Novel thiazole-piperazine derivatives as potential cholinesterase inhibitors

Article abstract of DOI:10.1002/jhet.3734

Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2-(4-(2/3/4-substituted phenyl)piperazin-1-yl)-4-phenylthiazol-5-yl][3/4-substituted phenyl]methanone derivatives (1-44), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty-four compounds were evaluated on AChE and BChE enzymes at 10^?3 and 10^?4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds (4, 5, 16, 27, 37, and 38) on AChE. Compound 5 including the 4-methoxy substituent (IC₅₀: 0.268μM) and compound 38 containing the 4-methoxy and 3-methyl substituents (IC₅₀: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar-Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed-type kinetic mode.

Full text of DOI:10.1002/jhet.3734

Received: 17 May 2019
DOI: 10.1002/jhet.3734
Revised: 21 August 2019
Accepted: 28 August 2019
A R T I C L E
Novel thiazole‐piperazine derivatives as potential
cholinesterase inhibitors
Şeref Demirayak1 | Zafer Şahin1
| Merve Ertaş1 | Emre Fatih Bülbül1 |
Ceysu Bender1 | Sevde Nur Biltekin2 | Barkin Berk1
| Begüm Nurpelin Sağlık3 |
Serkan Levent3 | Leyla Yurttaş3
1 Department of Pharmaceutical
Abstract
Chemistry, School of Pharmacy, İstanbul
Medipol University, İstanbul 34083,
Turkey
2 Department of Pharmaceutical
Microbiology, School of Pharmacy,
İstanbul Medipol University, İstanbul
34083, Turkey
Dementia is a cognitive disorder mostly associated with Alzheimer's disease
(AD) in addition to being seen in many other diseases of the central nervous
system (CNS). The limited number of drugs is not sufficient to provide ade-
quate improvement to increase the quality of life of patients suffering from this
symptom; therefore, all treatment options should be evaluated in detail. In this
study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐
phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives (1‐44), were
obtained and analyzed in terms of their anticholinesterase activities. Kinetic
mode and molecular interactions were also evaluated. An enzyme inhibition
study was undertaken on acetylcholinesterase (AChE) and butyrylcholinester-
ase (BChE) using the Ellman method. Maestro program was used in molecular
modeling studies. Forty‐four compounds were evaluated on AChE and BChE
enzymes at 10−3 and 10−4 concentrations. The inhibition concentrations were
calculated as 0.268μM to 2.104μM for six compounds (4, 5, 16, 27, 37, and
38) on AChE. Compound 5 including the 4‐methoxy substituent (IC50:
0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substitu-
ents (IC50: 0.286μM) showed the highest AChE inhibitory activity. They were
further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar inter-
action with Trp286. The activity of compound 5 was also assessed in mixed‐
type kinetic mode.
3 Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Anadolu
University, Eskişehir 26470, Turkey
Correspondence
Leyla Yurttaş, Department of
Pharmaceutical Chemistry, Faculty of
Pharmacy, Anadolu University, Eskişehir
26470, Turkey.
Email: lyurttas@anadolu.edu.tr
Funding information
Anadolu Üniversitesi, Grant/Award
Number: 1610S656
1 | INTRODUCTION
donepezil, rivastigmine, galantamine, and tacrine. The
most effective is donepezil, which acts at nanomolar
Alzheimer's disease (AD) is characterized by defects in
cholinergic neurotransmission and causes symptoms, such
as dementia and loss of cognitive abilities.[1,2] Although
various therapy strategies have been tried, focusing on
accumulation Aβ amyloid aggregates and Fe, Cu, and Zn
metals in AD, the current treatment approaches involve
the use of acetylcholinesterase (AChE) and butyrylcholin-
esterase (BChE) inhibitors.[3,4] Presently, the limited
number of cholinesterase inhibitor drugs in clinic use is
concentration by binding to both peripheral active and
catalytic anionic sites of AChE through aromatic and
ionic interactions.[5] The AChE active site is highly hydro-
phobic; hence, molecules possessing aromatic rings are
considered to increase the π‐π interactions between the
enzyme and the ligand, causing efficient binding for activ-
ity in the region of activity. In BChE, the presence of long
alkyl chains instead of bulk groups is preferred to provide
a better enzyme‐inhibitor interaction.[6] In cholinesterase
J Heterocyclic Chem. 2019;1–17.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
DEMIRAYAK ET AL.
drug design, structural modifications are carried out
based on existing drugs considering pharmacophoric
groups. For instance, benzophenone and tertiary amine
are subunits of donepezil and are essential for inhibiting
AChE.[7] Molecular docking studies including chemical
properties identify the affinity of the ligand to the
enzyme based on prediction of interaction calculations.
Docking studies suggest that compounds having an aro-
matic ring and a nitrogen atom (N‐aryl), such as other
ChE inhibitors, bind at the active site of both ChEs.[8]
Piperazine is an important ring included in a number of
drugs in different therapeutic areas.[9,10] The literature
reveals the significance of piperazine moiety for its high
potency, selectivity of action, and excellent therapeutic
profile in cognitive dysfunction, which has caught the
attention of many medicinal chemists and pharmacolo-
gists to further explore this group. Easy functionalization
of piperazine makes it an appealing building block for
designing and synthesizing new compounds of therapeutic
utility. Piperazine and its derivatives represent an impor-
tant class of molecules that exhibit a broad spectrum of
central nervous system activities. Several researchers also
debated that piperazine derivatives presented as potential
neuroprotective agents.[11,12] FK‐960, a novel putative
antidementia drug candidate, and some other piperazine
derivatives have been demonstrated to possess activities
against AD.[13,14] In particular, N‐arylpiperazine deriva-
tives have found a wide pharmacological application area
in central nervous system binding to certain enzymes such
as monoamine oxidase (MAO) A and B and receptors of
dopamine and serotonin receptors. The 5‐HT6 serotonin
receptor has attracted recent interest as cognitive
enhancers for the treatment of AD patients.[15] Ensaculin,
a N‐arylpiperazine‐based molecule, has shown improve-
ment in memory and cognitive functions, including slow-
down of progressive neurodegeneration. It is considered
as a dual binding site inhibitor of AChE and has been used
to treat AD clinically for a long time.[16] The piperazine
ring could be evaluated as a bioisostere of the piperazine
ring, considering the molecular framework of the anticho-
linesterase drug donepezil.[17,18] Literature survey also
supports the enzyme inhibitory efficiency of piperazine
derivatives confirmed by many studies.[19–28]
cholinergic neurons located in the stomach.[35] Consider-
ing the anticholinesterase activity of this agent, similar
derivatives have also been evaluated in AD.[36]
On the basis of the literature data given above and
extending our previous study,[37] we were encouraged to
design and develop [2‐(4‐(2/3/4‐substituted phenyl)
piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phe-
nyl]methanone derivatives (1‐44), considering the
benzophenone structure,[38] piperazine,[39] and thia-
zole[40] rings as pharmacophoric groups for cholinester-
ase inhibitory activity. We performed molecular
modeling studies using Schrödinger Maestro program.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
In this study, 44 compounds were synthesized and ana-
lyzed using spectroscopic techniques infrared (IR), 1H
nuclear magnetic resonance (NMR), 13C NMR, high‐
resolution mass spectrometry (HRMS), and elemental
analysis. The compounds were obtained with a three‐step
synthetic procedure (Figure 1) and performed with a yield
of 58% to 85%. Melting points were determined and
uncorrected.
As in our previous study,[37] aryl piperazine derivatives
were used as starting materials. First, the selected second-
ary amines were converted to the corresponding thioureide
compounds (A) with benzoyl chloride/ammonium thiocy-
anate and reacted with α‐bromoacetophenone derivatives
(B) to provide the final 2,4,5‐thiazole compounds (1‐44).
According to the applicated synthetic procedure,[41] first
nucleophilic alkylation reaction occurs through sulfur
atom via 2‐bromoacethophenone. After HBr elimination
and subsequent enolization, the obtained intermediate
product undergoes intramolecular cyclization. Eventually,
substituted thiazoles were acquired with loss of water
reaction.
All targeted [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐
1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted
phenyl]
methanone derivatives (1‐44) were successfully acquired
at 200 mg and over (Table 1). In the IR spectra of the
compounds, bands belonging to the carbonyl bond were
The thiazole ring is another bioactive structure known
for its broad spectrum of pharmacological activity and
favored for its synthetic accessibility and flexibility. The
biological diversity of this ring is based on cholinergic
action, which has been supported by several publications
investigating the effect of novel thiazole derivatives as
cholinesterase inhibitors.[29–34] Recently, a thiazole‐based
selective acetyl cholinesterase inhibitor (AChEI) mole-
cule, acotiamide hydrochloride, has been discovered to
treat functional dyspepsia by enhancing the actions of
1
prominently observed at 1593 to 1614 cm−1. In the H
NMR spectra, the aliphatic protons of the piperazine ring
were resonated at 2.50 to 3.88 and 3.72 to 4.28 ppm as
separate triplet peaks. In the aromatic region, the peaks
mostly overlapped due to the three phenyl rings. In car-
bon NMR, the signals belonging to carbonyl and thiazole
C2 carbons were seen in the upper section at about 185.62
to 188.24 ppm. The mass spectra and elemental analysis
revealed satisfying values.

DEMIRAYAK ET AL.
3
FIGURE 1 General synthetic method
for the synthesis of compounds 1‐44.
Reagents and solvents: (A) NH4SCN,
benzoyl chloride; (B) Br2, AcOH; and (C)
EtOH, reflux
TABLE 1 Structures of the synthesized compounds (1‐44)
Compound
R
R'
Compound
R
R'
Compound
R
R'
Compound
R
R'
1
H
H
H
H
H
H
H
H
H
H
H
H
12
13
14
2‐CH3
H
23
24
25
3‐CH3
H
34
35
36
4‐CH3
H
2
3‐CH3
4‐CH3
2‐CH3 3‐CH3
2‐CH3 4‐CH3
3‐CH3 3‐CH3
3‐CH3 4‐CH3
4‐CH3 3‐CH3
4‐CH3 4‐CH3
4‐CH3 3‐OCH3
4‐CH3 4‐OCH3
4‐CH3 3‐F
3
4
3‐OCH3 15
4‐OCH3 16
2‐CH3 3‐OCH3 26
2‐CH3 4‐OCH3 27
3‐CH3 3‐OCH3 37
3‐CH3 4‐OCH3 38
5
6
3‐F
17
18
19
20
21
22
2‐CH3 3‐F
2‐CH3 4‐F
2‐CH3 3‐Cl
2‐CH3 4‐Cl
2‐CH3 3‐NO2
2‐CH3 4‐NO2
28
29
30
31
32
33
3‐CH3 3‐F
3‐CH3 4‐F
3‐CH3 3‐Cl
3‐CH3 4‐Cl
3‐CH3 3‐NO2
3‐CH3 4‐NO2
39
40
41
42
43
44
7
4‐F
4‐CH3 4‐F
8
3‐Cl
4‐Cl
3‐NO2
4‐NO2
4‐CH3 3‐Cl
9
4‐CH3 4‐Cl
10
11
4‐CH3 3‐NO2
4‐CH3 4‐NO2
studied at lower concentrations (10−5M, 10−6M, 10−7M,
10−8M, and 10−9M) to determine their half inhibition
concentration (IC50) (Table 3).
2.2 | Enzyme inhibition
All synthesized compounds (1‐44) were tested to deter-
mine their anticholinesterase activity on AChE and
BChE. The AChE inhibition percentage was identified
for each compound at 10−3M and 10−4M concentrations
and standard drug donepezil as shown in Table 2.
Compounds 7, 18, 22, 28, 29, and 40 exhibited moder-
ate activity, inhibiting the enzyme AChE at the percent-
ages of 41.06 to 69.58 at aforementioned concentrations.
Compounds 4, 5, 16, 27, 37, and 38, which resulted in
an enzyme inhibition of more than 50%, were further
The lowest IC50 values were found for compounds 5
(IC50: 0.268μM) and 38 (IC50: 0.286μM), whereas
donepezil had an IC50 value of 0.029μM. These com-
pounds displayed about 30% enzyme inhibition, while
the standard drug had a value of 25% at the lowest tested
concentration (10−9). Compounds 16 and 27 had similar
values of 0.348μM and 0.327μM, respectively. Besides,
compound 16 exhibited the highest inhibition percentage
of 88.09 at 10−3 concentration. The IC50 values were also

