C, C7a), 152.96 (1C, C
), 155.34
162.9 C. IR (ATR) Vmax (cm ): 3390 (O-H stretching), 1670 (C¼O
2
6
5
6
þ
(
1C, C
), 192.26 (1C, C
1
). HRMS (ESI) (MþH) (m/z): For C23
26 2 3
H N O
stretching),1593-1514 (C¼C stretching),1192 (C-N stretching), 1064
Calculated: 379.2016. Found: 379.2021. Elemental analyses:
, Calculated (%): C, 72.99; H, 6.92; N, 7.40. Found (%): C,
2.98; H, 6.93; N, 7.39.
(C-O stretching), 819 (1,4-disubstitued benzene out of plane
1
C
7
H
23 26
N
2
O
3
bending). H NMR (500 MHz) (DMSO-d
6
)
d
(ppm): 2.45 (2H, t,
J ¼ 6.20 Hz, -CH
2
-CH
2
-OH), 2.55e2.57 (4H, m, H
2
00þH
6
00), 3.28e3.30
-CH -OH), 3.89 (3H,
2 2
4
.1.1.4.4. 2-(4-(4-Ethylpiperazin-1-yl)benzylidene)-5-methoxy-
,3-dihydro-1H-inden-1-one (18). Yield: 82%. Mp: 157.6 C. IR (ATR)
(4H, m, H
s, -OCH
þH
J ¼ 8.85 Hz, H
(125 MHz) (DMSO-d
3
00þH
5
00), 3.55 (2H, t, J ¼ 6.00 Hz, -CH
ꢃ
2
V
1
3
), 4.00 (2H, s, H
3
), 4.45 (1H, s, -OH), 7.01e7.04 (3H, m,
), 7.38 (1H, s, H ), 7.61 (2H, d,
ꢀ
1
max (cm ): 1681 (C¼O stretching), 1597-1581 (C¼C stretching),
H
3
0
5
0
þ ¼ CH-), 7.20 (1H, s, H
þH ), 7.70 (1H, d, J ¼ 8.45 Hz, H
(ppm): 32.62 (1C, C ), 47.45 (2C, C
00), 56.22 (1C, C
-OCH ), 59.07 (1C, -CH
-CH -OH), 110.65 (1C, C
), 125.56 (1C, C
), 132.59 (1C, ¼CH-), 132.67 (2C, C
), 152.97 (1C, C3a), 165.01 (1C, C ), 191.97 (1C, C
Calculated: 379.2016. Found:
, Calculated (%): C, 72.99;
6
4
13
195 (C-N stretching), 1101 (C-O stretching), 810 (1,4-disubstitued
2
0
6
0
7
). C-APT NMR
1
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
-CH ), 2.35e2.38 (6H, m,
00), 3.28e3.34 (4H, m, H
), 7.02e7.04 (3H, m, H
6
)
6
)
d
3
3
00þC
5
00),
d
(ppm): 1.04 (3H, t, J ¼ 3.55 Hz, -N-CH
2
3
53.40 (2C, C
60.70 (1C, -CH
2
00þC
6
5
3
2
2
-CH -OH),
-
-
N-CH
OCH
2
-CH
), 4.04 (2H, s, H
3
þH
3
00þH
5
2
þH
00þH
6
þH
00), 3.89 (3H, s,
), 7.19 (1H, s,
2
2
6
), 114.90 (2C, C
), 131.54 (1C, C7a),
þC ), 152.02 (1C,
). HRMS (ESI)
3
0
þC
5
0
),
0
0
115.63 (1C, C
131.83 (1C, C
), 125.09 (1C, C
0
3
3
3
5
6
4
1
7
H
4
), 7.38 (1H, s, ¼CH-), 7.61 (2H, d, J ¼ 8.70 Hz, H
2
0
þH
). C-APT NMR (125 MHz) (DMSO-d
-CH ), 32.62 (1C, C ), 39.52 (1C, -N-CH
00), 52.06 (2C, C 00), 56.21 (1C, C
-OCH
þC ), 125.10 (1C, C
6
0
), 7.70 (1H, d,
(ppm): 12.42
4
0
2
0
0
6
13
J ¼ 8.45 Hz, H
7
6
)
d
C
2
5
1
þ
(
1C, -N-CH
2
3
3
2
-CH
3
), 47.44 (2C,
(Mþ H) (m/z): For C23
H
26
N
2
O
3
C
1
1
C
C
3
3
00þC
5
2
00þC
6
5
3
), 110.64 (1C, C
), 125.56 (1C, C
6
),
),
379.2017. Elemental analyses: C23
H
26
N
2
O
3
14.91 (2C, C
3
0
5
0
), 115.63 (1C, C
4
1
0
7
H, 6.92; N, 7.40. Found (%): C, 72.97; H, 6.91; N, 7.41.
31.54 (1C, C7a), 131.83 (1C, C
4
0
), 132.58 (1C, ¼CH-), 132.66 (2C,
4.1.1.4.8. 2-(4-(4-(2-Hydroxyethyl)piperazin-1-yl)benzylidene)-6-
ꢃ
0
þC
0
), 152.01 (1C, C
), 152.96 (1C, C3a), 165.00 (1C, C
), 191.96 (1C,
Calculated:
methoxy-2,3-dihydro-1H-inden-1-one (22). Yield: 94%. Mp: 164 C.
2
1
6
2
5
þ
ꢀ1
). HRMS (ESI) (MþH) (m/z): For C23
H
26
N
2
O
2
IR (ATR) Vmax (cm ): 3381 (O-H stretching),1681 (C¼O stretching),
63.2067. Found: 363.2067. Elemental analyses: C23
26
H N
2
O
2
,
1593-1517 (C¼C stretching), 1180 (C-N stretching), 1016 (C-O
Calculated (%): C, 76.21; H, 7.23; N, 7.73. Found (%): C, 76.20; H, 7.22;
N, 7.72.
stretching), 813 (1,4-disubstitued benzene out of plane bending).
