Synthesis of some 1-[(N,N-disubstituted thiocarbamoylthio)acetyl]-3-(2- thienyl)-5-aryl-2-pyrazoline derivatives and investigation of their antibacterial and antifungal activities

Article abstract of DOI:10.1002/ardp.200400935

Fourteen new 1-[(N,N-disubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)- 5-aryl-2-pyrazoline derivatives (7a-n) were synthesised by reacting 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5a-g) and appropriate sodium salts of N,N-disubstituted dithiocarbamoic acids (6a, b). The structures of the synthesised compounds were confirmed by elemental analyses, UV, IR, ¹H-NMR and FAB⁺-MS spectral data. Their antibacterial activities against Proteus vulgaris (NRRL B-123), Escherichia coli (NRRL B-3704), Aeromonas hydrophila (Ankara University, Faculty of Veterinary Sciences), Salmonella typhimurium (NRRL B-4420), Streptococcus feacalis (NRRL B-14617), Micrococcus luteus (NRLL B-4375) were investigated and in this investigation, a significant level of activity was illustrated. Antifungal activities of the compounds against Candida albicans and Candida globrata (isolates obtained from Osmangazi Uni. Fac. of Medicine) were found to be inactive. Compounds 7c-n were also evaluated for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The preliminary results indicated that all of the tested compounds were inactive against the test organism.

Full text of DOI:10.1002/ardp.200400935

96
DOI 10.1002/ardp.200400935
Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
Synthesis of Some 1-[(N,N-Disubstituted thiocar-
bamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline
Derivatives and Investigation of Their Antibacterial
and Antifungal Activities
Gulhan Turan-Zitounia, Ahmet Özdemira, Kiymet Güvenb
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskis¸ehir,
Turkey
b Deparment of Microbiology, Faculty of Science, Anadolu University, 26470, Eskis¸ehir, Turkey
Fourteen new 1-[(N,N-disubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline deriva-
tives (7aϪn) were synthesised by reacting 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5aϪg)
and appropriate sodium salts of N,N-disubstituted dithiocarbamoic acids (6a, b). The structures of
1
the synthesised compounds were confirmed by elemental analyses, UV, IR, H-NMR and FABϩ-MS
spectral data. Their antibacterial activities against Proteus vulgaris (NRRL B-123), Escherichia coli
(NRRL B-3704), Aeromonas hydrophila (Ankara University, Faculty of Veterinary Sciences), Salmon-
ella typhimurium (NRRL B-4420), Streptococcus feacalis (NRRL B-14617), Micrococcus luteus (NRLL
B-4375) were investigated and in this investigation, a significant level of activity was illustrated. Anti-
fungal activities of the compounds against Candida albicans and Candida globrata (isolates obtained
from Osmangazi Uni. Fac. of Medicine) were found to be inactive. Compounds 7cϪn were also evalu-
ated for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460
radiometric system and BACTEC 12B medium. The preliminary results indicated that all of the tested
compounds were inactive against the test organism.
Keywords: 2-Pyrazoline; Sodium salts of N,N-disubstituted dithiocarbamoic acids; Antibacterial activity;
Antifungal activity; Antituberculosis activity
Received: October 10, 2004; Accepted: February 19, 2005 [FP 935]
Introduction
opportunistic fungi responsible for these kinds of infections.
Although there are new classes of compounds that are now
frequently used to treat fungal infections the frequency of
deeply invasive candidiasis has increased 10-fold during the
past decade. Moreover, many infections caused by the
Candida spp are actually refractory to antifungal therapy
[3, 4].
Antibiotics are among the most prescribed drugs in the
world today, and since their development and commerciali-
sation, have saved countless millions of lives. The ideal anti-
microbial agents are selective in only targeting the microor-
ganism but not host cells. However, resistance to anti-
microbial agents is now recognised as a major global public
health problem. With the emergence of new bacterial strains
resistant to many currently available antibiotic treatments,
there is increasing interest in the discovery of novel antibac-
terial agents [1, 2].
In order to overcome this rapid development of drug resist-
ance, new agents should preferably consist of chemical
characteristics that clearly differ from those of existing
agents. In drug designing programs an essential component
of the search for new leads is the synthesis of molecules,
which is novel yet resembles known biologically active mol-
ecules by virtue of the presence of critical structural fea-
tures. Certain small heterocyclic molecules act as highly
functionalised scaffolds and are known pharmacophores of
a number of biologically active and medicinally useful mol-
ecules [5, 6].
Apart from this, because of the increased number of
immunocompromised patients (AIDS, cancer and trans-
plants), primary and opportunistic fungal infections con-
tinue to increase rapidly, and as a consequence, invasive fun-
gal infections constitute a major cause of mortality for these
patients. Candida albicans is one of the most common
Electron-rich nitrogen heterocyclies play an important role
in diverse biological activities. Introducing a pyrazolidinone
[7, 8] ring in place of the β-lactam ring (in penicillins and
cephalosporins [9]) results in enhanced activity. A second
Correspondence: Gulhan Turan-Zitouni, Department of Pharma-
ceutical Chemistry, Faculty of Pharmacy, Anadolu University,
26470, Eskisehir, Turkey. Phone: ϩ90 222 3350580 / 3645, Fax: ϩ90
¸
222 3350750, e-mail: gturan@anadolu.edu.tr
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
Pyrazoline Derivatives and their Antifungal and -bacterial Activities
97
nitrogen in the five-membered ring also influences the anti-
bacterial or pharmacokinetic properties [10Ϫ14].
planned to synthesise a system that combines these two bi-
olabile components which are 2-pyrazolines and N-substi-
tuted/N,N-disubstituted dithiocarbamoic acid esters, to-
gether to give a compact structure like title compounds.