4
DEMIRAYAK ET AL.
TABLE 2 The AChE inhibition percentages of compounds 1‐44 at 10−3M and 10−4M concentrations
AChE % Inhibition
10−3M
AChE % Inhibition
Compound
10−4M
Compound
10−3M
10−4M
1
39.18 0.98
44.71 0.94
30.47 0.85
75.60 1.10
81.00 1.25
60.28 0.95
66.97 1.06
45.81 0.76
33.12 0.85
55.49 1.25
60.27 1.11
24.75 0.82
41.16 0.92
45.88 0.90
52.79 0.87
88.09 1.18
64.22 1.03
69.58 1.04
36.77 0.84
23.11 0.58
63.79 1.20
65.12 1.08
99.48 1.92
21.05 0.85
25.99 0.74
19.88 0.62
68.51 1.05
70.25 1.09
41.72 0.84
45.83 0.96
20.08 0.81
17.25 0.70
39.23 0.73
41.55 0.92
20.66 0.71
20.98 0.81
30.19 0.80
33.46 0.61
83.20 1.05
40.56 0.81
44.91 0.71
28.41 0.76
15.74 0.47
38.20 0.79
41.27 0.93
98.56 1.76
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
30.63 0.86
40.23 0.75
41.28 0.81
55.28 0.76
76.88 1.28
66.21 1.20
69.54 1.09
46.02 0.85
31.29 0.56
56.30 1.05
60.71 1.12
35.60 0.95
41.88 0.77
26.78 0.58
79.54 1.20
81.50 1.29
61.29 1.06
65.97 1.00
40.88 0.74
43.00 0.78
58.21 0.87
59.17 1.04
21.44 0.88
22.64 0.65
21.79 0.89
40.29 0.48
72.18 1.11
41.06 0.89
46.77 0.89
24.68 0.71
27.55 0.43
35.18 0.92
40.18 0.90
26.41 0.78
31.27 0.52
18.91 0.40
68.71 1.07
74.15 1.04
39.66 0.70
45.88 0.83
21.10 0.62
20.11 0.61
34.22 0.66
44.27 0.87
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Donepezil
TABLE 3 The AChE inhibition percentages of compounds 4, 5, 16, 27, 37, and 38 at 10−3M to 10−9M concentrations
AChE % Inhibition
AChE IC50
(μM)
Compound 10−3M
10−4M
10−5M
10−6M
10−7M
10−8M
10−9M
4
75.60 1.10 68.51 1.05 58.35 0.88 52.41 0.79 36.25 0.71 34.37 0.63 28.28 0.21
81.00 1.25 70.25 1.09 60.33 0.91 54.49 0.87 45.75 0.73 38.26 0.80 30.29 0.50
88.09 1.18 83.20 1.05 74.13 0.98 50.72 0.75 33.49 0.47 30.84 0.40 25.15 0.53
76.88 1.28 72.18 1.11 61.59 1.13 56.91 0.94 40.77 0.67 39.16 0.66 30.65 0.48
79.54 1.20 68.71 1.07 57.22 1.00 42.79 0.67 29.90 0.58 23.60 0.41 19.17 0.51
81.50 1.29 74.15 1.04 61.57 1.21 53.05 0.94 43.87 0.78 38.10 0.66 30.26 0.57
0.950 0.026
0.268 0.010
0.348 0.014
0.327 0.013
2.104 0.075
0.286 0.012
5
16
27
37
38
Donepezil
99.48 1.92 98.56 1.76 95.30 1.64 92.15 1.88 81.36 1.41 41.78 0.84 25.62 0.58 0.0287 0.0014
calculated as 0.950μM for compound 4 and 2.104μM for
compound 37. When the chemical structures of these
compounds were evaluated, the methoxy substituent on
the phenyl ring linked to the piperazine structure had
attracted attention,[37] and this substituent was revealed
in all compounds whose IC50 value was calculated.
Especially, compounds 5, 16, 27, and 38 containing 4‐
methoxyphenyl exhibited the highest enzyme inhibitory
activity. Two slight less active compounds were 4 and
37 that possessed 3‐methoxyphenyl moiety. The presence
of electron‐rich substituents such as hydroxy and
methoxy groups on the aromatic ring was identified to

DEMIRAYAK ET AL.
5
TABLE 4 The BChE inhibition percentages of compounds 1‐44 at 10−3M and 10−4M concentrations
BChE % Inhibition
10−3M
BChE % Inhibition
Compound
10−4M
Compound
10−3M
10−4M
1
27.83 0.87
34.25 0.91
18.10 0.41
31.08 0.76
20.79 0.48
17.88 0.42
21.34 0.48
25.66 0.84
26.84 0.61
32.28 0.83
22.65 0.47
22.85 0.38
30.31 0.76
16.95 0.51
30.26 0.46
22.95 0.63
26.09 0.79
14.05 0.58
25.17 0.82
18.62 0.40
22.43 0.58
27.30 0.74
99.27 2.86
13.62 0.52
27.12 0.80
10.23 0.37
14.77 0.53
13.65 0.40
11.53 0.33
16.22 0.38
15.97 0.60
14.60 0.55
17.52 0.59
13.00 0.28
15.30 0.30
18.25 0.68
10.88 0.42
14.08 0.40
12.41 0.50
15.21 0.42
12.49 0.46
15.25 0.60
10.11 0.36
17.02 0.59
11.10 0.41
98.61 3.71
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
19.88 0.73
17.49 0.66
19.28 0.58
22.17 0.88
34.63 0.48
20.75 0.78
35.28 0.59
33.30 0.81
19.13 0.66
27.21 0.40
25.81 0.45
24.59 0.68
15.43 0.26
27.81 0.60
19.31 0.30
27.80 0.46
37.26 0.28
29.90 0.67
18.77 0.88
32.76 0.62
27.32 0.36
30.74 0.42
15.23 0.47
10.71 0.43
11.75 0.33
16.20 0.41
20.74 0.36
14.27 0.57
25.55 0.40
21.74 0.69
14.88 0.50
16.87 0.38
20.21 0.41
16.62 0.44
10.79 0.30
13.62 0.43
12.45 0.14
20.11 0.37
20.13 0.33
12.14 0.42
12.63 0.41
18.85 0.44
19.79 0.27
17.89 0.30
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Tacrine
support anti‐Alzheimer activity via their antioxidant pro-
file.[42] However, this situation was not observed in com-
pounds 15 and 26 with the 3‐methoxy substituent, whose
IC50 values could not be calculated due to their weak
activity. The compounds and standard drug tacrine were
studied on BChE at concentrations 10−3M and 10−4M
(Table 4). Only two compounds (29 and 39) showed an
inhibition of greater than 35% at the highest tested con-
centration; thus, they were not tested at lower
concentrations.
2.4 | Molecular modeling
AChE possesses two main binding sites (CAS and PAS).
Amino acids in the catalytic anionic region of the enzyme
are mainly Ser203, Glu334, His447, Trp86, Tyr130,
Tyr133, Tyr337, and Phe338, and amino acids in the
peripheral anionic region are Tyr72, Asp74, Tyr124,
Tyr341, and Trp286. The AChE inhibitor drug donepezil
also interacts with these two binding regions. The benzyl
structure of donepezil enters the π‐π interaction with the
indole ring of Trp86. Phe295 and Arg296 are imperative
amino acids for hydrogen binding to the active district.[43]
The π‐π interaction occurs between the 1‐indanone ring
of ligand and the indole ring of Trp286 amino acid in
the peripheral anionic region. The indanone ring is also
fully settled into the active region and establishes an
interaction between the amino acids in CAS and rust
and the forces of Van der Waals. Besides, piperidine inter-
acts with Tyr337 and Tyr341 through hydrogen bonding.
The hydrogen binding potential of Phe295 and Arg296
2.3 | Kinetic study of AChE inhibition
The most active compound 5 was studied to determine
the kinetic mode of AChE inhibition. The enzyme rate
was calculated at three different concentrations (IC50/2,
IC50, and IC50 × 2) of this compound. The Lineweaver‐
Burk graph of compound 5 showed a mixed‐type inhibi-
tion pattern (Figure 2).

6
DEMIRAYAK ET AL.
FIGURE 2 The Lineweaver‐Burk graph of compound 5 (mixed‐type inhibition)
FIGURE 3 2D and 3D representation of the interactions of compound 5 [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 4 2D and 3D representation of the interactions of compound 38 [Color figure can be viewed at wileyonlinelibrary.com]

DEMIRAYAK ET AL.
7
made the carbonyl group of the synthesized compounds
more functional. In our previous study, similar structures
were evaluated, and the same amino acid interactions
were found. In this present study, all the most active com-
pounds had the methoxy substituent on the benzoyl
group attached to thiazole.
Compound 5 allows hydrogen bonding with Arg296
and Ar‐Ar interaction with Trp286 (Figure 3). Compound
38 results in the Ar‐Ar interaction between Trp286 and
the thiazolyl phenyl group (Figure 4). In addition, the thi-
azole part of this compound facilitates the Ar‐Ar interac-
tion with Tyr341. These two compounds were observed to
bind to the active site enclosing the key amino acids
Ser293, Trp286, Tyr341, and Trp86, and this positioning
was strengthened by the hydrogen bonding between
Arg296 and the carbonyl group in compound 5. Two aro-
matic phenyls on the same side enclose Ser293 and thus
hinder the nucleophilic behavior of amino acid, which
is essential for deacetylation of the enzyme.
was performed using a Leco TruSpec Micro CHN/CHNS
elemental analyzer (Saint Joseph, Michigan, USA). Spec-
troscopic data were determined with the following instru-
ments: Fourier transform IR (FT‐IR), Perkin Elmer
Spectrum Two FT‐IR Spectrometer (Perkin Elmer, Inc,
Waltham, Massachusetts, USA); 1H‐NMR, Bruker 300‐
MHz UltraShield NMR Spectrophotometer (Bruker Corp,
Billerica, Massachusetts, USA); and 13C‐NMR, Bruker 75‐
MHz UltraShield NMR Spectrophotometer (Bruker Corp,
Billerica, Massachusetts, USA) in DMSO‐d6 using standard
TMS. The mass spectra of the compounds were determined
on a Shimadzu 8040 LC/MS/MS ITTOF system (Shimadzu,
Tokyo, Japan) using a mass spectrometer with the electron
spray method (ESI).
4.2 | Synthesis of N‐[4‐(2/3/4‐substituted
phenyl)piperazine‐1‐carbonothioyl]
benzamide derivatives (A)
3 | CONCLUSION
A 0.5‐mol ammonium thiocyanate was dissolved in ace-
tone. When the solution was being stirred at room tem-
perature, benzoyl chloride was added dropwise. After
1 hour, the mixture was refluxed for 10 minutes, and an
appropriate piperazine derivative (0.5 mol) was added.
After the TLC check, the solution was poured into ice
water, and the obtained raw product was filtered, dried,
and recrystallized from ethanol.
The target molecules [2‐(4‐(2/3/4‐substituted phenyl)
piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phe-
nyl]methanone derivatives (1‐44) performed with a yield
of 58% to 85% and analyzed in detail using IR, NMR,
and MS spectroscopic techniques. Compounds 4, 5, 16,
27, 37, and 38 containing the 3‐/4‐methoxy substituent
on the benzoyl moiety showed the highest AChE inhibi-
tory activity. The IC50 values on AChE were calculated
as 0.264μM and 0.286μM for compounds 5 and 38, respec-
tively, and 0.029μM for donepezil. According to the
results of modeling studies, compounds 5 and 38 bound
to the active site enclosing the key amino acids Ser293,
Trp286, Tyr341, and Trp86, and this positioning was
strengthened by the hydrogen bonding between Arg296
and the carbonyl group in compound 5. The inhibitory
activity on BChE was not found remarkable.
4.3 | α‐Bromoacetophenone derivatives
(B)
Bromine was added dropwise to the acetophenone deriv-
ative in a flask and dissolved in acetic acid and catalytic
amount of hydrobromic acid by vigorous stirring. After
the reaction was completed, water was added to the mix-
ture, and the obtained intermediate was filtrated.
4 | EXPERIMENTAL
4.1 | Chemistry
4.4 | [2‐(4‐(2/3/4‐Substituted phenyl)
piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐
substituted phenyl]methanone derivatives
(1‐44)
All chemicals and biological materials were purchased
from Sigma‐Aldrich Chemical Corp (St. Louis, Missouri,
USA) and Merck KGaA (Merck, Darmstadt, Germany).
All intermediate compounds were checked for their
purities using thin‐layer chromatography (TLC) with a Sil-
ica Gel 60 F254 TLC plate (Merck KGaA, Darmstadt, Ger-
many). 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 compounds
Equimolar quantities (10 mmol) of intermediates, N′‐ben-
zoyl piperazine‐thiourea (A), and bromoacetophenones
(B) were refluxed in ethanol for 5 hours. At the end of
this period, the reaction mixture was cooled and treated
with excess water and NaHCO3 solution until neutraliza-
tion. The raw product was recrystallized from ethanol.