1
H NMR (500 MHz) (DMSO-d
6
)
d
(ppm): 2.45 (2H, t, J ¼ 6.20 Hz,

1036
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
-
H
CH
2
-CH
2
-OH), 2.55e2.57 (4H, m, H
2
00þH
6
00), 3.29e3.33 (4H, m,
d, J ¼ 8.40 Hz, H
4
), 7.64 (2H, d, J ¼ 8.90 Hz, H
2
0
þH
), 46.03 (2C, 2x-CH
00), 55.96 (1C, C
-OCH ), 56.28
-CH -), 105.98 (1C, C ), 114.84
), 132.03
6
0
). 13C-APT NMR
),
00þH
00), 3.55 (2H, t, J ¼ 6.15 Hz, -CH
-CH -OH), 3.84 (3H, s,
(125 MHz) (DMSO-d
)
d
(ppm): 31.85 (1C, C
3
5
2
2
6
3
3
-
OCH
3
), 3.97 (2H, s, H
3
), 4.46 (1H, s, -OH), 7.03 (2H, d, J ¼ 8.85 Hz,
), 7.28 (1H, dd, J ¼ 2.40 Hz and
), 7.64
). C-APT NMR (125 MHz) (DMSO-d
47.38 (2C, C
(1C, -N-CH
3
00þC
5
00), 53.30 (2C, C
-), 57.17 (1C, -N-CH
2
00þC
6
6
3
H
3
0
þH
5
0
), 7.23 (1H, d, J ¼ 2.35 Hz, H
5
2
-CH
2
2
2
7
J ¼ 8.35 Hz, H
7
), 7.49 (1H, s, ¼CH-), 7.58 (1H, d, J ¼ 8.35 Hz, H
4
(2C, C
(1C, C
3
0
þC
5
0
), 123.17 (1C, C
5
), 124.89 (1C, C
1
0
), 127.85 (1C, C
4
1
3
(
d
2H, d, J ¼ 8.85 Hz, H
2
0
þH
6
0
6
)
00),
-
4
0
), 132.95 (2C, C
2
0
þC
6
0
), 133.28 (1C, ¼CH-), 139.56 (1C, C
2
),
).
(ppm): 31.85 (1C, C
5.96 (1C, C -OCH
-OH), 105.97 (1C, C
1C, C ), 127.85 (1C, C
1C, ¼CH-), 139.56 (1C, C
1C, C ), 193.34 (1C, C
). HRMS (ESI) (MþH) (m/z): For C23
3
), 47.37 (2C, C
3
00þC
5
00), 53.38 (2C, C
-OH), 60.68 (1C, -CH
2
00þC
6
142.60 (1C, C3a), 152.17 (1C, C7a), 159.59 (1C, C
6
), 192.50 (1C, C
1
þ
5
CH
(
(
(
6
3
), 59.07 (1C, -CH
), 114.83 (2C, C
), 131.60 (1C, C
), 142.60 (1C, C3a), 152.19 (1C, C7a), 159.59
2
-CH
2
2
HRMS (ESI) (MþH) (m/z): For C25
H
31
N
3
O
2
Calculated: 406.2489.
, Calculated (%):
0
þC
0
), 123.17 (1C, C
þC
), 124.87
), 132.59
Found: 406.2493. Elemental analyses: C25
H
31
N
O
2
7
3
5
5
3
2
0
0
), 132.02 (2C, C
0
0
C, 74.04; H, 7.71; N, 10.36. Found (%): C, 74.05; H, 7.72; N, 10.37.
4.1.1.4.12. 2-(4-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)ben-
zylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
1
4
4
2
6
2
þ
6
1
H
26
N
2
O
3
(26).
ꢃ
ꢀ1
Calculated: 379.2016. Found: 379.2017. Elemental analyses:
, Calculated (%): C, 72.99; H, 6.92; N, 7.40. Found (%): C,
3.00; H, 6.93; N, 7.39.
.1.1.4.9. 2-(4-(4-(2-Hydroxyethyl)piperazin-1-yl)benzylidene)-
,6-dimethoxy-2,3-dihydro-1H-inden-1-one (23). Yield: 95%. Mp:
76 C. IR (ATR) Vmax (cm ): 3392 (O-H stretching), 1674 (C¼O
stretching), 1598-1581 (C¼C stretching), 1222 (C-N stretching),
093 (C-O stretching), 817 (1,4-disubstitued benzene out of plane
Yield: 89%. Mp: 135.7 C. IR (ATR) Vmax (cm ): 1676 (C¼O
C
7
23
H
26
N
2
O
3
stretching), 1579-1498 (C¼C stretching), 1298 (C-O stretching),
1
1091 (C-O stretching). H NMR (500 MHz) (DMSO-d
6
)
d
(ppm): 2.15
4
(6H, s, 2x-CH
-N-CH -CH -), 2.51e2.55 (4H, m, H
00), 3.84 (3H, s, C
-OCH
3
), 2.36e2.39 (2H, m, -N-CH
2
-CH
2
-), 2.42e2.43 (2H, m,
00), 3.26e3.28 (4H, m,
-OCH ), 3.93 (2H, s,
þH ),
). C-APT NMR
), 46.03 (2C, 2x-CH ),
-OCH ), 56.29
-), 57.17 (1C, -N-CH -CH -)),
þC ), 125.18 (1C, C ),
5
1
2
2
2
00þH
6
ꢃ
ꢀ1
H
H
3
3
00þH
5
5
3
), 3.90 (3H, s, C
6
3
), 7.01e7.03 (2H, m, ¼CH- þ H
4
), 7.22 (2H, d, J ¼ 6.10 Hz, H
3
0
0
5
13
1
7.36 (1H, s, H
(125 MHz) (DMSO-d
7
), 7.60 (2H, d, J ¼ 8.90 Hz, H
2
0
þH
6
0
1
bending). H NMR (500 MHz) (DMSO-d
-CH -OH), 2.55e2.57 (4H, m, H
00), 3.55 (2H, t, J ¼ 6.10 Hz, -CH
-OCH ), 3.94 (2H, s, H
þH ), 7.21 (1H, s, ¼CH-), 7.22 (1H, s, H
), 7.61 (2H, d, J ¼ 8.60 Hz, H
125 MHz) (DMSO-d (ppm): 32.22 (1C, C
00), 56.13 (1C, C
-OCH ), 56.43 (1C, C
-CH
), 125.16 (1C, C
6
)
d
(ppm): 2.45 (2H, t,
6
)
d
(ppm): 32.21 (1C, C
3
3
J ¼ 6.20 Hz, -CH
2
2
2
00þH
6
00), 3.28e3.30
-OH), 3.84 (3H, s,
47.38 (2C, C
(1C, C -OCH
105.00 (1C, C
130.94 (1C, C
3
00þC
5
00), 53.32 (2C, C
2
00þC
6
00), 56.12 (1C, C
5
3
(
C
4H, m, H
-OCH
3
00þH
5
2
-CH
2
6
3
), 56.42 (1C, -N-CH
2
-CH
2
2
2
5
3
), 3.91 (3H, s, C
6
3
3
), 4.45 (1H, s, -OH),
),
). C-APT NMR
7
), 108.59 (1C, C
4
), 114.92 (2C, C
3
0
5
0
0
1
7
7
(
.03 (2H, d, J ¼ 8.85 Hz, H
3
0
5
0
4
4
0
), 132.13 (1C, C
2
), 132.20 (1C, ¼CH-), 132.57 (2C,
13
.36 (1H, s, H
7
2
0
þH
), 47.47 (2C, C
-OCH
6
0
C
2
0
þC
6
5
0
), 144.97 (1C, C3a), 149.71 (1C, C7a), 152.21 (1C, C
6
), 155.34
þ
)
d
3
3
00þC
5
00),
(1C, C
), 192.25 (1C, C
1
). HRMS (ESI) (MþH) (m/z): For C26
33 3 3
H N O
6
5
(
1
3.41 (2C, C
1C, -CH
08.61 (1C, C
2
00þC
6
5
3
6
3
), 59.07
Calculated: 436.2595. Found: 436.2595. Elemental analyses:
26 33 3 3
C H N O , Calculated (%): C, 71.70; H, 7.64; N, 9.65. Found (%): C,
2
-CH
2
-OH), 60.70 (1C, -CH
2
2
-OH), 105.00 (1C, C
), 130.94 (1C, C
þC
), 199.30 (1C, C
Calculated: 409.2122.
