Synthesis and antimicrobial activity of some thiazolyl-pyrazoline derivatives

Article abstract of DOI:10.1080/10426500601047529

Some 1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (TP 1-28) were synthesized by reacting substituted 3-(2-thienyl)-5-aryl-1- thiocarbamoyl-2-pyrazolines (P 1-7) with phenacyl bromides in ethanol. Structures of the synthesized compounds were confirmed by elemental analyses and IR, 1H-NMR and MS-FAB+ spectral data. Their antimicrobial activities against Escherichia coli (NRRL B-3704), Staphylococcus aureus (NRLL B-767), Salmonella typhimurium (NRRL B-4420), Bacillus cereus (NRRL B-3711), Listeria monocytogenes (Ankara University, Faculty of Veterinary, Ankara, Turkey), Aeromonas hydrophila (Ankara University, Faculty of Veterinary, Ankara, Turkey), Candida albicans, and Candida glabrata (isolates obtained from Osmangazi University, Faculty of Medicine, Eskisehir Turkey) were investigated. A significant level of activity was illustrated. Copyright Taylor & Francis Group, LLC.

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Synthesis and Antimicrobial
Activity of Some Thiazolyl-
Pyrazoline Derivatives
Zafer Asım Kaplancıklı a , Gülhan Turan-Zitouni a
,
Ahmet Özdemir a , Gilbert Revial b & Kıymet Güven c
a Department of Pharmaceutical Chemistry, Anadolu
University, Eskişehir, Turkey
b Laboiratoire de Chimie Organique, CNRS (ESA
7084) ESPCI, Paris, France
c Department of Biology, Anadolu University,
Eskişehir, Turkey
Version of record first published: 24 Feb 2007.
To cite this article: Zafer Asım Kaplancıklı, Gülhan Turan-Zitouni, Ahmet Özdemir,
Gilbert Revial & Kıymet Güven (2007): Synthesis and Antimicrobial Activity of Some
Thiazolyl-Pyrazoline Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:4, 749-764
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Phosphorus, Sulfur, and Silicon, 182:749–764, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601047529
Synthesis and Antimicrobial Activity of Some
Thiazolyl-Pyrazoline Derivatives
Zafer Asım Kaplancıklı
¨
Gulhan Turan-Zitouni
¨
Ahmet Ozdemir
Department of Pharmaceutical Chemistry, Anadolu University,
Eskis¸ehir, Turkey
Gilbert Revial
Laboiratoire de Chimie Organique, CNRS (ESA 7084) ESPCI, Paris,
France
¨
Kıymet Guven
Department of Biology, Anadolu University, Eskis¸ehir, Turkey
Some 1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (TP 1–28)
were synthesized by reacting substituted 3-(2-thienyl)-5-aryl-1-thiocarbamoyl-2-
pyrazolines (P 1–7) with phenacyl bromides in ethanol. Structures of the synthe-
1
sized compounds were confirmed by elemental analyses and IR, H-NMR and MS-
FAB+ spectral data. Their antimicrobial activities against Escherichia coli (NRRL
B-3704), Staphylococcus aureus (NRLL B-767), Salmonella typhimurium (NRRL
B-4420), Bacillus cereus (NRRL B-3711), Listeria monocytogenes (Ankara Uni-
versity, Faculty of Veterinary, Ankara, Turkey), Aeromonas hydrophila (Ankara
University, Faculty of Veterinary, Ankara, Turkey), Candida albicans, and Can-
dida glabrata (isolates obtained from Osmangazi University, Faculty of Medicine,
Eskisehir Turkey) were investigated. A significant level of activity was illustrated.
Keywords 2-Pyrazoline; Antimicrobial activity; thiazole
INTRODUCTION
Antimicrobials are one of our most important weapons in fighting bac-
terial infections and have greatly benefited the health-related quality of
human life since their introduction. However, over the past few decades
Received June 26, 2006; accepted August 23, 2006.
Address correspondence to Zafer Asım Kaplancıklı, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Anadolu University, Eskis¸ehir 26470, Turkey. E-mail:
zakaplan@anadolu.edu.tr
749

750
Z. A. Kaplancıklı et al.
these health benefits have come under threat as many commonly used
antibiotics have become less and less effective against certain illnesses,
not only because many of them produce toxic reactions but also due to
the emergence of drug-resistant bacteria. It is essential to investigate
newer drugs with lesser resistance.1−4
At the same time, there has been significant increase in the fre-
quency of systematic fungal infection in humans. Patients undergoing
organ transplants, anticancer chemotherapy, or long treatment with
antimicrobial agents, and patients with AIDS, are immunosuppressed
and very susceptible to life-threatening systemic fungal infections like
Candidiasis, Cryptococcosis, and Aspergillosis. Reports are available on
the developments of resistance to currently available antifungal agents
in Candida species, as well as clinical failures in the treatment of fungal
infections.5−7
Development of resistance to existing drugs is a constant growing
phenomenon that has concerned researchers throughout the world and
now has reached alarming levels for certain infectious diseases. This
combined with recent decline in the development of new drugs to combat
them can be anticipated to lead to infectious diseases lacking ready
treatment regimens.8
There are two basic approaches to get a new drug for microbial infec-
tion treatment: (i) synthesis of analogues, modifications, or derivatives
of existing compounds for shortening and improving microbial infec-
tion treatment; and (ii) searching novel structures, which the pathogen
organism has never seen before, for treatment of multidrug-resistant
bacterial and fungal infections.9
To pursue this goal, our research efforts are directed to find new
chemical classes of active antimicrobial agents. The methods of inves-
tigation of structure-activity relationships enabled us to find some new
pharmacophores of the previously mentioned activity. Many studies
were carried out on heterocyclic systems bearing thiazole and pyra-
zoline groups as a pharmacophore.10−15
Electron-rich nitrogen heterocycles play an important role in diverse
biological activities. Introducing a pyrazolidinone16−17 ring in place of
the β-lactam ring (in penicillins and cephalosporins18) results in en-
hanced activity. A second nitrogen in the five-membered ring like pyra-
zoline also influences antibacterial or pharmacokinetic properties.19−25
On the other hand, sulfur and/or nitrogen heterocycles that possess
pharmaceutical activities widely occur in nature in the form of alka-
loids, vitamins, pigments, and as constituents of plant and animal cells.
Thiazoles especially exhibit antimicrobial,26−30 antituberculosis,31 anti-
HIV32 activities.

