Poly(ethylene glycol) (PEG-400) as an alternative reaction solvent for the synthesis of some new 1-(4-(4′-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazolines and their in vitro antimicrobial evaluation

Article abstract of DOI:10.1016/j.ejmech.2009.10.015

Several 1-(4-(4′-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline derivatives were prepared by the base catalyzed treatment of appropriate chalcones with 4-(4′-chlorophenyl)-2-hydrazino-thiazole in poly (ethylene glycol)

Full text of DOI:10.1016/j.ejmech.2009.10.015

European Journal of Medicinal Chemistry 45 (2010) 387–392
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Poly(ethylene glycol) (PEG-400) as an alternative reaction solvent
for the synthesis of some new 1-(4-(40-chlorophenyl)-2-thiazolyl)-
3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazolines
and their in vitro antimicrobial evaluation
*
Bhaskar S. Dawane , Shankaraiah G. Konda, Gajanan G. Mandawad, Baseer M. Shaikh
Organic Research Laboratory, Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, Maharashtra 431602, India
a r t i c l e i n f o
a b s t r a c t
Several 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline
derivatives were prepared by the base catalyzed treatment of appropriate chalcones with 4-(40-chlor-
ophenyl)-2-hydrazino-thiazole in poly (ethylene glycol) (PEG-400) as an alternative reaction solvent. All
the synthesized compounds were tested for their antimicrobial activities against Escherichia coli (MTCC
2939), Salmonella typhi (MTCC 98), Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC 441),
Aspergillus niger (MTCC 281), Trichoderma viridae (MTCC 167), Penicillium chrysogenum (MTCC 160),
Fusarium moniliforme (MTCC 156) and Candida albicans (MTCC 183). Most of the compounds showed
potent antibacterial and antifungal activity.
Article history:
Received 8 May 2009
Received in revised form
3 October 2009
Accepted 9 October 2009
Available online 14 October 2009
Keywords:
PEG-400
Chalcones
Ó 2009 Elsevier Masson SAS. All rights reserved.
2-Hydrazino-thiazole
1-Thiazolyl-2-pyrazolines
Antimicrobial activity
1. Introduction
virtue of the presence of critical structural features. Electron-rich
nitrogen heterocycles play an important role in diverse biological
There has been significant increase in the frequency of
systematic fungal infection in humans. Patients undergoing organ
transplants, anticancer chemotherapy, or long treatment with
antimicrobial agents, and patients with AIDS, are immunosup-
pressed and very susceptible to life-threatening systematic fungal
infections like Candidiasis, Cryptococcosis, and Aspergillosis.
Resistance to antibacterial agents is a significant problem since last
few decades [1–3]. In addition, primary and opportunistic fungal
infections continue to increase rapidly because of the increased
number of immunocompromised patients (AIDS, cancer and
transplants). Several reviews have appeared illustrating the prob-
lems encountered by today’s infectious disease clinicians [4,5].
To overcome this rapid development of drug resistance, new
agents should preferably consist of chemical characteristics that
clearly differ from those of existing agents. In the process of drug
designing an essential component of the search for new leads is the
synthesis of novel molecules, which are biologically active by the
activities. Introducing a pyrazolidinone ring [6,7] in place of the
-lactam ring (in penicillins and cephalosporins [8] results in
b
enhanced activity). Second nitrogen in the five-membered ring also
influences the antibacterial or pharmacokinetic properties [9,10].
Pyrazoline derivatives have also been reported in the literature to
exhibit various pharmacological activities such as anti-inflamma-
tory [11], antihypertensive [12], and antimicrobial [13–15]. On the
other hand, sulfur and/or nitrogen heterocycles having pharma-
ceutical activities are widely occur in nature in the form of alka-
loids, vitamins, pigments and as a constituents of plant and animal
cells. Penicillins containing a thiazole ring system (thiazolidine)
[16] are also important naturally occurring products. Thiazoles and
their derivatives are found to possess various biological activities
such as antituberculosis [17], anti-HIV [18].
2. Chemistry
The synthetic pathway of the compounds is outlined in the
scheme 1 and 2. The starting 4-(40-chlorophenyl)-2-hydrazino-
thiazole (I) was prepared by the treatment of 4-chloro-
a-hal-
* Corresponding author. Fax: þ91 2462 53726, þ91 9423584000.
E-mail address: bhaskardawane@rediffmail.com (B.S. Dawane).
oketone with thiosemicarbazide in PEG-400 (10 mL) at 40 ꢀC, while
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.10.015