, Calculated (%):
C, 70.57; H, 6.91; N, 6.86. Found (%): C, 70.56; H, 6.90; N, 6.85.
.1.1.4.10. 2-(4-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)ben-
zylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (24). Yield: 90%.
7
),
),
4
), 114.92 (2C, C
3
0
þC
5
0
1
0
4
0
71.69; H, 7.65; N, 9.64.
1
C
31.91 (1C, C
3a), 148.61 (1C, C7a), 151.96 (1C, C
2
), 132.28 (1C, ¼CH-), 132.58 (2C, C
2
0
6
0
), 144.98 (1C,
).
4.1.1.4.13. 2-(4-(4-(3-(Dimethylamino)propyl)piperazin-1-yl)ben-
zylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (27). Yield: 85%.
6
), 155.33 (1C, C
5
1
þ
ꢃ
ꢀ1
HRMS (ESI) (MþH) (m/z): For C24
H
28
N
2
O
4
Mp: 70.4 C. IR (ATR) Vmax (cm ): 1681 (C¼O stretching), 1666-
28 2 4
Found: 409.2126. Elemental analyses: C24H N O
1516 (C¼C stretching), 1192 (C-N stretching), 1085 (C-O stretching),
1
823 (1,4-disubstitued benzene out of plane bending). H NMR
4
(500 MHz) (DMSO-d
6
)
d
(ppm): 1.56e1.62 (2H, m, -N-CH
), 2.23 (2H, t, J ¼ 7.25 Hz, -N-CH -CH
-CH -CH
00), 3.89 (3H, s, -OCH
), 7.37 (1H, s,
), 7.69e7.70 (1H, m, H ).
(ppm): 24.95 (1C, -N-CH
2
-CH
2
-
CH ), 2.12 (6H, s, 2x-CH
2
3
2
2
-CH
2
-
ꢃ
ꢀ1
Mp: 109.8 C. IR (ATR) Vmax(cm ): 1681 (C¼O stretching), 1589-
516 (C¼C stretching), 1193 (C-N stretching), 1087 (C-O stretching),
), 2.33 (2H, t, J ¼ 7.40 Hz, -N-CH
2
2
2
-), 2.48e2.51 (4H,
), 4.00
1
8
(
m,H
(2H, s, H
3
00þH
5
00), 3.28e3.29 (4H, m, H
), 7.02 (3H, m, H
þH
2
00þH
6
3
1
15 (1,4-disubstitued benzene out of plane bending). H NMR
500 MHz) (DMSO-d (ppm): 2.15 (6H, s, 2x-CH ), 2.36e2.38 (2H,
-), 2.39e2.42 (2H, m, -N-CH -CH -), 2.51e2.55 (4H,
00), 3.89 (3H, s, -OCH
), 4.00
), 7.38
3
3
0
5
0
þ¼CH-), 7.19 (1H, s, H
6
)
d
3
H
4
), 7.60e7.62 (2H,d, J ¼ 8.85 Hz, H
2
0
þH
6
0
7
6
1
3
m, -N-CH
m, H
2
-CH
00), 3.27e3.29 (4H, m, H
2
2
2
C-APT NMR (125 MHz) (DMSO-d
CH -CH -), 32.62 (1C, C ), 45.67 (2C, 2x-CH
53.04 (2C, C -OCH
00), 56.21 (1C, C
CH -CH -CH -), 110.65 (1C, C
), 125.11 (1C, C ), 125.56 (1C, C
6
)
d
2
-
00),
00þH
00þH
), 48.66 (2C, C
00þC
2
6
3
5
3
2
2
3
3
3
5
(
(
2H, s, H
1H, s, H
3
), 7.01e7.04 (3H, m, H
3
0
þH
5
0
þ ¼ CH-), 7.19 (1H, s, H
6
2
00þC
6
5
3 2 2
), 56.46 (1C, -N-CH -CH -
13
), 7.61 (2H, d, J ¼ 8.75 Hz, H
2
0
þH
6
0
), 7.68 (1H, m, H
), 45.92 (2C,
00), 56.21 (1C, C
-CH -), 110.65
), 125.56
7
). C-
2
-), 57.77 (1C, -N-CH
2
2
2
6
), 114.90 (2C,
), 131.54 (1C,
þC ), 152.00
). HRMS (ESI)
4
APT NMR (125 MHz) (DMSO-d
2
OCH
6
)
d
(ppm): 32.62 (1C, C
3
C
C
3
0
þC
5
0
), 115.62 (1C, C
4
1
0
7
0
x-CH
3
), 47.76 (2C, C
3
00þC
5
00), 53.21 (2C, C
2
00þC
6
5
-
7a), 131.84 (1C, C
4
0
), 132.58 (1C, ¼CH-), 132.66 (2C, C
2
0
6
3
), 56.29 (1C, -N-CH
2
-CH
), 115.63 (1C, C
), 131.54 (1C, C7a), 131.84 (1C, C
2
-), 57.17 (1C, -N-CH
2
2
(1C, C
2
), 152.96 (1C, C3a), 165.00 (1C, C
5
), 191.96 (1C, C
1
þ
(1C, C
(1C, C
(2C, C
(1C, C
6
), 114.90 (2C, C
3
0
þC
5
0
4
), 125.11 (1C, C
1
0
(MþH) (m/z): For C26
H N
33 3
O
2
Calculated: 420.2646. Found:
, Calculated (%): C, 74.43;
H, 7.93; N, 10.02. Found (%): C, 74.42; H, 7.92; N, 10.01.
4.1.1.4.14. 2-(4-(4-(3-(Dimethylamino)propyl)piperazin-1-yl)ben-
zylidene)-6-methoxy-2,3-dihydro-1H-inden-1-one (28). Yield: 88%.
0
), 132.59 (1C, ¼CH-), 132.66
420.2647. Elemental analyses: C26
H N
33 3
O
7
4
2
0
þC
0
), 152.00 (1C, C
), 152.96 (1C, C3a), 165.01 (1C, C
), 191.96
2
6
2
5
þ
1
). HRMS (ESI) (MþH) (m/z): For C25
H
31
N
3
O
2
Calculated:
4
06.2489. Found: 406.2493. Elemental analyses: C25
Calculated (%): C, 74.04; H, 7.71; N, 10.36. Found (%): C, 74.03; H,
.70; N, 10.35.