Thiazolyl-Pyrazoline Derivatives
751
Given our interest in the pharmaceutical properties of these hete-
rocyclic compounds, we planned to synthesize a system that combines
these two biolabile components, which are pyrazolines and thiazoles,
together to give a compact structure like title compounds.
RESULTS AND DISCUSSION
Chemistry
In the present work, 28 new compounds were synthesized (Scheme
1, Table I). First, chalcones (1-(2-thienyl)-3-aryl-2-propen-1-ones)
A 1–7 were synthesized by literature methods as described33
and treated with thiosemicarbazide to obtain 3-(2-thienyl)-5-aryl-1-
thiocarbamoyl-2-pyrazolines P 1–7 (Scheme 1).
SCHEME 1 Synthetic route of the title compounds.
This reaction probably involved the intermediate formation of hy-
drazones and subsequent addition of N H on the olefinic bond of the
propenone moiety. Condensation of chalcones with thiosemicarbazide
can lead to two different pyrazolines, P 1–7 or Pꢀ 1–7, as shown in

752
Z. A. Kaplancıklı et al.
TABLE I Experimental Data for Compounds TP 1-28.
Compound R1 R2 R3
M.P. (◦C) Yield (%) Molecular Formula
M.W.
TP 1
TP 2
TP 3
TP 4
TP 5
TP 6
TP 7
TP 8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
H
H
H
H
H
H
H
H
Cl
Cl
H
CH3
176–177
206–208
72
74
70
75
69
73
70
68
66
63
61
65
69
71
73
68
80
77
79
76
65
62
67
63
68
71
73
70
C22H17N3S2
C23H19N3S2
387.53
401.56
417.56
421.97
421.97
436.00
452.00
456.42
417.56
431.58
447.58
452.00
401.56
415.58
431.58
436.00
432.53
446.55
462.55
466.97
431.54
445.57
461.57
465.98
405.52
419.55
435.55
439.96
OCH3 209–211
Cl
H
CH3
OCH3 237–238
Cl
H
C23H19N3OS2
C22H16ClN3S2
C22H16ClN3S2
C23H18ClN3S2
C23H18ClN3OS2
214–216
190–191
212–213
Cl
Cl
232–234
169–171
173–174
C22H15Cl2N3S2
TP 9
OCH3
OCH3 CH3
OCH3 OCH3 198–199
OCH3 Cl
CH3
CH3
CH3
C23H19N3OS2
C24H21N3OS2
C24H21N3O2S2
C23H18ClN3OS2
C23H19N3S2
TP 10
TP 11
TP 12
TP 13
TP 14
TP 15
TP 16
TP 17
TP 18
TP 19
TP 20
TP 21
TP 22
TP 23
TP 24
TP 25
TP 26
TP 27
TP 28
180–182
178–180
195–196
H
CH3
C24H21N3S2
OCH3 192–193
Cl
H
CH3
OCH3 188–189
Cl
H
C24H21N3OS2
C23H18ClN3S2
C22H16N4O2S2
C23H18N4O2S2
C23H18N4O3S2
C22H15ClN4O2S2
C23H17N3O2S2
C24H19N3O2S2
C24H19N3O3S2
C23H16ClN3O2S2
CH3
186–187
197–199
201–203
NO2
NO2
NO2
NO2
CH2-O
194–195
153–155
142–144
CH2-O CH3
CH2-O OCH3 165–167
CH2-O Cl
F
F
F
F
183–185
140–141
202–204
H
CH3
C22H16FN3S2
C23H18FN3S2
C23H18FN3OS2
OCH3 221–223
Cl 218–220
C
22H15ClFN3S2
Scheme 2. According to the currently accepted mechanism,34 the for-
mation of P 1–7, instead of the regioisomer Pꢀ 1–7, is favoured via
hydrazone or thiosemicarbazone formation.
Compounds TP 1–28 were obtained by reacting compounds P 1–7
with phenacyl bromide or its derivatives in ethanol35 Scheme 1. The
substitution on the para site of phenacyl bromide played an important
role in thiazole formation step.
The structure of compounds TP 1–28 were confirmed by elemental
analyses and IR, 1H-NMR, and MS-FAB+ spectral data. All compounds
gave satisfactory elemental analysis. IR spectra of compounds TP 1–
28 showed C N and C C stretching bands at 1640–1685 and 1570–
1
1596 cm−1 regions, respectively. H-NMR and MS-FAB+ spectral data
also were consistent with the assigned structures. In the 250-MHz 1H-
NMR spectrum of the compounds, the CH2 protons of the pyrazoline