On the other hand, the structure-activity relationship study
revealed that the antibacterial activity on thiocarbamoyl
aromatic compounds was significantly affected by the lipo-
philicity, that is obtained by thiocarbamoyl moiety, es-
pecially the calculated log P value and the balance between
hydrophilic substituent and hydrophobic substituent on the
aromatic compounds [15]. Some thiocarbomoyl aromatics
that were synthesised inspired by the above mentioned
rationale were found to possess good in vitro antibacterial
activity against gram-positive bacteria [15].
Results and discussion
In this study, the chalcones (1-(2-Thienyl)-3-aryl-2-propen-
1-ones) (3aϪg) were synthesised by literature methods as
described [34] and treated with hydrazine hydrate (80%) to
obtain 5-Aryl-3-(2-thienyl)-2-pyrazolines (4aϪg) (Figure 1).
This reaction probably involved in the intermediate forma-
tion of hydrozones and subsequent addition of N-H on the
olephinic bond of the propenone moiety. Condensation of
chalcones with hydrazine hydrate can lead to two different
pyrazolines (4aϪg or 4ЈaϪg), as shown in Figure 1. Accord-
ing to the currently accepted mechanism [35] the formation
2-Pyrazoline derivatives [16-26] and N-substituted/N,N-dis-
ubstituted dithiocarbamoic acid esters [27-33] have been re-
ported in the literature to exhibit various pharmacological
activities such as antibacterial, antifungal, herbicidal and
anticholinergic. In the interest of the above suggestion, we
Scheme 1. Proposed mechanisms of pyrazoline formation.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

98
Turan-Zitouni et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
of (4aϪg), instead of the regioisomer (4ЈaϪg), is favoured
via hydrazone formation. Under these reaction conditions,
the product stereochemistry is determined by the stereo-
chemistry of the step 4aϪg Ǟ 4aϪg where a stereoselective
enamine-imine tautomerism may take place [36] giving rise
to the preferred direction of the proton on C-4 trans to the
phenyl group at C-5 while 3-pyrazoline isomerizes to the
more stable 2-pyrazoline. But the lower J values compared
to what is described in the literature [37] may be attributed
to electronic environment effects.
In the present work, 14 new compounds were synthesised.
The reaction of 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyra-
zolines (5aϪg)with appropriate sodium salts of N,N-disub-
stituted dithiocarbamoic acids (6a, b) resulted 1-[(N,N-dis-
ubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-
pyrazolines (7aϪn) (Scheme 2, Table 1). The formulas of
compounds (5aϪg, 7aϪn) were by elemental analyses and
their structures were determined by UV, IR, H-NMR and
FABϩ-MS spectral data. The IR data were very informative
and provided evidence for the formation of the expected
1
Scheme 2. Synthetic route of the title compounds.
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Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
Pyrazoline Derivatives and their Antifungal and -bacterial Activities
99
Table 1. Physicochemical data of compounds 5aϪg and 7aϪn.
EtOH
Compd.
R1
R2
Molecular Formula
MW
Mp
[°C]
Yield
[%]
λmax
[nm]
5a
5b
5c
5d
5e
5f
5g
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
H
CH3
N(CH3)2
OH
OCH3
F
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
C15H13ClN2OS
C16H15ClN2OS
C17H18ClN3OS
C15H13ClN2O2S
C16H15ClN2O2S
C15H12ClFN2OS
C15H12Cl2N2OS
C20H21N3OS3
C21H23N3OS3
C21H23N3OS3
C22H25N3OS3
C22H26N4OS3
C23H28N4OS3
C20H21N3O2S3
C21H23N3O2S3
C21H23N3O2S3
C22H25N3O2S3
C20H20FN3OS3
C21H22FN3OS3
C20H20ClN3OS3
C21H22ClN3OS3
304.8
318.8
347.8
320.8
334.8
322.7
339.2
415.6
429.6
429.6
443.6
458.6
472.7
431.6
445.6
445.6
459.6
433.5
447.6
450.0
464.0
126
130
145
76
62
78
69
68
64
73
45
52
41
47
65
68
49
50
56
53
49
51
64
63
208.8, 318.4
208.4, 313.4
207.6, 317.4
207.8, 313.6
207.4, 315.4
208.4, 312.4
208.4, 319.4
208.4, 318.2
207.6, 315.3
210.4, 320.4
213.6, 318.7
208.4, 315.4
207.4, 317.9
208.2, 319.6
220.6, 315.2
207.8, 319.8
207.6, 318.9
207.6, 318.2
208.6, 319.7
208.4, 320.4
208.6, 320.2
250
120†
143Ϫ144
Cl
H
H
118†
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
149
105Ϫ106
98
110Ϫ113
83Ϫ84
89
121Ϫ123
180Ϫ182
73
79
139
77Ϫ78
108
109
CH3
CH3
N(CH3)2
N(CH3)2
OH
OH
OCH3
OCH3
F
F
Cl
7m
7n
Cl
†
Literature Mp from [38].
structures. CϭO, CϭN, CϭC and CϭS functions absorbed
cant antibacterial activity when compared with chloram-
phenicole.
strongly in the expected regions: CϭO at 1677Ϫ1643 cmϪ1
,
CϭN and CϭC at 1614Ϫ1402 cmϪ1 and CϭS at
The antibacterial assessment revealed that the compounds
possesses significant activity. The MIC values are generally
within the range of 62.5-500 μg/mL against all evaluated
strains.