.1.1.4.11. 2-(4-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)ben-
zylidene)-6-methoxy-2,3-dihydro-1H-inden-1-one (25). Yield: 93%.
31 3 2
H N O ,
ꢃ
ꢀ1
Mp: 126.5 C. IR (ATR) Vmax (cm ): 1681 (C¼O stretching), 1593-
1485 (C¼C stretching), 1232 (C-N stretching), 1103 (C-O stretching),
7
1
4
813 (1,4-disubstitued benzene out of plane bending). H NMR
(500 MHz) (DMSO-d
6
)
d
(ppm): 1.57e1.62 (2H, m, -N-CH
), 2.22 (2H, t, J ¼ 7.20 Hz, -N-CH -CH
-CH -CH
00), 3.84 (3H, s, -OCH
þH ), 7.23 (1H, d,
), 7.45
), 7.64 (2H, d, J ¼ 8.85 Hz,
). C-APT NMR (125 MHz) (DMSO-d (ppm): 24.99 (1C,
-CH -CH -), 31.86 (1C, C ), 45.71 (2C, 2x-CH ), 48.47 (2C,
2
-CH
2
-
ꢃ
ꢀ1
Mp: 130.3 C. IR (ATR) Vmax (cm ): 1681 (C¼O stretching), 1593-
CH -),2.12 (6H, s, 2x-CH
2
3
2
2
-CH
2
-
1
485 (C¼C stretching), 1232 (C-N stretching), 813 (1,4-disubstitued
), 2.33 (2H, t, J ¼ 7.40 Hz, -N-CH
2
2
2
-), 2.48e2.50 (4H, m,
), 3.96
1
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
6
)
H
2
00þH
6
00), 3.29e3.31 (4H, m, H
3
00þH
5
3
d
(ppm): 2.15 (6H, s, 2x-CH
.42e2.44 (2H, m, -N-CH -CH
00), 3.84 (3H, s, -OCH
þH ), 7.23 (1H, d, J ¼ 2.55 Hz, H
), 7.45 (1H, s, ¼CH-), 7.58 (1H,
3
), 2.38e2.39 (2H, m, -N-CH
2
-CH
2
-),
(2H, s, H
3
), 7.02e7.04 (2H, d, J ¼ 8.80 Hz, H
3
0
5
0
2
3
7
2
2
-), 2.50e2.55 (4H, m, H
2
00þH
6
00),
J ¼ 2.45 Hz, H
5
), 7.27 (1H, dd, J ¼ 2.50 Hz and J ¼ 8.30 Hz, H
7
.28e3.30 (4H, m, H
.03 (2H, d, J ¼ 8.90 Hz, H
3
00þH
5
3
), 3.97 (2H, s, H
3
),
(1H, s, ¼CH-), 7.58 (1H, d, J ¼ 8.35 Hz, H
4
13
0
0
), 7.27
H
0
þH
0
6
) d
3
5
5
2
6
2
(
1H, dd, J ¼ 2.60 Hz and J ¼ 8.30 Hz, H
7
-N-CH
2
2
3
3

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1037
C
CH
1
1
3
00þC
5
00), 53.04 (2C, C
-CH
2
00þC
6
00), 55.96 (1C, C
-CH -CH
), 124.89 (1C, C
6
-OCH
-), 105.98 (1C, C
), 127.85 (1C, C
3
), 56.47 (1C, -N-
(1C, C
132.23 (1C, C
5
), 125.22 (1C, C
), 132.98 (2C, C
3a), 149.34 (1C, C ), 151.29 (1C, C
), 192.15 (1C, C
1
0
), 127.87 (1C, C
4
), 129.47 (2C, C
3
000þC
000),
5
0
0
þC ), 133.86 (1C, ¼CH-), 142.63 (1C,
0
2
-CH
2
2
-), 57.79 (1C, -N-CH
2
2
2
7
),
),
4
2
6
14.84 (2C, C
32.03 (1C, C
3
0
þC
5
0
), 123.16 (1C, C
5
1
0
4
C
C
2
1
000), 152.01 (1C, C7a), 159.60 (1C,
þ
0
), 133.18 (2C, C
0
þC
0
), 133.75 (1C, ¼CH-), 139.57 (1C,
). HRMS (ESI) (MþH) (m/z): For C27
26 2 2
H N O
4
2
6
6
1
C
2
), 142.59 (1C, C3a), 152.18 (1C, C7a), 159.59 (1C, C
6
), 193.33 (1C, C
1
).
Calculated: 411.2067. Found: 411.2065. Elemental analyses:
27 26 2 2
C H N O , Calculated (%): C, 79.00; H, 6.38; N, 6.82. Found (%): C,
þ
HRMS (ESI) (MþH) (m/z): For C26
H N
33 3
O
2
Calculated: 420.2646.
, Calculated (%):
C, 74.43; H, 7.93; N, 10.02. Found (%): C, 74.44; H, 7.94; N, 10.00.
.1.1.4.15. 2-(4-(4-(3-(Dimethylamino)propyl)piperazin-1-yl)ben-
zylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (29).
Found: 420.2642. Elemental analyses: C26
33
H N
3
O
2
79.02; H, 6.37; N, 6.80.
