Synthesis of Some New Thiazole Derivatives and Their Biological Activity Evaluation

Article abstract of DOI:10.1155/2015/464379

New 2-(4-arylpiperazine-1-yl)-N-[4-(2-(4-substituted phenyl)thiazol-4-yl)phenyl]acetamide derivatives were synthesized and evaluated for their antimicrobial and anticholinesterase activities. Acetylcholinesterase inhibitory activities of the compounds were found weak contrary to expectations. It is unlikely that antifungal activity of the compounds was found significant, especially against Candida parapsilosis.

Full text of DOI:10.1155/2015/464379

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2015, Article ID 464379, 7 pages
http://dx.doi.org/10.1155/2015/464379
Research Article
Synthesis of Some New Thiazole Derivatives and Their
Biological Activity Evaluation
Leyla YurttaG,1 Yusuf Özkay,1 Hülya Karaca Gençer,2 and Ulviye Acar1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey
2Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey
Correspondence should be addressed to Leyla Yurtta¸s; lyurttas@anadolu.edu.tr
Received 6 April 2015; Accepted 12 May 2015
Academic Editor: Filomena Conforti
Copyright © 2015 Leyla Yurtta¸s et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
New 2-(4-arylpiperazine-1-yl)-N-[4-(2-(4-substituted phenyl)thiazol-4-yl)phenyl]acetamide derivatives were synthesized and
evaluated for their antimicrobial and anticholinesterase activities. Acetylcholinesterase inhibitory activities of the compounds were
found weak contrary to expectations. It is unlikely that antifungal activity of the compounds was found significant, especially against
Candida parapsilosis.
1. Introduction
micrococcin P1 [4, 5]. iazole derivatives are associated
with a broad spectrum of biological properties, including
anticonvulsant, antimicrobial, antituberculous, bacteriostatic
activities, antiviral, antimalarial, anticancer, hypertension,
inflammation, schizophrenia, HIV infections, hypnotics and
more recently for the treatment of pain, as fibrinojen receptor
antagonists with antithrombotic activity, as new inhibitors
of bacterial DNA gyrase B [6–10]. iazole derivatives are
also found in application in the drug development for the
treatment of allergies [11].
Many currently notable drugs contain piperazine ring
and amide moiety as part of their molecular structure [12].
Piperazines are also among the most important building
blocks in today’s drug discovery and are found in biologically
active compounds across a number of different therapeutic
areas such as antifungal, antibacterial, antimalarial, and
antipsychotic activities [13].
In our previous study, cholinesterase activity of some
thiazole-piperazine derivatives was reported [14]. Prompted
from the data we have obtained before and the above
literature research, we synthesized a new series of thiazole-
piperazine derivatives and investigated their antimicrobial
and anticholinesterase activities so as to obtain new biolog-
ically active compounds.
e treatment of infectious diseases still remains a challeng-
ing task because of combination of factors including increas-
ing number of multidrug resistant, microbial pathogens and
emerging newer infectious diseases [1]. e therapeutic prob-
lem is a crucial part of hospitalized patients, immunosup-
pressed patients with AIDS, and those undergoing anticancer
therapy or organ transplants. In spite of a large number of
antibiotics and chemotherapeutics available for medical use,
the emerging resistance to old and antibiotics has created a
substantial need for novel classes of antimicrobial agents [2].
So, it is necessary to design new and effective molecules as
antimicrobial agents.
Small-ring heterocycles including nitrogen and sulfur
have been under investigation for a long time on account of
their synthetic diversity and therapeutic relevance. Among
the wide range of heterocycles explored to privileged candi-
dates in drug discovery, thiazoles have been identified to play
a necessary role in medical chemistry [3].
iazole ring is a structural fragment of natural com-
pounds such as thiamine (vitamin B1), thiamine pyrophos-
phate (TPP, a coenzyme important in respiration in the
Krebs cycle), epothilones, carboxylase, and the large fam-
ily of macrocyclic thiopeptide antibiotics, thiostrepton and

2
Journal of Chemistry
2. Experimental
calculated: (%) C 68.55, H 5.53, N 15.37; found: (%) C 68.62,
H 5.63, N 15.40. MS: ꢃꢄ/ 456 (M + 1).
2.1. Material. Melting points (∘C, uncorrected) of the syn-
thesized compounds were determined by using electrother-
mal melting point apparatus (Electrothermal, Essex, UK).