Thiazolyl-Pyrazoline Derivatives
753
SCHEME 2 Proposed mechanisms of pyrazoline formation.
ring resonated as a pair of doublets of doublets at δ 3.15–3.50 ppm (Ha)
and 3.98–4.07 ppm (Hb). The CH (Hx) proton appeared as a doublet
of doublets at δ 5.59–5.70 ppm due to vicinal coupling with the two
magnetically non-equivalent protons of the methylene group at position
4 of the pyrazoline ring (J = 17.50–18.10 Hz, J = 6.00–6.80 Hz,
AB
AX
J
= 11.70–12.10 Hz). All other aromatic and aliphatic protons were
BX
observed at the expected regions.
Microbiology
The results of antimicrobial screening of newly prepared compounds
TP 1–28 expressed as the Minimum Inhibitory Concentration (MIC)
are summarized in Table II.
The most important part of the results was those that were ob-
tained from antifungal activity screening. Most of the compounds were

754

Thiazolyl-Pyrazoline Derivatives
755
effective against Candida albicans and Candida glabrata. When com-
pared with flucanazol, especially TP 1, TP 2, TP 3, TP 4, TP 6, TP 7,
TP 8, TP 9, TP 10, TP 11, TP 12, TP 14, TP 15, TP 16, TP 17, TP 19,
TP 20, TP 22, TP 26, TP 27, TP 28 showed strong activity; TP 5, TP
18, TP 21, TP 23, TP 24, TP 25 were similar to the reference agent;
and showed TP 13 moderate activity.
In the case of thiazole derivatives, a potent antifungal activity, com-
parable with a commercially available compound, was observed, in par-
ticular against C. albicans and C. glabrata.
Antibacterial assessment revealed that the compounds possess only
a moderate or slight activity. The MIC values were generally within the
range of 31.25–500 μg/mL against all evaluated strains. By comparing
their MIC values with chloramphenicol, the compounds were less ac-
tive against Escherichia coli, Salmonella typhimurium, Bacillas cereus,
and Listeria monocytogenes. On the other hand, the compounds exhib-
ited comparable or better activities against Aeromonas hydrophila and
Saureus aureus than those of chloramphenicol.
Considering all the results obtained from antifungal and antibacte-
rial tests, in comparision with reference agents, it is possible to say that
the tested compounds are mostly active toward fungi then bacteria.
When structure and activity relationships are investigated, we can
infer from the results that R3 substitions seem to be effective on an-
tifungal activity. Especially nonsubstituated and methyl substituated
derivatives are more active then other derivatives. For further studies,
we are planning to synthesize new compounds bearing methyl sub-
stituents at different positions which will also be evaluated against
important human pathogenic fungi for their inhibitory activity.
EXPERIMENTAL
Chemistry
All reagents were used as purchased from commercial suppliers with-
out further purification. Melting points were determined by using an
Electrothermal 9100 digital melting-point apparatus (Barnstead Inter-
national, Iowa, USA) and were uncorrected. Compounds were checked
for purity by TLC on silica gel 60 F254 (Merck, Darmstadt, Germany).
Spectroscopic data were recorded on the following instruments: elemen-
tal analyses were performed on a Perkin Elmer EAL 240 elemental ana-
lyzer (Perkin Elmer, Wellesly, MA, USA); IR (v, cm−1), were recorded on
a Shimadzu 435 IR spectrophotometer (Shimadzu, Tokyo, Japan); and
1H-NMR spectra (δ, ppm, Hz) were recorded on a Bruker 250 MHz spec-
trometer (Bruker, Billerica, MA, USA) in solvent DMSO-d6 with TMS
as an internal standard. MS-FAB+ was recorded, VG Quattro mass
spectrometer (Agilent, Minnesota, USA).