4.1.1.4.18. 2-(4-(4-Phenylpiperazin-1-yl)benzylidene)-5,6-
dimethoxy-2,3-dihydro-1H-inden-1-one (32). Yield: 93%. Mp:
4
ꢃ
ꢀ1
190.1 C. IR (ATR) Vmax (cm ): 1674 (C¼O stretching), 1595-1494
ꢃ
ꢀ1
Yield: 92%. Mp: 145.6 C. IR (ATR) Vmax (cm ): 1658 (C¼O
stretching),1591-1573 (C¼C stretching),1190 (C-N stretching),1095
(C¼C stretching), 1190 (C-N stretching), 1056 (C-O stretching), 759-
1
690 (Monosubstitued benzen out of plane bending). H NMR
(
C-O stretching), 819 (1,4-disubstitued benzene out of plane
(500 MHz) (DMSO-d
6
)
d
(ppm): 3.29e3.33 (4H, m, H
00), 3.84 (3H, s, C
-OCH ), 3.91 (3H, s, C -
3 6
2
00þH
6
00),
1
bending). H NMR (500 MHz) (DMSO-d
N-CH -CH -CH -), 2.12 (6H, s, 2x-CH
CH -CH -CH
.48e2.51 (4H, m, H
s, C -OCH
6
)
d
(ppm): 1.56e1.61(2H, m,
3.46e3.48 (4H, m, H
OCH ), 3.96 (2H, s, H
d, J ¼ 8.90 Hz, H þH
(1H, s, ¼CH-), 7.65 (2H, d, J ¼ 8.85 Hz, H
(125 MHz) (DMSO-d (ppm): 32.23 (1C, C
00), 56.44 (1C, C
-OCH ),105.02 (1C, C
þC ), 116.15 (2C, C
3
00þH
5
5
-
2
2
2
3
), 2.22 (2H, t, J ¼ 7.20 Hz, -N-
3
3
), 7.01e7.02 (3H, m, H
2
000þH
4
000þH
6
000), 7.11 (2H,
-), 2.33 (2H, t, J ¼ 7.375 Hz, -N-CH
2
-CH
2
-CH
2
-),
3
0
5
0
), 7.22e7.26 (4H, m, H
4
þH
6
þH
3
000þH
5
000), 7.38
2
2
2
1
3
2
2
00þH
6
00), 3.27e3.29 (4H, m, H
-OCH ), 3.94 (2H, s, H
þH
). C-APT NMR (125 MHz) (DMSO-d
-CH -CH -), 32.22 (1C, C ), 45.55 (2C, 2x-
00), 53.06 (2C, C 00), 56.13 (1C, C
-OCH ),
-CH -), 57.79 (1C, -N-
), 114.93 (2C, C ),
þC
), 131.91 (1C, C
3
00þH
5
00), 3.84 (3H,
2
0
þH
6
0
). C-APT NMR
), 3.91 (3H, s, C
6
3
3
), 7.01e7.03 (2H,
6
)
d
3
), 47.49 (2C, C
3
00þC
00),
5
5
3
m, ¼CH-þH
4
), 7.22 (2H, d, J ¼ 6.65 Hz, H
3
0
5
0
), 7.35 (1H, s, H
7
), 7.60
48.59 (2C, C
2
00þC
6
6
3
7
),108.62 (1C,
13
(
d
2H, d, J ¼ 9.90 Hz, H
2
0
þH
6
0
6
)
C
4
), 115.21 (2C, C
3
0
5
0
2
000þC
6
000), 119.69 (1C, C
000), 132.07 (1C, C
), 130.92 (1C,
5 2
4
000),
(ppm): 24.99 (1C, -N-CH
2
2
2
3
125.52 (1C, C
1
0
), 129.48 (2C, C
3
000þC
CH
6.42 (1C, C
CH -CH -CH
25.18 (1C, C
32.58 (2C, C
3
), 47.54 (2C, C
3
00þC
5
2
00þC
6
5
3
C
4
0
), 132.31 (1C, ¼CH-), 132.61 (2C, C
2
0
þC
6
0
), 145.02 (1C, C3a), 149.73
5
6
-OCH
3
), 56.48 (1C, -N-CH
2
-CH
2
2
(1C, C7a), 151.31 (1C, C
6
), 151.44 (1C, C
1
000), 155.40 (1C, C
5
), 192.27 (1C,
28 2 3
H N O Calculated:
þ
-), 105.00 (1C, C
), 130.94 (1C, C
7
), 108.60 (1C, C
4
3
0
5
0
C
1
). HRMS (ESI) (MþH) (m/z): For C28
2
2
2
1
1
C
C
1
0
4
0
2
), 132.13 (1C, ¼CH-),
28 28 2 3
441.2173. Found: 441.2178. Elemental analyses: C H N O ,
0
þC
0
), 144.98 (1C, C3a), 149.70 (1C, C7a), 151.95 (1C,
Calculated (%): C, 76.34; H, 6.41; N, 6.36. Found (%): C, 76.33; H,
6.40; N, 6.35.
4.1.1.4.19. 2-(4-(Pyrrolidin-1-yl)benzylidene)-5-methoxy-2,3-
dihydro-1H-inden-1-one (33). Yield: 89%. Mp: 188 C. IR (ATR) Vmax
2
6
þ
6
), 155.34 (1C, C
5
), 192.37 (1C, C
1
). HRMS (ESI) (MþH) (m/z): For
27
H
35
N
3
O
H
3
Calculated: 450.2751. Found: 450.2752. Elemental an-
, Calculated (%): C, 72.13; H, 7.85; N, 9.35. Found
ꢃ
alyses: C27
%): C, 72.12; H, 7.84; N, 9.36.
N
35 3
O
3
ꢀ
1
(
(cm ): 1676 (C¼O stretching), 1575-1521 (C¼C stretching), 1182
4.1.1.4.16. 2-(4-(4-Phenylpiperazin-1-yl)benzylidene)-5-methoxy-
(C-N stretching), 1056 (C-O stretching), 808 (1,4-disubstitued
ꢃ
1
2
V
1
,3-dihydro-1H-inden-1-one (30). Yield: 90%. Mp: 147.9 C. IR (ATR)
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
6
)
ꢀ1
max (cm ): 1680 (C¼O stretching), 1593-1496 (C¼C stretching),
d
(ppm): 1.97e2.00(4H, m,
H
3
00þH
4
00), 3.32e3.34 (4H, m,
), 6.65 (2H, d,
),
), 7.37 (1H, s, ¼CH-), 7.59 (2H, d,
192 (C-N stretching), 1076 (C-O stretching), 808 (1,4-disubstitued
H
2
00þH
5
00),3.89 (3H, s, -OCH
3 3
), 3.98 (2H, s, H
benzene out of plane bending), 759-692 (Monosubstitued benzen
out of plane bending). H NMR (500 MHz) (DMSO-d
.29e3.30 (4H, m, H
J ¼ 8.80 Hz, H
3
0
þH
5
0
), 7.01 (1H, dd, J ¼ 2.20 Hz and J ¼ 8.45 Hz, H
4
1
6
)
d
(ppm):
00), 3.55e3.57 (2H,
), 6.99e7.04 (4H, m, ¼CH-
þH ), 7.19e7.20 (2H,
), 7.66 (2H, d, J ¼ 8.96 Hz,
7.18 (1H, d, J ¼ 2.10 Hz, H
J ¼ 8.75 Hz, H þH
(125 MHz) (DMSO-d
6
13
3
2
00þH
6
00), 3.46e3.47 (2H, m, H
3
2
0
6
0
), 7.68 (1H, d, J ¼ 8.40 Hz, H
7
). C-APT NMR
00), 32.74 (1C, C
),
), 112.42 (2C,
), 129.98 (1C,
), 133.45 (1C, ¼CH-), 148.96
), 191.81 (1C, C ). HRMS (ESI)
m, H
5
00),3.90 (3H, s, -OCH
3
), 4.02 (2H, s, H
3
6
)
d
(ppm): 25.41 (2C, C
00), 56.18 (1C, C
-OCH
), 122.35 (1C, C
), 133.05 (2C, C
3
00þC
4
3
þH
2
000þH
4
000þH
6
000), 7.10 (2H, d, J ¼ 8.80 Hz, H
3
0
5
0
47.72 (2C, C
2
00þC
5
5
3 6
), 110.63 (1C, C
m, H
3
000þH
5
000), 7.22e7.26 (2H, m, H
4
þH
6
C
C
3
0
þC
5
0
), 115.48 (1C, C
4
1 7
0
), 125.39 (1C, C
1
3
H
(
C
1
2
0
H
þ 6
0
).7.75 (1H, d, J ¼ 8.90 Hz, H
7
). C-APT NMR (125 MHz)
7a), 131.31 (1C, C
4
0
2
0
þC
6
0
DMSO-d
6
)
d
(ppm): 32.63 (1C, C
00), 56.23 (1C, C
-OCH ), 110.67 (1C, C
þC ), 115.26 (1C, C
), 125.59 (1C, C ), 129.34 (2C, C
32.06 (1C, C
3
), 46.80 (2C, C
3
00þC
5
00), 48.58 (2C,
(1C, C
2
), 152.75 (1C, C3a), 164.80 (1C, C
5
1
þ
00þC
), 113.86 (1C, C
000),
(MþH) (m/z): For C21
H21NO
Calculated: 320.1645. Found:
, Calculated (%): C, 78.97;
2
6
5
3
6
4
2
14.53 (2C, C
3
0
5
0
4
), 119.67 (2C, C
2
000þC
6
000), 125.18
320.1646. Elemental analyses: C21
H
21NO
2
(
1C, C
1
0
7
3
000þC
5
000), 129.48 (1C, C7a),
H, 6.63; N, 4.39. Found (%): C, 78.98; H, 6.62; N, 4.38.