1
1245Ϫ1221 cmϪ1, respectively. The H-NMR spectral data
were also consistent with the assigned structures. In the 250
1
MHz H-NMR spectrum of compounds, the CH2 protons
of the pyrazoline ring resonated as a pair of doublets of
doublets at δ 3.10Ϫ3.40 ppm, 3.80Ϫ4.00 ppm. The CH pro-
ton appeared as doublet of doublets at δ 5.40-5.65 ppm due
to vicinal coupling with the two magnetically non-equiva-
lent protons of the methylene group at position 4 of the
pyrazoline ring (JAM ϭ 17.82Ϫ18.08 Hz, JAX ϭ 4.22Ϫ4.78
Hz, JMX ϭ 11.44Ϫ11.75 Hz). The CH2 protons of acetyl
which are on 1 position of pyrazoline (5aϪg) and (7aϪn)
are observed at 4.60Ϫ4.70 ppm as double doublets (J ϭ
13.71Ϫ16.18 Hz, J ϭ 13.77Ϫ16.21) this geminal coupling
is result from steric structure of compound. These geminal
protons are observed as double doublet because of possible
two different conformation since rigid protons were oc-
curred. All the other aromatic and aliphatic protons were
observed at expected regions. All compounds gave satisfac-
tory elemental analysis. The mass spectra (MS (FAB)) of
compounds showed [Mϩ1] peaks, in agreement with their
molecular formula.
In comparing their MIC values with chloramphenicole, all
of the compounds were effective against Proteus vulgaris;
7a, 7e, 7f, 7g and 7m especially showed strong activity. 7b,
7c, 7d, 7h, 7i, 7k and 7n showed a similar level of activity
with chloramphenicole and 7l showed moderate activity. All
of the compounds were effective against Aeromonas hydro-
phil. Compounds 7d, 7g, 7h and 7m especially showed
strong activity. 7a, 7c, 7e, 7f, 7i, 7j, 7k and 7n showed a
similar level of activity and 7b, 7l showed moderate activity
when compared with the reference agent.
In comparing their MIC values with chloramphenicole, all
of the compounds were effective against Escherichia coli;
The compound 7g especially showed strong activity. 7a, 7c,
7d, 7e, 7f, 7h, 7i, 7j, 7k, 7l, 7m and 7n showed a same level
of activity with chloramphenicole and 7b showed moder-
ate activity.
MICs were recorded as the minimum concentration of a
compound that inhibits the growth of tested microorgan-
isms. All of the compounds tested were illustrated signifi-
On the other hand the compounds exhibited comparable
activities against Salmonella typhimurium; Compounds 7g,
7h and 7m showed equal activity and the other compounds
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100
Turan-Zitouni et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
constant stirring. Later, the mixture was cooled in an ice bath, and
chloroacetylchloride (0.01 mol) was added dropwise with stirring.
The reaction mixture thus obtained was further agitated for 1 h
at room temperature. The precipitate was filtrated, the solvent was
evaporated to dryness under reduced pressure and the products were
recrystallised from ethanol [38].
were found less active than the reference agent. When com-
pared with chloramphenicole, the compounds 7a, 7d, 7e, 7f,
7g and 7n showed similar activity against Micrococcus
luteus, whereas all other compounds showed less activity.
From the similar results obtained from Streptococcus fea-
calis, compounds 7b, 7l and 7n showed moderate activity,
whereas remained compounds have same activity values
when compared with chloramphenicole. The compounds
were found inactive against Candida albicans and Candida
globrata when compared with ketoconazole.
Sodium salts of N, N-disubstitued dithiocarbamic acids (6a, b)
Sodium hydroxide (0.01mol) was dissolved in ethanol (80 mL) with
constant stirring. After addition of the secondary amine (0.01 mol)
the mixture was cooled in an ice bath and carbon disulphide (0.10
mol) was added dropwise with stirring. Further agitation of the re-
action mixture thus obtained for 1 h at room temperature, evapo-
ration of the solvent under reduced pressure, and subsequent
addition of dry ether until precipitation reached completion, fil-
tration afforded products which were recrystallised from ethanol
[39].
In conclusion, 1-[(N,N-disubstitutedthiocarbamoylthio)ace-
tyl]-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives showed sig-
nificant activities against gram-positive and gram negative
bacteria. However, all of the tested compounds were
inactive against Candida species and Mycobacterium tuber-
culosis H37Rv.
1-[(N,N-Disubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)-5-
aryl-2-pyrazolines (7aϪn)
A mixture of 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5)
(0.01 mol) and sodium salts of the appropriate N,N-disubstituted
dithiocarbamoic acid (6) (0.01 mol) was treated in acetone at room
temperature for 1 h. The solvent was evaporated, washed with water
and recrystallised from ethanol.
Acknowledgments
We thanks D. Joseph A. Maddry from the Tuberculosis
Antimicrobial Acquisition and Coordinating Facility
(TAACF), National Institute of Allergy and Infectious Dis-
eases Southern Research Institute, GWL Hansen’s Disease
Center, Colorado State University, Birmingham, Alabama,
USA for the in vitro evaluation of antituberculosis activity.
Some characteristics of the synthesised compounds are shown in
Table 1. Analytical and spectral data (IR, 1H-NMR, FABϩ-MS)
confirmed the structures of the new compounds.
1-(Chloroacetyl)-3-(2-thienyl)-5-phenyl-2-pyrazoline (5a)
(nm), log ε]: 208.8 (4.80), 318.4 (4.65). IR [ν, cmϪ1
,
EtOH
Experimental
UV [λmax
KBr]: 1658 (CϭO), 1591-1417 (CϭN, CϭC).