756
Z. A. Kaplancıklı et al.
General Synthesis Procedure
1-(2-Thienyl)-3-aryl-2-propen-1-ones (chalcones) (A 1−7). A mix-
ture of 2-acetylthiophene (40 mmol, 5.04 g), aromatic aldehyde (40
mmol, benzaldehyde = 4.24 g, 4-chlorobenzaldehyde = 5.62 g, 4-
methoxybenzaldehyde = 5.44 g, 4-methylbenzaldehyde = 4.80 g, 4-
nitrobenzaldehyde = 6.04 g, 1,3-benzodioxole-4-carbaldehyde = 6.00 g,
4-florobenzaldehyde = 4.96 g) and sodium hydroxide (1.00 g in water [10
ml]) in ethanol (30 mL) was stirred at r. t. for about 3 h. The resulting
solid was washed, dried, and crystallized from ethanol.33
3-(2-Thienyl)-5-aryl-1-thiocarbamoyl-2-pyrazolines (P 1−7). To a
suspension of chalcone derivatives A 1–7 (10 mmol, A 1 = 2.14 g, A
2 = 2.48 g, A 3 2.44 g, A 4 = 2.28 g, A 5 = 2.59 g, A 6 = 2.58 g, A 7
= 2.32 g) and sodium hydroxide (1.00 g) in ethanol (50 mL), thiosemi-
carbazide (12 mmol, 1.09 g) was added. The mixture was refluxed for 8
h. The products were poured into crushed ice, and the solid mass that
separated out was filtered, dried, and crystallized from ethanol.35
1-(4-Aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline (TP 1−28).
To a suspension of compound P 1–7 (10 mmol, P 1 = 2.87 g, P 2 =
3.21 g, P 3 = 3.17 g, P 4 = 3.01 g, P 5 = 3.32 g, P 6 = 3.31 g, P 7 =
3.05 g) in ethanol (15 mL) phenacyl bromide (10 mmol, phenacyl bro-
mide = 1.99 g, 4-methylphenacyl bromide = 2.13 g, 4-methoxyphenacyl
bromide = 2.29 g, 4-chloro phenacyl bromide = 2.33 g) was added and
heated to reflux for 1 h. After cooling, the precipitate was collected. The
product was crystallized from ethanol.
Some characteristics of the synthesized compounds are shown in
Table I. Analytical and spectral data (IR,1HNMR, MS-FAB+) confirmed
the structures of the new compounds.
IR spectra of compounds TP 1–28 showed C N and C C stretching
bands at 1640–1685 and 1570–1596 cm−1 regions respectively.
1-(4-Phenyl-2-thiazolyl)-3-(2-thienyl)-5-phenyl-2-pyrazoline (TP 1).
1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.37 (1H, dd, J = 17.7, 6.4 Hz),
4.07 (1H, dd, J = 17.7, 11.7 Hz), 5.70 (1H, dd, J = 11.7, 6.4 Hz), 7.17
(1H, dd, J = 5.1, 3.6 Hz), 7.21–7.44 (9H, m), 7.45 (1H, dd, J = 3.4, 1.1
Hz), 7.70 (2H, d, J = 6.8 Hz), 7.75 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+:
m/z: 387 [M], 388 [M+1]. For C22H17N3S2, calculated: C, 68.19; H, 4.42;
N, 10.84; found: C, 68.61; H, 4.77; N, 10.90%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-phenyl-2-
pyrazoline (TP 2). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.28
(3H, s), 3.36 (1H, dd, J = 17.5, 6.8 Hz), 4.06 (1H, dd, J = 17.5, 11.9

Thiazolyl-Pyrazoline Derivatives
757
Hz), 5.69 (1H, dd, J = 11.9, 6.8 Hz), 7.11–7.43 (9H, m), 7.44 (1H, dd,
J = 3.8, 1.1 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.74 (1H, dd, J = 4.9, 1.1
Hz). MS-FAB+: m/z: 401 [M], 402 [M + 1]. For C23H19N3S2, calculated:
C, 68.80; H, 4.77; N, 10.46; found: C, 68.91; H, 4.65; N, 10.49%.
1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(2-thienyl)-5-phenyl-2-
pyrazoline (TP 3). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.20–3.35
(1H, m), 3.66 (3H, s), 3.98 (1H, dd, J = 17.5, 11.9 Hz), 5.59 (1H, dd,
J = 11.9, 6.6 Hz), 6.82 (2H, d, J = 9.0 Hz), 7.05 (1H, s), 7.08 (1H, dd,
J = 5.3, 3.6 Hz), 7.15–7.34 (5H, m), 7.35 (1H, dd, J = 3.4, 1.1 Hz), 7.54
(2H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 417
[M], 418 [M+1]. For C23H19N3OS2 calculated: C, 66.16; H, 4.59; N,
10.06; found: C, 65.97; H, 4.68; N, 10.11%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-phenyl-2-
pyrazoline (TP 4). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.30–3.45
(1H, m), 4.07 (1H, dd, J = 17.7, 12.1 Hz), 5.70 (1H, dd, J = 12.1, 6.4
Hz), 7.17 (1H, dd, J = 5.3, 3.5 Hz), 7.24–7.43 (8H, m), 7.46 (1H, dd,
J = 3.8, 1.1 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.75 (1H, dd, J = 4.9, 1.1 Hz).
MS-FAB+: m/z: 421 [M], 422 [M+1], 423 [M+2]. For C22H16ClN3S2
calculated: C, 62.62; H, 3.82; N, 9.96; N; found: C, 62.75; H, 3.94; N,
10.01%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(p-chlorophenyl)-2-
pyrazoline (TP 5).
1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.25–3.40
(1H, m), 4.01 (1H, dd, J = 17.7, 11.9 Hz), 5.68 (1H, dd, J = 11.9,
6.5 Hz), 7.15 (1H, dd, J = 5.3, 3.8 Hz), 7.26–7.35 (8H, m), 7.44 (1H,
dd, J = 3.8, 1.1 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.74 (1H, dd, J
=
4.9, 1.1 Hz). MS-FAB+: m/z: 421 [M], 422 [M+1], 423 [M+2]. For
C22H16ClN3S2, calculated: C, 62.62; H, 3.82; N, 9.96; found: C, 62.75;
H, 3.94; N, 10.01%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-chlorophenyl)-
2-pyrazoline (TP 6).
1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.29
(3H, s), 3.35–3.45 (1H, m), 4.06 (1H, dd, J = 17.7, 11.9 Hz), 5.69 (1H,
dd, J = 11.9, 6.5 Hz), 7.13–7.19 (3H, m), 7.25 (1H, s), 7.41–7.46 (5H,
m), 7.59 (2H, d, J = 7.8 Hz), 7.74 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+:
m/z: 436 [M], 437 [M+1], 438 [M+2]. For C23H18ClN3S2, calculated: C,
63.36; H, 4.16; N, 9.64; found: C, 63.06; H, 4.18; N, 9.72%.
1-[4-(p-Methoxphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-chlorophenyl)-
2-pyrazoline (TP 7). 1H-NMR (250 MHz, δ ppm, DMSO-d6):