4.1.1.4.20. 2-(4-(Pyrrolidin-1-yl)benzylidene)-6-methoxy-2,3-
dihydro-1H-inden-1-one (34). Yield: 88%. Mp: 178.7 C. IR (ATR)
1
C
C
4
0
), 132.53 (1C, ¼CH-), 132.71 (2C, C
2
0
þC
6
0
), 151.84 (1C,
), 190.76 (1C,
Calculated:
ꢃ
000), 152.104 (1C, C
), 152.95 (1C, C3a), 166.26 (1C, C
1
2
5
þ
ꢀ1
1
). HRMS (ESI) (MþH) (m/z): For C27
H
26
N
2
O
2
V
max (cm ): 1676 (C¼O stretching), 1587-1521 (C¼C stretching),
4
11.2067. Found: 411.2063. Elemental analyses:
C
27
26
H N
2
O
2
,
1186 (C-N stretching), 1095 (C-O stretching), 812 (1,4-disubstitued
1
Calculated (%): C, 79.00; H, 6.38; N, 6.82. Found (%): C, 79.01; H,
6
benzene out of plane bending). H NMR (500 MHz) (DMSO-d )
6
.39; N, 6.81.
.1.1.4.17. 2-(4-(4-Phenylpiperazin-1-yl)benzylidene)-6-methoxy-
d
(ppm): 1.98e199 (4H, m,
H
3
00þH
4
00), 3.29e3.33 (4H, m,
), 6.64 (2H, d,
), 7.24e7.26 (1H, dd,
), 7.45 (1H, s, ¼CH-), 7.56 (1H, d,
4
H
2
00þH
5
00),3.84 (3H, s, -OCH
3 3
), 3.93 (2H, s, H
ꢃ
2,3-dihydro-1H-inden-1-one (31). Yield: 92%. Mp: 182.4 C. IR (ATR)
J ¼ 8.80 Hz, H
3
0
þH
5
0
), 7.22 (1H, d, J ¼ 2.40 Hz, H
5
ꢀ
1
V
max (cm ): 2987 (Aliphatic C-H stretching), 1689 (C¼O stretch-
J ¼ 2.55 Hz and J ¼ 7.75 Hz, H
J ¼ 8.30 Hz, H ), 7.61 (2H, d, J ¼ 8.75 Hz, H
(125 MHz) (DMSO-d (ppm): 25.40 (2C, C
7
13
ing), 1595-1489 (C¼C stretching), 1105 (C-N stretching), 1056 (C-O
4
2
0
þH
6
0
). C-APT NMR
00), 31.97 (1C, C
),
), 112.45 (2C,
), 130.20 (1C,
), 142.37
). HRMS (ESI)
stretching), 821 (1,4-disubstitued benzene out of plane bending),
6
)
d
3
00þC
4
3
1
765-754 (Monosubstitued benzen out of plane bending). H NMR
47.73 (2C, C
C
C
2
00þC
5
00), 55.94 (1C, C
6
-OCH
3
), 105.92 (1C, C
7
(
500 MHz) (DMSO-d
6
)
d
(ppm): 3.29e3.31 (4H, m, H
00), 3.84 (3H, s, -OCH
), 7.10e7.12 (2H, m, H
2
00þH
6
00),
3
0
þC
5
0
), 122.21 (1C, C
1
0
), 122.79 (1C, C
5
), 127.74 (1C, C
4
3
.47e3.49 (4H, m, H
3
00þH
5
3
), 3.99 (2H, s, H
3
),
4
0
), 133.33 (2C, C
2
0
þC
6
0
), 134.87 (1C, ¼CH-), 139.86 (1C, C
2
7
.01 (2H, d,J ¼ 7.95 Hz, H
3
0
þH
5
0
2
000þH6000),
(1C, C3a), 129.98 (1C, C7a), 149.15 (1C, C
6
), 193.11 (1C, C
1
þ
7
.23e7.29 (5H, m, ¼CH-þH
1H, d, J ¼ 8.30 Hz, H
NMR (125 MHz) (DMSO-d
6
þH
3
000þH
4
000þH
5
000), 7.48 (1H, s, H
4
), 7.59
(MþH) (m/z): For C21
H21NO
2
Calculated: 320.1645. Found:
, Calculated (%): C, 78.97;
1
3
(
7
), 7.68 (2H, d, J ¼ 8.90 Hz, H
2
0
þH
), 47.37 (2C,
), 106.00 (1C, C ),
000), 119.66 (1C, C 000), 123.21
6
0
). C-APT
320.1644. Elemental analyses: C21
H
21NO
2
6
)
d
(ppm): 31.86 (1C, C
3
H, 6.63; N, 4.39. Found (%): C, 78.99; H, 6.64; N, 4.40.