1H NMR spectra were recorded with a Bruker 500 MHz
digital FT-NMR spectrometer (Bruker Bioscience, Billerica,
MA, USA) and 13C NMR spectra were recorded with a
Bruker 125 MHz digital FT-NMR spectrometer in DMSO-
2.2.3. 2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-N-[4-(2-phenylthi-
azol-4-yl)phenyl]acetamide (6c). Yield 75–78 %, m.p. 210–
216∘C. IR (KBr) ]max (cm−1): 3253 (amide N-H), 3053 (aro-
matic C-H), 2987 (aliphatic C-H), 1674 (amide C=O), 1585–
1
1309 (C=C and C=N), 1228–979 (C-O and C-N). H-NMR
(500 MHz, DMSO-d6, ppm): ꢁ 2.59 (4H, t, ꢀ ꢂ = Hz, N-CH ),
2
d
solvent including TMS as an internal standard. Cou-
6
3.21 (2H, s, COCH ), 3.82 (4H, t, ꢀ ꢂ 4.= Hz, N-CH ), 6.62
2
2
pling constants (ꢀ) are reported as Hertz. IR spectra were
obtained in KBr pressed pellets via IR, Shimadzu 8400S
spectrophotometer (Shimadzu, Tokyo, Japan). Mass spectra
of fast atom bombardment (FAB) were obtained on a VG
Quattro mass spectrometer VG Quattro Mass spectrometer
(Fisons Instruments Vertriebs GmbH, Mainz, Germany). e
purities of compounds were checked by TLC on silica gel 60
(1H, t, ꢀ ꢂ 4.= Hz, Ar-H), 7.38 (2H, t, ꢀ ꢂ 7.= Hz, Ar-H),
7. 7 7 (2H, d, ꢀ ꢂ 8 Hz, Ar-H), 8.00 (2H, d, ꢀ ꢂ 8 Hz, Ar-H),
8.06–8.08 (4H, m, Ar-H), 8.35 (2H, d, ꢀ ꢂ 4.= Hz, Ar-H), 9.93
(1H, s, N-H). 13C-NMR (125 MHz, DMSO-d6, ppm): ꢁ 43.22,
52.48, 61.71, 110.08, 113.44, 119.57, 126.17, 126.52, 129.20, 129.24,
130.31, 133.02, 138.62, 154.97, 157.89, 161.20, 166.80, 168.28. For
C H N OS calculated: (%) C 65.77, H 5.30, N 18.41; found:
25 24
6
F
(Merck KGaA, Darmstadt, Germany). Starting materials
254
(%) C 65.67, H 5.33, N 18.36. MS: ꢃꢄ/ 457 (M + 1).
were either commercially available or synthesized according
to the methods given in the literature.
2.2.4. 2-[4-(2-Furoyl)piperazin-1-yl]-N-[4-(2-phenylthiazol-
4-yl)phenyl]acetamide (6d). Yield 70–72%, m.p. 144-145∘C.
IR (KBr) ]max (cm−1): 3215 (amide N-H), 3034 (aromatic C-
H), 2975 (aliphatic C-H), 1676 (amide C=O), 1625–1308 (C=C
2.2. General Procedure for the Synthesis of 2-(4-Arylpipera-
zine-1-yl)-N-[4-(2-(4-substituted phenyl)thiazol-4-yl)phe-
nyl]acetamide Derivatives (6a–6p). A mixture of compound
2-chloro-N-[4-(2-(4-substituted phenyl)-4-thiazolyl)phe-
nyl]acetamide 5 (1.5 mmol), appropriate piperazine deriva-
1
and C=N), 1263–978 (C-O and C-N). H-NMR (500 MHz,
DMSO-d6, ppm): ꢁ 2.62 (4H, t, ꢀ ꢂ 4.= Hz, N-CH ), 3.22 (2H,
2
s, COCH ), 3.75 (4H, t, ꢀ ꢂ 4.= Hz, N-CH ), 6.62-6.63 (1H, m,
tive (1.8 mmol) and K CO (1.5 mmol) in acetone, was
2
2
2
3
Ar-H), 7.03 (1H, d, ꢀ ꢂ 3.= Hz, Ar-H), 7.08 (2H, d, ꢀ ꢂ 8.= Hz,
Ar-H), 7.79 (3H, m, Ar-H), 7.87 (1H, s, Ar-H), 7.97–8.05 (5H,
m, Ar-H), 9.93 (1H, s, N-H). For C H N O S calculated:
refluxed for 2 h. Afer cooling, the solvent was evaporated
until dryness. e residue was treated with 25 mL of water.
Solidified product was filtered, washed with water, and
recrystallized from ethanol to give the compounds 6a–6p.
26 24
4
3
(%) C 66.08, H 5.12, N 11.86; found: (%) C 68.13, H 5.17, N
11.93. MS: ꢃꢄ/ 473 (M + 1).
2.2.1. 2-(4-Benzylpiperazin-1-yl)-N-[4-(2-phenylthiazol-4-yl)phe-
nyl]acetamide (6a). Yield 70–76%, m.p. 171–174∘C. IR (KBr)
2.2.5. 2-(4-Benzylpiperazin-1-yl)-N-[4-(2-(4-methoxyphen-
yl)thiazol-4-yl)phenyl]acetamide (6e). Yield 80–82%, m.p.