758
Z. A. Kaplancıklı et al.
3.35–3.45 (1H, m), 3.72 (3H, s), 4.05 (1H, dd, J = 17.7, 11.7 Hz),
5.68 (1H, dd, J = 11.7, 6.8 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.15–7.22
(4H, m), 7.40–7.48 (3H, m), 7.57 (2H, d, J = 9.0 Hz), 7.71 (1H, dd,
J = 4.9, 1.1 Hz). MS-FAB+: m/z: 452 [M], 453 [M+1], 454 [M+2]. For
C23H18ClN3OS2, calculated: C, 61.12; H, 4.01; N, 9.30; found: C, 61.01;
H, 4.08; N, 9.42%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-chlorophenyl)-
2-pyrazoline (TP 8).
1H-NMR (250 MHz, δ ppm, DMSO-d6):
3.20–3.35 (1H, m), 3.98 (1H, dd, J = 18.1, 12.1 Hz), 5.62 (1H, dd,
J = 12.1, 6.4 Hz), 7.09 (1H, dd, J = 5.3, 3.8 Hz), 7.31–7.38 (8H, m),
7.63 (2H, d, J = 8.7 Hz), 7.66 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z:
456 [M], 457 [M+1], 458 [M+2]. For C22H15Cl2N3S2, calculated: C,
57.90; H, 3.31; N, 9.21; found: C, 57.78; H, 3.45; N, 9.29%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(p-methoxphenyl)-2-
pyrazoline (TP 9). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.35–3.50
(1H, m), 3.69 (3H, s), 3.99 (1H, dd, J = 17.5, 11.9 Hz), 5.62 (1H, dd,
J = 11.9, 6.6 Hz), 6.85 (2H, d, J = 9.0 Hz), 7.10 (1H, s), 7.14 (1H, dd,
J = 4.9, 3.8 Hz), 7.18–7.34 (5H, m), 7.40 (1H, dd, J = 3.8, 1.1 Hz), 7.60
(2H, d, J = 9.0 Hz), 7.69 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 417
[M], 418 [M+1]. For C23H19N3OS2, calculated: C, 66.16; H, 4.59; N,
10.06; found: C, 65.97; H, 4.68; N, 10.11%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-
methoxyphenyl)-2-pyrazoline (TP 10).
1H-NMR (250 MHz,
δ
ppm, DMSO-d6): 2.23 (3H, s), 3.28 (1H, dd, J = 17.7, 6.4 Hz), 3.72 (3H,
s), 4.00 (1H, dd, J = 17.7, 12.1 Hz), 5.67 (1H, dd, J = 12.1, 6.4 Hz),
6.88 (2H, d, J = 8.7 Hz), 7.17 (1H, s), 7.19–7.26 (3H, m), 7.33 (2H, d,
J = 8.3 Hz), 7.46 (1H, dd, J = 3.8, 1.1 Hz), 7.71 (2H, d, J = 8.7 Hz),
7.77 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 431 [M], 432 [M+1]. For
C24H21N3OS2, calculated: C, 66.79; H, 4.90; N, 9.74; found: C, 66.54;
H, 4.75; N, 9.63%.
1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-
methoxphenyl))-2-pyrazoline (TP 11).
1H-NMR (250 MHz, δ ppm,
DMSO-d6): 3.35 (1H, dd, J = 17.7, 6.4 Hz), 3.71 (3H, s), 3.76 (3H,
s), 4.02 (1H, dd, J = 17.7, 11.9 Hz), 5.63 (1H, dd, J = 11.9, 6.4 Hz),
6.88–6.95 (4H, m), 7.13 (1H, s), 7.17 (1H, dd, J = 4.9, 3.8 Hz), 7.33 (2H,
d, J = 8.7 Hz), 7.44 (1H, dd, J = 3.8, 1.1 Hz), 7.66 (2H, d, J = 9.0 Hz),
7.73 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 447 [M], 448 [M+1]. For