Chemistry
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-methylphenyl)-2-pyrazoline (5b)
All reagents were used as purchased from commercial suppliers
without further purification. Melting points were determined by
using an Electrothermal 9100 digital melting point apparatus and
were uncorrected. The compounds were checked for purity by TLC
on silica gel 60 F254. Spectroscopic data were recorded on the fol-
lowing instruments: UV, Shimadzu Model 160A UV spectrophoto-
EtOH
UV [λmax
(nm), log ε]: 208.4 (5.06), 313.4 (4.92). IR [ν, cmϪ1
,
1
KBr]: 1672 (CϭO), 1514-1403 (CϭN, CϭC). H-NMR (250 MHz,
δ ppm, DMSO-d6,): 2.30 (3H, s, Ar-CH3), 3.40 (1H, dd JAM ϭ 17.98
Hz, JAX ϭ 4.47 Hz, C4-HA of pyrazoline ring), 4.00 (1H, dd JMA ϭ
17.98 Hz, JMX ϭ 11.62 Hz, C4-HM of pyrazoline ring), 4.65 (1H, d
J ϭ 13.78 Hz, COCH geminal proton), 4.70 (1H, d J ϭ 13.77 Hz,
COCH geminal proton), 5.60 (1H, dd JMX ϭ 11.60 Hz, JAX ϭ 4.46
Hz, C5-HX of pyrazoline ring), 7.15Ϫ7.25 (5H, m, phenyl protons
and thiophene C4-H), 7.55 (1H, dd J ϭ 2.64 Hz, J ϭ 1.01 Hz,
thiophene C3-H), 7.80 (1H, dd Jϭ 5.04 Hz, J ϭ 1.03 Hz thiophene
C5-H). MS-FABϩ: m/z: 318 [Mϩ], 319 [Mϩ1], 320 [Mϩ2]
1
meter; IR, Shimadzu 435 IR spectrophotometer; H-NMR, Bruker
250 MHz NMR spectrometer in DMSO-d6 using TMS as internal
standard; Elemental analyses were performed on a Perkin Elmer
EAL 240 elemental analyser; MS-FAB, VG Quattro mass spec-
trometer.
1-(2-Thienyl)-3-aryl-2-propen-1-ones (3aϪg)
A mixture of 2-acetylthiophene (0.04 mol) (1), aromatic aldehyde
(0.04 mol) (2) and 10% aqueous sodium hydroxide (10 mL) in etha-
nol (30 mL) was stirred at room temperature for about 3 h. The
resulting solid was washed, dried and crystallised from ethanol [34].
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-dimethylaminophenyl)-2-pyr-
azoline (5c)
EtOH
UV [λmax
(nm), log ε]: 207.6 (5.20), 317.4 (5.15). IR [ν, cmϪ1
,
KBr]: 1672 (CϭO), 1610-1415 (CϭN, CϭC).
5-Aryl-3-(2-thienyl)-2-pyrazolines (4aϪg)
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-hydroxyphenyl)-2-pyrazoline (5d)
A solution of the appropriate thienyl chalcone (0.01 mol) (3aϪg)
and hydrazine hydrate (80%) (0.02 mol) in ethanol (30 mL) was
refluxed for 3 h. The reaction mixture was cooled and kept at 0°C
overnight. The resulting solid was crystallised from ethanol [34].
UV [λmax
(nm), log ε]: 207.8 (4.91), 313.6 (4.94). IR [ν, cmϪ1
,
EtOH
KBr]: 3245 (O-H), 1654 (CϭO), 1614-1423 (CϭN, CϭC). 1H-NMR
(250 MHz, δ ppm, DMSO-d6,): 3.15 (1H, dd JAM ϭ 17.96 Hz,
JAX ϭ 4.33 Hz, C4-HA of pyrazoline ring), 3.90 (1H, dd JMA
ϭ
17.94 Hz, JMX ϭ 11.56 Hz, C4-HM of pyrazoline ring), 4.55 (1H, d
J ϭ 13.71 Hz, COCH geminal proton), 4.60 (1H, d J ϭ 13.78 Hz,
COCH geminal proton), 5.45 (1H, dd JMX ϭ 11.46 Hz, JAX ϭ 4.22
Hz, C5-HX of pyrazoline ring), 6.65 (2H, d J ϭ 8.50 Hz, phenyl
1-(Chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5aϪg)
The 5-Aryl-3-(2-thienyl)-2-pyrazolines (4aϪg) (0.01 mol) and tri-
ethylamine (0.01 mol) were dissolved in dry toluene (30 mL) with
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Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
Pyrazoline Derivatives and their Antifungal and -bacterial Activities
101
C2,6-H), 7.10 (2H, d J ϭ 8.52 Hz, phenyl C3,5-H), 7.15 (1H, t J ϭ
3.69 Hz, thiophene C4-H), 7.45 (1H, d J ϭ 2.62 Hz, thiophene C3-
H), 7.75 (1H, d J ϭ 5.07 Hz, thiophene C5-H), 9.40 (1H, s, Ar-
OH). MS-FABϩ: m/z: 320 [Mϩ], 321 [Mϩ1], 322 [Mϩ2]
C2,6-H), 4.60 (1H, d J ϭ 16.17 Hz, COCH geminal proton), 4.65
(1H, d J ϭ 16.20 Hz, COCH geminal proton), 5.57 (1H, dd JMX ϭ
11.70 Hz, JAX ϭ 4.60 Hz, C5-HX of pyrazoline ring), 7.10Ϫ7.20
(6H, m, phenyl protons and thiophene C4-H), 7.45 (1H, d Jϭ 2.69
Hz, thiophene C3-H), 7.75 (1H, d J ϭ 4.14 Hz, thiophene C5-H).