171–175∘C. IR (KBr) ]max (cm−1): 3302 (amide N-H), 3041
(aromatic C-H), 2952 (aliphatic C-H), 1653 (amide C=O),
]
(cm−1): 3281 (amide N-H), 3005 (aromatic C-H),
2m91a2x (aliphatic C-H), 1676 (amide C=O), 1512–1306 (C=C
1
and C=N), 1190–978 (C-O and C-N). H-NMR (125 MHz,
1
1587–1305 (C=C and C=N), 1244–978 (C-O and C-N). H-
DMSO-d6, ppm): ꢁ 2.45 (4H, t, ꢀ ꢂ = Hz, N-CH ), 2.55 (4H,
2
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.46 (4H, t, ꢀ ꢂ = Hz,
N-CH ), 2.56 (4H, t, ꢀ ꢂ 4.= Hz, N-CH ), 3.14 (2H, s,
t, ꢀ ꢂ 4.= Hz, N-CH ), 3.15 (2H, s, COCH ), 3.49 (2H, s, C-
2
2
CH ), 7.25–7.35 (5H, m, Ar-H), 7.51–7.56 (3H, m, Ar-H), 7.75
2
2
2
COCH ), 3.48 (2H, s, C-CH ), 3.83 (3H, s, OCH ), 7.08 (2H,
(2H, d, ꢀ ꢂ = Hz, Ar-H), 7.99–8.04 (4H, m, Ar-H), 8.09 (1H,
s, Ar-H), 9.82 (1H, s, N-H). 13C-NMR (500 MHz, DMSO-d6,
ppm): ꢁ 52.45, 52.80, 61.81, 62.04, 113.44, 119.49, 126.17, 126.53,
126.87, 128.14, 128.79, 129.17, 129.25, 130.32, 133.01, 138.22,
138.58, 154.96, 166.81, 168.35. For C H N OS calculated: (%)
2
2
3
d, ꢀ ꢂ = Hz, Ar-H), 7.30–7.32 (5H, m, Ar-H), 7.72 (2H, d,
ꢀ ꢂ 8.= Hz, Ar-H), 7.95–7.98 (5H, m, Ar-H), 9.82 (1H, s, N-
H). For C H N O S calculated: (%) C 69.85, H 6.06, N 11.24;
29 30
4
2
found: (%) C 69.92, H 6.14, N 11.31. MS: ꢃꢄ/ 499 (M + 1).
28 28
4
C 71.76, H 6.02, N 11.96; found: (%) C 71.71, H 6.10, N 11.91.
MS: ꢃꢄ/ 469 (M + 1).
2.2.6. 2-[4-(Pyridin-2-yl)piperazin-1-yl]-N-[4-(2-(4-methoxy-
phenyl)thiazol-4-yl)phenyl]acetamide (6f). Yield 78–80%,
m.p. 153-154∘C. IR (KBr) ]max (cm−1): 3317 (amide N-H),
3014 (aromatic C-H), 2941 (aliphatic C-H), 1656 (amide
C=O), 1589–1303 (C=C and C=N), 1247–978 (C-O and
C-N) .1H-NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.63 (4H,
t, ꢀ ꢂ = Hz, N-CH ), 3.21 (2H, s, COCH ), 3.56 (4H, t,
2.2.2. 2-[4-(Pyridin-2-yl)piperazin-1-yl]-N-[4-(2-phenylthia-
zol-4-yl)phenyl]acetamide (6b). Yield 70–76 %, m.p. 173–
176∘C. IR (KBr) ]max (cm−1): 3319 (amide N-H), 3091 (aro-
matic C-H), 2912 (aliphatic C-H), 1676 (amide C=O), 1524–
1
1309 (C=C and C=N), 1246–978 (C-O and C-N). H-NMR
2
2
(500 MHz, DMSO-d6, ppm): ꢁ 2.61 (4H, t, ꢀ ꢂ = Hz, N-CH ),
ꢀ
ꢂ
4.= Hz, N-CH ), 3.84 (3H, s, OCH ), 6.63 (1H, t,
2
2
3
3.23 (2H, s, COCH ), 3.76 (4H, brs, N-CH ), 6.63-6.64 (1H,
ꢀ ꢂ = Hz, Ar-H), 6.83 (1H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.08 (2H,
2
2
m, Ar-H), 6.99-7.00 (1H, m, Ar-H), 7.52–7.56 (4H, m, Ar-
d, ꢀ ꢂ = Hz, Ar-H), 7.52 (1H, t, ꢀ ꢂ = Hz, Ar-H), 7.76 (2H,
H), 7.76 (2H, d, ꢀ ꢂ = Hz, Ar-H), 7.84–7.85 (1H, m, Ar-H),
d, ꢀ ꢂ 8.= Hz, Ar-H), 7.95–7.99 (5H, m, Ar-H), 8.11 (1H,
8.00–8.09 (5H, m, Ar-H), 9.92 (1H, s, N-H). For C H N OS
d, ꢀ ꢂ = Hz, Ar-H), 9.90 (1H, s, N-H). For C H N O S
26 25
5
27 27
5
2

Journal of Chemistry
3
calculated: (%) C 66.78, H 5.60, N 14.42; found: (%) C 66.85,
ꢀ ꢂ 8.= Hz, Ar-H), 8.06 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 8.12 (2H,
H 5.68, N 14.50. MS: ꢃꢄ/ 486 (M + 1).