388
B.S. Dawane et al. / European Journal of Medicinal Chemistry 45 (2010) 387–392
Cl
Cl
S
N
PEG-400
stirred
CH2Br
H2N NH
C
NH2
+
NHNH2
S
O
I
R2
R2
Cl
Cl
R3
R4
R1
O
R3
R4
R1
N
N
PEG-400
KOH
+
OHC
N
H
N
O
H
II(a-p)
Scheme 1. Synthesis of 2-hydrazino-thiazole (I) and Chalcones (II).
the novel
a,
b-unsaturated carbonyl compounds (IIa–p) were
0.1 mL of target compound dilution ranging from 25 to 250 mg/mL
prepared by Claisen -Schmidt condensation by reacting substituted
acetophenones and 2-butyl-4-chloro-5-formyl-imidazole (BCFI) in
PEG-400 at 40 ꢀC for 1 h (Scheme 1). Finally, the synthesis of
1-thiazolyl-2-pyrazolines (IIIa–p) was attempted by the reacting
separately for each bacterial strain. All the plates were incubated at
37 ꢁ 0.5 ꢀC for 24 h. Zone of inhibition and minimum inhibitory
concentrations (MICs) were noted. The results of antibacterial
studies are given in Table 2.
For antifungal activity, all the culture strains of fungi
maintained on potato dextrose agar (PDA) slant at 27 ꢁ 0.2 ꢀC for
24–48 h, till sporulation. Spore of strains were transferred in to
5 mL of sterile distilled water containing 1% Tween-80 (to suspend
the spore properly). The spores were counted by haemocytometer
(106 CFU/mL). Sterile PDA plate was prepared containing 2% agar;
0.1 mL of each fungal spore suspension was spread on each plate
and incubated at 27 ꢁ 0.2 ꢀC for 12 h. After incubation well
prepared using sterile cork borer and each agar well was filled with
4-(40-chlorophenyl)-2-hydrazino-thiazole with
a
,b
-unsaturated
carbonyl compounds (chalcones) using NaOH in PEG-400 under
mild reaction condition (Scheme 2).
3. Biology
The antimicrobial activities of the synthesized compounds (IIIa–
p) were determined by agar diffusion method as recommended by
the National Committee for Clinical Laboratory Standards, (NCCLS)
[19–21]. The compounds were evaluated for antimicrobial activity
against bacteria viz. Escherichia coli (MTCC 2939), Salmonella typhi
(MTCC 98), Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC
441) and antifungal activity against various fungi viz. Aspergillus
niger (MTCC 281), Trichoderma viridae (MTCC 167), Penicillium
chrysogenum (MTCC 160), Candida albicans (MTCC 183) and Fusa-
0.1 mL compound solution of concentrations 25–250 mg/mL sepa-
rately to get minimum inhibitory concentration (MIC) value of 1-
thiazolyl-2-pyrazolines. The plates were kept in refrigerator for
20 min for diffusion and then incubated at 27 ꢁ 0.2 ꢀC for 24–28 h.
Zone of inhibition and minimum inhibitory concentrations (MICs)
were noted. The results of antifungal studies are given in Table 3.
rium moniliforme (MTCC 156). The antibiotic Tetracycline (25
mg/mL)
and Nystatin (25 g/mL) are used as reference antibacterial and
antifungal substances, respectively for comparison. Dimethyl
sulphoxide (1%, DMSO) was used a control.
The culture strains of bacteria were maintained on nutrient agar
slant at 37 ꢁ 0.5 ꢀC for 24 h. The antibacterial activity was evaluated
using nutrient agar plate seeded with 0.1 mL of respective bacterial
culture strain suspension prepared in sterile saline (0.85%) of
105 CFU/mL dilutions. The wells of 6 mm diameter were filled with
m
4. Results and discussion
Prompted by the above mentioned biological properties of
pyrazolines, it was contemplated to synthesize some new series of
Table 1
Synthesis of some new l-thiazolyl-2-pyrazolines using PEG-400.
Product
R1
R2
R3
R4
Timea
Yield(%)b
M.P.(ꢀC)
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIJ
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
OH
H
H
H
I
Br
H
I
Br
H
H
I
Br
H
H
I
H
Cl
H
H
Me
Me
Me
NH2
OMe
H
H
H
H
H
H
H
Cl
H
35
20
35
25
30
30
35
30
30
35
30
40
30
35
25
30
90
92
88
90
89
88
88
89
90
88
89
88
87
88
90
91
134
148
162
125
118
152
122
138
145
156
135
128
115
168
154
140
R2
OH
OH
OH
OH
OH
H
Cl
Cl
Cl
Cl
Cl
H
R3
R4
R1
Cl
N
NaOH, 80 oC
PEG-400
N
N
I
II
+
N
N
H
H
H
OH
OH
OH
OH
OH
OH
OH
Me
Me
Me
H
I
Br
Cl
S
III(a-p)
Br
Cl
Cl
a
Time in minutes.
Pure isolated yields of products.
b
Scheme 2. Synthesis of target molecules (1-thiazolyl-2-pyrazolines) (III).