MS-FABϩ: m/z: 430 [Mϩ1]
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-methoxyphenyl)-2-pyrazoline
(5e)
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
methylphenyl)-2-pyrazoline (7c)
(nm), log ε]: 207.4 (4.71), 315.4 (4.61). IR [ν, cmϪ1
,
EtOH
UV [λmax
KBr]: 1658 (CϭO), 1610-1406 (CϭN, CϭC).
(nm), log ε]: 210.4 (5.12), 320.4 (4.96). IR [ν, cmϪ1
,
EtOH
UV [λmax
KBr]: 1668 (CϭO), 1587Ϫ1406 (CϭN, CϭC), 1226 (CϭS).
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-fluorophenyl)-2-pyrazoline (5f)
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
methylphenyl)-2-pyrazoline (7d)
EtOH
UV [λmax
(nm), log ε]: 208.4 (4.87), 312.4 (4.83). IR [ν, cmϪ1
,
KBr]: 1674 (CϭO), 1602Ϫ1402 (CϭN, CϭC). 1H-NMR (250 MHz,
δ ppm, DMSO-d6): 3.30 (1H, dd JAM ϭ 18.03 Hz, JAX ϭ 4.62 Hz,
EtOH
UV [λmax
(nm), log ε]: 213.6 (4.97), 318.7 (4.50). IR [ν, cmϪ1
,
KBr]: 1674 (CϭO), 1515Ϫ1411 (CϭN, CϭC), 1224 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.55 (6H, m, piperidine
C3,4,5-H), 2.20 (3H, s, Ar-CH3), 3.15 (1H, dd JAM ϭ 17.96 Hz,
C4-HA of pyrazoline ring), 3.95 (1H, dd JMA ϭ 18.06 Hz, JMX
ϭ
11.68 Hz, C4-HM of pyrazoline ring), 4.70 (1H, d Jϭ 13.85 Hz,
COCH geminal proton), 4.75 (1H, d J ϭ 13.84 Hz, COCH geminal
proton), 5.65 (1H, dd JMX ϭ 11.64 Hz, JAX ϭ 4.60 Hz, C5-HX of
pyrazoline ring), 7.20Ϫ7.35 (5H, m, phenyl protons and thiophene
C4-H), 7.55 (1H, d J ϭ 3.63 Hz, thiophene C3-H), 7.85 (1H, dd J ϭ
5.04 Hz, J ϭ 0.96 Hz thiophene C5-H). MS-FABϩ: m/z: 322 [M],
323 [Mϩ1], 324 [Mϩ2]
JAX ϭ 4.51 Hz, C4-HA of pyrazoline ring), 3.90 (1H, dd JMA
ϭ
17.87 Hz, JMX ϭ 11.64 Hz, C4-HM of pyrazoline ring), 3.95Ϫ4.15
(4H, two br. s, piperidine C2,6-H), 4.70 (1H, d J ϭ 16.05 Hz, COCH
geminal proton), 4.75 (1H, d J ϭ 16.04 Hz, COCH geminal proton),
5.55 (1H, dd JMX ϭ 11.61 Hz, JAX ϭ 4.50 Hz, C5-HX of pyrazoline
ring), 7.00Ϫ7.20 (5H, m, phenyl protons and thiophene C4-H), 7.45
(1H, d J ϭ 2.69 Hz, thiophene C3-H), 7.75 (1H, d Jϭ 4.14 Hz,
thiophene C5-H). MS-FABϩ: m/z: 443 [M], 444 [Mϩ1]
1-(Chloroacetyl)-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (5g)
UV [λmax
(nm), log ε]: 208.4 (4.80), 319.4 (4.65). IR [ν, cmϪ1
,
EtOH
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
dimethylaminophenyl)-2-pyrazoline (7e)
KBr]: 1664 (CϭO), 1595Ϫ1413 (CϭN, CϭC). 1H-NMR (250 MHz,
δ ppm, DMSO-d6,): 3.25 (1H, dd JAM ϭ 18.08 Hz, JAX ϭ 4.71 Hz,
EtOH
C4-HA of pyrazoline ring), 3.95 (1H, dd JMA ϭ 18.07 Hz, JMX
ϭ
UV [λmax
(nm), log ε]: 208.4 (4.93), 315.4 (4.84). IR [ν, cmϪ1
,
KBr]: 1658 (CϭO), 1614Ϫ1413 (CϭN, CϭC), 1224 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.85Ϫ2.15 (4H, two m, pyr-
rolidine C3,4-H), 2.90 (6H, s, N(CH3)2), 3.20 (1H, dd JAM ϭ 17.84
Hz, JAX ϭ 4.34 Hz, C4-HA of pyrazoline ring), 3.70Ϫ3.80 (4H, two
t, pyrrolidine C2,5-H), 3.90 (1H, dd JMA ϭ 17.83 Hz, JMX ϭ 11.63
Hz, C4-HM of pyrazoline ring), 4.65 (1H, d J ϭ 15.97 Hz, COCH
geminal proton), 4.70 (1H, d J ϭ 16.00 Hz, COCH geminal proton),
5.50 (1H, dd JMX ϭ 11.66 Hz, JAX ϭ 4.37 Hz, C5-HX of pyrazoline
ring), 6.70 (2H, d J ϭ 8.44 Hz, phenyl C2,6-H), 7.10 (2H, d J ϭ