Thiazolyl-Pyrazoline Derivatives
759
C24H21N3O2S2, calculated: C, 64.41; H, 4.73; N, 9.39; found: C, 64.04;
H, 4.78; N, 9.58%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-
methoxyphenyl)-2-pyrazoline (TP 12).
1H-NMR (250 MHz,
δ
ppm, DMSO-d6): 3.32–3.47 (1H, m), 3.75 (3H, s), 4.01 (1H, dd, J = 17.7,
11.7 Hz), 5.62 (1H, dd, J = 11.7, 6.0 Hz), 6.88 (2H, d, J = 8.7 Hz),
7.11–7.18 (4H, m), 7.33–7.40 (3H, m), 7.53 (2H, d, J = 8.7 Hz), 7.67
(1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 452 [M], 453 [M+1], 454
[M+2]. For C23H18ClN3OS2, calculated: C, 61.12; H, 4.01; N, 9.30;
found: C, 61.01; H, 4.08; N, 9.42%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(p-methylphenyl)-2-
pyrazoline (TP 13). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.25
(3H, s), 3.38 (1H, dd, J = 17.7, 6.4 Hz), 4.01 (1H, dd, J = 17.7, 12.1
Hz), 5.64 (1H, dd, J = 12.1, 6.4 Hz), 7.10–7.41 (9H, m), 7.47 (1H,
dd, J = 3.8, 1.1 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.79 (1H, dd, J = 4.9,
1.1 Hz). MS-FAB+: m/z: 401 [M], 402 [M+1]. For C23H19N3S2, cal-
culated: C, 68.80; H, 4.77; N, 10.46; found: C, 68.95; H, 4.83; N,
10.44%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-methylphenyl)-
2-pyrazoline (TP 14). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.25
(3H, s), 2.30 (3H, s), 3.37 (1H, dd, J = 17.5, 6.6 Hz), 3.99 (1H, dd,
J = 17.5, 11.9 Hz), 5.61 (1H, dd, J = 11.9, 6.6 Hz), 6.85–6.91 (4H, m),
7.08 (1H, s), 7.14 (1H, dd, J = 5.3, 3.8 Hz), 7.29 (2H, d, J = 8.7 Hz),
7.41 (1H, dd, J = 3.8, 1.1 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.70 (1H, dd,
J = 5.3, 1.1 Hz). MS-FAB+: m/z: 415 [M], 416 [M+1]. For C24H21N3S2,
calculated: C, 69.36; H, 5.09; N, 10.11; found: C, 69.53; H, 5.17; N,
10.15%.
1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-
methylphenyl)-2-pyrazoline (TP 15). 1H-NMR (250 MHz, δ ppm,
DMSO-d6): 2.26 (3H, s), 3.33 (1H, dd, J = 17.7, 6.4 Hz), 3.76 (3H, s),
4.03 (1H, dd, J = 17.7, 12.1 Hz), 5.65 (1H, dd, J = 12.1, 6.4 Hz), 6.91
(2H, d, J = 8.7 Hz), 7.13 (1H, s), 7.14–7.19 (3H, m), 7.28 (2H, d, J =
8.3 Hz), 7.43 (1H, dd, J = 3.8, 1.1 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.73
(1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 431 [M], 432 [M+1]. For
C24H21N3OS2, calculated: C, 66.79; H, 4.90; N, 9.74; found: C, 66.54;
H, 4.75; N, 9.63%.

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Z. A. Kaplancıklı et al.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-methylphenyl)-
2-pyrazoline (TP 16).
1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.26
(3H, s), 3.34 (1H, dd, J = 17.7, 6.0 Hz), 4.04 (1H, dd, J = 17.7, 12.0
Hz), 5.66 (1H, dd, J = 12.0, 6.0 Hz), 7.13–7.19 (3H, m), 7.27 (2H, d,
J = 8.3 Hz), 7.38 (1H, s), 7.41 (2H, d, J = 9.0 Hz), 7.44 (1H, dd, J =
3.8, 1.1 Hz), 7.71–7.77 (3H, m). MS-FAB+: m/z: 436 [M], 437 [M+1],
438 [M+2]. For C23H18ClN3S2, calculated: C, 63.36; H, 4.16; N, 9.64;
found: C, 63.06; H, 4.18; N, 9.72%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(p-nitrophenyl)-2-pyrazoline
(TP 17). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.15–3.35 (1H, m),
4.01 (1H, dd, J = 17.9, 11.7 Hz), 5.64 (1H, dd, J = 11.7, 6.4 Hz), 7.10
(1H, dd, J = 4.9, 3.8 Hz), 7.16–7.37 (5H, m), 7.39 (1H, dd, J = 3.8, 1.1
Hz), 7.63 (1H, s), 7.68 (1H, dd, J = 4.9, 1.1 Hz), 7.87 (2H, d, J = 9.0
Hz), 8.14 (2H, d, J = 9.0 Hz). MS-FAB+: m/z: 432 [M], 433 [M+1]. For
C22H16N4O2S2, calculated: C, 61.09; H, 3.73; N, 12.95; found: C, 60.92;
H, 3.84; N, 12.82%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-nitrophenyl)-2-
pyrazoline (TP 18).
1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.29 (3H,
s), 3.35–3.45 (1H, m), 4.05 (1H, dd, J = 17.8, 11.7 Hz), 5.67 (1H, dd,
J = 11.7, 6.3 Hz), 6.94 (2H, d, J = 9.0 Hz), 7.18 (1H, dd, J = 4.9, 3.8
Hz), 7.36 (2H, d, J = 8.7 Hz), 7.48 (1H, dd, J = 3.8, 1.1 Hz), 7.70 (1H,
s), 7.76 (1H, dd, J = 4.9, 1.1 Hz), 7.99 (2H, d, J = 9.0 Hz), 8.24 (2H, d,
J = 9.0 Hz). MS-FAB+: m/z: 446 [M], 447 [M+1]. For C23H18N4O2S2,
calculated: C, 61.86; H, 4.06; N, 12.55; found: C, 62.09; H, 4.18; N,
12.67%.
1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-nitrophenyl)-
2-pyrazoline (TP 19). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.34
(1H, dd, J = 17.7, 6.0 Hz), 3.76 (3H, s), 4.00 (1H, dd, J = 17.7, 11.8
Hz), 5.62 (1H, dd, J = 11.8, 6.0 Hz), 6.92 (2H, d, J = 8.7 Hz), 7.13 (1H,
s), 7.17 (1H, dd, J = 4.9, 3.8 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.44 (1H,
dd, J = 3.8, 1.1 Hz), 7.48 (1H, d, J = 9.0 Hz), 7.68 (2H, d, J = 8.7 Hz),
7.73 (1H, dd, J = 5.3, 1.1 Hz), 7.77 (1H, d, J = 8.7 Hz). MS-FAB+: m/z:
462 [M], 463 [M+1]. For C23H18N4O3S2, calculated: C, 59.72; H, 3.92;
N, 12.11; found: C, 59.67; H, 4.01; N, 12.00%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-nitrophenyl)-2-
pyrazoline (TP 20). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.35
(1H, dd, J = 17.7, 6.4 Hz), 4.03 (1H, dd, J = 17.7, 11.7 Hz), 5.65 (1H,

