Thiazole-substituted benzoylpiperazine derivatives as acetylcholinesterase inhibitors

Article abstract of DOI:10.1002/ddr.21481

(Table presented.). After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic-framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified. The aim of this study was to design new donepezil analogs. In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piperazine N′-benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory effect among the series (80.36%–83.94% inhibition), and donepezil had a 96.42% inhibitory effect. The IC₅₀ values of compounds 35, 38, and 40, were calculated as 0.9767 μM, 0.9493 μM, and 0.8023 μM, respectively. Compound 45 (IC₅₀ = 1.122), Compound 57 (IC₅₀ = 1.2130) and 61 (IC₅₀ = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the active site. Both donepezil and synthesized compounds seemed to interact with these residues.

Full text of DOI:10.1002/ddr.21481

Received: 9 July 2018
Revised: 19 September 2018
Accepted: 22 September 2018
DOI: 10.1002/ddr.21481
R E S E A R C H A R T I C L E
Thiazole-substituted benzoylpiperazine derivatives as
acetylcholinesterase inhibitors
Zafer Sahin1 | Merve Ertas1 | Ceysu Bender† | Emre F. Bülbül† | Barkin Berk1
|
Sevde N. Biltekin2 | Leyla Yurttas¸3 | Şeref Demirayak1
Enabling Technologies
Strategy, Management & Health Policy
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& Development
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Research
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Research
1Department of Pharmaceutical Chemistry,
Abstract
Istanbul Medipol University, School of
Pharmacy, Istanbul, Turkey
After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetyl-
cholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that
cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine,
rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However,
these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase
activity of various heterocyclic-framed compounds, including piperazine derivatives, has been
investigated, and compounds with similar effects to known drugs have been identified. The aim
of this study was to design new donepezil analogs.
2Istanbul Medipol University, School of
Pharmacy, Department of Pharmaceutical
Microbiology, Istanbul, Turkey
3Department of Pharmaceutical Chemistry,
Anadolu University, Faculty of Pharmacy,
Eskis¸ehir, Turkey
Correspondence
Zafer Sahin, Department of Pharmaceutical
Chemistry, School of Pharmacy, Istanbul
Medipol University, 34083 Istanbul, Turkey.
Email: zsahin@medipol.edu.tr
In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piper-
azine N0-benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was
measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory
effect among the series (80.36%–83.94% inhibition), and donepezil had a 96.42% inhibitory effect.
The IC50 values of compounds 35, 38, and 40, were calculated as 0.9767 μM, 0.9493 μM, and
0.8023 μM, respectively. Compound 45 (IC50 = 1.122), Compound 57 (IC50 = 1.2130) and
61 (IC50 = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in
agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the
active site. Both donepezil and synthesized compounds seemed to interact with these residues.
Funding information
Anadolu Üniversitesi, Grant/Award Number:
Anatolian University Scientific Research
Projects
KEYWORDS
acetylcholinesterase, Alzheimer, piperazine, thiazole
of death in the United States (Murphy, Xu, & Kochanek, 2013).
Approximately 11% (nearly 6.5 million) of AD patients have been
1
| INTRODUCTION
Alzheimer's disease (AD) is the most common disease among all neu-
rodegenerative diseases, and it is also the sixth most common cause
reported and estimations point that by 2050, the prevalence of AD in
the United States will reach 13.8 million (Alzheimer's Association,
2014; Hebert, Weuve, Scherr, & Evans, 2013). The relationship
between memory loss and cholinergic deficits in the brain has become
a touchstone for AD neurochemistry proposed by Peter Davies in
1976 (Hebert et al., 2013). This relationship may be due to reduced
production of acetylcholine or increased degradation by the enzyme
acetylcholinesterase (Arce et al., 2009). Reduced level of neurotrans-
mitter causes impairment of cholinergic neurotransmission and
†The authors whose names are listed certify that they have no affiliations with
or involvement in any organization or entity with any financial interest (such as
honoraria; educational grants; participation in speakers' bureaus; membership,
employment, consultancies, stock ownership, or other equity interest; and
expert testimony or patent-licensing arrangements), or nonfinancial interest
(such as personal or professional relationships, affiliations, knowledge or beliefs)
in the subject matter or materials discussed in this manuscript.
Drug Dev Res. 2018;1–20.
wileyonlinelibrary.com/journal/ddr
© 2018 Wiley Periodicals, Inc.
1

2
SAHIN ET AL.
intellectual abilities. This theory, in general, predicts that regulation of
cholinergic transmission may lead to cognitive impairment. It has been
reported that acetylcholine release is severely reduced in AD patients,
associated with decreased cholinacetyltransferase activity (Bartus,
Dean, Beer, & Lippa, 1982), neuronal loss in the basal forebrain
(Whitehouse et al., 1982) or decrease in nicotinic acetylcholine recep-
tors (Sihver, Gillberg, Svensson, & Nordberg, 1999).
same time. Donepezil interacts with Trp286 and Arg296. The benzyl
group is a suitable substituent for the aromatic interaction region
immediately adjacent to the peripheral region. The free piperidine
ring seems to be necessary for the interaction with the locality
(Daoud, Melkemi, Salah, & Ghalem, 2018). Thus, in the ensaculin
compound, which is similar to donepezil, the ring system is
converted to coumarin (similar to the structure of natural flavones,
such as apigenin and luteolin) and the piperidine ring is converted
to bioisosteric piperazine.
Mental function impairments may include language impairment,
memory dysfunction, perception, personality and mood disorders, and
the loss of cognitive skills. Many of these conditions are irreversible
(Caselli & Boeve, 2006; Pievani, de Haan, Wu, Seeley, & Frisoni,
2011). AD is the main cause of dementia, which is a neurodegenera-
tive disease characterized by molecular changes, such as misfolding
and aggregation, oxidative stress, neuroinflammatory processes, and
mitochondrial abnormalities (Goedert & Spillantini, 2006) .
From the precursor compounds; for example, such as donepezil
and tacrine, clusters, such as coumarin and acridine have been
attempted to be bound with bridges; for example, piperazine and thio-
urea (Hamulakova et al., 2014).
There are many studies on novel AChE inhibitor compounds for
use as donepezil analogues having bioisosteric replacement of piper-
idine with another basic center like piperazine or pyrrolidine. The
compounds we synthesized in this study included piperazine and
thiazole bridges with aromatic groups at both ends. In the design of
our compounds, the aromatic core system consisted of phenyl and
benzoyl groups, the linker was a thiazole ring, and the basic center
was the piperazine moiety (Figure 2) (Ali et al., 2010; Mohsen,
Acetylcholine binds to specific receptors located on the postsynap-
tic membrane, allowing G protein complexes to form. The subtype of
muscarinic receptors plays a role in physiological events, such as emo-
tional, cognitive and memory, as well as in contracting the skeletal mus-
cle cells over nicotinic receptors (Bayrak, Taslimi, Gülçin, & Menzek,
2017; Katzung, Masters, & Trevor, 2012; Köse et al., 2015; Singh et al.,
2013). The primary physiological function of the acetylcholinesterase
enzyme is rapid hydrolysis of acetylcholine at the synapse and neuro-
muscular junction, thus ending the neural conduction (Johnson &
Moore, 2006). Most studies concerning acetylcholinesterase have been
performed on the enzymes isolated from mice or Pacific electric ray
(Torpedo californica). Until recently, only a few human enzymes had been
crystallographed and none had been studied in the complex form with a
therapeutic drug. Moreover, the resolution values of the crystallo-
graphic data of the enzymes were not sufficient for modeling. However,
in the last decade, the enzyme has been crystallized in the complex form
with different drugs (galantamine, donepezil, etc.). These studies indi-
cate that the phosphorylation site of human enzymes is different from
the regular binding site of these enzymes, thus the active site of human
enzyme could be defined more clearly (Cheung et al., 2012a; Cheung
et al., 2012b; Shafferman et al., 1992; Shafferman et al., 2005).
ꢀ
Kaplancikli, Özkay, & Yurttas¸, 2015; Saglık, Ilgın, & Özkay, 2016;
Sang et al., 2015; Yurttas¸, Kaplancıklı, & Özkay, 2013) In this study,
we used the chemical design explained above to synthesize 66 new
compounds (Table 1) and measured their acetylcholinesterase inhibi-
tor activity.
2
| METHODS
2.1 | General
All the chemicals used in the synthesis and biological activity analysis
were purchased from Sigma Aldrich Chemical Corp. (St. Louis, Mis-
souri) and Merck KGaA (Merck, Darmstadt, Germany). During the
reactions, all the compounds were checked for their purities using an
Alliance HPLC System (Waters Inc., Milford, Massachusetts), as well
as thin layer chromatography (TLC) with a Silica Gel 60 F254 TLC
plate (Merck KGaA, Darmstadt, Germany). All the melting points were
measured by a Stuart melting point apparatus (SMP30, Staffordshire,
UK). The analysis of the C, H and N fractions of the crystallized com-
pounds was performed using a Leco TruSpec Micro CHN/CHNS ele-
mental analyzer (Saint Joseph, Michigan). The spectroscopic data
were determined with the following instruments: Fourier-transform
infrared spectroscopy (FT-IR), Perkin Elmer Spectrum Two FT-IR
spectrometer (Perkin Elmer, Inc., Waltham, Massachusetts); 1H-NMR,
Bruker 300 MHz UltraShield NMR spectrophotometer (Bruker Corp.,
Billerica, Massachusetts), and 13C-NMR, Bruker 75 MHz UltraShield
NMR spectrophotometer (Bruker Corp., Billerica, Massachusetts) in
DMSO-d6 using the standard TMS. The mass spectra of the com-
pounds were determined on a Shimadzu 8,040 LC/MS/MS ITTOF
system (Shimadzu, Tokyo, Japan) mass spectrometer by the electron
spray method (ESI). The IC50 values of the compounds were
recorded using GraphPad Prism software version 7.02 (La Jolla,
California).
Acetylcholinesterase has a narrow cavity of two separate ligand
binding sites; peripheral anionic site (PAS) and catalytic site (CAS)
(Atanasova et al., 2015; Blichfeldt-Lauridsen & Hansen, 2006). There
are two types of cholinesterases in the vertebrates; acetylcholinester-
ase (AChE) and butyrylcholinesterase (BChE). Both these enzymes cat-
alyze the hydrolysis of acetylcholine and are very similar. The point
which separates these two enzymes is their substrate selectivity,
tissue localization, and sensitivity (Lane, Potkin, & Enz, 2006; Zimmer-
man & Soreq, 2006).
The first generation of drugs is tacrine (Figure 1) (Summers,
Majovski, Marsh, Tachiki, & Kling, 1986), and the second-generation
drugs include donepezil (1996), rivastigmine (1998–2000) and galan-
tamine, which can bind to two parts of the active site of AChE and
can be better tolerated.
The key binding sites within AChE include a tryptophan which
is capable of cation–π bonding, two glycines for the hydrogen bond-
ing potential, and an esteratic nucleophilic serine hydroxyl group.
For donepezil, the part of the condensed ring system is also
attached to the peripheral anionic locus with the catalytic site at the

SAHIN ET AL.
3
FIGURE 1 Commonly used AChE inhibitors
to cool. The cooling reaction was released and filtered. The product
was crystallized from ethanol twice (Cowper, 1943).
2.2 | Chemistry
2.2.1
|
General synthesis of piperazine N0-
benzoylthioamides
2.2.3
| General synthesis of substituted phenylthiazoles
Ammonium thiocyanate (100 mmol) was dissolved in excess acetone
at room temperature. The reaction mixture was stirred, and then ben-
zoyl chloride was added dropwise to the mixture. After mixing for
about 1 hr, it was boiled for 10 min and the piperazine derivative
(100 mmol) was added to the mixture. After cooling, the reaction was
poured into iced water and decanted. The resulting product was ben-
zoylpiperazine thioamide, which was filtered, washed with ethanol,
and dried (Rasmussen et al., 1988).
(final compounds 1–66)
The resulting compounds were synthesized by the reaction of N0-
benzoyl piperazine thioureas (10 mmol) and bromoacetophenones
(10 mmol). The equivalent mole of materials was boiled in ethyl alco-
hol until the reaction was completed. After cooling, it was added to
water and neutralized with NaHCO3 solution. The products were
crystallized from ethanol (Belveren et al., 2017; Ried, 1976; Sabba-
ghan, Alidoust, & Hossaini, 2011) (Figure 3).
2.3 | Enzymatic assay
2.2.2
| General synthesis of bromoacetophenones
The appropriate acetophenone derivative (1 mol) was dissolved in
acetic acid and heated followed by the addition of an equimolar
amount of bromine dropwise. After boiling for 3–4 hr, and it was left
In order to determine the acetylcholinesterase enzyme inhibitions,
experiments were carried out by making some changes to the method
developed by Ellman (Ellman, Courtney, Andres, & Feather-Stone,
Basic center
(piperidine, piperazine)
Core system
Linker
Design of donepezil analogues
Core system
O
O
B
a
B
a
s
i
s
i
c
c
N
e
n
t
e
c
r
c
e
n
N
O
t
e
r
S
N
R
Linker
O
N
Synthesized compounds
Donepezil
FIGURE 2 The design of donepezil analogues