8
DEMIRAYAK ET AL.
4.4.1 | Phenyl[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 1)
4.4.4 | (3‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 4)
Yield 70%, light yellow solid, mp 209°C. FT‐IR ῡmax (cm−1):
2822 to 2990 (C─H), 1607 (C═O), 1336 to 1519 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.31 (t,
Yield 70%, yellow solid, mp 159.1°C. FT‐IR ῡmax (cm−1):
2835 to 3062 (C─H), 1597 (C═O), 1429 to 1515 (C═C,
C═N), 1228 (C─O). 1H‐NMR (300 MHz, DMSO‐d6, δ,
ppm): 3.30 (m, 4H, pip‐2,6), 3.56 (s, 3H, OCH3), 3.75 (t,
4H, J: 6 Hz, pip‐2,6), 6.81 to 6.88 (m, 3H, Ar), 6.99 to
7.02 (m, 3H, Ar), 7.06 to 7.11 (m, 3H, Ar), 7.18 (d, 1H,
J: 3 Hz, Ar), 7.22 to 7.31 (m, 4H, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.94, 48.25, 55.48, 113.61,
115.31, 116.56, 118.36, 120.05, 121.48, 122.14, 122.51,
127.93, 128.16, 129.09, 129.44, 129.53, 130.07, 135.31,
140.00, 151.01, 158.92, 159.38, 171.28, 187.69. For
C27H25N3O2S; 71.18% C; 5.53% H; 9.22% N, found:
71.15% C, 5.57% H, 9.26% N. HRMS (m/z): [M + H]+
calcd 456.1740; found: 456.1744.
1
4H, J: 3 Hz, pip‐2,6), 3.74 (t, 4H, J: 3 Hz, pip‐2,6), 6.84 (t,
1H, J: 9 Hz, pip‐Ar), 7.00 (d, 2H, J: 3 Hz, pip‐Ar), 7.07 to
7.18 (m, 5H, Ar), 7.23 to 7.34 (m, 5H, Ar), 7.40 (d, 2H, J:
3 Hz, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 44.89,
47.11, 47.96, 48.25, 51.03, 116.56, 117.45, 120.05, 122.03,
127.95, 128.19, 128.68, 129.05, 129.09, 129.53, 130.12,
131.81, 135.18, 138.70, 151.01, 159.36, 171.25, 188.05. For
C26H23N3OS; 73.38% C; 5.45% H; 9.87% N, found: 73.35%
C, 5.47% H, 9.88% N. HRMS (m/z): [M + H]+ calcd
426.1635; found: 426.1624.
4.4.2 | [4‐Phenyl‐2‐(4‐phenylpiperazin‐1‐
yl)thiazol‐5‐yl](m‐tolyl)methanone (com-
pound 2)
4.4.5 | (4‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 5)
Yield 65%, light yellow solid, mp 195°C. FT‐IR ῡmax
(cm−1): 2901 to 2987 (C─H), 1597 (C═O), 1332 to 1496
Yield 74%, light yellow solid, mp 172.9°C. FT‐IR ῡmax
(cm−1): 2842 to 3059 (C─H), 1597 (C═O), 1339 to 1503
(C═C, C═N), 1228 (C─O). 1H‐NMR (300 MHz,
DMSO‐d6, δ, ppm): 3.32 (d, 4H, J: 6 Hz, pip‐2,6), 3.71 to
3.73 (m, 7H, pip‐3,5, OCH3), 6.71 (d, 2H, J: 6 Hz, Ar), 6.84
(t, 1H, J: 9 Hz, Ar), 7.01 (2H, d, J: 6 Hz, Ar), 7.13 to 7.34
(m, 7H, Ar), 7.44 (dt, 2H, J: 9 and 3 Hz, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.96, 48.26, 55.82, 113.63,
116.56, 120.04, 121.66, 128.11, 128.96, 129.52, 130.06,
130.96, 131.59, 135.31, 151.05, 157.93, 162.50, 170.87,
186.80. For C27H25N3O2S; 71.18% C; 5.53% H; 9.22% N,
found: 71.18% C, 5.55% H, 9.24% N. HRMS (m/z):
[M + H]+ calcd 456.1740; found: 456.1736.
1
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
2.07 (s, 3H, CH3), 3.32 (t, 4H, J: 3 Hz, pip‐2,6), 3.75 (t,
4H, J: 3 Hz, pip‐2,6), 6.84 (t, 1H, J: 9 Hz, pip‐Ar), 7.00
(d, 2H, J: 3 Hz, pip‐Ar), 7.04 to 7.39 (m, 11H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 47.94, 48.26, 48.72,
51.02, 51.32, 116.56, 117.48, 120.05, 122.31, 126.16,
127.89, 128.92, 129.97, 131.03, 132.37, 134.91, 135.38,
137.38, 138.83, 151.00, 159.29, 159.54, 171.24, 188.24.
For C27H25N3OS; 73.77% C; 5.73% H; 9.56% N, found:
73.75% C, 5.70% H, 9.58% N. HRMS (m/z): [M + H]+
calcd 440.1791; found: 440.1788.
4.4.3 | [4‐Phenyl‐2‐(4‐phenylpiperazin‐1‐
yl)thiazol‐5‐yl](p‐tolyl)methanone (com-
pound 3)
4.4.6 | (3‐Fluorophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 6)
Yield 85%, light yellow solid, mp 194°C. FT‐IR ῡmax (cm−1):
2819 to 3036 (C─H), 1595 (C═O), 1337 to 1494 (C═C,
Yield 80%, yellow solid, mp 205°C. FT‐IR ῡmax (cm−1):
2829 to 3065 (C─H), 1597 (C═O), 1333 to 1522 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
1
3H, CH3), 3.31 (t, 4H, J: 3 Hz, pip‐2,6), 3.73 (t, 4H, J:
6 Hz, pip‐2,6), 6.82 (t, 1H, J: 5 Hz, pip‐Ar), 6.99 (d, 4H, J:
9 Hz, pip‐Ar), 7.10 to 7.36 (m, 9H, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.96, 48.25, 116.56, 120.03,
121.76, 128.02, 128.25, 128.51, 128.80, 128.97, 129.09,
129.33, 129.52, 130.08, 135.27, 136.01, 142.14, 151.03,
158.67, 171.05, 187.68. For C27H25N3OS; 73.77% C; 5.73%
H; 9.56% N, found: 73.78% C, 5.72% H, 9.59% N. HRMS
(m/z): [M + H]+ calcd 440.1791; found: 440.1786.
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.32 (m,
4H, pip‐2,6), 3.76 (brs, 4H, J: 3 Hz, pip‐3,5), 6.84 (t, 1H,
J: 9 Hz, pip‐Ar), 7.01 (d, 2H, J: 9 Hz, pip‐Ar), 7.05 to
7.28 (m, 10H, Ar), 7.42 (d, 1H, J: 6 Hz). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.99, 48.24, 115.55,
115.85, 115.99, 116.56, 116.90, 118.25, 118.53, 120.06,
122.03, 125.16, 126.30, 127.96, 128.25, 129.01, 129.23,
129.53, 129.89, 130.08, 130.25, 130.35, 131.96, 135.11,
138.74, 140.89, 140.98, 150.99, 160.12, 160.23, 163.36,