Thiazolyl-Pyrazoline Derivatives
761
dd, J = 11.7, 6.4 Hz), 6.79 (2H, d, J = 8.7 Hz), 7.17 (1H, dd, J = 5.3,
3.8 Hz), 7.30–7.52 (3H, m), 7.72–7.78 (3H, m), 7.86 (2H, d, J = 8.3
Hz), 7.93 (1H, s). MS-FAB+: m/z: 466 [M], 467 [M+1], 468 [M+2]. For
C22H15ClN4O2S2, calculated: C, 56.59; H, 3.24; N, 12.00; found: C,
56.46; H, 3.17; N, 11.89%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(3,4-methylenedioxyphenyl)-
2-pyrazoline (TP 21).
1H-NMR (250 MHz, δ ppm, DMSO-d6):
3.23–3.44 (1H, m), 4.03 (1H, dd, J = 17.7, 11.7 Hz), 5.64 (1H, dd,
J = 11.7, 6.0 Hz), 5.93 (1H, d, J = 15.7 Hz), 6.00 (1H, d, J = 15.7
Hz), 6.83–6.92 (3H, m), 7.18 (1H, dd, J = 4.9, 3.8 Hz), 7.34–7.42
(5H, m), 7.70–7.76 (3H, m). MS-FAB+: m/z: 431 [M], 432 [M+1]. For
C23H17N3O2S2, calculated: C, 64.02; H, 3.97; N, 9.74; found: C, 64.06;
H, 4.01; N, 9.81%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(3,4-
methylenedioxyphenyl)-2-pyrazoline (TP 22).
1H-NMR (250 MHz, δ
ppm, DMSO-d6): 2.29 (3H, s), 3.36 (1H, dd, J = 17.7, 6.4 Hz), 4.00 (1H,
dd, J = 17.7, 11.7 Hz), 5.62 (1H, dd, J = 11.7, 6.4 Hz), 5.95 (1H, d, J =
15.5 Hz), 6.02 (1H, d, J = 15.5 Hz), 6.88–6.95 (3H, m), 7.14–7.19 (3H,
m), 7.24 (1H, s), 7.44 (1H, dd, J = 3.8, 1.1 Hz), 7.63 (2H, d, J = 8.3
Hz), 7.73 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z: 445 [M], 446 [M+1].
For C24H19N3O2S2, calculated: C, 64.70; H, 4.30; N, 9.43; N; found: C,
64.68; H, 4.26; N, 9.42%.
1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(3,4-
methylenedioxyphenyl)-2-pyrazoline (TP 23).
1H-NMR (250 MHz, δ
ppm, DMSO-d6): 3.36 (1H, dd, J = 17.5, 6.6 Hz), 3.70 (3H, s), 4.02 (1H,
dd, J = 17.5, 11.7 Hz), 5.66 (1H, dd, J = 11.7, 6.6 Hz), 5.93 (1H, d, J =
15.5 Hz), 6.04 (1H, d, J = 15.5 Hz), 6.85–6.92 (3H, m), 7.12–7.17 (3H,
m), 7.29 (1H, s), 7.40 (1H, dd, J = 3.8, 1.1 Hz), 7.61 (2H, d, J = 8.7 Hz),
7.69 (1H, dd, J = 5.3, 1.1 Hz). MS-FAB+: m/z: 461 [M], 462 [M+1]. For
C24H19N3O3S2, calculated: C, 62.45; H, 4.15; N, 9.10; found: C, 62.68;
H, 4.26; N, 9.15%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(3,4-
methylenedioxyphenyl)-2-pyrazoline (TP 24).
1H-NMR (250 MHz, δ
ppm, DMSO-d6): 3.20–3.42 (1H, m), 4.01 (1H, dd, J = 17.7, 11.7 Hz),
5.62 (1H, dd, J = 11.7, 6.0 Hz), 5.95 (1H, d, J = 15.7 Hz), 6.02 (1H,
d, J = 15.7 Hz), 6.87–6.95 (3H, m), 7.17 (1H, dd, J = 4.9, 3.8 Hz),