4
SAHIN ET AL.
TABLE 1 The structure of the synthesized compounds
C. no
1
R
R’
C. no
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
R
R’
C. no
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
R
R’
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
H
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
2-Cl
H
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
2
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
R
3
4
N
N
5
6
7
4-F
4-F
4-F
N
S
8
3-Cl
3-Cl
3-Cl
O
9
4-Cl
4-Cl
4-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
3-NO2
4-NO2
H
3-NO2
4-NO2
H
3-NO2
4-NO2
H
R'
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
2-Cl
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
3-CH3
4-CH3
3-OCH3
4-OCH3
3-F
2-Cl
2-Cl
2-Cl
2-Cl
4-F
2-Cl
4-F
4-F
3-Cl
2-Cl
3-Cl
3-Cl
4-Cl
2-Cl
4-Cl
4-Cl
3-NO2
4-NO2
2-Cl
3-NO2
4-NO2
3-NO2
4-NO2
2-Cl
1961). During the experiments, the following instructions provided by
the “Elite™ Acetylcholinesterase Assay Kit (Green Fluorescence)”
(MyBiosource, Catalog number: 433569) were followed: Acetylcholin-
esterase enzyme solutions were prepared in double distilled H2O with
0.1% BSA at a concentration of 10 mU/mL. The acetylthiocholine
reaction mixture (1:2,5:500 [v/v] Acetylthiocholine stock solution:
Elite™ Green stock solution: Assay buffer, 50 μL) and the compound
solution (50 μL), prepared in 1% DMSO at a concentration range of
10−4–10−9 M, were added to each well and incubated at 25 ꢀC for
20 min. For the blank control group, only solvent was added instead
of the sample solution, but the protocol was the same. After the incu-
bation period, fluorescence was measured at 490 nm (excitation) and
520 nm (emission) using a fluorescence plate reader. All processes
were assayed in triplicate in three independent assays. The inhibition
rate (%) was calculated by the following Equation I (%) = 100 − (Abs
pH range of 7 ꢁ 2 using the same module. The repetitive and salt
forms of the molecules were removed.
2.4.2
| Preparation of the target
The preparation of the protein structure and ligand, GRID files, dock-
ing, and scoring were performed using the algorithms available in the
Maestro modules. The X-ray crystallographic structure of the human
acetylcholinesterase enzyme (PDB ID: 4EY7) was obtained from the
Protein Data Bank (RCSB) (Berman et al., 2000; Cheung et al., 2012a;
Cheung et al., 2012b).
The PDB file was edited by utilizing the protein preparation wiz-
ard in Maestro for hydrogen insertion, rotamer adjustment, and
H-bond optimization using the OPLS 2005 energy parameters. The
graphs for the analysis of the nature of interaction between the active
site and ligands were also processed by the same module. All compu-
tational operations were undertaken using workstations in the School
of Pharmacy of Istanbul Medipol University.
− Abscontrol) × 100.
sample
The inhibition rate of the compounds and IC50 values were
recorded using GraphPad Prism software version 7.02 (La Jolla, Cali-
fornia). The data were expressed as mean ꢁ standard deviation (SD).
2.4.3
| Preparation of the GRID file
The grid file for the human acetylcholinesterase active site was pre-
pared using the Maestro Glide-Receptor Grid Generation tool. A
receptor-binding pocket was defined by taking 6 Aꢀ surrounding area
of the existing ligand as the centroid. During preparation, the original
ligand was excluded and a scaling factor of 1.0 and a partial charge
cut-off of 0.25 were used as the parameters for the Van der Walls
radius-scaling factor.
2.4 | Molecular modeling
2.4.1
| Preparation of the ligand set
The structures of the compounds were drawn using the LigPrep mod-
ule in the Maestro Suite (Schrödinger LCC, Oregon) and were mini-
mized by means of the OPLS_2005 force field. The partial atomic
charges, ionization, and tautomerization states were computed at a

SAHIN ET AL.
5
(300 MHz, DMSO-d6, δ, ppm): 2.07 (s, 3H, CH3), 3.11 (t, 4H, J: 4.5 Hz,
pip-2,6), 3.74 (t, 4H, J: 4.5 Hz, pip-3,5), 3.81 (s, 3H, OCH3) 6.87–7.01
(m, 4H, pip-Ar), 7.01–7.39 (m, 9H, Ar). 13C-NMR (75 MHz, DMSO-d6,
δ, ppm): 20.98, 39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 48.44,
49.91, 55.85, 55.89, 112.39, 118.91, 121.29, 122.21, 123.58, 126.15,
127.14, 127.88, 128.10, 128.21, 128.91, 128.99, 129.63, 129.97,
131.03, 131.66, 132.35, 135.41, 137.00, 137.38, 138.42, 138.87,
141.01, 152.49, 159.34, 171.30, 188.08. For C28H27N3O2S;
71.61% C, 5.80% H, 8.95% N, found: 71.62% C, 5.81% H, 8.96%
N. Mass (HRMS), m/z: 470.18 (M + 1).
2.4.4
| Docking and scoring
A series of docking experiments were performed on all compounds to
identify the probable interactions between the ligands and the active
site. Ligand docking was performed with the Glide module in the Extra
Precision (XP) mode. The poses of the compounds with the highest
IC50 values were then subjected to induced-fit protocols with the
default parameter settings.
2.5 | Statistical analysis
The quantitative data were presented as mean ꢁ SD with n denoting
the number of experiments. Statistical analysis and graph generation
were performed using GraphPad Prism Software version 7.02
(La Jolla, California). The statistical evaluation was performed with
one-way ANOVA test followed by Dunnet's multiple comparison test. A
p value of <.05 was taken as the criterion of statistical significance.
3.1.3
|
5-(40-methylbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 3)
Yield 72%, mp 144.4 ꢀC. FT-IR Umax (cm−1): 2838–3,062 (C H), 1,598
(C O), 1,339–1,518 (C C, C N), 1,238 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 2.22 (s, 3H, CH3), 3.11 (t, 4H, J: 4.5 Hz, pip-2,6),
3.73 (t, 4H, J: 6 Hz, pip-3,5), 3.81(s, 3H, OCH3), 6.90–7.01 (m, 6H, Ar),
7.10–7.23 (m, 3H, Ar), 7.29–7.35 (m, 4H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 21.44, 39.16, 39.43, 39.71, 39.99, 40.27, 40.55,
40.82, 48.44, 49.91, 55.85, 112.38, 118.91, 121.29, 121.66, 123.57,
128.00, 128.79, 128.96, 129.32, 130.07, 135.28, 136.03, 141.02,
142.11, 152.48, 158.73, 171.11, 187.68. For C28H27N3O2S;
71.61% C, 5.80% H, 8.95% N, found: 71.62% C, 5.81% H, 8.96%
N. Mass (HRMS), m/z: 470.18 (M + 1).
3
| RESULTS
3.1 | Chemistry
The synthesis of the compounds was carried out with a yield of 64%–
85%. In the FT-IR analyses of these compounds, C H stretching at
the 2,800–3,000 cm−1 band,
C
C,
C
N
stretching at the
1,350–1,600 cm−1 band, and particularly the C O stretching band of
benzoyl around 1,600 cm−1 were observed. The proton numbers in
the aromatic region were provided by the 1H-NMR analyses. The sym-
metrical methylene groups on the piperazine ring were observed in
the 4H-integral and in the triple or wide singlet (brs) in the form of
two peak groups at 3.2–4.01 ppm. The CH3 singlet peaks of the com-
pounds with methyl or methoxy groups on the rings were determined.
The carbon numbers in the 13C-NMR analyses were also examined. In
the mass analysis, the M + 1 peaks of the compounds were correctly
detected.
3.1.4
|
5-(30-methoxylbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 4)
Yield 75%, mp 101.5 ꢀC. FT-IR Umax (cm−1): 2832–3,065 (C H),
1,613.7 (C O), 1,255–1,510 (C C, C N), 1,227.82 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm):3.11 (t, 4H, J: 6 Hz, pip-2,6), 3.57 (s, 3H,
OCH3), 3.75 (t, 4H, J: 4.5 Hz, pip-3,5), 3.81 (s, 3H, OCH3), 6.86–7.03
(m, 7H, Ar), 7.07–7.22 (m, 4H, Ar), 7.30 (d, 2H, J:9 Hz Bz-Ar). 13C-
NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72, 40.00, 40.28,
40.55, 40.83, 48.44, 49.91, 55.48, 55.85, 55.88, 112.39, 113.62,
115.31, 118.33, 118.91,121.29, 121.48, 122.05, 122.52, 123.58,
127.91, 128.15, 129.07, 129.43, 130.07, 131.79, 135.34, 138.78,
140.05, 141.00, 152.49, 158.79, 158.93, 159.07, 159.43, 171.34,
187.67. For C28H27N3O3S; 69.25% C, 5.60% H, 8.65% N, found:
69.24% C, 5.61% H, 8.65% N. Mass (HRMS), m/z: 486.18 (M + 1).
3.1.1
| 5-benzoyl-4-phenyl-2-[4-(2-methoxyphenyl)-
piperazine-1-yl]thiazole (Compound 1)
Yield 69%, mp 170 ꢀC. FT-IR Umax (cm−1): 2842–3,059 (C H), 1,597.6
(C O), 1,339–1,503 (C C, C N), 1,269 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.11 (t, 4H, J: 4,5 Hz, pip-2,6), 3.75 (t, 4H, J:
4,5 Hz, pip-3,5),3.81 (s, 3H, OCH3), 6.90–7.01 (m, 4H, pip-Ar),
7.07–7.18 (m, 5H, Ar), 7.27–7.34 (m, 3H, Ar), 7.38–7.41 (m, 2H, Bz-
Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):39.16, 39.44, 39.71,
39.99, 40.27, 40.55, 40.83, 48.45, 49.92, 55.89, 112.40, 118.92,
121.30, 121.93, 123.58, 127.94, 128.19, 129.08, 130.12, 131.79,
135.21, 138.74, 141.01, 152.49, 159.42, 171.32, 188.05. For
3.1.5
|
5-(40-methoxylbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 5)
Yield 74%, mp 130.6 ꢀC. FT-IR Umax (cm−1): 2760–3,013 (C H),
1,613.7 (C O), 1,294–1,501 (C C, C N), 1,222.66 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.11 (t, 4H, J: 4.5 Hz, pip-2,6), 3.72
(brs, 7H, pip-3,5, OCH3), 3.81 (s, 3H, OCH3), 6.71 (d, 2H, J: 9 Hz, Ar),
6.90–7.01 (m, 4H, Ar), 7.12–7.22 (m, 3H, Ar), 7.31–7.34 (d, 2H, J:
9 Hz Ar), 7.43–7.46 (d, 2H, J: 9 Hz, Ar), 7.45 (d, 2H, J: 6 Hz, Ar).13C-
NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72, 40.00, 40.28,
40.55, 40.83, 48.44, 49.91, 55.84, 112.39, 113.40, 113.62, 118.90,
121.29, 121.59, 123.56, 128.08, 128.94, 130.06, 131.00, 131.58,
C
27H25N3O2S; 71.61% C; 5.53% H; 9.22% N, found: 71.60% C;
5.54% H; 9.23% N. Mass (HRMS), m/z: 456.17 (M + 1).
3.1.2
|
5-(30-methylbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 2)
Yield 77%, mp 169.4 ꢀC. FT-IR Umax (cm−1): 2825–3,055 (C H),
1,613.7 (C O), 1,331–1,523 (C C, C N), 1,206 (C O). 1H-NMR