DEMIRAYAK ET AL.
9
171.29, 171.51. For C26H22FN3OS; 70.41% C; 5.00% H;
9.47% N, found: 70.45% C, 5.00% H, 9.47% N. HRMS
(m/z): [M + H]+ calcd 444.1540; found: 444.1536.
116.56, 120.05, 121.98, 128.02, 128.20, 128.32, 129.16,
129.53, 130.21, 130.90, 131.82, 131.95, 135.04, 136.39,
137.43, 150.99, 159.88, 171.42, 186.84, 196.58. For
C26H22ClN3OS; 67.89% C; 4.82% H; 7.71% N, found:
70.45% C, 5.00% H, 9.47% N. HRMS (m/z): [M + H]+
calcd 460.1245; found: 460.1245.
4.4.7 | (4‐Fluorophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 7)
4.4.10 | (3‐Nitrophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 10)
Yield 85%, yellow solid, mp 199.5°C. FT‐IR ῡmax (cm−1):
2838 to 3065 (C‐H), 1595 (C═O), 1431 to 1522 (C═C,
C═N). 1H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.30
(brs, 4H, pip‐2,6), 3.75 (brs, 4H, pip‐3,5), 6.84 (t, 1H, J:
7.5 Hz, pip‐Ar), 6.92 (t, 1H, J: 6 Hz, pip‐Ar), 6.99 (d, J:
6 Hz, 2H, Ar), 7.08 to 7.28 (m, 9H, Ar), 7.43 (q, 1H, J:
6 Hz, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 47.97,
48.25, 115.00, 115.29, 115.85, 116.56, 120.05, 125.14,
127.96, 128.01, 128.25, 129.12, 129.24, 129.53, 130.08,
130.19, 131.78, 131.90, 135.11, 151.00, 171.32, 186.75.
For C26H22FN3OS; 70.41% C; 5.00% H; 9.47% N, found:
70.38% C, 5.02% H, 9.49% N. HRMS (m/z): [M + H]+
calcd 444.1540; found: 444.1538.
Yield 80%, yellow solid, mp 166°C. FT‐IR ῡmax (cm−1):
2826 to 3090 (C─H), 1596 (C═O), 1339 to 1522 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.32 (m,
4H, pip‐2,6), 3.76 (bs, 4H, J: 3 Hz, pip‐3,5), 7.35 (t, 1H,
J: 6 Hz, pip‐Ar), 7.45 to 8.00 (m, 10H, Ar), 8.29 (t, 1H, J:
6 Hz, Ar), 8.42 to 8.62 (m, 2H, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 48.55, 48.74, 117.07, 120.58, 124.22,
124.49, 125.22, 126.23, 128.49, 128.85, 129.54, 129.75,
130.04, 130.21, 130.56, 130.73, 132.45, 135.30, 135.60,
136.92, 137.00, 139.06, 140.26, 147.48, 147.75, 151.46,
157.16, 161.52, 172.03, 172.35, 186.13, 188.22. For
C26H22N4O3S; 66.37% C; 4.71% H; 11.91% N, found:
70.45% C, 5.00% H, 9.47% N. HRMS (m/z): [M + H]+
calcd 471.1485; found: 471.1494.
4.4.8 | (3‐Chlorophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 8)
Yield 70%, yellow solid, mp 189.5°C. FT‐IR ῡmax (cm−1):
2822 to 3056 (C─H), 1597 (C═O), 1331 to 1523 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.32 (m,
4.4.11 | (4‐Nitrophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 11)
1
4H, pip‐2,6), 3.76 (brs, 4H, J: 3 Hz, pip‐3,5), 6.84 (t, 1H,
J: 9 Hz, pip‐Ar), 7.01 (d, 2H, J: 9 Hz, pip‐Ar), 7.05 to
7.28 (m, 10H, Ar), 7.42 (d, 1H, J: 6 Hz, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.99, 48.24, 116.56,
120.06, 122.11, 127.52, 127.98, 128.29, 128.74, 128.89,
128.97, 129.28, 129.53, 129.77, 129.81, 130.06, 131.26,
132.96, 135.05, 140.48, 150.97, 160.33, 171.56, 186.42.
For C26H22ClN3OS; 67.89% C; 4.82% H; 7.71% N, found:
70.45% C, 5.00% H, 9.47% N. HRMS (m/z): [M + H]+
calcd 460.1245; found: 460.1242.
Yield 85%, yellow solid, mp 236.5°C. FT‐IR ῡmax (cm−1):
2840 to 3106 (C─H), 1595 (C═O), 1344 to 1503 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.88 (brs,
1
4H, pip‐2,6), 4.28 (brs, 4H, pip‐3,5), 7.35 (t, 1H, J: 7.5 Hz,
pip‐Ar), 6.99 to 7.09 (m, 3H, pip‐Ar), 7.14 to 7.28 (m, 5H,
Ar), 7.44 (d, J: 4.5 Hz, 1H, Ar), 7.52 to 7.60 (m, 2H, Ar),
7.90 (dd, 1H, J: 6 Hz, J: 3 Hz, Ar), 7.97 (dd, 1H, J: 6 Hz, J:
3 Hz, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 48.06,
48.24, 100.47, 116.56, 120.07, 122.29, 123.04, 123.12,
127.96, 128.41, 129.15, 129.35, 129.54, 130.19, 130.25,
131.36, 132.21, 134.80, 144.64, 148.54, 150.95, 161.36,
171.86, 186.29. For C26H22N4O3S; 66.37% C; 4.71% H;
11.91% N, found: 70.45% C, 5.00% H, 9.47% N. HRMS (m/
z): [M + H]+ calcd 471.1485; found: 471.1473.
4.4.9 | (4‐Chlorophenyl)[4‐phenyl‐2‐(4‐
phenylpiperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 9)
Yield 74%, orange solid, mp 225°C. FT‐IR ῡmax (cm−1):
2845 to 3063 (C─H), 1594 (C═O), 1343 to 1519 (C═C,
C═N). 1H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 3.30
(brs, 4H, pip‐2,6), 3.75 (brs, 4H, pip‐3,5), 6.84 (t, 1H, J:
7.5 Hz, pip‐Ar), 7.00 (d, J: 6 Hz, 2H, Ar), 7.09 to 7.30
(m, 9H, Ar), 7.36 (d, 2H, J: 6 Hz, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 47.99, 48.24, 53.04, 115.88,
4.4.12 | Phenyl [4‐phenyl‐2‐(4‐(o‐tolyl)
piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 12)
Yield 70%, light yellow solid, mp 149.3°C. FT‐IR ῡmax
(cm−1): 2825 to 3075 (C─H), 1607 (C═O), 1341 to 1497

10
DEMIRAYAK ET AL.
1
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
2.30 (s, 3H, CH3), 2.98 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.75
(t, 4H, J: 4.5 Hz, pip‐2,6), 7.00 (t, 1H, J: 7.5 Hz, pip‐Ar),
7.07 to 7.21 (m, 8H, Ar), 7.27 to 7.34 (m, 3H, Ar), 7.40
(dd, J: 8 Hz, J: 3 Hz, 2H, Bz‐Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 40.83, 48.74, 51.16, 119.63, 121.95,
123.89, 127.10, 127.94, 128.19, 129.05, 129.09, 130.12,
131.37, 131.81, 132.45, 135.20, 151.21, 159.38, 171.35,
188.05. For C27H25N3OS; 73.77% C; 5.73% H; 9.56% N,
found: 73.75% C, 5.70% H, 9.58% N. HRMS (m/z):
[M + H]+ calcd 440.1791; found: 440.1790.
4.4.15 | (3‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(o‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 15)
Yield 65%, beige solid, mp 135.6°C. FT‐IR ῡmax (cm−1):
2832 to 3062 (C─H), 1603 (C═O), 1341 to 1496 (C═C,
C═N), 1234 (C─O). 1H‐NMR (300 MHz, DMSO‐d6, δ,
ppm): 2.31 (s, 3H, CH3), 2.99 (t, 4H, J: 6 Hz, pip‐2,6),
3.57 (s, 3H, OCH3), 3.76 (t, 4H, J: 4.5 Hz, pip‐3,5), 6.85
to 6.89 (m, 2H, pip‐Ar), 6.97 to 7.05 (m, 2H, Ar), 7.07 to
7.12 (m, 3H, Ar), 7.14 to 7.21 (m, 4H, Ar), 7.29 to 7.32
(m, 2H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm):
18.05, 48.73, 51.17, 55.46, 113.63, 118.35, 119.64, 121.48,
122.05, 123.89, 127.10, 127.92, 129.09, 129.44, 130.07,
131.37, 132.45, 135.33, 140.03, 151.21, 158.93, 159.40,
171.37, 187.68. For C28H27N3O2S; 71.61% C; 5.80% H;
8.95% N, found: 71.63% C, 5.81% H, 8.94% N. HRMS
(m/z): [M + H]+ calcd 470.1897; found: 470.1903.
4.4.13 | [4‐Phenyl‐2‐(4‐(o‐tolyl)piperazin‐1‐
yl)thiazol‐5‐yl](m‐tolyl)methanone (com-
pound 13)
Yield 65%, light yellow solid, mp 163.2°C. FT‐IR ῡmax
(cm−1): 2829 to 2986 (C─H), 1607 (C═O), 1329 to 1493
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
4.4.16 | (4‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(o‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 16)
1
2.07 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.98 (t, 4H, J:
4.5 Hz, pip‐2,6), 3.75 (t, 4H, J: 4.5 Hz, pip‐2,6), 7.00 (t,
2H, J: 8 Hz, J: 3 Hz, pip‐Ar), 7.04 to 7.10 (m, 4H, Ar),
7.12 to 7.26 (m, 6H, Ar), 7.27 to 7.29 (m, 1H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 18.03, 20.98, 48.73,
51.16, 119.62, 122.23, 123.88, 126.16, 127.10, 127.88,
128.21, 128.92, 129.00, 129.97, 131.37, 132.37, 132.45,
135.40, 137.39, 138.41, 151.21, 159.30, 171.33, 188.08.
For C28H27N3OS; 74.14% C; 6.00% H; 9.26% N, found:
74.15% C, 5.96% H, 9.28% N. HRMS (m/z): [M + H]+
calcd 454.1948; found: 454.1931.
Yield 68%, yellow solid, mp 152.4°C. FT‐IR ῡmax (cm−1):
2825 to 3055 (C─H), 1604 (C═O), 1331 to 1523 (C═C,
C═N), 1231 (C─O). 1H‐NMR (300 MHz, DMSO‐d6, δ,
ppm): 2.30 (s, 3H, CH3), 2.99 (t, 4H, J: 4.5 Hz, pip‐2,6),
3.71 to 3.75 (m, 7H, pip‐3,5, OCH3), 6.77 to 6.97 (m, 2H,
Ar), 6.97 to 7.05 (m, 2H, pip‐Ar), 7.12 to 7.25 (m, 5H,
Ar), 7.31 to 7.34 (m, 2H, Ar), 7.45 (d, 2H, J: 6 Hz, Ar).
13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 18.03, 55.81,
55.84, 113.63, 119.62, 121.60, 123.87, 127.10, 128.09,
128.95, 130.06, 130.99, 131.37, 131.59, 132.45, 135.33,
151.24, 157.93, 162.50, 170.95, 186.79. For C28H27N3O2S;
71.61% C; 5.80% H; 8.95% N, found: 71.62% C, 5.80% H,
8.97% N. HRMS (m/z): [M + H]+ calcd 470.1897; found:
470.1882.
4.4.14 | [4‐Phenyl‐2‐(4‐(o‐tolyl)piperazin‐1‐
yl)thiazol‐5‐yl](p‐tolyl)methanone (com-
pound 14)
Yield 65%, light yellow solid, mp 164.8°C. FT‐IR ῡmax
(cm−1): 2825 to 3062 (C─H), 1600 (C═O), 1331 to 1495
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
4.4.17 | (3‐Fluorophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 17)
1
2.22 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.99 (t, 4H, J:
6 Hz, pip‐2,6), 3.75 (t, 4H, J: 3 Hz, pip‐3,5), 6.98 (d, 2H,
J: 9 Hz, J: 3 Hz, pip‐Ar), 7.02 to 7.13 (m, 2H, Ar), 7.15
to 7.22 (m, 5H, Ar), 7.30 to 7.36 (m, 4H, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 18.05, 21.47, 48.74, 51.16,
119.64, 121.68, 123.88, 127.10, 128.01, 128.80, 128.97,
129.34, 130.08, 131.37, 132.45, 135.28, 136.02, 142.14,
151.23, 158.70, 171.14, 187.70. For C28H27N3OS; 74.14%
C; 6.00% H; 9.26% N, found: 74.17% C, 6.01% H, 9.27%
N. HRMS (m/z): [M + H]+ calcd 454.1948; found:
454.1930.
Yield 80%, light yellow solid, mp 154°C. FT‐IR ῡmax
(cm−1): 2825 to 3079 (C─H), 1614 (C═O), 1343 to 1497
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
2.31 (s, 3H, CH3), 2.99 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.77 (t,
4H, J: 4.5 Hz, pip‐3,5), 6.97 to 7.44 (m, 13H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 18.02, 48.78, 51.16,
115.55, 115.85, 118.25, 118.53, 119.65, 121.96, 123.90,
125.14, 126.34, 127.11, 127.95, 128.25, 129.02, 129.23,
129.88, 130.08, 130.25, 130.35, 131.37, 131.95, 132.46,
135.13, 140.92, 141.01, 151.19, 160.13, 160.24, 163.38,
1