4.1.1.4.21. 2-(4-(Pyrrolidin-1-yl)benzylidene)-5,6-dimethoxy-2,3-
dihydro-1H-inden-1-one (35). Yield: 84%. Mp: 209.8 C. IR (ATR)
C
3
00þC
5
00), 48.56 (2C, C
2
00þC
6
00), 55.97 (1C, C
6
-OCH
3
7
ꢃ
115.10 (2C, C
3
0
þC
5
0
), 116.14 (2C, C
2
000þC
6
4

1038
B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
max (cm 1): 1672 (C¼O stretching), 1573-1521 (C¼C stretching),
ꢀ
). HRMS (ESI) (MþH)þ (m/z): For
V
1
5 1
155.12 (1C, C ), 192.17 (1C, C
184 (C-N stretching), 1091 (C-O stretching), 812 (1,4-disubstitued
benzene out of plane bending). H NMR (500 MHz) (DMSO-d
C
22
H25NO
3
Calculated: 352.1907. Found: 352.1911. Elemental ana-
1
6
)
lyses: C22
H25NO
3
, Calculated (%): C, 75.19; H, 7.17; N, 3.99. Found
d
(ppm): 1.97e2.00 (4H, m, H
.84 (3H, s, C -OCH
þH
s, ¼CH-), 7.58 (2H, d, J ¼ 8.75 Hz, H
DMSO-d (ppm): 25.41 (2C, C
00), 56.11 (1C, C
-OCH
), 112.42 (2C, C
), 132.91 (2C, C
3a), 148.90 (1C, C7a), 151.04 (1C, C
3
00þH
4
00), 3.31e3.32 (4H, m, H
2
00þH
5
00),
(%): C, 75.20; H, 7.16; N, 4.00.
3
5
3
0
), 3.91 (5H, s, H
3
þ C -OCH
6
3
), 6.64 (2H, d,
J ¼ 8.80 Hz, H
3
0
5
), 7.20 (2H, d, J ¼ 4.85 Hz, H
4
þH
). C-APT NMR (125 MHz)
00), 32.33 (1C, C
), 47.72 (2C,
-OCH ), 104.97 (1C, C
), 130.32 (1C, C
7
), 7.35 (1H,
4.2. Anticholinesterase activity assay
13
0
þH
0
6
2
(
C
1
1
6
)
d
3
00þC
4
3
Acetylcholinesterase (AChE, E.C.3.1.1.7, from electric eel), butyr-
ylcholinesterase (BChE, E.C. 3.1.1.8, from equine serum), 5,5'-
dithiobis-(2-nitrobenzoic acide) (DTNB), tacrine and DNP hydro-
chloride were purchased from Sigma-Aldrich (Steinheim, Ger-
many). Acetylthiocholine iodide (ATC) and butyrylthiocholine
iodide (BTC) were obtained from Fluka (Germany). All pipetting
processes were performed using a Biotek Precision XS robotic
system (USA). Measurements of the percentage inhibition were
carried out at 412 nm by using a BioTek-Synergy H1 microplate
reader (USA). The inhibitory activities of the compounds against
AChE and BChE were determined in 96-well plates by modified
Ellman's method [51] using DNP and tacrine as reference drugs.
Initially, the synthesized compounds (1e38) were prepared at two
00þC
), 6.40 (1C, C
),
),
2
5
5
3
6
3
7
08.59 (1C, C
31.18 (1C, C
4
3
0
þC
5
þC
0
), 122.40 (1C, C
0
1
0
4
0
0
), 132.95 (1C, ¼CH-), 144.70 (1C,
), 155.10 (1C, C ), 192.15 (1C, C ).
HRMS (ESI) (MþH) (m/z): For C22 Calculated: 350.1751.
Found: 350.1748. Elemental analyses: C22 , Calculated (%): C,
5.62; H, 6.63; N, 4.01. Found (%): C, 75.61; H, 6.62; N, 4.00.
2
2
6
C
6
5
1
þ
H23NO
3
H23NO
3
7
4
.1.1.4.22. 2-(4-(Diethylamino)benzylidene)-5-methoxy-2,3-
dihydro-1H-inden-1-one (36). Yield: 87%. Mp: 270 C. IR (ATR) Vmax
ꢃ
ꢀ
1
(
(
cm ): 1680 (C¼O stretching), 1593-1519 (C¼C stretching), 1249
C-N stretching), 1188 (C-O stretching), 812 (1,4-disubstitued ben-
1
zene out of plane bending). H NMR (500 MHz) (DMSO-d
6
)
d
(ppm):
), 3.41e3.45 (4H, m, 2x -N-
),3.98 (2H, s, H ), 6.77 (2H, d,
), 7.02 (1H, d, J ¼ 10.60 Hz, H ), 7.18 (1H, s, ¼CH-
), 7.58 (2H, d, J ¼ 8.85 Hz, H þH ), 7.68 (1H, d,
). C-APT NMR (125 MHz) (DMSO-d (ppm): 12.94
), 32.62 (1C, C ), 47.44 (2C, 2x-CH -CH ), 56.11 (1C,
), 114.89 (2C, C ), 115.46 (1C, C
þC
), 125.92 (1C, C ), 131.13 (1C, C7a), 131.84 (1C, C
þC ), 132.65 (1C, ¼CH-), 152.25 (1C, C
3a), 165.02 (1C, C ), 191.95 (1C, C
ꢀ3
ꢀ4
1
.14 (6H, t, J ¼ 7.00 Hz, 2x -N-CH
2
-CH
3
concentrations (10 and 10 M) using 2% DMSO and inhibition
potencies were measured. Then the selected compounds (26e29)
displaying more than 50% inhibition were tested at further con-
CH -CH ), 3.83 (3H, s, -OCH
2
3
3
3
J ¼ 8.90 Hz, H
3
0
þH
5
0
6
ꢀ
5
ꢀ9
)
, 7.36 (1H, s, H
4
2
0
6
0
centrations (10 -10 M).
13
J ¼ 8.45 Hz, H
7
6
)
d
The final volume of a well was 210
m
L consisting of 140
L inhibitor solution, 20
L DTNB (0.01 M) and 10
m
m
L
L
(
2C, 2x-CH
2
-CH
3
3
2
3
phosphate buffer (0.1 M, pH ¼ 8), 20
m
C
1
1
C
C
5
-OCH
22.22 (1C, C
32.53 (2C, C
3
), 110.32 (1C, C
6
3
0
5
0
4
),
),
enzyme solution (2.5 U/mL), 20
m
m
L sub-
0
0
strate solution (0.075 M ATC or BTC). First of all, the solutions of
inhibitor, enzyme and DTNB were added to phosphate buffer and
1
7
4
0
0
), 152.91 (1C,
2
6
2
þ
ꢃ
5
1
). HRMS (ESI) (MþH) (m/z): For
incubated at 25 C for 15 min. After the incubation, the substrate
21
H23NO
2
Calculated: 322.1802. Found: 322.1798. Elemental ana-
, Calculated (%): C, 78.47; H, 7.21; N, 4.36. Found
(ATC or BTC) was added to the enzyme-inhibitor mixture. The
production of the yellow anion (5-thio-2-nitrobenzoic acid) was
recorded for 5 min at 412 nm. As a control, an identical solution of
the enzyme without the inhibitor was processed. Control and in-
hibitor readings were corrected with blank-readings. Each con-
centration was analyzed in quadruplicate. The IC50 values were
calculated from a dose-response curve obtained by plotting the
percentage inhibition versus the log concentration with the use of
GraphPad ‘PRISM’ software (version 5.0). The results were dis-
played as mean ± standard deviation (SD).
lyses: C21
H23NO
2
(
%): C, 78.46; H, 7.20; N, 4.35.