6
SAHIN ET AL.
|
5-(40-chlorolbenzoyl)-4-phenyl-
135.34, 141.04, 152.49, 157.98, 162.49, 170.93, 186.79. For
3.1.9
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 9)
C
28H27N3O3S; 69.25% C, 5.60% H, 8.65% N, found: 69.26% C,
5.61% H, 8.66% N. Mass (HRMS), m/z: 486.18 (M + 1).
Yield 80%, mp 143.9 ꢀC. FT-IR Umax (cm−1): 2832–3,062 (C H),
1,589.9 (C O), 1,342–1,473 (C C, C N), 1,252 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.11 (t, 4H, J: 4.5 Hz pip-2,6), 3.76 (brs,
4H, pip-3,5), 3.8 (s, 3H, OCH3), 6.87–7.01 (m, 4H, Ar), 7.10–7.33 (m,
7H, Ar), 7.35–7.43 (m, 2H, Ar).13C-NMR (75 MHz, DMSO-d6, δ, ppm):
48.49, 49.91, 55.89, 112.39, 118.92, 121.29, 121.90, 123.60, 128.01,
128.19, 128.32, 129.14, 130.21, 130.90, 131.82, 135.08, 136.36,
137.48, 140.98, 152.49, 159.93, 171.48, 186.82. For C27H24ClN3O2S;
66.18% C, 4.94% H, 8.58% N, found: 66.19% C, 4.93% H, 8.59%
N. Mass (HRMS), m/z: 490.13 (M + 1).
3.1.6
|
5-(30-fluorolbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(compound 6)
Yield 75%, mp 134 ꢀC. FT-IR Umax (cm−1): 2832–3,075 (C H), 1,597.3
(C O), 1,454–1,571 (C C, C N), 1,239 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm), 3.11(t, 4H, J:4.5 Hz, pip-2,6), 3.75 (brs, 4H, pip-
3,5), 3.81 (s, 3H, OCH3), 6.91–6.99 (m, 4H, pip-Ar), 7.01–7.21 (m, 6H,
Ar), 7.22–7.33 (m, 2H, Ar), 7.35–7.43 (m, 1H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 48.49, 49.91, 55.86, 55.89, 112.39, 115.54,
115.70, 115.84, 116.91, 118.22, 118.51, 118.92, 121.29, 123.60,
125.13, 126.31, 127.94, 128.25, 129.01, 129.21, 130.08, 130.24,
130.34, 131.94, 135.14, 138.78, 140.98, 152.49, 160.13,160.28,
163.37, 171.35, 171.57. For C27H24FN3O2S; 68.48% C, 5.11% H,
8.87% N, found 68.49% C, 5.10% H, 8.87% N. Mass (HRMS), m/z:
474.16 (M + 1).
3.1.10
|
5-(30-nitrobenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 10)
Yield 82%, mp 127.8 ꢀC. FT-IR Umax (cm−1): 2832–3,062 (C H), 1,594
(C O), 1,258–1,480 (C C, C N) 1,225 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.11 (t, 4H, J: 4.5 Hz, pip-2,6), 3.75 (t, 4H, J:
4.5 Hz pip-3,5), 3.81 (s, 3H, OCH3), 6.88–7.06 (m, 5H, Ar), 7.10–7.34
(m, 3H, Ar), 7.40–7.47 (m, 2H, Ar), 7.76–7.82 (m, 1H, Ar), 7.96–8.11
(m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 48.55, 49.90,
55.86, 55.89, 112.39, 118.91, 121.29, 122.21, 122.70, 122.98,
123.61, 123.70, 123.98, 124.71, 125.70, 127.97, 128.34, 129.03,
129.22, 129.69, 130.05, 130.22, 131.92, 134.82, 135.09, 136.41,
136.53, 138.60, 139.80, 140.95, 146.99, 147.25, 152.48, 156.69,
3.1.7
|
5-(40-fluorolbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 7)
Yield 76%, mp 128.4 ꢀC. FT-IR Umax (cm−1): 2832–3,062 (C H),
1,607.1 (C O), 1,339–1,587 (C C, C N), 1,228 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.11 (t, 4H, J: 4.5 Hz, pip-2,6), 3.75
(brs, 4H, pip-3,5), 3.81 (s, 3H, OCH3), 6.87–6.99 (m, 5H, Ar),
7.01–7.20 (m, 4H, Ar), 7.23–7.29 (m, 2H, Ar), 7.33–7.46 (m, 2H, Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 48.48, 49.91, 55.86, 55.89,
112.39, 114.72, 114.99, 115.27, 115.55, 115.84, 118.22, 118.51,
118.91, 121.29, 121.95, 123.59, 125.13, 127.94, 127.99, 128.24,
129.01, 129.10, 129.21, 130.08, 130.19, 130.34, 131.77, 131.89,
135.13, 135.23, 140.99, 152.49, 159.59, 160.13, 160.27, 163.37,
165.73, 171.38, 171.57, 186.74. For C27H24FN3O2S, 68.48% C,
5.11% H, 8.87% N, found: 68.49% C, 5.12% H, 8.88% N. Mass
(HRMS), m/z: 474.16 (M + 1).
161.06, 171.59, 171.91, 185.59, 187.69. For
C27H24N4O4S;
64.78% C, 4.83% H, 11.19% N, found: 64.77% C, 4.82% H, 11.18%
N. Mass (HRMS), m/z: 501.15 (M + 1).
3.1.11
|
5-(40-nitrobenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(compound 11)
Yield 82%, mp 149.1 ꢀC. FT-IR Umax (cm−1): 2836–3,102 (C H), 1,613.7
(C O), 1,347–1,517 (C C, C N), 1,293 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.11 (brs, 4H, pip-2,6), 3.77 (brs, 4H, pip-3,5), 3.81
(s, 3H, OCH3), 6.89–6.98 (m, 5H, Ar), 7.14–7.24 (m, 3H, Ar), 7.34–7.59
(m, 3H, Ar), 7.89–7.98 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 48.58, 49.91, 55.90, 112.40, 118.93, 121.30, 123.03, 123.11,
123.62, 127.95, 128.41, 129.14, 129.33, 130.18, 130.25, 131.35,
132.19, 134.83, 138.71, 140.94, 144.68, 148.54, 152.49, 171.93. For
C27H24N4O4S; 64.78% C, 4.83% H, 11.19% N, found: 64.79% C,
4.82% H, 11.18% N. Mass (HRMS), m/z: 501.15 (M + 1).
3.1.8
|
5-(30-chlorolbenzoyl)-4-phenyl-
2-[4-(2-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 8)
Yield 84%, mp 150.1 ꢀC. FT-IR Umax (cm−1): 2832–3,072 (C H),
1,610.4 (C O), 1,304–1,509 (C C, C N), 1,224 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.11 (brs, 4H, pip-2,6), 3.76 (brs, 4H,
pip-3,5), 3.81 (s, 3H, OCH3), 6.90–7.01 (m, 4H, Ar), 7.09–7.44 (m, 9H,
Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.17, 39.44, 39.72,
40.00, 40.28, 40.55, 40.83, 48.50, 49.90, 55.86, 55.88, 112.39,
118.91, 121.29, 122.03, 123.60, 127.51, 127.97, 128.29128.74,
128.88, 128.96, 129.26, 129.78, 130.06, 131.24, 131.97, 132.72,
132.96, 135.08, 137.08, 138.75, 140.52, 140.97, 152.48, 157.53,
3.1.12
| 5-benzoyl-4-phenyl-2-[4-(3-methoxyphenyl)-
piperazine-1-yl]thiazole (Compound 12)
Yield 65%, mp 144.9 ꢀC. FT-IR Umax (cm−1): 2829–3,065 (C H),
1,597.3 (C O), 1,333–1,522 (C C, C N), 1,210 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.32 (t, 4H, J: 6 Hz, pip-2,6), 3.72–3.75
(brs, 7H, pip-3,5, OCH3), 6.43 (dd, 1H, J: 9 Hz Ar), 6.53 (t, 1H, J:
4.5 Hz, Ar),6.59 (dd, 1H, J: 9 Hz, Ar), 7.07–7.21(m, 6H, Ar), 7.27–7.34
(m, 3H, Ar), 7.38–7.41 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.72, 40.00, 40.28, 40.56, 40.83, 47.92, 48.18,
160.39, 171.40, 171.63, 186.39, 187.84. For
C27H24ClN3O2S;
66.18% C, 4.94% H, 8.58% N, found: 66.17% C, 4.93% H, 8.58%
N. Mass (HRMS), m/z: 490.13 (M + 1).

SAHIN ET AL.
7
FIGURE 3 General synthetic method for compounds 1–66 [Color figure can be viewed at wileyonlinelibrary.com]
55.40, 55.42, 102.68, 105.30, 109.07, 122.01, 127.95, 128.19,
129.08, 130.12, 130.24, 131.81, 135.19, 138.71, 152.35, 159.36,
160.73, 171.23, 188.06. For C27H25N3O2S; 71.18% C; 5.53% H;
9.22% N, found: 71.19% C, 5.54% H, 9.23% N. Mass (HRMS), m/z:
456.17 (M + 1).
152.36, 158.68, 160.72, 171.04, 187.69. For C28H27N3O2S; 71.61%
C; 5.80% H; 8.95% N, found: 71.61% C, 5.81% H, 8.96% N. Mass
(HRMS), m/z: 470.18 (M + 1).
3.1.14
|
5-(40-methylbenzoyl)-4-phenyl-
|
5-(30-methylbenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 14)
3.1.13
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 13)
Yield75%, mp 175.4 C. FT-IR Umax (cm−1): 2835–3,065 (C H),
1,598.05 (C O), 1,341–1,528 (C C, C N), 1,219 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 2.07 (s, 3H, CH3), 3.32 (brs, 4H, pip-
2,6), 3.71–3.80 (brs, 7H, pip-3,5 and OCH3), 6.41–6.71 (m, 3H, Ar),
6.98–7.38 (m, 10H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 21.22,
48.18, 102.68, 105.30, 109.07, 126.15, 127.90, 128.22, 129.01,
129.96, 130.24, 132.38, 135.38, 137.39, 138.39, 152.35, 159.13,
160.55, 171.63, 188.13. For C28H27N3O2S; 71.61% C; 5.80% H;
8.95% N, found: 71.62% C, 5.81% H, 8.96% N. Mass (HRMS), m/z:
470.18 (M + 1).
ꢀ
ꢁ
Yield 80%, mp 250ꢀC. FT-IR Umax (cm−1): 2825–3,078 (C H), 1,613.7
(C O), 1,343–1,580 (C C, C N), 1,227 (C O).1H-NMR (300 MHz, D
SO-d6, δ, ppm): 2.22 (s, 3H, CH3), 3.32 (t, 4H, J: 4.5 Hz, pip-2,6),
3.71–3.73 (brs, 7H, pip-3,5 and OCH3), 6.43 (dd, 1H, J: 9 Hz Ar), 6.53
(t, 1H, J: 1.5 Hz, Ar), 6.59 (dd, 1H, J: 9 Hz, Ar), 6.97 (dd, 2H, J: 4.5 Hz,
Ar), 7.10–7.21 (m, 4H, Ar), 7.29–7.35 (m, 4H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 21.47, 39.16, 39.44, 39.72, 39.99, 40.27, 40.55,
40.83, 47.91, 48.18, 55.39, 102.68, 105.30, 109.08, 121.75, 128.02,
128.80, 128.97,129.33, 130.07, 130.24, 135.27, 136.01, 142.14,

8
SAHIN ET AL.
|
5-(30-methoxybenzoyl)-4-phenyl-
DMSO-d6, δ, ppm): 3.32 (brs, 5H, pip-2,6), 3.74 (brs, 7H, pip-3,5 and
OCH3), 6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 (t, 1H,J: 3 Hz, Ar), 6.59 (dd, 1H,
J: 12 Hz, Ar), 6.91–6.97 (m, 1H, Ar), 7.09–7.15 (m, 5H, Ar), 7.17–7.28
(m, 2H, Ar), 7.41–7.46 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.44, 39.72, 39.99, 40.27, 40.55, 47.93, 48.17, 55.43, 102.68,
105.31, 109.07, 114.99, 115.29, 115.55, 115.85, 118.25, 118.54,
122.03, 125.13, 127.96, 128.01, 128.25, 129.01, 129.11, 129.23,
130.08, 130.19, 130.24, 130.35, 131.78, 131.90, 135.11, 152.32,
159.53, 160.73, 165.74, 171.30, 171.49. For C27H24FN3O2S; 68.48%
C; 5.11% H; 8.87% N, found: 68.49% C, 5.12% H, 8.88% N. Mass
(HRMS), m/z: 474.16 (M + 1).
3.1.15
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 15)
Yield 70%, mp 129.5 ꢀC. FT-IR Umax (cm−1): 2848–3,059 (C H),
1,610.4 (C O), 1,344–1,580 (C C, C N), 1,212 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.32 (t, 4H, J: 6 Hz, pip-2,6), 3.56 (s, 3H,
OCH3), 3.72–3.75 (brs, 7H, pip-3,5 and OCH3), 6.42 (dd, 1H, J: 9 Hz,
Ar), 6.53 (t, 1H, J: 3 Hz, Ar), 6.59 (dd, 1H, J: 12 Hz, Ar), 6.85–6.88 (m,
2H, Ar), 6.99–7.03 (m, 1H, Ar), 7.07–7.20 (m, 5H, Ar), 7.28–7.31 (m, 2H,
Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.72,, 40.27, 47.90, 55.40,
55.45, 55.48, 102.68, 105.30, 109.07, 113.62, 115.31, 118.35, 121.48,
122.13, 122.51, 127.93, 128.16, 129.09, 129.44, 130.07, 130.24,
135.31, 140.01, 152.34, 158.93, 159.37, 160.73, 171.27, 187.69. For
3.1.19
|
5-(30-chlorobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 19)
C
28H27N3O3S; 69.25% C; 5.60% H; 8.65% N, found: 69.24% C,
5.61% H, 8.66% N. Mass (HRMS), m/z: 486.18 (M + 1).
Yield 75%, mp 157.6 ꢀC. FT-IR Umax (cm−1): 2815–3,075 (C H),
1,597.3 (C O), 1,348–1,536 (C C, C N), 1,217 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.32 (brs, 4H, pip-2,6), 3.73 (brs, 7H,
pip-3,5 and OCH3),6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 (t, 1H, J: 3 Hz, Ar),
6.59 (dd, 1H, J: 12 Hz, Ar), 7.09–7.15 (m, 3H, Ar), 7.17–7.23 (m, 2H,
Ar), 7.23–7.29 (m, 2H, Ar), 7.29–7.43 (m, 3H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 39.71, 39.99, 40.27, 47.94, 48.17, 55.43, 102.68,
105.31, 109.07, 122.09, 127.51, 127.99, 128.30, 128.87, 128.96,
129.28, 129.82, 130.06, 130.10, 130.25, 131.26, 131.99, 132.95,
135.05, 140.49, 152.31, 160.35, 160.73, 171.55, 186.43. For
C27H24ClN3O2S; 66.18% C; 4.94% H; 8.58% N, found: 66.20% C,
4.95% H, 8.59% N. Mass (HRMS), m/z: 490.13 (M + 1).
3.1.16
|
5-(40-methoxybenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 16)
Yield 70%, mp 162.8 ꢀC. FT-IR Umax (cm−1): 2760–3,072 (C H), 1,617
(C O), 1,336–1,518 (C C, C N), 1,221 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.33 (brs, 4H, pip-2,6), 3.72 (d, 10H, J: 9 Hz, pip-3,5
and OCH3), 6.43 (d, 1H, J:9 Hz, Ar), 6.53 (s, 1H, Ar), 6.59 (d, 1H, J: 9 Hz,
Ar), 6.71 (d, 2H, J: 9 Hz, Ar), 7.13–7.22 (m, 4H, Ar), 7.33 (d, 2H, J: 9 Hz,
Ar), 7.45 (d, 2H, J: 9 Hz, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm):39.16, 39.44, 39.72, 40.00, 40.28, 40.55, 40.83, 47.91, 48.19,
55.39, 55.42, 55.84, 102.69, 105.29, 109.08, 113.62, 121.68, 128.10,
128.95, 130.05, 130.23, 130.97, 131.59, 135.32, 152.38, 157.92,
160.73, 162.50, 170.85, 186.79. For C28H27N3O3S; 69.25% C; 5.60% H;
8.65% N, found: 69.26% C, 5.61% H, 8.66% N. Mass (HRMS), m/z:
486.18 (M + 1).
3.1.20
|
5-(40-chlorobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 20)
Yield 78%, mp 205.5 ꢀC. FT-IR Umax (cm−1): 2832–3,062 (C H), 1,590
(C O), 1,340–1,522 (C C, C N), 1,234 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.32 (brs, 4H, pip-2,6), 3.73 (brs, 7H, pip-3,5 ve
OCH3), 6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 (t, 1H, J: 3 Hz, Ar), 6.59 (dd, 1H,
J: 9 Hz, Ar), 7.10–7.16 (m, 5H, Ar), 7.19–7.28 (m, 3H, Ar), 7.35–7.38
(m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.99, 47.95,
48.17, 55.43, 102.68, 105.31, 109.07, 128.02, 128.20, 129.16,
130.21, 130.90, 135.05, 136.39, 137.44, 152.32, 159.88, 160.72,
171.40, 186.84. For C27H24ClN3O2S; 66.18% C; 4.94% H; 8.58% N,
found: 66.19% C, 4.95% H, 8.59% N. Mass (HRMS), m/z:
490.13 (M + 1).
3.1.17
|
5-(30-fluorobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 17)
Yield 77%, mp 143.2 ꢀC. FT-IR Umax (cm−1): 2832–3,082 (C H),
1,607.1 (C O), 1,341–1,524 (C C, C N), 1,218 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.32 (brs, 4H, pip-2,6), 3.74 (brs, 7H,
pip-3,5 and OCH3), 6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 t, 1H,J: 3 Hz, Ar),
6.59 (dd, 1H, J: 12 Hz, Ar), 7.02–7.15 (m, 7H, Ar), 7.17–7.33 (m, 2H,
Ar), 7.36–7.43 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
39.16, 39.44, 39.71, 39.99, 40.27, 40.55, 40.82, 47.94, 48.17, 55.43,
102.68, 105.31, 109.07, 115.55, 115.85, 115.99, 118.25, 118.53,
122.02, 125.13, 126.30, 127.96, 128.25, 129.01, 129.23, 129.90,
130.08130.25, 130.35, 131.96, 135.12, 140.98152.32, 160.12,
160.22, 160.73, 163.37, 171.27, 171.49, 186.56. For C27H24FN3O2S;
69.48% C; 5.11% H; 8.87% N, found: 69.49% C, 5.12% H, 8.87%
N. Mass (HRMS), m/z: 474.16 (M + 1).
3.1.21
|
5-(30-nitrobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(compound 21)
Yield 76%, mp 157.6ꢀC. FT-IR Umax (cm−1): 2845–3,068 (C H), 1,594
(C O), 1,341–1,525 (C C, C N), 1,216 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.33 (brs, 4H, pip-2,6), 3.71–3.80 (m, 7H, pip-3,5
and OCH3), 6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 (brs, 1H, Ar), 6.59 (d, 1H, J:
6 Hz, Ar), 7.01–7.06 (m, 1H, Ar), 7.10–7.18 (m, 2H, Ar), 7.21–7.24 (m,
1H, Ar), 7.29–7.34 (m, 1H, Ar), 7.40–7.47 (m, 2H, Ar), 7.77–7.82 (m,
1H, Ar), 7.95–8.05 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
47.96, 115.55, 115.85, 116.59, 116.90, 117.96, 118.27, 118.55,
3.1.18
|
5-(40-fluorobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 18)
Yield 80%, mp 165.8 ꢀC. FT-IR Umax (cm−1): 2829–3,065 (C H), 1,600
(C O), 1,339–1,519 (C C, C N), 1,229 (C O). 1H-NMR (300 MHz,