DEMIRAYAK ET AL.
11
171.61, 186.58. For C27H24FN3OS; 70.87% C; 5.29% H;
9.18% N, found: 70.85% C, 5.26% H, 9.22% N. HRMS
(m/z): [M + H]+ calcd 458.1697; found: 458.1675.
NMR (75 MHz, DMSO‐d6, δ, ppm): 18.02, 48.79, 51.16,
119.64, 121.91, 123.90, 127.11, 128.01, 128.20, 128.32,
129.16, 130.21, 130.91, 131.37, 131.82, 132.46, 135.06,
136.39, 137.46, 151.19, 159.88, 171.52, 186.83. For
C27H24ClN3OS; 68.41% C; 5.10% H; 7.48% N, found:
68.43% C, 5.12% H, 7.48% N. HRMS (m/z): [M + H]+
calcd 474.1401; found: 474.1399.
4.4.18 | (4‐Fluorophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 18)
Yield 80%, light yellow solid, mp 144°C. FT‐IR ῡmax
(cm−1): 2825 to 3062 (C─H), 1600 (C═O), 1341 to 1451
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
4.4.21 | (3‐Nitrophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 21)
1
2.31 (s, 3H, CH3), 2.99 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.77
(brs, 4H, pip‐3,5), 6.91 to 7.21 (m, 10H, Ar), 7.25 to 7.29
(m, 2H, Ar), 7.42 to 7.47 (m, 1H, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 18.02, 48.78, 51.16, 115.00,
115.29, 115.55, 115.85, 118.25, 118.53, 119.64, 121.96,
123.90, 125.14, 127.11, 127.95, 128.00, 128.25, 129.12,
129.23, 130.09, 130.20, 130.35, 131.37, 131.78, 131.91,
132.46, 135.13, 135.26, 140.92, 141.01, 151.19, 159.55,
160.13, 160.24, 163.38, 171.41, 171.61, 186.55. For
C27H24FN3OS; 70.87% C; 5.29% H; 9.18% N, found:
70.85% C, 5.28% H, 9.20% N. HRMS (m/z): [M + H]+
calcd 458.1697; found: 458.1707.
Yield 68%, beige solid, mp 131.2°C. FT‐IR ῡmax (cm−1):
2825 to 3062 (C─H), 1600 (C═O), 1333 to 1514 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.31 (s,
1
3H, CH3), 3.00 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.78 (brs, 4H,
pip‐3,5), 6.97 to 7.07 (m, 3H, Ar), 7.10 to 7.32 (m, 5H,
Ar), 7.40 to 7.47 (m, 2H, Ar), 7.97 to 8.14 (m, 3H, Ar).
13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 18.02, 48.83,
51.15, 119.64, 122.20, 122.98, 123.71, 123.92, 123.98,
124.70, 125.72, 127.11, 127.98, 128.35, 129.03, 129.24,
129.71, 130.08, 130.22, 131.38, 131.95, 132.46, 134.80,
135.10, 136.41, 136.50, 138.57, 139.77, 146.99, 147.25,
151.15, 156.68, 161.05, 171.63, 171.96, 185.63, 187.73.
C27H24N4O3S; 66.92% C; 4.99% H; 11.56% N, found:
66.95% C, 5.00% H, 11.57% N. HRMS (m/z): [M + H]+
calcd 485.1462; found: 485.1621.
4.4.19 | (3‐Chlorophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 19)
Yield 70%, light yellow solid, mp 130.2°C. FT‐IR ῡmax
(cm−1): 2825 to 3065 (C─H), 1610 (C═O), 1341 to 1495
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
4.4.22 | (4‐Nitrophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 22)
1
2.30 (s, 3H, CH3), 2.98 (brs, 4H, pip‐2,6), 3.76 (brs, 4H,
pip‐3,5), 6.97 to 7.34 (m, 13H, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 18.05, 48.78, 51.15, 119.63, 122.04,
123.90, 127.10, 127.52, 127.98, 128.30, 128.89, 128.97,
129.27, 129.79, 130.07, 130.42, 131.26, 131.37, 131.98,
132.46, 132.97, 135.06, 137.06, 140.51, 151.17, 160.34,
171.66, 186.40. For C27H24ClN3OS; 68.41% C; 5.10% H;
7.48% N, found: 68.45% C, 5.13% H, 7.46% N. HRMS
(m/z): [M + H]+ calcd 474.1401; found: 474.1389.
Yield 68%, yellow solid, mp 133°C. FT‐IR ῡmax (cm−1):
2826 to 3053 (C─H), 1596 (C═O), 1341 to 1495 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.31 (s,
1
3H, CH3), 3.00 (t, 4H, J: 6 Hz, pip‐2,6), 3.78 (brs, 4H,
pip‐3,5), 6.97 to 7.37 (m, 9H, Ar), 7.44 to 7.60 (m, 2H,
Ar), 7.89 to 7.96 (m, 2H, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 48.86, 51.16, 119.66, 122.23, 123.03,
123.11, 123.92, 127.11, 127.95, 128.41, 129.02, 129.15,
130.25, 131.37, 132.46, 134.81, 144.66, 148.54, 151.14,
161.35, 171.96, 186.27. C27H24N4O3S; 66.92% C; 4.99% H;
11.56% N, found: 66.95% C, 5.01% H, 11.55% N. HRMS
(m/z): [M + H]+ calcd 485.1462; found: 485.1640.
4.4.20 | (4‐Chlorophenyl)[4‐phenyl‐2‐(4‐(o‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 20)
Yield 76%, orange solid, mp 127.6°C. FT‐IR ῡmax (cm−1):
2825 to 3013 (C─H), 1597 (C═O), 1350 to 1544 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.31 (s,
4.4.23 | Phenyl[4‐phenyl‐2‐(4‐(m‐tolyl)
piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 23)
1
3H, CH3), 2.99 (brs, 4H, pip‐2,6), 3.77 (brs, 4H, pip‐3,5),
6.98 (t, 1H, J: 4.5 Hz, pip‐Ar), 7.05 (t, 1H, J: 4.5 Hz, Ar),
7.10 to 7.31 (m, 9H, Ar), 7.35 to 7.39 (m, 2H, Ar). 13C‐
Yield 72%, yellow solid, mp 170°C. FT‐IR ῡmax (cm−1):
2825 to 3075 (C─H), 1596 (C═O), 1342 to 1510 (C═C,

12
DEMIRAYAK ET AL.
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,
3H, CH3), 3.30 (t, 4H, J: 6 Hz, pip‐2,6), 3.74 (t, 4H, J:
6 Hz, pip‐2,6), 6.66 (d, 1H, J: 6 Hz, pip‐Ar), 6.80 (dd,
2H, J: 12 Hz, J: 3 Hz, Ar), 7.07 to 7.21 (m, 6H,Ar), 7.27
to 7.41 (m, 5H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 21.84, 39.16, 39.44, 39.72, 40.00, 40.27, 40.55,
40.83, 47.99, 48.33, 113.79, 117.24, 120.88, 122.00,
127.95, 128.19, 129.08, 129.35, 130.12, 131.81, 135.19,
138.63, 138.71, 151.06, 159.37, 171.27, 188.05. For
C27H25N3OS; 73.77% C; 5.73% H; 9.56% N, found:
73.76% C, 5.74% H, 9.55% N. HRMS (m/z): [M + H]+
calcd 440.1791; found: 440.1791.
4.4.26 | (3‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 26)
Yield 59%, yellow solid, mp 129.7°C. FT‐IR ῡmax (cm−1):
2832 to 2993 (C─H), 1597 (C═O), 1400 to 1500 (C═C,
C═N), 1237 (C─O). 1H‐NMR (300 MHz, DMSO‐d6, δ,
ppm): 2.27 (s, 3H, CH3), 3.30 (m, 4H, pip‐2,6), 3.56 (s,
3H, CH3), 3.74 (t, 4H, J: 4.5 Hz, pip‐2,6), 6.66 (d, 1H, J:
6 Hz, pip‐Ar), 6.78 to 6.88 (m, 4H, Ar), 7.00 to 7.20 (m,
6H, Ar), 7.30 (dd, 2H, J: 6 and 3 Hz, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 21.84, 113.62, 113.79,
115.33, 117.23, 118.35, 120.88, 121.47, 122.12, 127.93,
128.16, 129.08, 129.35, 129.44, 130.07, 135.32, 138.63,
140.02, 151.05, 158.93, 159.38, 171.30, 187.68. For
C28H27N3O2S; 71.61% C; 5.80% H; 8.95% N, found:
71.65% C, 5.82% H, 8.97% N. HRMS (m/z): [M + H]+
calcd 470.1897; found: 470.1892.
4.4.24 | [4‐Phenyl‐2‐(4‐(m‐tolyl)piperazin‐
1‐yl)thiazol‐5‐yl](m‐tolyl)methanone (com-
pound 24)
Yield 74%, orange solid, mp 140°C. FT‐IR ῡmax (cm−1):
2901 to 2986 (C─H), 1597 (C═O), 1342 to 1527 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.07 (s,
4.4.27 | (4‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 27)
1
3H, CH3), 2.27 (s, 3H, CH3), 3.30 (m, 4H, pip‐2,6), 3.73
(t, 4H, J: 4.5 Hz, pip‐2,6), 6.66 (d, 1H, J: 6 Hz, pip‐Ar),
6.80 (m, 2H, Ar), 7.01 (t, 1H, J: 9 Hz, pip‐Ar), 7.06 to
7.39 (m, 9H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 20.96, 21.86, 47.97, 48.33, 113.79, 117.24, 120.88,
126.15, 127.89, 128.11, 128.21, 128.91, 129.00, 129.35,
129.97, 132.37, 135.39, 137.39, 138.63, 151.06, 159.29,
171.25, 188.09. For C28H27N3OS; 74.14% C; 6.00% H;
9.26% N, found: 74.17% C, 5.99% H, 9.26% N. HRMS
(m/z): [M + H]+ calcd 454.1948; found: 454.1948.
Yield 75%, light yellow solid, mp 165.6°C. FT‐IR ῡmax
(cm−1): 2838 to 3063 (C─H), 1598 (C═O), 1339 to 1518
(C═C, C═N), 1238.14 (C─O). 1H‐NMR (300 MHz,
DMSO‐d6, δ, ppm): 2.27 (s, 3H, CH3), 3.29 (m, 4H, pip‐
2,6), 3.71 to 3.75 (m, 4H, pip‐3,5), 6.75 to 6.72 (m, 3H,
Ar), 6.79 to 6.83 (m, 2H, Ar), 7.11 to 7.21 (m, 5H, Ar),
7.31 to 7.34 (m, 2H, Ar), 7.42 to 7.46 (m, 2H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 21.84, 113.63,
113.80, 117.24, 120.88, 121.66, 128.10, 128.95, 129.34,
130.05, 130.97, 131.59, 135.32, 138.62, 151.09, 157.93,
162.50, 170.88, 186.79. For C28H27N3O2S; 71.61% C;
5.80% H; 8.95% N, found: 71.59% C, 5.78% H, 8.96% N.
HRMS (m/z): [M + H]+ calcd 470.1897; found: 470.1884.
4.4.25 | [4‐Phenyl‐2‐(4‐(m‐tolyl)piperazin‐
1‐yl)thiazol‐5‐yl](p‐tolyl)methanone (com-
pound 25)
4.4.28 | (3‐Fluorophenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 28)
Yield 60%, light yellow solid, mp 177°C. FT‐IR ῡmax
(cm−1): 2819 to 3032 (C─H), 1597 (C═O), 1342 to 1519
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
1
2.22 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.30 (m, 4H, pip‐
2,6), 3.72 (t, 4H, J: 4.5 Hz, pip‐2,6), 6.66 (d, 1H, J: 6 Hz,
pip‐Ar), 6.80 (dd, 2H, J: 9 and 3 Hz, Ar), 6.97 (d, 2H, J:
9 Hz, Ar), 7.11 to 7.21 (m, 4H, Ar), 7.29 to 7.35 (m, 4H,
Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 21.47,
21.84, 113.79, 117.24, 120.88, 121.74, 128.02, 128.24,
128.52, 128.80, 128.97, 129.33, 130.07, 135.27, 136.02,
138.63, 142.14, 151.07, 158.69, 171.07, 187.68. For
C28H27N3OS; 74.14% C; 6.00% H; 9.26% N, found:
74.12% C, 6.03% H, 9.24% N. HRMS (m/z): [M + H]+
calcd 454.1948; found: 454.1930.
Yield 80%, yellow solid, mp 175.8°C. FT‐IR ῡmax (cm−1):
2835 to 3066 (C─H), 1598 (C═O), 1341 to 1519 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,
3H, CH3), 3.30 (m, 4H, pip‐2,6), 3.75 (m, 4H, pip‐3,5),
6.66 (d, 1H, J: 6 Hz, pip‐Ar), 6.79 to 6.83 (m, 2H, Ar),
7.07 to 7.43 (m, 10H, Ar). 13C‐NMR (75 MHz, DMSO‐d6,
δ, ppm): 21.84, 48.01, 48.32, 113.79, 115.55, 115.71,
115.85, 115.99, 116.60, 116.91, 117.24, 118.25, 118.53,
120.89, 122.02, 125.16, 126.33, 127.96, 128.25, 129.01,
129.22, 129.35, 129.89, 130.08, 130.24, 130.35, 131.95,
135.12, 137.32, 138.64, 138.75, 140.91, 140.99, 151.03,