s, Ar-H), 9.92 (1H, s, N-H). 13C-NMR (125 MHz, DMSO-d6,
ppm): ꢁ 45.05, 52.98, 62.25, 107.58, 113.45, 114.44, 120.06,
127.05, 128.37, 129.53, 129.81, 132.34, 135.33, 137.98, 139.19,
148.04, 155.60, 159.51, 165.95, 168.80. For C H ClN OS
2.2.7. 2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-N-[4-(2-(4-methox-
yphenyl)thiazol-4-yl)phenyl]acetamide (6g). Yield 78–80%,
m.p. 160–163∘C. IR (KBr) ]max (cm−1): 3315 (amide N-H),
3038 (aromatic C-H), 2951 (aliphatic C-H), 1676 (amide
C=O), 1596–1307 (C=C and C=N), 1261–978 (C-O and
26 24
5
calculated: (%) C 63.73, H 4.94, N 14.29; found: (%) C 63.81,
H 4.98, N 14.32. MS: ꢃꢄ/ 489.5 (M + 1).
1
2.2.11. 2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-N-[4-(2-(4-chloro-
phenyl)thiazol-4-yl)phenyl]acetamide (6k). Yield 70–74%,
m.p. 196–198∘C. IR (KBr) ]max (cm−1): 3290 (amide N-H),
C-N). H-NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.59 (4H, t,
ꢀ ꢂ = Hz, N-CH ), 3.21 (2H, s, COCH ), 3.81 (4H, t, ꢀ ꢂ = Hz,
2
2
N-CH ), 3.83 (3H, s, OCH ), 6.63 (1H, t, ꢀ ꢂ 4.= Hz, Ar-H),
2
3
7. 08 (2H, d, ꢀ ꢂ = Hz, Ar-H), 7.76 (2H, d, ꢀ ꢂ = Hz, Ar-H),
7.95-7.96 (5H, m, Ar-H), 8.36 (2H, d, ꢀ ꢂ = Hz, Ar-H), 9.91
(1H, s, N-H). For C H N O S calculated: (%) C 64.18, H
3022 (aromatic C-H), 2931 (aliphatic C-H), 1670 (amide
C=O), 1585–1309 (C=C and C=N), 1256–979 (C-O and
1
C-N). H-NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.59 (4H,
26 26
6
2
5.39, N 17.27; found: (%) C 64.25, H 5.44, N 17.32. MS: ꢃꢄ/
t, ꢀ ꢂ 4.= Hz, N-CH ), 3.21 (2H, s, COCH ), 3.81 (4H, t,
2
2
487 (M + 1).
ꢀ ꢂ 4.= Hz, N-CH ), 6.62 (1H, t, ꢀ ꢂ = Hz, Ar-H), 7.59 (2H, d,
2
ꢀ ꢂ 8.= Hz, Ar-H), 7.77 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 8.02 (2H,
d, ꢀ ꢂ 8.= Hz, Ar-H), 8.05 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 8.12 (1H,
s, Ar-H), 8.35 (2H, d, ꢀ ꢂ 4.= Hz, Ar-H), 9.92 (1H, s, N-H).
For C H ClN OS calculated: (%) C 61.15, H 4.72, N 17.12;
2.2.8. 2-[4-(2-Furoyl)piperazin-1-yl]-N-[4-(2-(4-methoxyphen-
yl)thiazol-4-yl)phenyl]acetamide (6h). Yield 74–76%, m.p.
136–138∘C. IR (KBr) ]max (cm−1): 3279 (amide N-H), 3063
(aromatic C-H), 2927 (aliphatic C-H), 1658 (amide C=O),
25 23
6
found: (%) C 61.23, H 4.80, N 17.16. MS: ꢃꢄ/ 490.5 (M + 1).
1
1604–1306 (C=C and C=N), 1236–978 (C-O and C-N). H-
2.2.12. 2-[4-(2-Furoyl)piperazin-1-yl]-N-[4-(2-(4-chlorophen-
yl)thiazol-4-yl)phenyl]acetamide (6l). Yield 72–75%, m.p.