SAHIN ET AL.
9
122.08, 123.50, 125.13, 126.33, 127.96, 128.26, 129.01, 129.23,
130.08, 130.25, 130.36, 131.97135.10, 140.88, 140.97, 149.77,
160.13, 160.18, 163.37, 171.48, 186.56. For C27H24N4O4S; 64.78%
C; 4.83% H; 11.19% N, found: 64.79% C, 4.84% H, 11.20% N. Mass
(HRMS), m/z: 501.15 (M + 1).
3.1.25
|
5-(40-methylbenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 25)
Yield 78%, mp 174.8 ꢀC. FT-IR Umax (cm−1): 2842–3,065 (C H),
1,633.8 (C O), 1,343–1,520 (C C, C N), 1,239 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 2.22 (s, 3H, CH3), 3.16 (t, 4H, J: 6 Hz,
pip-2,6), 3.68 (s, 3H, OCH3), 3.72 (t, 4H, J: 6 Hz, pip-3,5), 6.84–6.88
(m, 2H, Ar), 6.90–6.99 (m, 3H, Ar), 7.10–7.23 (m, 3H, Ar), 7.29–7.42
(m, 4H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 21.26, 21.45,
39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 48.17, 49.79, 55.65,
55.68, 114.80, 118.79, 121.74, 128.01, 128.24, 128.51, 128.80,
128.96, 129.08, 129.33, 130.08, 131.78, 132.37, 135.27, 136.02,
138.59, 138.86, 142.13, 145.39, 153.98, 158.69, 171.06, 171.15,
187.68. For C28H27N3O2S; 71.61% C; 5.80% H; 8.95% N, found:
71.64% C, 5.82% H, 8.93% N. Mass (HRMS), m/z: 470.19 (M + 1).
3.1.22
|
5-(40-nitrobenzoyl)-4-phenyl-
2-[4-(3-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 22)
Yield 78%, mp 189.6 ꢀC. FT-IR Umax (cm−1): 2833–3,066 (C H), 1,594
(C O), 1,343–1,518 (C C, C N), 1,244 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.32 (brs, 4H, pip-2,6), 3.71–3.80 (m, 7H, pip-3,5
and OCH3), 6.43 (dd, 1H, J: 9 Hz, Ar), 6.53 (brs, 1H, Ar), 6.59 (dd, 1H,
J: 9 Hz, Ar), 7.04–7.25 (m, 5H, Ar), 7.34–7.60 (m, 3H, Ar), 7.89–7.99
(m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.43,
39.71, 39.99, 40.27, 40.55, 40.82, 48.01, 48.17, 55.43, 102.69,
105.31, 109.07, 122.29, 123.04, 123.11, 127.96, 128.41, 129.15,
129.35, 130.18, 130.25, 131.35, 132.21,134.81, 138.68, 144.64,
148.55, 152.27, 160.73, 161.34, 171.84, 186.27. For C27H24FN3OS;
64.78% C; 4.83% H; 11.19% N, found: 64.80% C, 4.82% H, 11.20%
N. Mass (HRMS), m/z: 501.15 (M + 1).
3.1.26
|
5-(30-methoxylbenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 26)
Yield 75%, mp 147.3 ꢀC. FT-IR Umax (cm−1): 2832–3,065.5 (C H),
1,613.7 (C O), 1,341–1,510 (C C, C N), 1,208.4 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4.5 Hz, pip-2,6), 3.56 (s, 3H,
OCH3), 3.68 (s, 3H, OCH3), 3.72 (t, 4H, J: 6 Hz, pip-3,5), 6.76–6.88 (m,
4H, Ar), 6.91–7.04 (m, 3H, Ar), 7.07–7.15 (m, 3H, Ar), 7.18–7.23 (m,
1H,Ar), 7.28–7.41 (m, 2H,Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 48.16, 49.79, 55.48,
55.68, 113.62, 114.81, 115.31, 118.35, 118.79, 121.48, 122.11, 122.51,
127.92, 128.16, 129.08, 129.44, 130.07, 131.81, 135.32, 136.42,
140.02, 145.37, 153.98, 158.79, 158.93, 159.39, 171.22, 171.30,
187.68. For C28H27N3O3S; 69,25% C; 5.60% H; 8.65% N, found:
64.27% C, 5.62% H, 8.63% N. Mass (HRMS), m/z: 486.18 (M + 1).
3.1.23
| 5-benzoyl-4-phenyl-2-[4-(4-methoxyphenyl)-
piperazine-1-yl]thiazole (Compound 23)
Yield 68%, mp 173.1 ꢀC. FT-IR Umax (cm−1): 2838–3,065 (C H),
1,595.8 (C O), 1,341–1,522 (C C, C N), 1,227 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4.5 Hz, pip-2,6), 3.69 (s,
3H, OCH3), 3.73 (t, 4H, J: 6 Hz, pip-3,5), 6.84–6.87 (m, 2H, Ar),
6.94–6.98 (m, 2H, Ar), 7.07–7.18 (m, 5H,Ar), 7.27–7.34 (m, 3H, Ar),
7.38–7.41 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16,
39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 48.18, 49.79, 55.67, 56.50,
114.80, 118.79, 122.00, 127.94, 128.19, 129.08, 129.49, 130.12,
131.81, 135.19, 138.72, 145.37, 153.98, 159.38, 171.26, 188.04. For
3.1.27
|
5-(40-methoxylbenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 27)
C
27H25N3O2S; 71.18% C; 5.53% H; 9.22% N, found: 71.19% C,
Yield 70%, mp 162 ꢀC. FT-IR Umax (cm−1): 2763–3,068 (C H), 1,610.4
(C O), 1,336–1,518 (C C, C N), 1,220 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4.5 Hz, pip-2,6), 3.71 (brs, 10H, pip-
3,5 and OCH3), 6.68–6.73 (m, 2H, Ar), 6.84–6.88 (m, 2H, Ar),
6.94–6.98 (m, 2H, Ar), 7.12–7.24 (m, 3H, Ar), 7.31–7.34 (m, 2H,Ar),
7.42–7.46 (m, 2H,Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
39.1597, 39.4393, 39.7179, 39.9956, 40.2737, 40.5525, 40.8307,
48.1722, 49.7899, 55.6489, 55.6784, 55.8096, 55.8394, 113.4089,
113.6249, 114.8023, 118.7831, 121.6517, 128.0948, 128.2491,
128.9478, 129.0784, 130.0535, 130.9745, 131.5881, 135.3177,
145.4064, 153.9740, 157.941, 162.5012, 170.8820, 186.7933. For
C28H27N3O3S; 69,25% C; 5.60% H; 8.65% N, found: 64.27% C,
5.62% H, 8.63% N.Mass (HRMS), m/z: 486.18 (M + 1).
5.51% H, 9.23% N. Mass (HRMS), m/z: 456.17 (M + 1).
3.1.24
|
5-(30-methylbenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 24)
Yield 69%, mp 149.5 ꢀC. FT-IR Umax (cm−1): 2825–3,062 (C H),
1,613.7 (C O), 1,322–1,451 (C C, C N), 1,228 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 2.07 (s, 3H, CH3), 3.17 (t, 4H, J: 6 Hz,
pip-2,6), 3.69 (s, 3H, OCH3), 3.74 (t, 4H, J: 6 Hz, pip-3,5), 6.84–6.88
(m, 2H, Ar), 6.94–7.06 (m, 3H, Ar), 7.07–7.17 (m, 4H, Ar), 7.17–7.22
(m, 1H,Ar), 7.25–7.29 (m, 2H, Ar), 7.31–7.39 (m, 1H, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 20.98, 39.16, 39.44, 39.72, 39.99,
40.27, 40.55, 40.83, 48.17, 49.80, 55.68, 114.81, 118.80, 122.27,
126.15, 127.14, 127.89, 128.11, 128.21, 128.91, 129.00, 129.64,
129.96, 131.02, 131.69, 132.37, 134.91, 135.39, 137.02, 137.39,
138.40, 138.84, 145.37, 153.99, 159.31, 159.56, 171.25, 188.09. For
3.1.28
|
5-(30-fluorobenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 28)
Yield 80%, mp 179.1 ꢀC. FT-IR Umax (cm−1): 2835–3,059 (C H),
1,607.1 (C O), 1,342–1,514 (C C, C N), 1,202 (C O). 1H-NMR
C
28H27N3O2S; 71.61% C; 5.80% H; 8.95% N, found: 71.64% C,
5.82% H, 8.93% N. Mass (HRMS), m/z: 470.19 (M + 1).