DEMIRAYAK ET AL.
13
160.13, 160.22, 163.37, 171.30, 171.53, 186.58, 187.89. For
C27H24FN3OS; 70.87% C; 5.29% H; 9.18% N, found: 70.88%
C, 5.28% H, 9.20% N. HRMS (m/z): [M + H]+ calcd
458.1697; found: 458.1684.
3H, CH3), 3.30 (brs, 4H, pip‐2,6), 3.75 (brs, 4H, pip‐3,5),
6.66 (d, 1H, J: 6 Hz, pip‐Ar), 6.81 (d, 2H, J: 6 Hz, pip‐
Ar), 7.10 to 7.38 (m, 10H, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 21.86, 48.01, 48.32, 113.79, 117.23,
120.89, 128.02, 128.20, 128.32, 129.16, 129.35, 130.21,
130.90, 131.82, 135.06, 136.39, 137.45, 138.63, 151.03,
159.88, 171.43, 186.83. For C27H24ClN3OS; 68.41% C;
5.10% H; 7.48% N, found: 68.44% C, 5.10% H, 7.49% N.
HRMS (m/z): [M + H]+ calcd 474.1401; found: 474.1391.
4.4.29 | (4‐Fluorophenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 29)
Yield 68%, light yellow solid, mp 193°C. FT‐IR ῡmax
(cm−1): 2842 to 3066 (C─H), 1604 (C═O), 1343 to
1520 (C═C, C═N). 1H‐NMR (300 MHz, DMSO‐d6, δ,
ppm): 2.27 (s, 3H, CH3), 3.30 (m, 4H, pip‐2,6), 3.74
(brs, 4H, pip‐3,5), 6.66 (d, 1H, J: 6 Hz, pip‐Ar), 6.81
(d, 2H, J: 6 Hz, pip‐Ar), 6.91 to 6.97 (m, 1H, Ar), 7.10
to 7.46 (m, 9H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 21.85, 48.33, 113.79, 114.99, 115.28, 115.55,
115.85, 117.24, 118.24, 118.53, 120.89, 122.02, 125.13,
127.96, 128.01, 128.25, 129.11, 129.23, 129.35, 130.08,
130.19, 131.78, 131.90, 135.11, 138.63, 151.04, 159.54,
165.74, 171.33, 171.53, 186.75. For C27H24FN3OS;
70.87% C; 5.29% H; 9.18% N, found: 70.87% C, 5.30%
H, 9.19% N. HRMS (m/z): [M + H]+ calcd 458.1697;
found: 458.1702.
4.4.32 | (3‐Nitrophenyl)[4‐phenyl‐2‐(4‐(m‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 32)
Yield 78%, orange solid, mp 140°C. FT‐IR ῡmax (cm−1):
2845 to 2993 (C─H), 1597 (C═O), 1342 to 1530 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,
3H, CH3), 2.50 (m, 4H, pip‐2,6), 3.77 (m, 4H, pip‐3,5),
6.66 (d, 1H, J: 9 Hz, pip‐Ar), 6.81 (d, 2H, J: 12 Hz, pip‐
Ar), 7.03 (t, 1H, J: 6 Hz, Ar), 7.11 to 7.18 (m, 2H, Ar),
7.23 (d, 1H, J: 9 Hz, Ar), 7.32 (t, 1H, J: 6 Hz, Ar), 7.40
to 7.47 (m, 2H, Ar), 7.77 to 8.11 (m, 3H, Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 21.84, 48.32, 113.79,
117.24, 120.90, 123.71, 123.98, 124.71, 125.72, 127.98,
128.35, 129.03, 129.24, 129.36, 129.71, 130.06, 130.22,
131.94, 134.80, 135.09, 136.41, 136.51, 138.58, 138.64,
139.78, 147.00, 147.26, 151.00, 161.02, 171.54, 171.87,
185.62. For C27H24N4O3S; 66.92% C; 4.99% H; 11.56% N,
found: 66.94% C, 5.00% H, 11.54% N. HRMS (m/z):
[M + H]+ calcd 485.1619; found: 485.1642.
4.4.30 | (3‐Chlorophenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 30)
Yield 71%, yellow solid, mp 173°C. FT‐IR ῡmax (cm−1):
2838 to 3039 (C─H), 1596 (C═O), 1342 to 1526 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,
3H, CH3), 3.30 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.75 (t, 4H, J:
4.5 Hz, pip‐3,5), 6.66 (d, 1H, J: 6 Hz, pip‐Ar), 6.81 (d,
2H, J: 6 Hz, pip‐Ar), 7.08 to 7.43 (m, 10H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 21.84, 48.02, 48.32,
113.79, 117.24, 120.90, 122.10, 127.51, 127.98, 128.29,
128.74, 128.88, 128.96, 129.27, 129.35, 129.76, 129.81,
130.06, 131.26, 131.99, 132.73, 132.96, 135.06, 137.06,
138.64, 138.73, 140.49, 151.02, 157.50, 160.34, 171.35,
171.58, 186.41, 187.85. For C27H24ClN3OS; 68.41% C;
5.10% H; 7.48% N, found: 68.43% C, 5.09% H, 7.47% N.
HRMS (m/z): [M + H]+ calcd 474.1401; found: 474.1390.
4.4.33 | (4‐Nitrophenyl)[4‐phenyl‐2‐(4‐(m‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 33)
Yield 58%, orange solid, mp 218°C. FT‐IR ῡmax (cm−1):
2845 to 3108 (C─H), 1593 (C═O), 1343 to 1518 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,
3H, CH3), 3.31 (brs, 4H, J: 6 Hz, pip‐2,6), 3.78 (m, 4H,
pip‐3,5), 6.66 (d, 1H, J: 9 Hz, pip‐Ar), 6.81 (d, 2H, J:
9 Hz, pip‐Ar), 7.04 to 7.25 (m, 5H, Ar), 7.35 to 7.69 (m,
3H, Ar), 7.87 to 7.90 (m, 2H, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 21.83, 48.08, 48.32, 113.78, 117.23,
120.90, 123.04, 123.12, 127.96, 128.41, 129.14, 129.36,
130.18, 130.25, 131.36, 132.20, 134.81, 138.64, 144.65,
150.99, 161.35, 171.87, 186.27. For C27H24N4O3S; 66.92%
C; 4.99% H; 11.56% N, found: 66.89% C, 5.01% H,
11.58% N. HRMS (m/z): [M + H]+ calcd 485.1619; found:
485.1642.
4.4.31 | (4‐Chlorophenyl)[4‐phenyl‐2‐(4‐
(m‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 31)
Yield 80%, orange solid, mp 204°C. FT‐IR ῡmax (cm−1):
2838 to 2990 (C─H), 1598 (C═O), 1341 to 1517 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.27 (s,

14
DEMIRAYAK ET AL.
4.4.34 | Phenyl[4‐phenyl‐2‐(4‐(p‐tolyl)
piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 34)
4.4.37 | (3‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(p‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 37)
Yield 68%, yellow solid, mp 171.2°C. FT‐IR ῡmax (cm−1):
2815 to 3062 (C─H), 1597 (C═O), 1343 to 1509 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
Yield 65%, light yellow solid, mp 153.4°C. FT‐IR ῡmax
(cm−1): 2832 to 3026 (C─H), 1614 (C═O), 1341 to 1511
(C═C, C═N), 1226.41 (C─O). 1H‐NMR (300 MHz,
DMSO‐d6, δ, ppm): 2.22 (s, 3H, CH3), 3.24 (t, 4H, J: 6 Hz,
pip‐2,6), 3.56 (s, 3H, OCH3), 3.74 (t, 4H, J: 4.5 Hz, pip‐
3,5), 6.85 to 6.92 (m, 4H, pip‐Ar), 6.99 to 7.14 (m, 6H, Ar),
7.18 to 7.31 (m, 3H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 20.53, 48.01, 48.80, 55.48, 113.61, 115.31, 116.90,
118.35, 121.47, 122.12, 127.92, 128.16, 129.00, 129.08,
129.44, 129.96, 130.07, 135.31, 140.02, 148.95, 158.92,
159.38, 171.29, 187.68. For C28H27N3O2S; 71.61% C; 5.80%
H; 8.95% N, found: 71.63% C, 5.84% H, 8.93% N. HRMS
(m/z): [M + H]+ calcd 470.1897; found: 470.1897.
1
3H, CH3), 3.24 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.73 (t, 4H, J:
4.5 Hz, pip‐2,6), 6.91 (d, 2H, J: 9 Hz, pip‐Ar), 7.03 to 7.18
(m, 7H,Ar), 7.27 to 7.31 (m, 3H, Ar), 7.38 to 7.41 (m, 2H,
Bz‐Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 20.56,
48.02, 48.80, 116.90, 122.00, 127.94, 128.19, 129.01,
129.08, 129.96, 130.12, 131.81, 135.19, 138.71, 148.95,
159.36, 171.26, 188.04. For C27H25N3OS; 73.77% C; 5.73%
H; 9.56% N, found: 73.74% C, 5.75% H, 9.53% N. HRMS
(m/z): [M + H]+ calcd 440.1791; found: 440.1789.
4.4.35 | [4‐Phenyl‐2‐(4‐(p‐tolyl)piperazin‐1‐
yl)thiazol‐5‐yl](m‐tolyl)methanone (com-
pound 35)
4.4.38 | (4‐Methoxyphenyl)[4‐phenyl‐2‐(4‐
(p‐tolyl)piperazin‐1‐yl)thiazol‐5‐yl]
methanone (compound 38)
Yield 79%, light yellow solid, mp 133°C. FT‐IR ῡmax
(cm−1): 2904 to 3062 (C─H), 1600 (C═O), 1342 to 1513
Yield 75%, light yellow solid, mp 169.9°C. FT‐IR ῡmax
(cm−1): 2832 to 3065 (C─H), 1614 (C═O), 1400 to 1510
(C═C, C═N), 1225 (C─O). 1H‐NMR (300 MHz,
DMSO‐d6, δ, ppm): 2.22 (s, 3H, CH3), 3.24 (t, 4H, J:
4.5 Hz, pip‐2,6), 3.72 (brs, 7H, pip‐3,5, OCH3), 6.71 (d,
2H, J: 9 Hz, Ar), 6.91 (d, 2H, J: 9 Hz, Ar), 7.07 (d, 2H, J:
9 Hz, pip‐Ar), 7.13 to 7.22 (m, 3H, Ar), 7.32 (d, 2H, J:
6 Hz, Ar), 7.45 (d, 2H, J: 6 Hz, Ar). 13C‐NMR (75 MHz,
DMSO‐d6, δ, ppm): 20.53, 48.02, 48.80, 55.81, 55.84,
113.63, 116.90, 121.65, 128.10, 128.95, 128.99, 129.95,
130.05, 130.97, 131.59, 135.32, 148.98, 157.93, 162.50,
170.88, 186.79. For C28H27N3O2S; 71.61% C; 5.80% H;
8.95% N, found: 71.62% C, 5.82% H, 8.98% N. HRMS
(m/z): [M + H]+ calcd 470.1897; found: 470.1896.
1
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
2.07 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.24 (t, 4H, J:
4.5 Hz, pip‐2,6), 3.74 (t, 4H, J: 4.5 Hz, pip‐2,6), 6.91 (d,
2H, J: 9 Hz, pip‐Ar), 6.96 to 7.38 (m, 11H, Ar). 13C‐
NMR (75 MHz, DMSO‐d6, δ, ppm): 20.53, 20.95, 48.02,
48.80, 116.90, 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, 135.39, 137.02, 137.38, 138.40, 138.84, 148.96,
159.30, 171.25, 188.09. For C28H27N3OS; 74.14% C; 6.00%
H; 9.26% N, found: 74.13% C, 5.98% H, 9.23% N. HRMS
(m/z): [M + H]+ calcd 454.1948; found: 454.1943.
4.4.36 | [4‐Phenyl‐2‐(4‐(p‐tolyl)piperazin‐1‐
yl)thiazol‐5‐yl](p‐tolyl)methanone (com-
pound 36)
4.4.39 | (3‐Fluorophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 39)
Yield 70%, light yellow solid, mp 176.5°C. FT‐IR ῡmax
(cm−1): 2852 to 3029 (C─H), 1600 (C═O), 1331 to 1511
1
(C═C, C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm):
Yield 85%, yellow solid, mp 157°C. FT‐IR ῡmax (cm−1):
2848 to 3059 (C─H), 1610 (C═O), 1344 to 1514 (C═C,
2.22 (s, 6H, CH3), 3.23 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.75 (t,
4H, J: 6 Hz, pip‐3,5), 6.91 (d, 2H, J: 9 Hz, pip‐Ar), 6.97
(d, 2H, J: 9 Hz, Ar), 7.03 to 7.21 (m, 5H, Ar), 7.29 to
7.35 (m, 4H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 20.53, 21.45, 48.02, 48.80, 116.90, 121.75, 128.01,
128.24, 128.51, 128.80, 128.99, 129.08, 129.33, 129.68,
129.95, 130.07, 135.27, 136.02, 142.13, 148.97, 158.68,
171.06, 187.68. For C28H27N3OS; 74.14% C; 6.00% H;
9.26% N, found: 74.15% C, 6.03% H, 9.23% N. HRMS
(m/z): [M + H]+ calcd 454.1935; found: 454.1948.
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
3H, CH3), 3.24 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.77 (brs, 4H,
pip‐3,5), 6.70 (d, 2H, J: 9 Hz, Ar‐H), 6.91 (d, 2H, J:
9 Hz, pip‐Ar), 7.08 (d, 2H, J: 9 Hz, pip‐Ar), 7.13 to 7.22
(m, 3H, Ar), 7.32 (d, 2H, J: 9 Hz, pip‐Ar), 7.44 (d, 2H, J:
9 Hz, pip‐Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm):
20.52, 48.04, 48.79, 115.54, 115.70, 115.84, 115.98,
116.59, 116.90, 118.24, 118.57, 122.02, 122.52, 125.13,
125.16, 126.33, 127.95, 128.24, 129.01, 129.22, 129.95,