762
Z. A. Kaplancıklı et al.
7.38–7.47 (4H, m), 7.72–7.78 (3H, m). MS-FAB+: m/z: 465 [M], 466
[M+1], 467 [M+2]. For C23H16ClN3O2S2, calculated: C, 59.28; H, 3.46;
N, 9.02; found: C, 59.47; H, 3.58; N, 9.12%.
1-[4-Phenyl-2-thiazolyl]-3-(2-thienyl)-5-(p-fluoro phenyl)-2-pyrazo-
line (TP 25). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.38 (1H, dd,
J = 17.7, 6.4 Hz), 4.05 (1H, dd, J = 17.7, 12.0 Hz), 5.70 (1H, dd, J =
12.0, 6.4 Hz), 7.15–7.28 (4H, m), 7.31–7.38 (3H, m), 7.43–7.50 (3H, m),
7.70 (2H, d, J = 8.3 Hz), 7.74 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+: m/z:
405 [M], 406 [M+1]. For C22H16FN3S2, calculated: C, 65.16; H, 3.98; N,
10.36; found: C, 65.06; H, 3.93; N, 10.38%.
1-[4-(p-Methylphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-fluorophenyl)-
2-pyrazoline (TP 26). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 2.29
(3H, s), 3.41 (1H, dd, J = 17.7, 6.8 Hz), 4.05 (1H, dd, J = 17.7, 11.7
Hz), 5.69 (1H, dd, J = 11.7, 6.8 Hz), 7.12–7.25 (6H, m), 7.42–7.50 (3H,
m), 7.60 (2H, d, J = 8.3 Hz), 7.74 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+:
m/z: 419 [M], 420 [M+1]. For C23H18FN3S2, calculated: C, 65.85; H,
4.32; N, 10.02; found: C, 65.85; H, 4.30; N, 10.01%.
1-[4-(p-Methoxphenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-fluorophenyl)-
2-pyrazoline (TP 27). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.37
(1H, dd, J = 17.7, 6.8 Hz), 3.76 (3H, s), 4.05 (1H, dd, J = 17.7, 11.7
Hz), 5.68 (1H, dd, J = 11.7, 6.8 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.13–7.25
(4H, m), 7.42–7.50 (3H, m), 7.60 (2H, d, J = 9.0 Hz), 7.74 (1H, dd, J =
5.3, 1.1 Hz). MS-FAB+: m/z: 435 [M], 436 [M+1]. For C23H18FN3OS2,
calculated: C, 63.43; H, 4.17; N, 9.65; found: C, 63.56; H, 4.30; N, 9.74%.
1-[4-(p-Chlorophenyl)-2-thiazolyl]-3-(2-thienyl)-5-(p-fluorophenyl)-
2-pyrazoline (TP 28). 1H-NMR (250 MHz, δ ppm, DMSO-d6): 3.40
(1H, dd, J = 17.7, 6.4 Hz), 3.98 (1H, dd, J = 17.7, 12.0 Hz), 5.62 (1H,
dd, J = 12.0, 6.4 Hz), 7.09 (1H, dd, J = 5.3, 3.8 Hz), 7.31–7.38 (8H,
m), 7.63 (2H, d, J = 8.7 Hz), 7.70 (1H, dd, J = 4.9, 1.1 Hz). MS-FAB+:
m/z: 439 [M], 440 [M+1], 441 [M+2]. For C22H15ClFN3S2, calculated:
C, 60.06; H, 3.44; N, 9.55; found: C, 60.01; H, 3.53; N, 9.52%.
Microbiology
Antimicrobial activities of compounds were tested using the microbroth
dilution method.36 Tested microorganism strains were; E. coli (NRRL

Thiazolyl-Pyrazoline Derivatives
763
B-3704), S. aureus (NRLL B-767), S. typhimurium (NRRL B-4420), B.
cereus (NRRL B-3711), L. monocytogenes (Ankara Uni. Fac. of Veteri-
nary), A. hydrophila (Ankara Uni. Fac. of Veterinary), C. albicans, and
C. glabrata (isolates obtained from Osmangazi Uni. Fac. of Medicine).
Microbroth dilution susceptibility assay was used for antimicrobial
evaluation of the compounds. Stock solutions of the samples were pre-
pared in dimethylsulfoxide. Dilution series using sterile distilled water
were prepared from 4 mg/mL to 0.007 mg/mL in micro-test tubes that
were transferred to 96-well microtiter plates. Overnight grown bacte-
rial and Candida suspensions in double-strength Mueller-Hinton broth
were standardized to 108 Colony Forming Units/mL using McFarland
No. 0.5 standard solution. hundred mul of each microorganism sus-
pension then was added into the wells. The last well-chain without a
microorganism was used as a negative control. Sterile distilled water
and the medium served as a positive growth control. After incubation
at 37◦C for 18–24 h, the first well without turbidity was determined as
the MIC. Chloramphenicol was used as standard antibacterial agent,
whereas flucanazol was used as an antifungal agent. The observed data
on the antimicrobial activity of the compounds and control drugs are
given in Table II.
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