139–141∘C. IR (KBr) ]max (cm−1): 3317 (amide N-H), 3042
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.61 (4H, t, ꢀ ꢂ = Hz,
N-CH ), 3.24 (2H, s, COCH ), 3.76 (4H, t, ꢀ ꢂ = Hz, N-CH ),
2
2
2
3.87 (3H, s, OCH ), 6.63-6.64 (1H, m, Ar-H), 7.01 (1H, d,
3
ꢀ ꢂ 3.= Hz, Ar-H), 7.08 (2H, d, ꢀ ꢂ = Hz, Ar-H), 7.77 (2H,
(aromatic C-H), 2962 (aliphatic C-H), 1676 (amide C=O),
1
d, ꢀ ꢂ 8.= Hz, Ar-H), 7.85 (1H, s, Ar-H), 7.96–8.01 (5H, m,
1625–1305 (C=C and C=N), 1261–978 (C-O and C-N). H-
Ar-H), 9.94 (1H, s, N-H). 13C-NMR (125 MHz, DMSO-d6,
ppm): ꢁ 53.18, 53.55, 55.87, 61.82, 111.76, 112.85, 115.06, 115.40,
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.60 (4H, t, ꢀ ꢂ = Hz,
N-CH ), 3.34 (2H, s, COCH ), 3.74 (4H, t, ꢀ ꢂ = Hz, N-CH ),
2
2
2
115.99, 120.08, 126.37, 126.96, 128.25, 129.84, 139.00, 145.15,
147.48, 155.17, 158.79, 161.41, 167.21, 168.66. For C H N O S
6.62-6.63 (1H, m, Ar-H), 7.01 (1H, d, ꢀ ꢂ 3.= Hz, Ar-H), 7.59
(2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.76–7.83 (2H, m, Ar-H), 7.95–8.15
(6H, s, Ar-H), 9.96 (1H, s, N-H). For C H ClN O S
27 26
4
4
calculated: (%) C 64.52, H 5.21, N 11.15; found: (%) C 64.46,
26 23
4
3
H 5.29, N 11.24. MS: ꢃꢄ/ 503 (M + 1).
calculated: (%) C 61.59, H 4.57, N 11.05; found: (%) C 61.65, H
4.63, N 11.12. MS: ꢃꢄ/ 506.5 (M + 1).
2.2.9. 2-(4-Benzylpiperazin-1-yl)-N-[4-(2-(4-chlorophenyl)thia-
zol-4-yl)phenyl]acetamide (6i). Yield 70–73%, m.p. 171–
173∘C. IR (KBr) ]max (cm−1): 3288 (amide N-H), 3013 (aro-
matic C-H), 2966 (aliphatic C-H), 1664 (amide C=O), 1591–
2.2.13. 2-(4-Benzylpiperazin-1-yl)-N-[4-(2-(4-florophenyl)thia-
zol-4-yl)phenyl]acetamide (6m). Yield 69–73%, m.p. 171-
172∘C. IR (KBr) ]max (cm−1): 3317 (amide N-H), 3015
(aromatic C-H), 2970 (aliphatic C-H), 1678 (amide C=O),
1
1315 (C=C and C=N), 1234–978 (C-O and C-N). H-NMR
1
(500 MHz, DMSO-d6, ppm): ꢁ 2.50 (4H, brs, N-CH ), 3.14
1502–1306 (C=C and C=N), 1234–978 (C-O and C-N). H-
2
(2H, s, COCH ), 3.48 (2H, s, C-CH ), 7.08 (2H, d, ꢀ ꢂ = Hz,
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.45 (4H, t, ꢀ ꢂ = Hz,
2
2
Ar-H), 7.29–7.32 (5H, m, Ar-H), 7.60 (2H, d, ꢀ ꢂ 8.= Hz,
Ar-H), 7.75 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.97 (1H, d, ꢀ ꢂ 8.= Hz,
Ar-H), 8.04 (1H, d, ꢀ ꢂ 8.= Hz, Ar-H), 8.11 (1H, s, Ar-H), 9.82
(1H, s, N-H). For C H ClN OS calculated: (%) C 66.85, H
N-CH ), 2.54 (4H, t, ꢀ ꢂ 4.= Hz, N-CH ), 3.14 (2H, s,
2
2
COCH ), 3.48 (2H, s, C-CH ), 7.24–7.39 (7H, m, Ar-H),
2
2
7. 73 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.99 (2H, d, ꢀ ꢂ 8.= Hz,
Ar-H), 8.06–8.11 (3H, m, Ar-H), 9.85 (1H, s, N-H). For
C H FN OS calculated: (%) C 69.11, H 5.59, N 11.51; found:
28 27
4
5.41, N 11.14; found: (%) C 66.94, H 5.47, N 11.20. MS: ꢃꢄ/
28 27
4
502.5 (M + 1).
(%) C 69.18, H 5.65, N 11.63. MS: ꢃꢄ/ 487 (M + 1).
2.2.10. 2-[4-(Pyridin-2-yl)piperazin-1-yl]-N-[4-(2-(4-chloro-
phenyl)thiazol-4-yl)phenyl]acetamide (6j). Yield 73–76%,
m.p. 220–225∘C. IR (KBr) ]max (cm−1): 3300 (amide N-H),
3002 (aromatic C-H), 2924 (aliphatic C-H), 1666 (amide
C=O), 1591–1305 (C=C and C=N), 1244–1018 (C-O and
2.2.14. 2-[4-(Pyridin-2-yl)piperazin-1-yl]-N-[4-(2-(4-florophen-
yl)thiazol-4-yl)phenyl]acetamide (6n). Yield 70–74%, m.p.