10
SAHIN ET AL.
(300 MHz, DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4.5 Hz, pip-2,6), 3.70 (s,
3H, OCH3),3.72 (brs, 4H, pip-3,5), 6.84–6.88 (m, 2H, Ar), 6.94–6.98
(m, 2H, Ar), 7.00–7.23 (m, 6H, Ar), 7.26–7.28 (m, 1H, Ar), 7.33–7.38
(m, 1H, Ar), 7.40–7.43 (m, 1H,Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.99, 48.21, 49.78, 55.65, 55.68, 114.81, 115.55, 115.71,
115.85, 115.99, 116.60, 116.90, 118.24, 118.52, 118.79, 122.02,
122.52, 125.13, 125.16, 126.34, 127.95, 128.25, 129.01, 129.22,
129.88, 129.99, 130.08, 130.24, 130.34, 131.95, 135.12, 137.32,
137.43, 138.76, 140.91, 141.00, 145.35, 153.99, 157.68, 160.13,
160.23, 163.37, 171.30, 171.52, 186.55, 187.88. For C27H24FN3O2S;
68,48% C; 5.11% H; 8.87% N, found: 68.45% C, 5.12% H, 8.85%
N. Mass (HRMS), m/z: 474.16 (M + 1).
(300 MHz, DMSO-d6, δ, ppm): 3.18 (t, 4H, J: 4.5 Hz, pip-2,6), 3.69 (s,
3H, OCH3),3.75 (brs, 4H, pip-3,5), 6.79–6.89 (m, 2H, Ar), 6.94–6.99
(m, 2H, Ar), 7.09–7.20 (m, 4H, Ar), 7.22–7.28 (m, 2H, Ar), 7.29–7.36
(m, 1H,Ar), 7.38–7.43 (m, 2H,Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.71, 39.99, 40.27, 40.55, 40.83, 48.21, 49.78,
50.06, 53.19, 55.65, 114.69, 114.81, 117.87, 118.79, 121.97, 128.01,
128.20, 128.32, 129.11, 129.15, 130.21, 130.59, 130.90, 131.82,
131.94, 133.79, 135.06, 136.39, 137.45, 145.35, 153.99, 159.89,
171.30, 171.43, 186.83, 187.83. For C27H24ClN3O2S; 66,18% C;
4.94% H; 8.58% N, found: 66.15% C, 4.92% H, 8.55% N. Mass
(HRMS), m/z: 490.13 (M + 1).
3.1.32
|
5-(30-nitrobenzoyl)-4-phenyl-
|
5-(40-fluorobenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 32)
3.1.29
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 29)
Yield 73%, mp 127.1 ꢀC. FT-IR Umax (cm−1): 2822–3,065 (C H),
C
N), 1,231 (C O). 1H-NMR
Yield 82%, mp 174.6 ꢀC. FT-IR Umax (cm−1): 2829–3,065 (C H),
1,597.3 (C O), 1,340–1,518 (C C, C N), 1,226 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4,5 Hz, pip-2,6), 3.76 (s,
3H, OCH3), 3.74 (brs, 4H, pip-3,5), 6.85 (d, J: 9 Hz, 2H, Ar), 6.90–6.99
(m, 3H, Ar), 7.09–7.16 (m, 3H, Ar), 7.17–7.21 (m, 1H, Ar), 7.22–7.29
(m, 2H,Ar), 7.30–7.46 (m, 2H,Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 48.20, 49.79,
55.65, 55.68, 114.81, 114.99, 115.28, 115.55, 115.85, 116.60,
118.23, 118.53, 118.79, 122.02, 125.13, 126.34, 127.95, 128.00,
128.25, 129.01, 129.11, 129.22, 129.88, 130.08, 130.19, 130.35,
131.78131.90, 132.24, 132.36, 135.11, 135.20, 138.76, 141.00,
145.36, 153.99, 159.54, 160.13, 160.23, 162.43, 163.37, 165.74,
171.33, 171.52, 186.74. For C27H24FN3O2S; 68,48% C; 5.11% H;
8.87% N, found: 68.45% C, 5.12% H, 8.85% N. Mass (HRMS), m/z:
474.16 (M + 1).
1,597.3 (C O), 1,340–1,510 (C C,
(300 MHz, DMSO-d6, δ, ppm): 3.19 (t, 4H, J: 4.5 Hz, pip-2,6), 3.70 (s, 3H,
OCH3),3.77 (brs, 4H, pip-3,5), 6.87 (d, J: 9 Hz, 2H, Ar), 6.98 (d, J: 9 Hz,
2H, Ar), 7.03–7.06 (m, 1H, Ar), 7.10–7.24 (m, 2H, Ar), 7.29–7.34 (m,
1H,Ar), 7.40–7.47 (m, 2H,Ar), 7.77–7.82 (m, 1H,Ar), 7.96–8.08 (m, 2H,Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 48.27, 49.79, 55.69, 114.82,
118.81, 123.71, 123.99, 124.71, 125.71, 127.98, 128.35, 129.03, 129.24,
129.70, 130.06, 130.22, 131.94, 134.80, 135.10, 136.41, 136.51, 138.58,
139.78, 145.32, 147.00, 147.26, 154.00, 156.68, 171.54, 171.86. For
C27H24N4O4S; 64.78% C; 4.83% H; 11.19% N, found: 64.74% C,
4.85% H, 11.20% N. Mass (HRMS), m/z: 501.16 (M + 1).
3.1.33
|
5-(40-nitrobenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 33)
Yield 76%, mp 168,5 ꢀC. FT-IR Umax (cm−1): 2826–2,994 (C H), 1,606
(C O), 1,345–1,513 (C C, C N), 1,229 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.18 (brs, 4H, pip-2,6), 3.70 (s, 3H, OCH3),3.77
(brs, 4H, pip-3,5), 6.86 (d, J: 9 Hz, 2H, Ar), 6.97 (d, J: 6 Hz, 2H, Ar),
7.04–7.09 (m, 1H, Ar), 7.14–7.25 (m, 2H, Ar), 7.34–7.39 (m, 1H,Ar),
7.43–7.46 (m, 1H,Ar), 7.52–7.59 (m, 2H,Ar),7.89–7.98 (m, 2H,Ar). 13C-
NMR (75 MHz, DMSO-d6, δ, ppm): 48.28, 49.78, 55.68, 114.82,
118.80, 123.03, 123.11, 127.96, 128.41, 129.15, 129.34, 130.18,
130.25, 131.35, 132.20, 134.81, 138.68, 141.66, 144.65, 145.31,
147.35, 148.54, 154.00, 156.75, 161.36, 171.45, 171.87, 186.27,
187.61. For C27H24N4O4S; 64.78% C; 4.83% H; 11.19% N, found:
64.74% C, 4.85% H, 11.20% N. Mass (HRMS), m/z: 501.16 (M + 1).
3.1.30
|
5-(30-chlorobenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 30)
Yield 69%, mp 157.5 ꢀC. FT-IR Umax (cm−1): 2809–3,059 (C H),
1,597.3 (C O), 1,342–1,540 (C C, C N), 1,228 (C O). 1H-NMR
(300 MHz, DMSO-d6, δ, ppm): 3.17 (t, 4H, J: 4.5 Hz, pip-2,6), 3.69 (s,
3H, OCH3),3.74–3.76 (brs, 4H, pip-3,5), 6.84–6.88 (m, 2H, Ar),
6.94–6.98 (m, 2H, Ar), 7.08–7.36 (m, 8H, Ar), 7.37–7.41 (m, 1H,
Ar)13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72, 39.99,
40.27, 40.55, 40.83, 48.22, 49.78, 55.68, 114.81, 118.80, 122.08,
127.51, 127.98, 128.29, 128.74, 128.88, 128.96, 129.27, 129.76,
129.81, 130.06, 130.10, 131.26, 131.99, 132.72, 132.95, 135.06,
137.06, 138.73, 140.50, 145.35, 153.99, 157.52, 160.36, 171.35,
171.58, 186.42, 187.86. For C27H24ClN3O2S; 66,18% C; 4.94% H;
8.58% N, found: 66.15% C, 4.92% H, 8.55% N. Mass (HRMS), m/z:
490.13 (M + 1).
3.1.34
| 5-benzoyl-4-phenyl-2-[4-(2-chlorophenyl)-
piperazine-1-yl]thiazole (Compound 34)
Yield 83%, mp 171.4 ꢀC. FT-IR Umax (cm−1): 2822–3,055 (C H),
1,597.3 (C O), 1,331–1,523 (C C,
C
N). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.14 (t, 4H, J:4.5 Hz, pip-2,6), 3.78 (t, 4H,
J:4.5 Hz,pip-3,5), 7.07–7.23 (m, 7H, Ar), 7.27–7.36 (m, 4H, Ar),
7.39–7.41 (m, 1H, Ar), 7.41–7.44 (m, 1H, Ar), 7.45–7.47 (m, 1H, Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72, 40.00,
40.28, 40.55, 40.83, 48.45, 50.65, 121.74, 122.03, 124.96, 127.95,
128.20, 128.63, 129.09, 130.13, 130.84, 131.83, 135.17, 138.71,
3.1.31
|
5-(40-chlorobenzoyl)-4-phenyl-
2-[4-(4-methoxyphenyl)-piperazine-1-yl]thiazole
(Compound 31)
Yield 68%, mp 170.6 ꢀC. FT-IR Umax (cm−1): 2825–3,062 (C H),
1,589.3 (C O), 1,340–1,520 (C C, C N), 1,233 (C O). 1H-NMR

SAHIN ET AL.
11
148.92, 159.33, 171.31, 188.06. For C26H22ClN3OS; 67,89% C;
4.82% H; 9.13% N, found: 67.85% C, 4.83% H, 9.15% N. Mass
(HRMS), m/z: 460.12 (M + 1).
DMSO-d6, δ, ppm): 3.13 (brs, 4H, pip-2,6), 3.70 (s, 3H, OCH3), 3.75
(brs, 4H, pip-3,5), 6.71 (d, J: 6 Hz, 2H, Ar), 7.06–7.24 (m, 5H, Ar),
7.31–7.34 (m, 3H, Ar), 7.45 (d, J: 6 Hz, 3H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 39.16, 39.43, 39.71, 39.99, 40.27, 40.55, 40.82,
48.44, 50.65, 55.84, 113.63, 121.71, 124.94, 128.10, 128.24, 128.62,
128.96, 130.06, 130.84, 130.96, 131.60, 135.30, 148.94, 157.89,
162.52, 170.91, 186.80. For C27H24ClN3O2S; 66,18% C; 4.94% H;
8.58% N, found: 66.20% C, 4.93% H, 8.59% N. Mass (HRMS), m/z:
490.14 (M + 1).
3.1.35
|
5-(30-methylbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 35)
Yield 69%, mp 188.7 ꢀC. FT-IR Umax (cm−1): 2825–3,065 (C H),
1,610.4 (C O), 1,331–1,495 (C C,
C
N). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 2.07 (s, 3H, CH3), 3.14 (brs, 4H, pip-2,6), 3.78 (brs,
4H, pip-3,5), 6.98–7.39 (m, 12H, Ar), 7.44–7.47 (m, 1H, Ar), 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 20.96, 39.16, 39.44, 39.72, 40.00,
40.28, 40.56, 40.82, 48.45, 50.65, 121.74, 122.30, 124.96, 126.16,
127.89, 128.12, 128.22, 128.63, 128.92, 129.01, 129.65, 129.97,
130.84, 131.03, 131.71, 132.39, 135.38, 137.40, 138.39, 138.83,
148.92, 159.26, 171.30, 188.10. For C27H24ClN3OS; 68,41% C;
5.10% H; 8.86% N, found: 68.42% C, 5.13% H, 8.85% N. Mass
(HRMS), m/z: 474.14 (M + 1).
3.1.39
|
5-(30-fluorolbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 39)
Yield 83%, mp 173 ꢀC. FT-IR Umax (cm−1): 2835–3,062 (C H), 1,604.7
(C O), 1,342–1,513 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.14 (t, 4H, J:4.5 Hz, pip-2,6), 3.79 (brs, 4H, pip-3,5), 7.07–7.22
(m, 9H, Ar), 7.26–7.31 (m, 2H, Ar), 7.33–7.36 (m, 1H, Ar), 7.41–7.47
(m,1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44,
39.72, 40.00, 40.27, 40.55, 40.83, 48.49, 50.64, 115.56, 115.86,
116.00, 116.61, 116.91, 118.27, 118.55, 121.74, 122.05, 124.97,
125.14, 125.17, 126.34, 127.95, 128.24, 128.63, 129.02, 129.23,
130.09, 130.25, 130.36, 130.85, 131.97, 135.11, 138.74, 140.89,
140.98, 148.89, 160.14, 160.18, 163.38, 171.35, 171.58, 186.56. For
C26H21ClFN3OS; 65,33% C; 4.43% H; 8.79% N, found: 65.32% C,
4.44% H, 8.77% N. Mass (HRMS), m/z: 478.12 (M + 1).
3.1.36
|
5-(40-methylbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(compound 36)
Yield 71%, mp 152.1 ꢀC. FT-IR Umax (cm−1): 2838–3,039 (C H),
1,596.8 (C O), 1,342–1,526 (C C,
C
N). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 2.22 (s, 3H, CH3), 3.13 (brs, 4H, pip-2,6), 3.76 (brs,
4H, pip-3,5), 6.97 (d, J: 6 Hz, 2H, Ar), 7.07–7.15 (m, 3H, Ar),
7.18–7.23 (m, 2H, Ar), 7.30–7.36 (m, 5H, Ar), 7.44–7.47 (m, 1H,Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 21.45, 39.15, 39.43, 39.71,
39.99, 40.27, 40.54, 40.82, 47.63, 48.44, 50.64, 121.73, 124.95,
128.02, 128.24, 128.63, 128.81, 128.98, 129.34, 130.08, 130.84,
135.25, 136.00, 142.16, 148.93, 158.65, 171.10, 187.69. For
C27H24ClN3OS; 68,41% C; 5.10% H; 8.86% N, found: 68.42% C,
5.13% H, 8.85% N. Mass (HRMS), m/z: 474.14 (M + 1).
3.1.40
|
5-(40-fluorolbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 40)
Yield 68%, mp 171.2 ꢀC. FT-IR Umax (cm−1): 2832–3,065 (C H), 1,594
(C O), 1,342–1,510 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.14 (t, 4H, J: 4.5 Hz, pip-2,6), 3.79 (brs, 4H, pip-3,5), 6.92–6.98
(m,1H,Ar) 7.07–7.15 (m, 4H, Ar), 7.16–7.24 (m, 3H, Ar), 7.25–7.31 (m,
2H, Ar), 7.33–7.36 (m, 1H, Ar), 7.42–7.47 (m,2H, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 48.48, 50.64, 115.01, 115.30, 115.55,
115.85, 118.28, 118.55, 121.75, 122.04, 124.98, 125.14, 127.96,
128.01, 128.24, 128.64, 129.13, 129.24, 130.09, 130.20, 130.36,
130.85, 131.79, 131.91, 135.10, 148.90, 159.51, 160.13, 160.20,
171.38, 171.58. For C26H21ClFN3OS; 65,33% C; 4.43% H; 8.79% N,
found: 65.32% C, 4.44% H, 8.77% N. Mass (HRMS), m/z:
478.12 (M + 1).
3.1.37
|
5-(30-methoxylbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 37)
Yield 74%, mp 139 ꢀC. FT-IR Umax (cm−1): 2845–3,065 (C H), 1,603.8
(C O), 1,343–1,513 (C C, C N), 1,212 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.15 (brs, 4H, pip-2,6), 3.56 (s, 3H, OCH3), 3.78
(brs, 4H, pip-3,5), 6.85–6.89 (m, 2H, Ar), 7.00–7.03 (m, 1H, Ar),
7.07–7.14 (m, 4H, Ar), 7.18–7.23 (m, 2H, Ar), 7.29–7.36 (m, 3H,Ar),
7.44–7.47 (m,1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 40.00,
48.44, 50.65, 55.49, 113.63, 118.37, 121.48, 121.74, 122.13, 124.97,
127.93, 128.23, 128.64, 129.10, 129.45, 130.07, 130.85, 135.30,
140.01, 148.92, 158.93, 159.35, 171.34, 187.69. For C27H24ClN3O2S;
66,18% C; 4.94% H; 8.58% N, found: 66.20% C, 4.93% H, 8.59%
N. Mass (HRMS), m/z: 490.14 (M + 1).
3.1.41
|
5-(30-chlorolbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 41)
Yield 78%, mp 151.3 ꢀC. FT-IR Umax (cm−1): 2812–3,062 (C H),
1,597.3 (C O), 1,348–1,531 (C C,
C
N). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.14 (t, 4H, J:4.5 Hz, pip-2,6), 3.79 (brs, 4H, pip-
3,5), 7.06–7.12 (m, 2H, Ar) 7.14–7.16 (m, 1H, Ar), 7.17–7.24 (m, 3H,
Ar), 7.26–7.28 (m, 2H, Ar), 7.31–7.34 (m, 3H, Ar), 7.35–7.42 (m, 1H,
Ar), 7.44–7.47 (m,1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
39.16, 39.44, 39.72, 40.00, 40.28, 40.55, 40.83, 48.50, 50.64, 121.73,
122.12, 124.97, 127.52, 127.98, 128.24, 128.30, 128.63, 128.74,
128.89, 128.97, 129.28, 129.76, 130.07, 130.10, 130.84, 131.28,
3.1.38
|
5-(40-methoxylbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 38)
Yield 77%, mp 172.5 ꢀC. FT-IR Umax (cm−1): 2835–3,062 (C H), 1,600
(C O), 1,315–1,530 (C C, C N), 1,243 (C O). 1H-NMR (300 MHz,