8.65 Hz, phenyl C3,5-H), 7.20 (1H, t J ϭ 3.73 Hz, thiophene C4-H),
7.55 (1H, d J ϭ 2.93 Hz, thiophene C3-H), 7.80 (1H, d Jϭ 4.46 Hz,
thiophene C5-H). MS-FABϩ: m/z: 458 [M], 459 [Mϩ1]
11.74 Hz, C4-HM of pyrazoline ring), 4.65 (1H, d Jϭ 13.88 Hz,
COCH geminal proton), 4.70 (1H, d J ϭ 13.85 Hz, COCH geminal
proton), 5.60 (1H, dd JMX ϭ 11.75 Hz, JAX ϭ 4.68 Hz, C5-HX of
pyrazoline ring), 7.20 (1H, t J ϭ 3.70 Hz, thiophene C4-H), 7.30
(2H, d J ϭ 8.48 Hz, phenyl C2,6-H), 7.45 (2H, d Jϭ 8.47 Hz, phenyl
C
3,5-H), 7.50 (1H, d J ϭ 2.68 Hz, thiophene C3-H), 7.80 (1H, d Jϭ
5.08 Hz, thiophene C5-H). MS-FABϩ: m/z: 339 [M], 340 [Mϩ1],
341 [Mϩ2]
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-phenyl-
2-pyrazoline (7a)
(nm), log ε]: 208.4 (4.94), 318.2 (4.74). IR [ν, cmϪ1
,
EtOH
UV [λmax
KBr]: 1654 (CϭO), 1519Ϫ1406 (CϭN, CϭC), 1222 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.80Ϫ2.10 (4H, two m, pyr-
rolidine C3,4-H), 3.17 (1H, dd JAM ϭ 18.00 Hz, JAX ϭ 4.60 Hz, C4-
HA of pyrazoline ring), 3.55Ϫ3.75 (4H, two d, pyrrolidine C2,5-H),
3.91 (1H, dd JMA ϭ 18.00 Hz, JMX ϭ 11.70 Hz, C4-HM of pyrazo-
line ring), 4.60 (1H, d J ϭ 16.10 Hz, COCH geminal proton), 4.65
(1H, d J ϭ 16.08 Hz, COCH geminal proton), 5.57 (1H, dd JMX ϭ
11.70 Hz, JAX ϭ 4.60 Hz, C5-HX of pyrazoline ring), 6.60 (2H, d
J ϭ 8.49 Hz, phenyl C2,6-H), 7.20Ϫ7.40 (4H, m, phenyl protons
and thiophene C4-H), 7.55 (1H, s, thiophene C3-H), 7.75 (1H, s,
thiophene C5-H). MS-FABϩ: m/z: 415 [Mϩ], 416 [Mϩ1]
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
dimethylaminophenyl)-2-pyrazoline (7f)
EtOH
UV [λmax
(nm), log ε]: 207.4 (5.11), 317.9 (4.76). IR [ν, cmϪ1
,
KBr]: 1656 (CϭO), 1613Ϫ1413 (CϭN, CϭC), 1225 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.55 (6H, m, piperidine
C3,4,5-H), 2.85 (6H, s, N(CH3)2), 3.15 (1H, dd JAM ϭ 17.82 Hz,
JAX ϭ 4.42 Hz, C4-HA of pyrazoline ring), 3.80 (1H, dd JMA
ϭ
17.88 Hz, JMX ϭ 11.52 Hz, C4-HM of pyrazoline ring), 4.15 (4H,
m, piperidine C2,6-H), 4.60 (1H, d J ϭ 15.92 Hz, COCH geminal
proton), 4.65 (1H, d J ϭ 15.90 Hz, COCH geminal proton), 5.45
(1H, dd JMX ϭ 11.44 Hz, JAX ϭ 4.30 Hz, C5-HX of pyrazoline
ring), 6.60 (2H, d J ϭ 8.70 Hz, phenyl C2,6-H), 7.00 ( 3H, d J ϭ
8.65 Hz, phenyl C3,5-H and thiophene C4-H), 7.45 (1H, d J ϭ 2.86
Hz, thiophene C3-H), 7.75 (1H, d J ϭ 4.30 Hz, thiophene C5-H).
MS-FABϩ: m/z: 472 [M], 473 [Mϩ1]
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-phenyl-
2-pyrazoline (7b)
EtOH
UV [λmax
(nm), log ε]: 207.6 (4.96), 315.3 (4.85). IR [ν, cmϪ1
,
KBr]: 1666 (CϭO), 1471Ϫ1404 (CϭN, CϭC), 1228 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.50Ϫ1.70 (6H, br. s, piperi-
dine C3,4,5-H), 3.17 (1H, dd JAM ϭ 17.90 Hz, JAX ϭ 4.60 Hz, C4-
HA of pyrazoline ring), 3.80 (1H, dd JMAϭ 17.90 Hz, JMX ϭ 11.70
Hz, C4-HM of pyrazoline ring), 3.90Ϫ4.20 (4H, two br. s, piperidine
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
hydroxyphenyl)-2-pyrazoline (7g)
EtOH
UV [λmax
(nm), log ε]: 208.2 (4.90), 319.6 (4.55). IR [ν, cmϪ1
,
KBr]: 3247 (O-H), 1643 (CϭO), 1614Ϫ1421 (CϭN, CϭC), 1228
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