163-164∘C. IR (KBr) ]max (cm−1): 3317 (amide N-H), 3023
(aromatic C-H), 2987 (aliphatic C-H), 1678 (amide C=O),
1
1591–1305 (C=C and C=N), 1247–978 (C-O and C-N). H-
ꢀ ꢂ 8.=1Hz, Ar-H), 7.53 (1H, t, ꢀ ꢂ 4.= Hz, Ar-H), 7.60 (2H, d,
ꢀ ꢂ 4.= Hz, N-CH ), 6.63–6.65 (1H, m, Ar-H), 6.83 (1H, d,
C-N). H-NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.63 (4H,
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.63 (4H, t, ꢀ ꢂ 4.= Hz,
N-CH ), 3.22 (2H, s, COCH ), 3.56 (4H, t, ꢀ ꢂ = Hz, N-CH ),
t, ꢀ ꢂ 4.= Hz, N-CH ), 3.22 (2H, s, COCH ), 3.56 (4H, t,
2
2
2
2
2
6.62–6.65 (1H, m, Ar-H), 6.83 (1H, d, ꢀ ꢂ 8.= Hz, Ar-H),
7.35–7.39 (2H, m, Ar-H), 7.53 (1H, t, ꢀ ꢂ 4.= Hz, Ar-H),
7. 76 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.99 (2H, d, ꢀ ꢂ 8.= Hz,
2
ꢀ ꢂ 8.= Hz, Ar-H), 7.78 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 8.03 (2H, d,

4
Journal of Chemistry
Ar-H), 8.06–8.12 (4H, m, Ar-H), 9.91 (1H, s, N-H). For
C H FN OS calculated: (%) C 65.94, H 5.11, N 14.79;
was started by adding 5,5-dithio-bis(2-nitrobenzoic)acid,
DTNB (50 ꢅL), and ATC (10 ꢅL) to the enzyme-inhibitor
mixture. Spectrophotometric measurements were performed
on a 1700 Shimadzu UV-1700 UV–Vis spectrophotometer
at 412 nm. Donepezil hydrochloride was used as a positive
control and all processes were assayed in triplicate [17].
26 24
5
found: (%) C 65.86, H 5.18, N 14.65. MS: ꢃꢄ/ 474 (M + 1).
2.2.15. 2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-N-[4-(2-(4-floro-
phenyl)thiazol-4-yl)phenyl]acetamide (6o). Yield 70–74%,
m.p. 187-188∘C. IR (KBr) ]max (cm−1): 3317 (amide N-H),
3036 (aromatic C-H), 2954 (aliphatic C-H), 1677 (amide
C=O), 1583-1307 (C=C and C=N), 1257–978 (C-O and
3. Results and Discussion
1
C-N). H-NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.61 (4H,
e final compounds (6a–6n) were synthesized by a five-step
(Figure 1), convenient synthetic routeaccording to the litera-
turereported before [14]. Different 4-substituted thiobenzam-
t, ꢀ ꢂ 3 Hz, N-CH ), 3.22 (2H, s, COCH ), 3.83 (4H, t,
2
2
ꢀ ꢂ 4.= Hz, N-CH ), 6.63 (1H, t, ꢀ ꢂ 4.= Hz, Ar-H), 7.50–7.56
2
(3H, m, Ar-H), 7.78 (2H, d, ꢀ ꢂ = Hz, Ar-H), 7.98–8.06 (4H,
m, Ar-H), 8.09 (1H, s, Ar-H), 8.37 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H),
9.93 (1H, s, N-H). 13C-NMR (125 MHz, DMSO-d6, ppm): ꢁ
43.71, 52.97, 62.19, 110.59, 114.03, 116.68, 116.85, 120.07, 127.02,
128.95, 129.02, 129.62, 130.19, 139.14, 155.44, 158.40, 161.70,
162.74, 166.13, 168.80. For C H FN OS calculated: (%) C
ides (H, OCH , Cl, F) were used as starting materials. ey
3
have reacted with N-[4-(2-bromoacetyl)phenyl]acetamide to
obtain thiazole compounds (3). Afer deacetylation of these
intermediates, 2-chloro-N-[4-(2-(4-substituted phenyl)-4-
thiazolyl)phenyl]acetamides (5) were gained with chloro-
acetyl chloride. Finally, 2-[4-(aryl)piperazin-1-yl]-N-[4-(2-
(4-substituted phenyl)thiazol-4-yl)phenyl]acetamide deriva-
tives (6a–6n) were afforded by the reaction of compound
5 and corresponding piperazine derivatives. Synthetic pro-
tocol for the compounds is outlined in Figure 1. Structure
elucidations of the final compounds were performed with IR,
1H NMR, and MS spectroscopic methods. In the IR spectra
of the final compounds, characteristic stretching bands were
observed at 3253–3319 cm−1 for N-H bond, 1303–1625 cm−1
for C=C and C=N bonds, 978–1263 cm−1 for C-N and C-
O bonds, and 1653–1678 cm−1 for C=O bond, respectively.
In the NMR spectra of the compounds 6a–6n, protons
25 23
6
63.27, H 4.89, N 17.71; found: (%) C 63.19, H 4.94, N 17.66.