12
SAHIN ET AL.
132.97, 135.04, 140.48, 148.88, 160.30, 171.64, 186.42. For
C26H21Cl2N3OS; 63,16% C; 4.28% H; 8.50% N, found: 63.12% C,
4.24% H, 8.51% N. Mass (HRMS), m/z: 494.09 (M + 1).
δ, ppm): 3.38 (brs, 4H, pip-2,6), 3.73 (brs, 4H, pip-3,5), 6.84 (d, 1H, J: 9 Hz
Ar), 6.97 (t, 1H, J:9 Hz, Ar), 7.02 (brs, 1H, Ar), 7.06–7.20 (m, 5H, Ar),
7.22–7.35 (m, 4H, Ar), 7.39 (d, 2H, J: 6 Hz, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 47.53, 47.71, 114.66, 115.60, 119.13, 127.96,
128.20, 129.08, 130.11, 131.03, 131.83, 134.35, 152.18, 168.37, 171.25,
177.45. For C26H22ClN3OS; 67.89% C; 4.82% H; 9.13% N, found:
67.90% C, 4.83% H, 9.14% N. Mass (HRMS), m/z: 460.12 (M + 1).
3.1.42
|
5-(40-chlorolbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 42)
Yield 67%, mp 186.7 ꢀC. FT-IR Umax (cm−1): 2835–3,065 (C H),
C
N). 1H-NMR (300 MHz,
3.1.46
|
5-(30-methylbenzoyl)-4-phenyl-
1,589.3 (C O), 1,340–1,520 (C C,
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 46)
DMSO-d6, δ, ppm): 3.14 (t, 4H, J: 4.5 Hz, pip-2,6), 3.79 (brs, 4H, pip-
3,5), 7.07–7.12 (m, 2H, Ar) 7.15–7.33 (m, 8H, Ar), 7.36–7.41 (m, 2H,
Ar), 7.44–7.47 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm):
48.4936, 50.6438, 121.7456, 122.0030, 124.9767, 128.0197,
128.2096, 128.6378, 129.1679, 130.2145, 130.8466, 130.9082,
131.8268, 135.0398, 136.4077, 137.4396, 148.8954, 159.8451,
171.4848, 186.8463. For C26H21Cl2N3OS; 63,16% C; 4.28% H;
8.50% N, found: 63.12% C, 4.24% H, 8.51% N. Mass (HRMS), m/z:
494.09 (M + 1).
Yield 69%, mp 185.9 ꢀC. FT-IR Umax (cm−1): 2822–3,013 (C H),
1,597.3 (C O), 1,336–1,544 (C C,
C
N). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 2.07 (s, 3H, CH3), 3.39 (t, 4H, J: 4.5 Hz, pip-2,6),
3.74 (t, 4H, J: 4.5 Hz, pip-3,5), 6.84 (dd, 1H, J: 6 Hz, Ar), 6.97 (dd, 1H,
J:9 Hz, Ar), 7.02 (t, 1H, J: 3 Hz, Ar), 7.07–7.19 (m, 6H, Ar), 7.21–7.28
(m, 4H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 20.98, 47.53,
114.66, 115.60, 119.13, 126.15, 127.90, 128.11, 128.22, 129.01,
129.96, 131.02, 132.39, 134.35, 135.37, 137.39, 138.37, 152.18,
159.25, 171.19, 188.10. For C27H24ClN3OS; 68.41% C; 5.10% H;
8.86% N, found: 68.42% C, 5.11% H, 8.87% N. Mass (HRMS), m/z:
474.14 (M + 1).
3.1.43
|
5-(30-nitrolbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 43)
Yield 74%, mp 137.4 ꢀC. FT-IR Umax (cm−1): 2845–3,065 (C H),
C
N). 1H-NMR (300 MHz,
3.1.47
|
5-(40-methylbenzoyl)-4-phenyl-
1,597.3 (C O), 1,286–1,513 (C C,
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 47)
DMSO-d6, δ, ppm): 3.15 (s, 4H, pip-2,6), 3.81 (brs, 4H, pip-3,5),
7.01–7.08 (m, 1H, Ar), 7.10–7.16 (m, 2H, Ar), 7.19–7.25 (m, 2H, Ar),
7.30–7.37 (m, 2H, Ar), 7.41–7.48 (m, 3H, Ar), 7.77–7.82 (m, 1H, Ar),
7.96–8.11 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 48.55,
50.63, 121.75, 123.09, 123.72, 123.99, 124.71, 124.99, 125.74,
127.98, 128.24, 128.36, 128.64, 129.04, 129.25, 129.70, 130.07,
130.23, 130.85, 131.96, 134.79, 135.10, 136.42, 136.49, 138.57,
139.76, 147.00, 147.26, 148.87, 156.62, 160.98, 171.59, 171.93,
185.63, 187.71. For C26H21ClN4O3S; 61,84% C; 4.19% H; 11.09% N,
found: 61.82% C, 4.20% H, 11.11% N. Mass (HRMS), m/z:
505.11 (M + 1).
Yield 60%, mp 220 ꢀC. FT-IR Umax (cm−1): 2838–2,999 (C H), 1,598
(C O), 1,341–1,517 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 2.22 (s, 3H, CH3), 3.38 (t, 4H, J: 4.5 Hz, pip-2,6), 3.72 (t, 4H, J:
4.5 Hz, pip-3,5), 6.84 (dd, 1H, J: 9 Hz, Ar), 6.93–7.00 (m, 3H, Ar), 7.03
(t, 1H, J: 3 Hz, Ar), 7.09–7.27 (m, 4H, Ar), 7.27–7.36 (m, 4H, Ar). 13C-
NMR (75 MHz, DMSO-d6, δ, ppm): 47.54, 47.72, 114.66, 115.60,
119.13, 128.03, 128.81, 128.98, 129.33, 130.07, 131.03, 134.35,
135.25, 135.99, 142.16, 152.20, 171.01, 187.98. For C27H24ClN3OS;
68.41% C; 5.10% H; 8.86% N, found: 68.42% C, 5.11% H, 8.87%
N. Mass (HRMS), m/z: 474.14 (M + 1).
3.1.44
|
5-(40-nitrolbenzoyl)-4-phenyl-
3.1.48
|
5-(30-methoxylbenzoyl)-4-phenyl-
2-[4-(2-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 44)
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 48)
Yield 72%, mp 163 ꢀC. FT-IR Umax (cm−1): 2836–3,105 (C H), 1,596.2
(C O), 1,302–1,536 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.15 (t, 4H, J: 4.5 Hz, pip-2,6), 3.82 (brs, 4H, pip-3,5), 7.04–7.09
(m, 2H, Ar), 7.12–7.18 (m, 1H, Ar), 7.19–7.25 (m, 3H, Ar), 7.31–7.48
(m, 3H, Ar), 7.53–7.60 (m, 2H, Ar), 7.90–7.99 (m, 2H, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 48.57, 50.65, 121.76, 123.13, 125.00,
127.96, 128.43, 128.65, 129.16, 129.36, 130.19, 130.26, 130.85,
134.79, 144.64, 148.86, 171.95. For C26H21ClN4O3S; 61,84% C;
4.19% H; 11.09% N, found: 61.82% C, 4.20% H, 11.11% N. Mass
(HRMS), m/z: 505.11 (M + 1).
Yield 70%, mp 154.5 ꢀC. FT-IR Umax (cm−1): 2832–3,065 (C H), 1,607
(C O), 1,472–1,510 (C C, C N), 1,206 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.39 (t, 4H, J: 4.5 Hz, pip-2,6), 3.57(s, 3H, CH3),
3.74 (t, 4H, J: 4.5 Hz, pip-3,5), 6.82 (d, 1H, J: 3 Hz, Ar), 6.85 (d, 1H, J:
3 Hz, Ar), 6.88 (d, 1H, J: 3 Hz, Ar), 6.87 (d, 1H, J: 3 Hz, Ar), 7.00 (t, 1H,
J:3 Hz, Ar), 7.02 (d, 1H, J: 3 Hz, Ar), 7.09 (d, 1H, J: 3 Hz, Ar), 7.11 (d,
1H, J: 3 Hz, Ar), 7.14 (s, 1H, Ar), 7.18–7.23 (m, 1H, Ar), 7.25 (s, 1H,
Ar), 7.28 (d, 1H, J: 3 Hz, Ar), 7.31 (d, 1H, J: 3 Hz, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 47.53, 47.69, 55.48, 113.62, 114.65,
115.60, 118.37, 119.13, 121.48, 122.17, 127.94, 128.17, 129.09,
129.45, 130.07, 131.02, 134.36, 135.30, 139.99, 152.17, 158.93,
159.33, 171.24, 187.69. For C27H24ClN3O2S; 66.18% C; 4.94% H;
8.58% N, found: 66.19% C, 4.95% H, 8.58% N. Mass (HRMS), m/z:
490.14 (M + 1).
3.1.45
| 5-benzoyl-4-phenyl-2-[4-(3-chlorophenyl)-
piperazine-1-yl]thiazole (Compound 45)
Yield 68%, mp 218.1 ꢀC. FT-IR Umax (cm−1): 2845–3,062 (C H),
1,594.3 (C O), 1,343–15`9 (C C, C N). 1H-NMR (300 MHz, DMSO-d6,

SAHIN ET AL.
13
DMSO-d6, δ, ppm): 3.39 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (brs, 4H, pip-
3.5), 6.84 (dd, 1H, J: 4.5 Hz, Ar), 6.97 (dd, 1H, J: 6 Hz, Ar), 7.03 (t, 1H,
J: 1.5 Hz, Ar), 7.09–7.15 (m, 3H, Ar), 7.18–7.33 (m, 7H, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 47.52, 47.75, 114.65, 115.60, 119.14,
122.14, 127.51, 128.00, 128.30, 128.88, 129.28, 129.83, 130.06,
130.11, 131.03, 131.28, 132.96,134.36, 135.03, 140.47, 152.14,
160.30, 171.53, 186.43. For C26H21Cl2N3OS; 63.16% C; 4.28% H;
8.50% N, found: 63.17% C, 4.29% H, 8.51% N. Mass (HRMS), m/z:
494.09 (M + 1).
3.1.49
|
5-(40-methoxylbenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 49)
Yield 75%, mp 208 ꢀC. FT-IR Umax (cm−1): 2832–3,003 (C H), 1,610
(C O), 1,302–1,522 (C C, C N), 1,221 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.38 (t, 4H, J: 6 Hz, pip-2,6), 3.73(brs, 7H, pip-3.5,
OCH3), 6.69–6.73 (m, 2H, Ar), 6.84 (dd, 1H, J: 6 Hz, Ar), 6.97 (dd, 1H,
J: 4.5 Hz, Ar), 7.03 (t, 1H, J:3 Hz, Ar), 7.13–7.28 (m, 4H, Ar), 7.31–7.34
(m, 2H, Ar), 7.42–7.46 (m, 2H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.72, 39.99, 40.27, 40.55, 40.83, 47.55, 47.71,
55.85, 113.64, 114.67, 115.61, 119.13, 121.71, 128.11, 128.97,
130.05, 130.95, 131.02, 131.59, 131.93, 134.35, 135.30, 152.21,
157.89, 162.52, 170.82, 186.80. For C27H24ClN3O2S; 66.18% C;
4.94% H; 8.58% N, found: 66.19% C, 4.94% H, 8.59% N. Mass
(HRMS), m/z: 490.14 (M + 1).
3.1.53
|
5-(40-chlorolbenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 53)
Yield 62%, mp 221.8 ꢀC. FT-IR Umax (cm−1): 2842–3,059 (C H), 1,589
(C O), 1,342–1,518 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.39 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (brs, 4H, pip-3.5), 6.84 (dd,
1H, J: 9 Hz, Ar), 6.97 (dd, 1H, J: 9 Hz, Ar), 7.03 (t, 1H, J: 1.5 Hz, Ar),
7.10–7.28 (m, 8H, Ar), 7.30–7.38 (m, 2H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 47.53, 47.74, 114.66, 115.60, 119.14, 128.03,
128.21, 129.17, 130.21, 130.90, 131.03, 134.36, 135.04, 136.41,
137.43, 152.15, 159.83, 171.38, 186.84. For C26H21Cl2N3OS; 63.16%
C; 4.28% H; 8.50% N, found: 63.17% C, 4.29% H, 8.51% N. Mass
(HRMS), m/z: 494.09 (M + 1).
3.1.50
|
5-(30-fluorolbenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 50)
Yield 72%, mp 210.5 ꢀC. FT-IR Umax (cm−1): 2832–3,005 (C H), 1,603
(C O), 1,342–1,519 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.39 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (brs, 4H, pip-3.5), 6.85 (d,
1H, J: 9 Hz, Ar), 6.97 (d, 1H, J: 9 Hz, Ar), 7.03 (s, 1H, Ar), 7.06–7.23
(m, 7H, Ar), 7.28 (d, 2H, J: 9 Hz, Ar), 7.33–7.41 (m, 1H, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 39.17, 39.44, 39.72, 40.00, 40.28,
40.56, 40.83, 47.52, 47.73, 114.65, 115.60, 115.85, 116.02,
116.60118.27, 118.55, 119.14, 122.08, 125.13, 126.31, 127.97,
128.26, 129.01, 129.24, 130.08, 130.25, 130.36, 131.03, 131.97,
134.36, 135.10, 138.73, 140.88, 140.97, 152.15, 160.13, 160.18,
163.37, 171.47, 186.56, 187.90. For C26H21ClFN3OS; 65.33% C;
4.43% H; 8.79% N, found: 65.34% C, 4.44% H, 8.78% N. Mass
(HRMS), m/z: 478.12 (M + 1).
3.1.54
|
5-(30-nitrobenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 54)
Yield 77%, mp 192.4 ꢀC. FT-IR Umax (cm−1): 2845–3,059 (C H), 1,594
(C O), 1,342–1,512 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.41 (t, 4H, J: 4.5 Hz, pip-2,6), 3.78 (t, 4H, J: 6 Hz, pip-3.5), 6.85
(dd, 1H, J: 6 Hz, Ar), 6.97 (dd, 1H, J: 12 Hz, Ar), 7.01–7.06 (m, 3H, Ar),
7.10–7.14 (m, 1H, Ar), 7.22–7.29 (m, 3H, Ar), 7.40–7.47 (m, 1H, Ar),
7.77–7.82 (m, 1H, Ar), 7.96 (t, 1H, J: 3 Hz, Ar), 8.04–8.11 (m, 1H, Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 47.52, 47.80, 114.65, 115.60,
119.14, 122.32, 123.98, 125.74, 127.99, 128.36, 129.04, 129.26,
130.07, 130.22, 131.04, 134.36, 134.78, 135.09, 139.75, 147.00,
152.12, 160.97, 171.82, 185.64. For C26H21ClN4O3S; 61.84% C;
4.19% H;11.09% N, found: 61.85% C, 4.20% H,11.10% N. Mass
(HRMS), m/z: 505.11 (M + 1).
3.1.51
|
5-(40-fluorolbenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 51)
Yield 75%, mp 204 ꢀC. FT-IR Umax (cm−1): 2825–3,062 (C H), 1,610
(C O), 1,338–1,508 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.39 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (brs, 4H, pip-3.5), 6.85 (dd,
1H, J: 6 Hz, Ar), 6.96 (dd, 2H, J: 9 Hz, Ar), 7.03 (brs, 1H, Ar), 7.09–7.28
(m, 8H, Ar), 7.41–7.46 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.72, 40.00, 40.28, 40.55, 40.83, 47.53, 47.73,
114.65, 115.00, 115.29, 115.60, 115.86, 118.27, 118.55, 119.14,
122.08, 125.17, 127.97,128.02, 128.26, 129.01, 129.12, 129.24,
130.08, 130.19, 130.25, 130.36, 131.03, 131.78, 131.90, 134.36,
135.10, 140.88, 152.15, 160.18, 171.47. For C26H21ClFN3OS;
65.33% C; 4.43% H; 8.79% N, found: 65.34% C, 4.44% H, 8.80%
N. Mass (HRMS), m/z: 478.12 (M + 1).
3.1.55
|
5-(40-nitrobenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 55)
Yield 73%, mp 194.7 ꢀC. FT-IR Umax (cm−1): 2846–3,066 (C H), 1,588
(C O), 1,343–1,516 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.40 (t, 4H, J: 4.5 Hz, pip-2,6), 3.77 (brs, 4H, pip-3.5), 6.85 (dd,
1H, J: 4.5 Hz, Ar), 6.84 (dd, 1H, J: 9 Hz, Ar), 6.97 (dd, 1H, J: 9 Hz, Ar),
7.03 (brs, 1H, Ar), 7.08 (dd, 1H, J: 9 Hz, Ar), 7.14–7.29 (m, 4H, Ar),
7.35–7.46 (m, 1H, Ar), 7.52–7.61 (m, 2H, Ar), 7.89–7.99 (m, 2H, Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 47.51, 47.80, 114.65, 115.60,
119.15, 123.05, 123.12, 127.97, 128.42, 129.15, 129.36, 130.19,
130.25, 131.04, 131.35, 134.36, 134.79, 141.63, 144.63, 148.56,
152.11, 161.30, 171.83, 186.29. For C26H21ClN4O3S; 61.84% C;
3.1.52
|
5-(30-chlorolbenzoyl)-4-phenyl-
2-[4-(3-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 52)
Yield 68%, mp 193.2 ꢀC. FT-IR Umax (cm−1): 2832–3,068 (C H),
1,587.4 (C O), 1,338–1,542 (C C,
C
N). 1H-NMR (300 MHz,