102
Turan-Zitouni et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
(CϭS). 1H-NMR (250 MHz, δ ppm, DMSO-d6,): 1.85Ϫ2.00 (4H,
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
two m, pyrrolidine C3,4-H), 3.10 (1H, dd JAM ϭ 17.96 Hz, JAX
ϭ
chlorophenyl)-2-pyrazoline (7m)
4.25 Hz, C4-HA of pyrazoline ring), 3.55Ϫ3.75 (4H, two t, pyrroli-
dine C2,5-H), 3.85 (1H, dd JMA ϭ 17.91 Hz, JMX ϭ 11.58 Hz, C4-
HM of pyrazoline ring), 4.60 (1H, d J ϭ 16.03 Hz, COCH geminal
proton), 4.65 (1H, d J ϭ 16.00 Hz, COCH geminal proton), 5.40
(1H, dd JMX ϭ 11.61 Hz, JAX ϭ 4.32 Hz, C5-HX of pyrazoline
ring), 6.60 (2H, d J ϭ 8.49 Hz, phenyl C2,6-H), 7.00 (2H, d J ϭ
8.52 Hz, phenyl C3,5-H), 7.10 (1H, t J ϭ 3.71 Hz, thiophene C4-H),
7.45 (1H, d Jϭ 2.70 Hz, thiophene C3-H), 7.75 (1H, d J ϭ 4.96 Hz,
thiophene C5-H), 9.30 (1H, s, Ar-OH). MS-FABϩ: m/z: 431 [M],
432 [Mϩ1]
(nm), log ε]: 208.4 (5.07), 320.4 (4.68). IR [ν, cmϪ1
,
EtOH
UV [λmax
KBr]: 1677 (CϭO), 1595Ϫ1406 (CϭN, CϭC), 1234 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.80Ϫ2.00 (4H, m, pyrroli-
dine C3,4-H), 3.20 (1H, dd JAM ϭ 17.97 Hz, JAX ϭ 4.76 Hz, C4-HA
of pyrazoline ring), 3.55Ϫ3.75 (4H, two t, pyrrolidine C2,5-H), 3.90
(1H, dd JMA ϭ 18.01 Hz, JMX ϭ 11.79 Hz, C4-HM of pyrazoline
ring), 4.60 (1H, d J ϭ 16.18 Hz, COCH geminal proton), 4.65 (1H,
d J ϭ 16.19 Hz, COCH geminal proton), 5.55 (1H, dd JMX ϭ 11.66
Hz, JAX ϭ 4.67 Hz, C5-HX of pyrazoline ring), 7.10 (1H, t J ϭ 2.51
Hz, thiophene C4-H), 7.20 (2H, d J ϭ 8.51 Hz, phenyl C2,6-H), 7.40
(2H, d J ϭ 8.48 Hz, phenyl C3,5-H), 7.45 (1H, d J ϭ 2.73 Hz,
thiophene C3-H), 7.75 (1H, d J ϭ 5.04 Hz, thiophene C5-H). MS-
FABϩ: m/z: 450 [M], 451 [Mϩ1], 452 [Mϩ2]
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
hydroxyphenyl)-2-pyrazoline (7h)
(nm), log ε]: 220.6 (5.14), 315.2 (5.08). IR [ν, cmϪ1
,
EtOH
UV [λmax
KBr]: 3307 (O-H), 1647 (CϭO), 1595Ϫ1417 (CϭN, CϭC), 1226
(CϭS).
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
chlorophenyl)-2-pyrazoline (7n)
UV [λmax
(nm), log ε]: 208.6 (5.11), 320.2 (4.77). IR [ν, cmϪ1
,
EtOH
KBr]: 1664 (CϭO), 1593Ϫ1409 (CϭN, CϭC), 1224 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.60 (6H, m, piperidine
C3,4,5-H), 3.25 (1H, dd JAM ϭ 17.96 Hz, JAX ϭ 4.78 Hz, C4-HA of
pyrazoline ring), 3.95 (1H, dd JMA ϭ 17.90 Hz, JMX ϭ 11.80 Hz,
C4-HM of pyrazoline ring), 4.20 (4H, m, piperidine C2,6-H), 4.70
(1H, d J ϭ 16.18 Hz, COCH geminal proton), 4.75 (1H, d J ϭ
16.21 Hz, COCH geminal proton), 5.60 (1H, dd JMX ϭ 11.55 Hz,
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
methoxyphenyl)-2-pyrazoline (7i)
EtOH
UV [λmax
(nm), log ε]: 207.8 (4.92), 319.8 (4.54). IR [ν, cm-1,
KBr]: 1662 (CϭO), 1610Ϫ1411 (CϭN, CϭC), 1245 (CϭS).
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
methoxyphenyl)-2-pyrazoline (7j)
JAX ϭ 4.72 Hz, C5-HX of pyrazoline ring), 7.20 (1H, t J ϭ 4.35 Hz,
thiophene C4-H), 7.30 (2H, d J ϭ 8.52 Hz, phenyl C2,6-H), 7.45
(2H, d J ϭ 8.42 Hz, phenyl C3,5-H), 7.50 (1H, d J ϭ 3.54 Hz,
thiophene C3-H), 7.80 (1H, d J ϭ 4.97 Hz, thiophene C5-H). MS-
FABϩ: m/z: 464 [M], 465 [Mϩ1], 466 [Mϩ2].