4
.1.1.4.23. 2-(4-(Diethylamino)benzylidene)-6-methoxy-2,3-
dihydro-1H-inden-1-one (37). Yield: 83%. Mp: 137.4 C. IR (ATR)
ꢃ
ꢀ1
V
1
max (cm ): 1678 (C¼O stretching), 1589-1485 (C¼C stretching),
186 (C-O stretching), 1095 (C-N stretching), 810 (1,4-disubstitued
1
6
benzene out of plane bending). H NMR (500 MHz) (DMSO-d )
d
(ppm): 1.14 (6H, t, J ¼ 7.00 Hz, 2x -N-CH
x -N-CH -CH ), 3.84 (3H, s, -OCH ),3.94 (2H, s, H
þH ), 7.22 (1H, d, J ¼ 2.45 Hz, H ), 7.25 (1H, dd,
J ¼ 2.55 Hz and J ¼ 8.30 Hz, H ), 7.44 (1H, s, ¼CH-), 7.56 (1H, d,
2
3
-CH ), 3.41e3.45 (4H, m,
2
2
3
3
3
), 6.77 (2H, d,
J ¼ 8.95 Hz, H
3
0
5
0
5
7
4.3. Kinetic studies of enzyme inhibition
1
3
J ¼ 8.30 Hz, H
4
), 7.60 (2H, d, J ¼ 8.90 Hz, H
125 MHz) (DMSO-d (ppm): 12.94 (2C, 2x-CH
-CH ), 55.94 (1C, C -OCH ), 105.93 (1C, C
), 121.95 (1C, C ), 122.80 (1C, C ), 127.75 (1C, C
), 133.34 (2C, C
2
0
þH
6
0
). C-APT NMR
(
C
6
)
d
2
-CH ), 31.94 (1C,
3
Kinetic studies were performed by using Ellman's method. The
compounds 26 were tested at their IC50 and 2x IC50 concentrations.
3
), 44.27 (2C, 2x-CH
þC
2
3
6
3
7
4
),
),
111.90 (2C, C
3
0
5
0
1
0
5
The solution of phosphate buffer (0.1 M, pH ¼ 8, 140
mL/well), in-
1
C
29.54 (1C, C
4
0
2
0
þC
6
0
), 133.84 (1C, ¼CH-), 139.87 (1C,
hibitor (20
20
m
L/well), AChE (2.5 U/mL, 20
m
L/well) and DTNB (10
m
M,
ꢃ
2
), 142.36 (1C, C3a), 149.19 (1C, C7a), 159.55 (1C, C
6
), 193.13 (1C, C
1
).
m
L/well) was added to the wells and incubated at 25 C for
þ
HRMS (ESI) (MþH) (m/z):For C21
H23NO
2
Calculated: 322.1802.
, Calculated (%): C,
8.47; H, 7.21; N, 4.36. Found (%): C, 78.48; H, 7.22; N, 4.37.
15 min. After incubation period, the solutions, including various
concentrations (150, 75, 37.5, 18.75, 9.375, 4.6875, 2.3437, 1.1718,
0.5859 and 0.2929 mM) of substrate (ATCI) (10 mL/well) were added.
Found: 322.1797. Elemental analyses: C21
H23NO
2
7
4
.1.1.4.24. 2-(4-(Diethylamino)benzylidene)-5,6-dimethoxy-2,3-
The increase of the absorbance was recorded for 5 min at 412 nm. A
parallel experiment was carried out without inhibitor. All processes
were assayed in quadruplicate. The results were analyzed as
Lineweaver-Burk plots using Microsoft Office Excel 2013.
ꢃ
dihydro-1H-inden-1-one (38). Yield: 89%. Mp: 179.3 C. IR (ATR)
ꢀ1
V
1
max (cm ): 1668 (C¼O stretching), 1573-1460 (C¼C stretching),
120 (C-O stretching), 1076 (C-N stretching), 813 (1,4-disubstitued
1
6
benzene out of plane bending). H NMR (500 MHz) (DMSO-d )
d
(ppm): 1.14 (6H, t, J ¼ 7.00 Hz, 2x -N-CH
x -N-CH -CH ), 3.84 (3H, s, C -OCH ), 3.90 (5H, s, C
.76 (2H, d, J ¼ 8.90 Hz, H þH ), 7.20 (2H, d, J ¼ 1.75 Hz, ¼CH-
), 7.34 (1H, s, H
), 7.56 (2H, d, J ¼ 8.90 Hz, H
NMR (125 MHz) (DMSO-d (ppm): 12.94 (2C, 2x-CH
1C, C ), 44.22 (2C, 2x-CH -CH ), 56.11 (1C, C -OCH ), 56.40 (1C, C
OCH ), 104.97 (1C, C ), 108.59 (1C, C ), 111.88 (2C, C ), 122.13
þC
), 130.35 (1C, C ), 131.20 (1C, C
), 132.76 (1C, ¼CH-), 133.15
þC ), 144.68 (1C, C3a), 148.42 (1C, C7a), 148.89 (1C, C ),
2
-CH
3
), 3.40e3.44 (4H, m,
4.4. Cytotoxicity test
2
6
þ H
2
3
5
3
6
-OCH ),
3
þH
3
0
0
NIH/3T3 mouse embryonic fibroblast cell lines (ATCC CRL 1658)
was used for cytotoxicity study. Cells were replicated into Dulbec-
co's Modified Eagle's Medium (DMEM) containing 10% fetal bovine
3
5
1
3
0
þH
0
). C-APT
), 32.29
4
7
2
6
6
)
d
2
-CH
3
(
3
2
3
5
3
6
-
serum (FBS), 1% 100 IU/mL penicillin/100 mg/mL streptomycin, at
ꢃ
0
0
37 C in a humidified atmosphere of 95% air and 5% CO
. The pro-
3
7
4
3
5
2
(
(
1C, C
2C, C
1
0
4
0
2
liferation of the NIH/3T3 cell line was assessed by MTT (3-(4,5-
Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide) assay.
0
0
2
6
6

B.N. Sa gꢀ lık et al. / European Journal of Medicinal Chemistry 124 (2016) 1026e1040
1039
Briefly, cells were inoculated into 96-well culture plates at densities
of 10,000 cells per well. After 24 h, they were treated with syn-
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2
ꢀ6
thesized compounds (concentrations of 10 M ꢀ 3.16 ꢁ 10 M)
€
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Appendix A. Supplementary data
€
1
Supplementary data related to this article can be found at http://
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[70] W. Humphrey, A. Dalke, K. Schulten, J. Mole. Graph. 14 (1996) 33e38.
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