14
SAHIN ET AL.
4.19% H; 11.09% N, found: 61.85% C, 4.20% H, 11.10% N. Mass
(HRMS), m/z: 505.11 (M + 1).
39.72, 40.00, 40.28, 40.55, 40.83, 47.76, 47.97, 55.48, 113.62,
115.32, 117.96, 118.36, 121.48, 122.17, 122.50, 123.49, 127.93,
128.17, 129.09, 129.23, 129.45, 130.06, 135.29, 139.99, 149.79,
158.93, 159.34, 171.26, 187.69. For C27H24ClN3O2S; 66.18% C;
4.94% H; 8.58% N, found: 66.19% C, 4.95% H, 8.56% N. Mass
(HRMS), m/z: 490.14 (M + 1).
3.1.56
| 5-benzoyl-4-phenyl-2-[4-(4-chlorophenyl)-
piperazine-1-yl]thiazole (Compound 56)
Yield 72%, mp 190.7 ꢀC. FT-IR Umax (cm−1): 2826–3,089 (C H),
1,596.4 (C O), 1,339–1,535 (C C,
C
N). 1H-NMR (300 MHz,
3.1.60
|
5-(40-methoxylbenzoyl)-4-phenyl-
DMSO-d6, δ, ppm): 3.32 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (t, 4H, J:
4.5 Hz, pip-3,5), 7.02 (d, 2H, J: 9 Hz, Ar), 7.04–7.21 (m, 5H, Ar),
7.25–7.34 (m, 5H, Ar), 7.40 (d, 2H, J:9 Hz, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 39.17, 39.45, 39.72, 40.00, 40.28, 40.56, 40.83,
47.78, 47.97, 117.96, 122.06, 123.50, 127.95, 128.19, 129.08,
129.22, 130.12, 131.83, 135.17, 138.69, 149.79, 159.32, 171.22,
188.05. For C26H22ClN3OS; 67.89% C; 4.82% H; 9.13% N, found:
67.90% C, 4.83% H, 9.14% N. Mass (HRMS), m/z: 460.12 (M + 1).
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 60)
Yield 75%, mp 186 ꢀC. FT-IR Umax (cm-1): 2836–3,092 (C H), 1,609
(C O), 1,300–1,522 (C C, C N), 1,208 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.32 (t, 4H, J: 4.5 Hz, pip-2,6), 3.71(brs, 7H, pip-3.5,
OCH3), 6.71 (d, 2H, J:9 Hz, Ar), 7.02 (d, 2H, J: 9 Hz, Ar), 7.12–7.22 (m,
3H, Ar), 7.25–7.33 (m, 4H, Ar), 7.45 (d, 2H, J:9 Hz, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72, 40.00, 40.27, 40.55,
40.83, 47.78, 47.98, 55.85, 113.63, 117.96, 121.71, 123.49, 128.11,
128.96, 129.22, 130.05, 130.95, 131.59, 135.29, 149.82, 157.88, 162.51,
170.84, 186.79. For C27H24ClN3O2S; 66.18% C; 4.94% H; 8.58% N,
found: 66.19% C, 4.92% H, 8.57% N. Mass (HRMS), m/z: 490.14 (M + 1).
3.1.57
|
5-(30-methylbenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(compound 57)
Yield 73%, mp 167.2 ꢀC. FT-IR Umax (cm-1): 2813–3,056 (C H), 1,625
(C O), 1,333–1,514 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 2.07 (s, 3H, CH3), 3.32 (t, 4H, J: 4.5 Hz, pip-2,6), 3.74 (t, 4H, J:
4.5 Hz, pip-3,5), 6.98–7.03 (m, 3H, Ar), 7.05–7.13 (m, 5H, Ar),
7.14–7.21 (m, 1H, Ar), 7.24–7.29 (m, 4H, Ar). 13C-NMR (75 MHz,
DMSO-d6, δ, ppm): 20.98, 39.16, 39.44, 39.72, 40.00, 40.27, 40.55,
40.83, 47.77, 47.97, 117.96, 122.33, 123.49, 126.15, 127.14, 127.89,
128.11, 128.22, 128.91, 129.01, 129.22, 129.65, 129.96, 131.02,
132.39, 135.37, 137.03, 137.39, 138.38, 149.79, 159.25, 171.21,
188.10. For C27H24ClN3OS; 68.41% C; 5.10% H; 8.86% N, found:
68.42% C, 5.11% H, 8.87% N. Mass (HRMS), m/z: 474.14 (M + 1).
3.1.61
|
5-(30-fluorobenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(compound 61)
Yield 70%, mp 180.6 ꢀC. FT-IR Umax (cm-1): 2833–3,086 (C H), 1,606
(C O), 1,342–1,525 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.33 (brs, 4H, pip-2,6), 3.76 (brs, 4H, pip-3.5), 7.02 (d, 2H, J: 7.5 Hz,
Ar), 7.04–7.19 (m, 7H, Ar), 7.26–7.29 (m, 3H, Ar), 7.33–7.43 (m, 1H, Ar)+.
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 47.96, 115.55, 115.85, 116.59,
116.90, 117.96, 118.27, 118.55, 122.08, 123.50, 125.13, 126.33, 127.96,
128.26, 129.01, 129.23, 130.08, 130.25, 130.36, 131.97, 135.10, 140.88,
140.97, 149.77, 160.13, 160.18, 163.37, 171.48, 186.56. For
C26H21ClFN3OS; 65.33% C; 4.43% H; 8.79% N, found: 65.34% C,
4.42% H, 8.76% N. Mass (HRMS), m/z: 478.12 (M + 1).
3.1.58
|
5-(40-methylbenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 58)
Yield 60%, mp 207.5 ꢀC. FT-IR Umax (cm-1): 2845–2,993 (C H), 1,597
(C O), 1,342–1,530 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 2.22 (s, 3H, CH3), 3.32 (t, 4H, J: 4.5 Hz, pip-2,6), 3.73(t, 4H, J:
3.1.62
|
5-(40-fluorobenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 62)
6
Hz, pip-3,5), 6.96–7.03 (m, 4H, Ar), 7.10–7.21 (m, 3H, Ar),
7.25–7.35 (m, 6H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 21.45,
39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 47.78, 47.97, 117.96,
121.80, 123.48, 128.02, 128.81, 128.98, 129.22, 129.33, 130.07,
135.25, 135.99, 142.16, 149.81, 158.64, 171.02, 187.69. For
C27H24ClN3OS; 68.41% C; 5.10% H; 8.86% N, found: 68.42% C,
5.11% H, 8.87% N. Mass (HRMS), m/z: 474.14 (M + 1).
Yield 65%, mp 175 ꢀC. FT-IR Umax (cm-1): 2830–3,076 (C H), 1,596
(C O), 1,342–1,509 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.33 (t, 4H, J: 4.5 Hz, pip-2,6), 3.76 (brs, 4H, pip-3.5), 7.00–7.03
(d, 2H, J: 9 Hz, Ar), 7.08–7.19 (m, 6H, Ar), 7.25–7.31 (m, 4H, Ar),
7.41–7.44 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 47.97,
115.55, 115.85, 117.96, 118.26, 118.55, 123.50, 125.13, 127.96,
128.26, 129.23, 130.08, 130.19, 130.25, 130.36, 135.10, 140.88,
140.97, 149.77, 160.18, 163.37, 171.49. For C26H21ClFN3OS;
65.33% C; 4.43% H; 8.79% N, found: 65.34% C, 4.45% H, 8.80%
N. Mass (HRMS), m/z: 478.12 (M + 1).
3.1.59
|
5-(30-methoxylbenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 59)
Yield 74%, mp 143.5 ꢀC. FT-IR Umax (cm-1): 2833–2,981 (C H), 1,606
(C O), 1,293–1,531 (C C, C N), 1,228 (C O). 1H-NMR (300 MHz,
DMSO-d6, δ, ppm): 3.33 (brs, 4H, pip-2,6), 3.57(s, 3H, CH3), 3.74 (t,
4H, J: 4.5 Hz, pip-3,5), 6.87 (d, 2H, J: 3 Hz, Ar), 6.99–7.02 (m, 3H, Ar),
7.04–7.11 (m, 3H, Ar), 7.19 (dt, 1H, J: 6 Hz, Ar), 7.26–7.31 (m, 4H, Ar).
13C-NMR (75 MHz, DMSO-d6, δ, ppm): 47.53, 47.69, 39.16, 39.44,
3.1.63
|
5-(30-chlorobenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(compound 63)
Yield 70%, mp 174 ꢀC. FT-IR Umax (cm-1): 2823–3,095 (C H), 1,608
(C O), 1,337–1,514 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,