EtOH
UV [λmax
(nm), log ε]: 207.6 (4.89), 318.9 (4.54). IR [ν, cmϪ1
,
KBr]: 1662 (CϭO), 1610Ϫ1415 (CϭN, CϭC), 1228 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.55 (6H, m, piperidine
C3,4,5-H), 3.20 (1H, dd JAM ϭ 17.87 Hz, JAX ϭ 4.47 Hz, C4-HA of
pyrazoline ring), 3.70 (3H, s, Ar-OCH3), 3.90 (1H, dd JMA ϭ 17.88
Hz, JMX ϭ 11.52 Hz, C4-HM of pyrazoline ring), 4.15 (4H, m, pip-
eridine C2,6-H), 4.70 (1H, d J ϭ 16.02 Hz, COCH geminal proton),
4.75 (1H, d J ϭ 16.00 Hz, COCH geminal proton), 5.50 (1H, dd
JMX ϭ 11.57 Hz, JAX ϭ 4.30 Hz, C5-HX of pyrazoline ring), 6.85
(2H, d J ϭ 8.68 Hz, phenyl C2,6-H), 7.15 (3H, d J ϭ 8.59 Hz, phenyl
Microbiology
Antimicrobial activities of compounds were tested using microbroth
dilution method [40]. Tested microorganism strains were; Proteus
vulgaris (NRRL B-123), Escherichia coli (NRRL B-3704), Aero-
monas hydrophila (Ankara University, Faculty of Veterinary
Sciences), Salmonella typhimurium (NRRL B-4420), Streptococcus
feacalis (NRRL B-14617), Micrococcus luteus (NRLL B-4375),
Candida albicans and Candida globrata (isolates obtained from Os-
mangazi University, Faculty of Medicine). Microbroth dilution sus-
ceptibility assay was used for the antimicrobial evaluation of the
compounds. Stock solutions of the samples were prepared in di-
methylsulfoxide. 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 microtitre plates. Overnight grown bac-
terial and Candida suspensions in double-strength Mueller-Hinton
broth were standardised to 108 CFU/mL using McFarland No: 0.5
standard solution. 100 μL of each microorganism suspension was
then added into the wells. The last well-chain without microorgan-
ism was used as a negative control. Sterile distilled water and the
medium served as a positive growth control. After incubation at
37°C for 18Ϫ24 h the first well without turbidity was determined
as the minimal inhibitory concentration (MIC). Chloramphenicol
was used as standard antibacterial agent whereas ketoconazole was
used as antifungal. The observed data on the antimicrobial activity
of the compounds and control drugs are given in Table 2.
C
3,5-H and thiophene C4-H), 7.50 (1H, d J ϭ 3.63 Hz, thiophene
C3-H), 7.75 (1H, d J ϭ 4.16 Hz, thiophene C5-H). MS-FABϩ: m/z:
459 [M], 460 [Mϩ1]
1-[(1-Pyrrolidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
fluorophenyl)-2-pyrazoline (7k)
EtOH
UV [λmax
(nm), log ε]: 207.6 (5.13), 318.2 (4.67). IR [ν, cmϪ1
,
KBr]: 1657 (CϭO), 1603Ϫ1409 (CϭN, CϭC), 1221 (CϭS). 1H-
NMR (250 MHz, δ ppm, DMSO-d6,): 1.85Ϫ2.00 (4H, m, pyrroli-
dine C3,4-H), 3.20 (1H, dd JAM ϭ 18.05 Hz, JAX ϭ 4.69 Hz, C4-HA
of pyrazoline ring), 3.55Ϫ3.70 (4H, two t, pyrrolidine C2,5-H), 3.85
(1H, dd JMAϭ 17.94 Hz, JMX ϭ 11.66 Hz, C4-HM of pyrazoline
ring), 4.65 (1H, d J ϭ 16.18 Hz, COCH geminal proton), 4.70 (1H,
d J ϭ 16.15 Hz, COCH geminal proton), 5.55 (1H, dd JMX ϭ 11.75
Hz, JAX ϭ 4.67 Hz, C5-HX of pyrazoline ring), 7.10Ϫ7.25 (5H, m,
phenyl protons and thiophene C4-H), 7.45 (1H, d J ϭ 2.72 Hz,
thiophene C3-H), 7.75 (1H, d J ϭ 4.12 Hz, thiophene C5-H). MS-
FABϩ: m/z: 433 [M], 434 [Mϩ1], 456 [MϩNa]
Compounds 7cϪn were also evaluated for antituberculosis activity
against Mycobacterium tuberculosis H37Rv (ATCC 27294) using the
BACTEC 460 radiometric system and BACTEC 12B medium. The
preliminary results indicated that all of the tested compounds were
inactive against the test organism.
1-[(1-Piperidinylthiocarbamoylthio)acetyl]-3-(2-thienyl)-5-(4-
fluorophenyl)-2-pyrazoline (7l)
EtOH
UV [λmax
(nm), log ε]: 208.6 (5.43), 319.7 (5.26). IR [ν, cmϪ1
,
KBr]: 1652 (CϭO), 1508Ϫ1415 (CϭN, CϭC), 1224 (CϭS).
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 96−104
Pyrazoline Derivatives and their Antifungal and -bacterial Activities
103
Table 2. MIC values μg/mL of compounds 7aϪn†.
Compounds
A
B
C
D
E
F
G
H
7a
125
250
250
250
125
125
125
250
250
250
250
500
125
250
250
Ϫ
250
500
250
250
250
250
125
250
250
250
250
250
250
250
250
Ϫ
250
500
250
125
250
250
125
125
250
250
250
500
125
250
250
Ϫ
250
500
250
250
250
250
125
125
250
250
250
500
125
250
125
Ϫ
250
500
250
250
250
250
250
250
250
250
250
500
250
500
250
Ϫ
62.5
250
250
62.5
62.5
62.5
62.5
125
125
125
125
125
125
62.5
62.5
Ϫ
250
500
250
250
125
125
125
250
250
250
250
500
250
250
Ϫ
250
500
250
250
125
125
62.5
250
250
250
250
250
250
250
Ϫ
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
Reference-1
Reference-2
15.6
3.9
†
Reference-1: Chloramphenicole, Reference-2: Ketoconazole; A: Proteus vulgaris (NRRL B-123), B: Escherichia coli (NRRL B-3704),
C: Aeromonas hydrophila (Ankara Uni. Fac.of Veterinary), D: Salmonella typhimurium (NRRL B-4420), E: Streptococcus feacalis (NRRL
B-14617), F: Micrococcus luteus (NRRL B-4375), G: Candida albicans (isolates obtained from Osmangazi Uni. Fac.of Medicine),
H: Candida globrata (isolates obtained from Osmangazi University, Faculty of Medicine).
[15] R. Tokuyama, Y. Takahashi, M. Tsubouchi, et al., Chem.
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