DEMIRAYAK ET AL.
15
130.07, 130.23, 130.34, 131.95, 135.12, 138.75, 140.90,
140.99, 148.92, 160.13, 160.22, 163.37, 171.29, 171.51,
186.54, 187.87. For C27H24FN3OS; 70.87% C; 5.29% H;
9.18% N, found: 70.90% C, 5.26% H, 9.20% N. HRMS
(m/z): [M + H]+ calcd 458.1697; found: 458.1691.
13C‐NMR (75 MHz, DMSO‐d6, δ, ppm): 20.54, 34.30,
48.05, 48.79, 53.11, 116.90, 121.97, 128.01, 128.19, 128.32,
129.01, 129.15, 129.96, 130.21, 130.58, 130.90, 131.82,
133.79, 134.02, 135.05, 136.39, 137.45, 138.75, 148.93,
159.87, 171.42, 186.82. For C27H24ClN3OS; 68.41% C;
5.10% H; 7.48% N, found: 68.42% C, 5.12% H, 7.50% N.
HRMS (m/z): [M + H]+ calcd 474.1401; found: 474.1404.
4.4.40 | (4‐Fluorophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 40)
4.4.43 | (3‐Nitrophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 43)
Yield 80%, yellow solid, mp 169.4°C. FT‐IR ῡmax (cm−1):
2832 to 3065 (C─H), 1614 (C═O), 1341 to 1510 (C═C,
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
Yield 70%, orange solid, mp 128.7°C. FT‐IR ῡmax (cm−1):
2826 to 3105 (C─H), 1613 (C═O), 1348 to 1511 (C═C,
1
3H, CH3), 3.24 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.77 (brs, 4H,
pip‐3,5), 6.89 to 6.97 (m, 3H, Ar), 7.03 to 7.28 (m, 9H, Ar),
7.33 to 7.46 (m, 1H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ,
ppm): 20.55, 48.04, 48.79, 114.99, 115.28, 115.55, 115.85,
116.90, 118.25, 118.52, 122.01, 125.13, 127.95, 128.01,
128.25, 129.01, 129.11, 129.22, 129.96, 130.08, 130.19,
130.35, 131.78, 131.90, 135.11, 135.20, 141.00, 148.94,
159.54, 160.12, 160.23, 162.43, 163.37, 165.74, 171.33,
171.52, 186.74. For C27H24FN3OS; 70.87% C; 5.29% H;
9.18% N, found: 70.85% C, 5.32% H, 9.20% N. HRMS (m/
z): [M + H]+ calcd 458.1697; found: 458.1699.
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
3H, CH3), 3.26 (brs, 4H, pip‐2,6), 3.77 (brs, 4H, pip‐2,6),
6.91 (d, 2H, J: 6 Hz, pip‐Ar), 7.01 to 7.34 (m, 6H, Ar), 7.41
to 7.47 (m, 2H, Ar), 7.79 (t, 1H, J: 6 Hz, Ar), 7.93 to 8.11
(m, 2H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm):
20.55, 48.11, 48.79, 116.91, 123.71, 123.98, 124.71, 125.72,
127.98, 128.35, 129.03, 129.24, 129.71, 129.97, 130.06,
130.22, 131.94, 134.81, 135.09, 136.41, 136.51, 138.58,
139.77, 147.00, 147.26, 148.91, 156.66, 161.02, 171.53,
171.85, 185.62. For C27H24N4O3S; 66.92% C; 4.99% H;
11.56% N, found: 66.95% C, 5.02% H, 11.56% N. HRMS
(m/z): [M + H]+ calcd 485.1642; found: 485.1640.
4.4.41 | (3‐Chlorophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 41)
4.4.44 | (4‐Nitrophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 44)
Yield 75%, orange solid, mp 167.2°C. FT‐IR ῡmax (cm−1):
2845 to 3066 (C─H), 1604 (C═O), 1343 to 1513 (C═C,
Yield 68%, orange solid, mp 171°C. FT‐IR ῡmax (cm−1):
2826 to 3105 (C─H), 1613 (C═O), 1346 to 1512 (C═C,
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
3H, CH3), 3.25 (t, 4H, J: 4.5 Hz, pip‐2,6), 3.76 (t, 4H, J:
4.5 Hz, pip‐3,5), 6.91 (d, 2H, J: 9 Hz, pip‐Ar), 7.03 to 7.43
(m, 11H, Ar). 13C‐NMR (75 MHz, DMSO‐d6, δ, ppm):
20.53, 48.06, 48.79, 116.90, 122.08, 127.51, 127.98, 128.30,
128.74, 128.87, 128.96, 129.01, 129.27, 129.96, 130.06,
130.10, 131.26, 132.95, 135.05, 137.06, 140.50, 148.92,
160.35, 171.34, 171.57, 186.42. For C27H24ClN3OS; 68.41%
C; 5.10% H; 7.48% N, found: 68.44% C, 5.12% H, 7.50% N.
HRMS (m/z): [M + H]+ calcd 474.1401; found: 474.1401.
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.22 (s,
3H, CH3), 3.25 (brs, 4H, pip‐2,6), 3.75 (brs, 4H, pip‐2,6),
6.91 (d, 2H, J: 9 Hz, pip‐Ar), 7.04 to 7.25 (m, 6H,Ar), 7.34
to 7.60 (m, 3H, Ar), 7.89 to 7.99 (m, 2H, Bz‐Ar). 13C‐NMR
(75 MHz, DMSO‐d6, δ, ppm): 20.55, 48.12, 48.79, 116.90,
123.03, 123.11, 127.96, 128.41, 129.04, 129.15, 129.34,
129.97, 130.18, 130.25, 131.35, 132.20, 134.81, 138.68,
144.65, 147.36, 148.54, 148.89, 156.73, 161.35, 171.87,
186.26. For C27H24N4O3S; 66.92% C; 4.99% H; 11.56% N,
found: 66.93% C, 5.02% H, 11.55% N. HRMS (m/z):
[M + H]+ calcd 485.1642; found: 485.1645.
4.4.42 | (4‐Chlorophenyl)[4‐phenyl‐2‐(4‐(p‐
tolyl)piperazin‐1‐yl)thiazol‐5‐yl]methanone
(compound 42)
4.5 | Enzyme assay
Yield 76%, orange solid, mp 209.7°C. FT‐IR ῡmax (cm−1):
2832 to 3065 (C─H), 1607 (C═O), 1400 to 1510 (C═C,
An enzymatic assay was performed according to the well‐
known Ellman method with slight modifications.[44]
Before the test process is started, all solutions were
brought to 20°C to 25°C. 96‐well plates were used with
1
C═N). H‐NMR (300 MHz, DMSO‐d6, δ, ppm): 2.21 (s,
3H, CH3), 3.24 (brs, 4H, pip‐2,6), 3.74 (brs, 4H, pip‐3,5),
6.91 (d, 2H, J: 9 Hz, pip‐Ar), 7.05 to 7.43 (m, 11H, Ar).