MS: ꢃꢄ/ 475 (M + 1).
2.2.16. 2-[4-(2-Furoyl)piperazin-1-yl]-N-[4-(2-(4-florophen-
yl)thiazol-4-yl)phenyl]acetamide (6p). Yield 74–78%, m.p.
146–148∘C. IR (KBr) ]max (cm−1): 3319 (amide N-H), 3031
(aromatic C-H), 2927 (aliphatic C-H), 1674 (amide C=O),
1
1589–1307 (C=C and C=N), 1232–978 (C-O and C-N). H-
NMR (500 MHz, DMSO-d6, ppm): ꢁ 2.60 (4H, t, ꢀ ꢂ = Hz,
N-CH ), 3.34 (2H, s, COCH ), 3.74 (4H, t, ꢀ ꢂ = Hz, N-
2
2
CH ), 6.61–6.62 (1H, m, Ar-H), 7.03 (1H, d, ꢀ ꢂ 3.= Hz, Ar-
2
H), 7.61 (2H, d, ꢀ ꢂ 8.= Hz, Ar-H), 7.75–7.80 (2H, m, Ar-H),
of piperazine CH were observed at about 2.50–2.63 ppm
2
7.98–8.16 (6H, s, Ar-H), 9.92 (1H, s, N-H). For C H FN O S
26 23
4
3
and 3.56–3.82 ppm ranges as triplets or broad singlets. e
protons bonded to carbonyl were assigned at 3.14–3.34 ppm
and heterocyclic rings and chloro/fluoro substituted phenyl
rings were given peaks near to downfield region. Aromatic
protons resonated at a large area between 6.62 and 8.37 ppm
and amide protons were determined at about 9.82–9.96 ppm,
as singlet peaks. Regarding to the mass spectra, all final
compounds exhibited similar behavior in their fragmentation
pattern, showing the molecular ion peak.
calculated: (%) C 63.66, H 4.73, N 11.42; found: (%) C 63.72,
H 4.81, N 11.46. MS: ꢃꢄ/ 491 (M + 1).
2.3. Antimicrobial Activity. e study was designed to com-
pare MICs obtained by the CLSI reference M7–A7 broth
microdilution method [15]. MIC readings were performed
twice for each chemical agent. Final products were tested
for their in vitro growth inhibitory activity against human
pathogenic microorganisms as Gram-positive bacteria, Ente-
rococcus faecalis (ATCC 29212) and as Gram-negative bac-
teria, Pseudomonas aeruginosa (ATCC 27853), Klebsiella
pneumoniae (ATCC 700603), Escherichia coli (ATCC 35218),
and E. coli (ATCC 25922) and yeast as Candida albicans
(90028), Candida glabrata (ATCC 90030), Candida krusei
(ATCC 6258), and Candida parapsilosis (ATCC 7330). Chlo-
ramphenicol and ketoconazole were used as control drugs.
All final compounds were screened for their acetylcholin-
esterase inhibitory activities and antimicrobial activities. Ini-
tially, 2-(4-arylpiperazine-1-yl)-N-[4-(2-(4-substituted phen-
yl)thiazol-4-yl)phenyl]acetamide derivatives (6a–6p) have
been designed and synthesizedfor investigation of their
potential anticholinesterase activity. According to our pre-
vious study [14], 2-(4-substituted piperazine-1-yl)-N-[4-(2-
methylthiazol-4-yl)phenyl]acetamide derivatives based on
the structure of AChE inhibitors donepezil, BYYT-25 and
acotiamide were investigated and compounds with pyridyl,
benzyl, and furoyl piperazine substituents were observed with
high anticholinesterase activity. is study was planned to
improve new anticholinesterase compounds using the same
skeleton, but with different substitutions. However, in con-
trast to expectations the synthesized compounds (6a–6n) did
not show any noticeable anticholinesterase activity (Table 2).
It is evident that phenyl/4-substituted phenyl moiety at the
second position of thiazole ring has eliminated activity. Only
2.4. Anticholinesterase Activity. e inhibition of acetyl-
cholinesterase enzyme, AChE (E.C.3.1.1.7 from Electric Eel,
500 units), was determined spectrophotometrically using
acetylthiocholine (ATC) as substrate according to the mod-
ified method of Ellman’s test [16]. Enzyme solutions were
prepared in gelatin solution (1%), at a concentration of
2.5 units/mL. AChE and compound solution (50 ꢅL) which
is prepared in 2% dimethyl sulfoxide at 0.1 and 1 mM
concentrations were added to 3.0 mL phosphate buffer (pH
8
0.1) and incubated at 25∘C for 5 min. e reaction

Journal of Chemistry
5
H
N
O
O
ii
i
NH2
O
1
S
H
N
O
iv
NH
O
iii
N
Br
O
2
3
R
R = H, OCH3, Cl, F
S
S
v
Cl
NH
NH2
vi
N
N
O
4
5
R
Rꢀ
N
Rꢀ = benzyl, 2-pyridyl,
2-pyrimidinyl, 2-furoyl
S
NH
N
N
O
R
6a–6p
Figure 1: Synthesis of the compounds(6a–6p). Reagents are (i) acetyl chloride, TEA, THF, 0–5∘C; (ii) Br , AcOH; (iii) thiobenzamide
2
derivatives, EtOH, r.t.; (iv) 10 % HCl, EtOH, reflux; (v) chloroacetyl chloride, TEA, THF, r.t.; and (vi) appropriate 4-substituted piperazine
derivatives, K CO , acetone, reflux.