SAHIN ET AL.
15
ppm): 3.32 (brs, 4H, pip-2,6), 3.74 (t, 4H, J: 6 Hz, pip-3.5), 7.02 (d, 2H,
J: 6 Hz, Ar), 7.08–7.15 (m, 3H, Ar), 7.17–7.20 (m, 1H, Ar), 7.21–7.32
(m, 6H, Ar), 7.34–7.43 (m, 1H, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.44, 39.72, 40.00, 40.27, 40.55, 47.96, 117.96, 122.14,
123.51, 127.51, 127.99, 128.30, 128.73, 128.88, 128.96, 129.23,
129.28, 129.82, 130.06, 130.11, 131.28, 132.96, 135.03, 140.47,
149.76, 160.30, 171.54, 186.43 For C26H21Cl2N3OS; 63.16% C;
4.28% H; 8.50% N, found: 63.15% C, 4.26% H, 8.51% N. Mass
(HRMS), m/z: 494.09 (M + 1).
3.2 | Enzymatic assay
First, all the synthesized compounds were tested at 10−4 M concentra-
tions. Then, the IC50 values of the active compounds were determined
using 10−5–10−9 M concentrations. Figure 4 presents the acetylcholin-
esterase inhibition graph of active compounds and donepezil at initial
concentrations. At the 10−4
M concentration, many compounds
indicated more than 50% activity (Table 2). Therefore, the compounds
with an inhibition value of over 80% were tested at 10−5–10−9 M con-
centrations against AChE along with the reference drug donepezil
(Table 3). The IC50 value was recorded as 0.0878 μM for donepezil.
The most active compounds among the series were those having
the Cl substituent on the phenyl attached to piperazine at the second,
third, and fourth positions.
3.1.64
|
5-(40-chlorobenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 64)
Yield 66%, mp 196.6 ꢀC. FT-IR Umax (cm-1): 2849–3,086 (C H),
1,593.7 (C O), 1,343–1,530 (C C, C N). 1H-NMR (300 MHz, DMSO-
d6, δ, ppm): 3.33 (brs, 4H, pip-2,6), 3.75 (t, 4H, J: 4.5 Hz, pip-3.5), 7.02 (d,
2H, J: 9 Hz, Ar), 7.10–7.16 (m, 3H, Ar), 7.18–7.23 (m, 2H, Ar), 7.25–7.30
(m, 4H, Ar), 7.37 (d, 2H, J:9 Hz, Ar). 13C-NMR (75 MHz, DMSO-d6, δ,
ppm): 39.16, 39.44, 39.72, 40.00, 40.27, 40.55, 40.83, 47.80, 47.97,
117.04, 117.96, 123.50, 128.03, 128.21, 129.17, 129.23, 130.21,
130.90, 135.04, 136.41, 137.43, 149.77, 159.84, 171.39, 186.84. For
C26H21Cl2N3OS; 63.16% C; 4.28% H; 8.50% N, found: 63.15% C,
4.26% H, 8.51% N. Mass (HRMS), m/z: 494.09 (M + 1).
The IC50 values of the compounds in the series of 2-chlorophenyl
piperazine (34–44), compounds 35 (3-methylbenzoyl), 38 (4-methoxyben-
zoyl), and 40 (4-fluorobenzoyl), were calculated as 0.9767 μM,
0.9493 μM, and 0.8023 μM, respectively (Table 3). Compound 45 (IC50
=
1.122) had 3-chlorophenylpiperazine and no substituent on the benzoyl
group. In the 4-chlorophenyl piperazine series (56–66), compounds
57 (3-methylbenzoyl) (IC50 = 1.2130) and 61 (3-fluorobenzoyl)
(IC50 = 0.9193) exhibited good activity on AChE. The experiments
showed that compounds 35, 38, 40, 45, 57, and 61 were good AChE
inhibitors.
|
5-(30-nitrobenzoyl)-4-phenyl-
Six of the 66 compounds showed inhibition of 80% or above, and
all six belonged to the last three series. As will be discussed in the
modeling and conclusion sections, two aromatic rings attached to thia-
zole are important for enclosing the key amino-acids. The carbonyl
group in all compounds were able to make a hydrogen bound with
Arg296; thus, the position of the compounds was stabilized. All the
compounds in the last three series carried a chloro (Cl) substituent on
phenyl that directly attached to the piperazine ring. As a result, the
chloro substituents on the phenyl that directly attach to tertier
3.1.65
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 65)
Yield 67%, mp 169.2 ꢀC. FT-IR Umax (cm-1): 2817–3,069 (C H), 1,596
(C O), 1,342–1,506 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.35 (t, 4H, J: 4.5 Hz, pip-2,6), 3.79 (t, 4H, J: 4.5 Hz, pip-3.5),
7.03 (t, 4H, J: 4.5 Hz, Ar), 7.10–7.32 (m, 5H, Ar), 7.40–7.47 (m, 1H,
Ar), 7.77–7.82 (m, 1H, Ar), 7.96 (t, 1H, J:3 Hz, Ar), 8.04–8.11 (m, 1H,
Ar). 13C-NMR (75 MHz, DMSO-d6, δ, ppm): 39.16, 39.44, 39.72,
39.99, 40.27, 40.55, 40.83, 47.87, 47.96, 117.96, 122.33, 123.51,
123.72, 123.98, 124.71, 125.74, 127.99, 128.36, 129.04, 129.24,
129.71, 130.07, 130.22, 131.96, 134.78, 135.09, 136.41, 139.75,
147.00, 149.74, 160.97, 171.50, 171.83, 185.63. For C26H21ClN4O3S;
61.84% C; 4.19% H;11.09% N, found: 61.85% C, 4.21% H,11.11%
N. Mass (HRMS), m/z: 505.11 (M + 1).
3.1.66
|
5-(40-nitrobenzoyl)-4-phenyl-
2-[4-(4-chlorophenyl)-piperazine-1-yl]thiazole
(Compound 66)
Yield 76%, mp 201.9 ꢀC. FT-IR Umax (cm-1): 2830–3,112 (C H), 1,592
(C O), 1,293–1,514 (C C, C N). 1H-NMR (300 MHz, DMSO-d6, δ,
ppm): 3.34 (brs, 4H, pip-2,6), 3.79 (brs, 4H, pip-3.5), 7.01–7.07 (m, 3H,
Ar), 7.14–7.30 (m, 5H, Ar), 7.44 (d, 1H, J: 3 Hz, Ar), 7.52–7.60 (m, 2H,
Ar), 7.90 (dt, 1H, J: 6 Hz, Ar), 7.98 (dt, 1H, J: 4.5 Hz, Ar). 13C-NMR
(75 MHz, DMSO-d6, δ, ppm): 39.15, 39.43, 39.71, 39.99, 40.27,
40.55, 40.83, 47.95, 117.96, 123.12, 123.51, 127.96, 128.42, 129.15,
129.23, 129.35, 130.18, 130.25, 131.35, 134.79, 144.63, 148.55,
149.73, 161.30. For C26H21ClN4O3S; 61.84% C; 4.19% H; 11.09% N,
found: 61.86% C, 4.20% H, 11.10% N. Mass (HRMS), m/z:
505.11 (M + 1).
FIGURE 4 The inhibition graph of the active compounds and
donepezil, presenting the mean ꢁ SD values (n = 6). ***p < .001 was
determined by one-way ANOVA using Dunnet's multiple
comparison test

16
SAHIN ET AL.
TABLE 2 The inhibition percent of compounds 1–66 against AChE at 10−4 M concentrations. The inhibition values higher than 80% are shown
in bold
Compound
AChE % inhibition 10−4
M
Compound
AChE % inhibition 10−4
M
Compound
45
AChE % inhibition 10−4
83.90
M
1
56.84
23
24.10
ꢁ0.68
ꢁ0.57
ꢁ0.91
2
38.22
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
9.04
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
68.27
ꢁ0.76
ꢁ0.41
ꢁ0.52
3
68.79
62.69
72.05
ꢁ0.65
ꢁ0.92
ꢁ1.02
4
15.37
20.49
77.66
ꢁ0.89
ꢁ0.73
ꢁ0.51
5
34.75
22.14
44.83
ꢁ0.97
ꢁ0.51
ꢁ0.32
6
40.18
57.26
56.70
ꢁ0.56
ꢁ0.69
ꢁ0.97
7
36.14
65.12
44.69
ꢁ0.65
ꢁ0.72
ꢁ0.52
8
50.72
65.45
79.61
ꢁ0.58
ꢁ1.03
ꢁ0.84
9
43.68
20.34
50.18
ꢁ0.76
ꢁ0.86
ꢁ0.65
10
11
12
13
14
15
16
17
18
19
14.28
33.71
41.24
ꢁ0.83
ꢁ0.87
ꢁ0.69
2.85
38.76
24.57
ꢁ0.52
ꢁ0.54
ꢁ0.41
18.19
75.34
68.82
ꢁ0.92
ꢁ0.98
ꢁ0.86
51.61
80.36
80.40
ꢁ1.02
ꢁ0.65
ꢁ0.67
37.74
78.50
69.91
ꢁ0.71
ꢁ0.72
ꢁ0.67
32.72
78.27
66.81
ꢁ0.51
ꢁ0.87
ꢁ0.75
14.68
83.02
54.87
ꢁ0.64
ꢁ0.71
ꢁ0.93
23.56
79.75
83.94
ꢁ0.49
ꢁ0.41
ꢁ0.56
2.46
82.65
70.41
ꢁ1.14
ꢁ0.81
ꢁ0.51
35.47
78.43
78.83
ꢁ0.43
ꢁ0.47
ꢁ0.83
(Continues)

SAHIN ET AL.
17
TABLE 2 (Continued)
Compound
AChE % inhibition 10−4
M
Compound
AChE % inhibition 10−4
M
Compound
AChE % inhibition 10−4
M
20
8.97
42
77.41
64
70.61
ꢁ0.98
ꢁ0.79
ꢁ0.49
21
22
14.02
43
44
53.23
65
66
15.57
ꢁ0.45
ꢁ0.48
ꢁ0.69
21.99
48.72
8.76
ꢁ0.68
ꢁ0.67
ꢁ0.49
Donepezil %96.42 ꢁ 0.45
TABLE 3 The inhibition percent and IC50 (μM) of the active compounds against AChE at 10−4 M–10−9 M concentrations
Concentrations
Compound
10−4
M
10−5
M
10−6
M
10−7
M
10−8
M
10−9
M
IC50 (μM)
35
80.36 ꢁ 0.65
83.02 ꢁ 0.71
82.65 ꢁ 0.81
83.90 ꢁ 0.91
80.40 ꢁ 0.67
83.94 ꢁ 0.56
96.42 ꢁ 0.45
68.01 ꢁ 0.79
73.52 ꢁ 0.68
65.09 ꢁ 0.70
62.80 ꢁ 0.61
68.37 ꢁ 0.66
71.85 ꢁ 0.51
94.82 ꢁ 0.50
44.72 ꢁ 0.31
40.23 ꢁ 0.33
48.46 ꢁ 0.33
48.07 ꢁ 0.42
41.15 ꢁ 0.47
45.14 ꢁ 0.30
91.67 ꢁ 0.36
33.29 ꢁ 1.10
34.26 ꢁ 0.92
38.74 ꢁ 0.77
31.71 ꢁ 1.12
34.25 ꢁ 0.88
31.36 ꢁ 0.25
37.90 ꢁ 0.35
27.43 ꢁ 0.22
22.48 ꢁ 0.12
23.73 ꢁ 0.73
20.44 ꢁ 0.55
22.03 ꢁ 0.34
21.28 ꢁ 0.65
29.78 ꢁ 0.37
11.52 ꢁ 0.87
12.74 ꢁ 0.22
11.49 ꢁ 0.25
13.48 ꢁ 0.75
10.83 ꢁ 0.43
13.19 ꢁ 0.21
11.85 ꢁ 0.12
0.9767 ꢁ 0.21
0.9493 ꢁ 0.33
0.8023 ꢁ 0.12
1.1220 ꢁ 0.09
1.2130 ꢁ 0.15
0.9193 ꢁ 0.56
0.0878 ꢁ 0.03
38
40
45
57
61
Donepezil
FIGURE 5 The 2D and 3D positions of compound 35 at the active site (C = Orange, N = Blue, O = Red, S = Yellow) [Color figure can be viewed
at wileyonlinelibrary.com]
FIGURE 6 The 2D and 3D positions of compound 38 at the active site (C = Pink, N = Blue, O = Red, S = Yellow) [Color figure can be viewed at
wileyonlinelibrary.com]

18
SAHIN ET AL.
FIGURE 7 The 2D and 3D positions of compound 40 at the active site (C = Pink, N = Blue, O = Red, S = Yellow) [Color figure can be viewed at
wileyonlinelibrary.com]
FIGURE 8 The 2D and 3D positions of compound 45 at the active site (C = Pink, N = Blue, O = Red, S = Yellow) [Color figure can be viewed at
wileyonlinelibrary.com]
nitrogen including the ring may be useful for acetylcholinesterase
inhibitor activity.
interaction appeared to be supportive of the association of
activity with the substituent volume.
•
Compounds 57 and 61 having 4-chlorophenyl piperazine
interacted with Tyr341 by aromatic and hydrophobic interactions.
The benzoyl groups (R’) attached to the thiazole ring were in an
aren-aren and hydrophobic interaction with Trp286. Although the
carbonyl positioning of all active compounds was appropriate for
a dipole interaction, only compounds 38 and 45 established a
dipole–dipole interaction with Arg296.
3.3 | Molecular modeling
The docking results of the six compounds with high inhibitory activity
and two and three-dimensional poles in the active area are given in
Figures 5–10. Below is a summary of these interactions;
•
The substituted phenyl group (R) on piperazine directly interacted
with Tyr337 or Trp86 producing Ar-Ar hydrophobic forces. This
The compounds were observed to bind to the active site enclos-
ing the key amino acids Ser293, Trp296, Tyr341, Trp86, and this
FIGURE 9 The 2D and 3D positions of compound 57 at the active site (C = Green, N = Blue, O = Red, S = Yellow) [Color figure can be viewed at
wileyonlinelibrary.com]

SAHIN ET AL.
19
FIGURE 10 The 2D and 3D positions of compound 61 at the active site (C = Pink, N = Blue, O = Red, S = Yellow) [Color figure can be viewed at
wileyonlinelibrary.com]
positioning is strengthened by a hydrogen bonding between Arg296
and the carbonyl group. Two aromatic phenyls on the same side
enclose Ser293, and thus hinder the nucleophilic behavior of the
amino acid.
ACKNOWLEDGMENTS
This project was financially supported by the Anatolian University
Scientific Research Projects Coordination Unit 1610S656.
ORCID
Zafer Sahin
Barkin Berk
http://orcid.org/0000-0002-5976-676X
http://orcid.org/0000-0001-6047-2796
4
| DISCUSSION
Despite being clinically used for dementia, donepezil's side-effects and
limited use in advanced AD require the discovery of new therapeutics.
As mentioned in the introduction section, the AChE X-Ray crystallogra-
phy structure (PDB ID: 4EY7) represents two main binding sites (CAS
and PAS). The catalytic anionic region consists mainly of Ser203,
Glu334, His447, Trp86, Tyr130, Tyr133, Tyr337, and Phe338, and the
peripheral anionic region comprises Tyr72, Asp74, Tyr124, Tyr341, and
Trp286 amino acids. Donepezil also interacts with these two binding
regions. In this way, it has dual connectors (Shafferman et al., 2005;
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