16
DEMIRAYAK ET AL.
a total volume of 210 μL in each cell, containing 140 μL of
phosphate buffer, 20 μL of enzyme solution (AChE, E.
C.3.1.1.7, from electric eel/BChE, E.C. 3.1.1.8, from equine
serum), 20 μL of inhibitor solution, 20 μL of 5,5′‐
dithiobis‐(2‐nitrobenzoic acide) (DTNB) solution, and
compounds were used. The measurements were per-
formed with and without the inhibitor substance. The
absorbance values obtained as a result of the tests were
analyzed in Microsoft Office Excel‐2013 computer pro-
gram against varying substrate concentrations, and
Lineweaver‐Burk graphs were drawn.
10
μL
of
acetylthiocholine
iodide
(ATC)/
butyrylthiocholine iodide (BTC) solution. The enzyme
inhibitory activities of the compounds were determined
at two concentrations (10−3M and 10−4M), which were
the primary prescreening activity values evaluated as inhi-
bition in the range of 0% to 100%. If the compounds inhibit
the enzyme by 50% or more at a 10−4M concentration, the
inhibition rates were decreased at subconcentrations up to
10−9M concentration. The plates were placed in a BioTek‐
Synergy H1 microplate reader and mixed for 5 minutes and
then left to incubate for 15 minutes at 25°C. At the end of
the incubation period, the microplate reader was allowed
to add the second test solution from the dispenser reservoir
to 80 μL of each buffer. At this stage, the first absorbance
reading was performed at 412 nm. The microplates were
allowed to mix for a further 5 minutes to allow the reaction
to proceed, after which time a second absorbance reading
was performed.
4.7 | Molecular modeling
The modeling studies were undertaken as in our previous
study.[37] The structure of the compounds was obtained
from the LigPrep module in the Maestro Suite
(Scrödinger LCC, Oregon) and minimized using the
OPLS 2005 force field. The X‐ray structure of human
AChE (PDB ID:4EY7) was used in the analysis.[45,46]
The PDB file was edited using the protein preparation
module of Maestro. The GRID file was prepared using
the Maestro Glide‐Receptor Grid Generation Tool. Ligand
docking was performed with the GlideModule in the
extra precision (XP) mode. The poses of the most active
compounds were subjected to induced fit protocols with
default parameter settings and visualized in Molecular
Operation Environments (MOE) program.
The absorbance differences between the two readings
were taken into account, and the % inhibition rates
according to the following formula were calculated:
ACKNOWLEDGMENT
This project was supported by Anadolu Üniversitesi Sci-
entific Research Projects Eskişehir, Turkey (project no:
1610S656).
½½A½Kꢀ‐A½Bꢀꢀ‐½A½Iꢀ‐A½Bꢀꢀꢀ
%Inhibition ¼
× 100
ðAðKÞ‐AðBÞÞ
B
blank (the well containing the inhibitor com-
pound to which the substrate was not added)
control (the well not containing the inhibitor
compound or the substrate)
CONFLICT OF INTEREST
K
The authors confirm that there is no conflict of interest
regarding the content of this article content.
A (B) absorbance reading difference for the blank
A (K) absorbance reading difference of the control
probe
ORCID
Zafer Şahin https://orcid.org/0000-0002-5976-676X
Barkin Berk https://orcid.org/0000-0001-6047-2796
Leyla Yurttaş https://orcid.org/0000-0002-0957-6044
A (I)
absorbance difference of the inhibitor substances
Each concentration of inhibitor compounds was
applied to the plates four times. The IC50 values of the
compounds were calculated from the inhibition curves
plotted using the sigmoid dose‐response model of nonlin-
ear regression analysis in Microsoft Office Excel‐2013
program.
REFERENCES AND NOTES
[1] M. Bajda, D. Panek, M. Hebda, A. W. Ckowska, N. Guzıor, B.
Malawska, Acta Pol Pharm 2015, 72, 737.
[2] A. Speck‐Planche, F. Luan, M. N. D. S. Cordeiro, Mini Rev Med
Chem 2012, 12, 583.
4.6 | Kinetic studies of enzyme inhibition
[3] S. S. Xie, X. B. Wang, J. Y. Li, L. Yang, L. Y. Kong, Eur. J. Med.
Chem. 2013, 64, 540.
In kinetic studies, the identity experiment protocol was
applied following the same procedure as in inhibition
studies. However, unlike the inhibition method, the cal-
culated 2 × IC50, IC50, and IC50/2 values of the inhibitor
[4] H. O. Gulcan, S. Unlu, İ. Esiringu, T. Ercetin, Y. Sahin, D. Oz,
M. F. Sahin, Bioorg. Med. Chem. 2014, 22, 5141.
[5] X. Barril, S. G. Kalko, M. Orozco, F. J. Luque, Mini Rev Med
Chem 2002, 2, 27.

DEMIRAYAK ET AL.
17
[6] A. Basiri, B. M. Abd Razik, M. O. Ezzat, Y. Kia, R. S. Kumar, A.
I. Almansour, N. Arumugam, V. Murugaiyah, Bioorg. Chem.
2017, 75, 210.
[29] A. Andreani, S. Burnelli, M. Granaiola, M. Guardigli, A. Leoni,
A. Locatelli, R. Morigi, M. Rambaldi, M. Rizzoli, L. Varoli, A.
Roda, Eur. J. Med. Chem. 2008, 43, 657.
[30] P. A. Channar, M. S. Shah, A. Saeed, S. U. Khan, F. A. Larik, G.
[7] M. C. Rodrigues Simões, F. P. Dias Viegas, M. S. Moreira, M. de
Freitas Silva, M. M. Riquie, P. M. da Rosa, M. R. Castelli, M. H.
dos Santos, M. G. Soares, C. Viegas Jr., Mini‐Rev. Med. Chem.
2014, 14, 2.
Shabir, J. Iqbal, Med. Chem. 2017, 13(7), 648.
[31] A. Mumtaz, M. Shoaib, S. Zaib, M. S. Shah, H. A. Bhatti, A.
Saeed, I. Hussain, J. Iqbal, Bioorg. Chem. 2018, 78, 141.
[8] M. T. H. Khan, New Biotechnol. 2009, 25(5), 331.
[32] L. Yurttas, Z. A. Kaplancikli, Y. Ozkay, J. Enzyme Inhib. Med.
Chem. 2013, 28, 1040.
[9] K. R. Varadaraju, J. R. Kumar, L. Mallesha, A. Muruli, K. N.
Shetty Mohana, C. Kumar Mukunda, U. Sharanaiah, Int. J.
Alzheimers Dis 2013, 13, 653962.
[33] F. Rahim, M. T. Javed, H. Ullah, A. Wadood, M. Taha, M.
Ashraf, M. A. Khan, F. Khan, S. Mirza, K. M. Khan, Bioorg.
Chem. 2015, 62, 106.
[10] R. Bikshapathi, P. S. Prathima, B. Yashwanth, P. Rajesh, J. V.
Rao, G. J. Kumar, N. Jagadeesh, V. J. Rao, Res. Chem. Intermed.
2018, 44, 553.
[34] B. Z. Kurt, I. Gazioglu, F. Sonmez, M. Kucukislamoglu, Bioorg.
Chem. 2015, 59, 80.
[35] K. Matsueda, M. Hongo, J. Tack, H. Aoki, Y. Saito, H. Kato,
[11] C. B. Mishra, S. Kumari, A. Manral, A. Prakash, V. Saini, A. M.
Neurogastroenterol Motil 2010, 22, 618.
Lynn, M. Tiwari, Eur. J. Med. Chem. 2017, 125, 736.
[36] Z. Q. Sun, L. X. Tu, F. J. Zhuo, S. X. Liu, Bioorg. Med. Chem.
Lett. 2016, 26(3), 747.
[12] A. Sharma, P. Piplani, Chem. Biol. Drug Des. 2017, 90, 926.
[13] P. Meena, A. Manral, V. Saini, M. Tiwari, Neurotox Res 2015,
27, 314.
[37] Z. Şahin, M. Ertaş, C. Bender, E. F. Bülbül, B. Berk, S. Biltekin,
L. Yurttaş, Ş. Demirayak, Drug Dev. Res. 2018, 79(8), 406.
[14] Z. Tozuka, A. Kunisawa, F. Shirai, Y. Ishii, Trends in Res 2018,
1(3), 1.
[38] Z. Özdemir, H. Yılmaz, S. Sarı, A. Karakurt, F. Sezer Şenol, M.
Uysal, Med. Chem. Res. 2017, 26, 2293.
[15] H. A. Saadeh, M. A. Khasawneh, A. Samadi, I. A. ElHaty, G.
Satała, A. J. Bojarski, L. Ismaili, O. M. B. Aguilera, M. Yanez,
J. Mestres, J. Marco‐Contelles, ChemistrySelect 2017, 2, 3854.
[39] M. Berkheij, L. van der Sluis, C. Sewing, D. J. den Boer, J. W.
Terpstra, H. Hiemstra, W. I. Iwema Bakker, A. van den
Hoogenbandb, J. H. van Maarseveen, Tetrahedron Lett. 2005,
46, 2369.
[16] P. Piplani, C. C. Danta, Bioorg. Chem. 2015, 60, 64.
[17] J. Zhang, C. S. Jiang, Med. Chem. Res. 2018, 27, 1717.
[40] V. Pejchal, S. Štepánková, M. Pejchalová, K. Královec, R.
Havelek, Z. Ru Zicková, H. Ajani, R. Lod, M. Lepšík, Bioorg.
Med. Chem. 2016, 24, 1560.
[18] S. Levent, U. Acar Çevik, B. N. Sağlık, Y. Özkay, Ö. D. Can, Ö.
Demir, Ü. Uçucu, Phosphorus Sulfur 2017, 192(4), 469.
[19] S. Hamulakova, J. Imrich, L. Janovec, P. Kristian, I. Danihel, O.
Holas, M. Pohanka, S. Böhm, M. Kozurkova, K. Kuca, Int. J.
Biol. Macromol. 2014, 70, 435.
[41] M. Sabbaghan, M. Alidoust, Z. Hossaini, Comb Chem High T
Scr 2011, 14, 824.
[42] P. Meena, V. Nemaysh, M. Khatri, A. Manral, P. M. Luthra, M.
[20] S. Y. Li, X. B. Wang, S. S. Xie, N. Jiang, K. D. G. Wang, H. Q.
Tiwari, Bioorg. Med. Chem. 2015, 23, 1135.
Yao, H. B. Sun, L. Y. Kong, Eur. J. Med. Chem. 2013, 69, 632.
[43] P. Camps, X. Formosa, C. Galdeano, T. Gomez, D. Munoz‐
Torrero, M. Scarpellini, F. J. Luque, J. Med. Chem. 2008, 51, 3588.
[21] B. C. Kim, S. H. Lee, M. Jang, M. Y. Shon, J. H. Park, Bull.
Korean Chem Soc 2013, 34(11), 3322.
[44] G. L. Ellman, K. D. Courtney, V. Andres, R. M. Feather‐Stone,
Biochem. Pharmacol. 1961, 7, 88.
[22] P. Szymanski, A. Janik, E. Zurek, E. Mikiciuk‐Olasik,
Pharmazie 2011, 66, 399.
[45] H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat,
[23] D. Kumar, S. K. Gupta, A. Ganeshpurkar, G. Gutti, S.
Krishnamurthy, G. Modi, S. K. Singh, Eur. J. Med. Chem.
2018, 150, 87.
H. Weissig, P. E. Bourne, Nucleic Acids Res 2000, 28(1), 235.
[46] J. Cheung, M. J. Rudolph, F. Burshteyn, M. S. Cassidy, E. N.
Gary, J. Love, M. C. Franklin, J. J. Height, J. Med. Chem.
2012, 55(22), 10282.
[24] A. Zhou, H. Wu, J. Pan, X. Wang, J. Li, Z. Wu, A. Hui, Mole-
cules 2015, 20, 1304.
[25] A. R. Foroumadi, A. Mohammadi‐Farani, M. Garmsiri Mahvar,
A. R. Aliabadi, Iran J Basic Med Sci 2013, 16, 1049.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[26] B. Pouramiri, S. Moghimi, M. Mahdavi, H. Nadri, A. Moradi, E.
Tavakolinejad‐Kermani, L. Firoozpour, A. Asadipour, A.
Foroumadi, Chem. Biol. Drug Des. 2017, 89, 783.
[27] S. Hamulakova, L. Janovec, M. Hrabinova, P. Kristian, K.
Kuca, M. Banasova, J. Imrich, Eur. J. Med. Chem. 2012,
55, 23.
[28] A. Wieckowska, M. Kołaczkowski, A. Bucki, J. Godyn, M.
Marcinkowska, K. Wieckowski, P. Zareba, A. Siwek, G. Kazek,
M. Głuch‐Lutwin, P. Mierzejewski, P. Bienkowski, H. Sienkie-
wicz‐Jarosz, D. Knez, T. Wichur, S. Gobec, B. Malawska, Eur.
J. Med. Chem. 2016, 9(124), 63.
How to cite this article: Demirayak Ş, Şahin Z,
Ertaş M, et al. Novel thiazole‐piperazine derivatives
as potential cholinesterase inhibitors. J Heterocyclic
Chem. 2019;1–17. https://doi.org/10.1002/jhet.3734