2
3
two compounds 6j and 6m have exhibited inhibition over
50% at the highest tested dose (1 mM).
Among all Candida species, the most sensitive Candida was
established as C. parapsilosis. Compounds6b, 6c, and6h were
found twice as active as standard drug, whereas compounds
6a, 6d, 6e, 6f, 6m, and 6n showed equipotent activity. All the
other compounds displayed half the potency of ketoconazole
against the same microorganism.
e structures of the tested compounds were based on
a thiazole ring which has phenyl moiety at second and
fourth positions of it. e substitutions of the phenyl ring at
second position are methoxy, chloro and fluoro groups. e
difference at the fourth position of the thiazole ring is pyridyl,
pyrimidinyl benzyl, and furoyl piperazine moieties bonded
to phenyl ring with an amide linker. 2-Furoyl piperazine
substitution has attracted attention for its antibacterial activ-
ity. In antifungal activity evaluation, nonsubstituted phenyl
group and different substituted piperazine substitutions were
observed with significant activity according to Candida
species.
Whereupon considering many studies on thiazole deriva-
tives biological profile, we tend to screen antimicrobial
activity of the synthesized 2,4-disubstituted thiazole com-
pounds. Sixteen new compounds were tested for their
antibacterial and antifungal activities. e antifungal activ-
ity of the compounds was found to be higher than their
antimicrobial activities (Table 1). Compounds 6c and 6d
showed higher activity than the other compounds against
E. faecalis which is a Gram-positive bacterium. Among the
tested Gram-negative bacteria, compounds 6c–6f, 6i and 6j
exhibited the highest activity against K. pneumonia with a
MIC value of 100 ꢅg/mL which is two-fold standard drug’s
MIC value. Compound 6l showed equipotent activity to
standard drug againstanother Gram-negative bacterium P.
aeruginosa. Against two tested E. coli species (ATCC 35218
and ATCC 25922), only compounds 6d and 6m displayed
moderate antibacterial activity compared with standard drug
chloramphenicol. As for the antifungal activity, compounds
showed higher activities against four tested Candida species.
Compounds 6a, 6b, 6i, and 6m exhibited same efficiency
with ketoconazole against C. albicans and also compound
6f towards C. glabrata. Against C. krusei, the MIC value
was found as 50 ꢅg/mL for compound 6a which was very
high according to ketoconazole’s MIC value (3.13 ꢅg/mL).
4. Conclusion
Sixteen new 2-(4-substituted phenyl)-4-(acetamidophen-
yl)thiazole including compounds were synthesized. All final
compounds were screened for their antibacterial, antifungal,
and anticholinesterase activities. None of the compounds
showed prominent anticholinesterase activity. Antifungal

6
Journal of Chemistry
Table 1: Antimicrobial activity of the compounds 6a–6p (MIC,
Conflict of Interests
ꢅg/mL).
e authors report no conflict of interests.
Comp.
6a
A
B
C
D
E
F
G
100
100 100
H
50
I
100
50
200 200 200 200 200 50
200 200 200 200 200 50
Acknowledgments
6b
6c
6d
6e
6f
6g
6h
6i
100 100 200 200 200 200 100 200 50
100 100 200 200 100 200 100 100 100
200 100 200 200 400 200 100 100 100
e study was supported by the Anadolu University Scientific
Research Project, Eski¸sehir, Turkey (Project no. 1505S407).
e authors present their thanks to Anadolu University
Medicinal Plants, Drugs and Scientific Research Center
200 100 100 200 200 100
200 100 100 200 200 100 100 100 200
200 200 200 400 200 200 100 100 50
200 100 200 200 400 50 100 100 200
50
100 100
¨ ˙
(AUBIBAM) for NMR analyses. e assistance of the staff is
gratefully appreciated.
6j
6k
6l
6m
6n
6o
6p
Ref. 1
Ref. 2
200 100 200 200 400 100 200 200 200
200 200 100 200 400 100 200 200 200
200 200 50 200 200 100 200 200 200
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Compounds
IC50 (mM)
1 mM
3.45 5.10
7. 19 8.45
—
0.1 mM
—
—
—
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6k
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6o
6p
Donepezil
10.16 10.12
2.86 2.15
2.03 3.21
7. 28 4.69
8.63 3.25
57.04 10.65
37.09 5.16
29.59 11.23
58.79 5.61
—
—
—
—
—
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98.24 1.87
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ND: Not determined. ꢀ
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pared with ketoconazole against C. parapsilosis.

Journal of Chemistry
7
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