B.S. Dawane et al. / European Journal of Medicinal Chemistry 45 (2010) 387–392
389
Table 2
All the structures of products were appropriately established
by spectroscopic data and analytical methods. The IR spectra of all
the products showed disappearance of band at 1640–1655 cmꢂ1
due to >C]O of chalcones. The 1H NMR spectra of the
compounds, the CH2 protons of the pyrazoline ring resonated as
Antibacterial activities of 1-thiazolyl-2-pyrazolines (IIIa–p).
Compound
Ec
St
Sa
Bs
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
18 (25)
16 (25)
20 (25)
21 (25)
14 (50)
18 (25)
15 (25)
12 (50)
16 (25)
14 (50)
16 (25)
11 (50)
15 (50)
20 (25)
22 (25)
21 (25)
30 (25)
12 (50)
10 (50)
16 (25)
18 (25)
09 (50)
16 (25)
12 (50)
–
14 (50)
15 (25)
12 (50)
–
10 (50)
18 (25)
19 (25)
18 (25)
28 (25)
16 (25)
12 (50)
18 (25)
16 (25)
12 (50)
14 (50)
11 (50)
10 (50)
18 (25)
15 (25)
12 (50)
–
13 (50)
16 (25)
18 (25)
16 (25)
30 (25)
18 (25)
14 (50)
21 (25)
15 (25)
–
19 (25)
18 (25)
08 (50)
16 (25)
12 (50)
14 (50)
12 (50)
16 (50)
20 (25)
21 (25)
22 (25)
32 (25)
a pair of doublets of doublets at
4.21 ppm (HB). The –CH (Hx) proton appeared as a doublet of
doublets at 5.23–5.71 ppm due to vicinal coupling with the two
d 3.34–3.62 ppm (HA), d 3.92–
d
magnetically non-equivalent protons of the methylene group at
position 4 of the pyrazoline ring (JAB ¼ 17.7–18.3 Hz, JAx ¼ 8.1–8.4,
JBx ¼ 12.0–12.3). The -5H of thiazole was observed as singlet in the
range of 6.95–7.15 ppm. Phenolic proton appeared as a singlet
IIIk
IIIl
near
d 11.0–13.0 due to the hydrogen bonding, while other
IIm
IIIn
IIIo
IIIp
Tetracycline
aromatic and aliphatic protons were observed at excepted
regions. 13C NMR data of compound IIIe exhibited the chemical
shift values of the carbon atoms at
and 154 ppm (C-3) of the 2-pyrazoline ring. The chemical shift
value at 168 ppm corroborates the C-2 of the thiazole. The mass
d 43 ppm (C-4), d 66 ppm (C-5)
d
d
Zone of inhibition measured in mm; MIC values (
Ec-Escherichia coli; St-Salmonella typhi.
Sa-Staphylococcus aureus; Bs-Bacillis subtilis.
mg/mL) are given in brackets.
spectra (EIMS) of compounds were also in agreement with their
molecular formula.
‘‘–’’ Indicates the concentration > 100 mg/mL.
The results of in vitro antibacterial activities of compounds
(IIIa–p) against various bacterial strains are summarized in Table 2.
It has been observed that some of compounds exhibited interesting
antibacterial activities. Compounds IIIa, IIIb, IIIf, IIIg, IIIi and IIIk
showed effective activity against E. coli, and compounds IIIa, IIIf,
IIIg and IIIi were displayed a good zone of inhibition against
B. subtilis. Compounds IIIb, IIIg and IIIk displayed a slightly active
towards S. typhi and S. aureus. Compounds IIIe, IIIl, IIIh, and IIIm
were displayed less active against all tested bacteria. On the other
hand, it was found that compounds IIIc, IIId, IIIn, IIIo and IIIp were
showed stronger inhibitory activity against all bacteria than other
compounds.
thiazolyl pyrazolines under the frame of ‘green chemistry’. In recent
years, poly (ethylene glycol) prompted reactions [22–26] have
attracted the attention of organic chemists due to their solvating
ability and aptitude to act as a phase transfer catalyst, negligible
vapor pressure, easy recyclability, ease of work-up, eco-friendly
nature and economical cost. PEG is non-toxic, non-halogenated,
inexpensive potentially recyclable and water soluble which facili-
tate its removal from reaction product. To best of our knowledge,
there are no earlier reports for the synthesis of 1-thiazolyl-2-pyr-
azolines using poly (ethylene glycol) (PEG-400) as green reaction
medium.
The results of antifungal activities of synthesized compounds
(IIIa–p) were summarized in Table 3. Most of the compounds were
In this report, we wish to describe a mild and efficient method for
the synthesis of 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-
butyl-4-chloro-1H-imidazol-5yl)-2-pyrazolines using poly (ethylene
glycol) (PEG-400) as an alternative reaction solvent. The target
molecules were attempted by the treatment of 4-(40-chlorophenyl)-
showed a significant level of activity at concentration 25 mg/mL, in
comparison with standard antifungal. Compounds IIIa, IIIc, IIId,
and IIIi were showed a good inhibitory activity against A. niger and
the compounds IIIn, IIIo, and IIIp exhibited greater antifungal
activity than standard Nystatin against A. niger. Compounds IIIa,
IIIc, IIId, IIIf, IIIi, IIIj, IIIk and IIIm were showed good activity
against T. viridae. Compounds IIIo and IIIp were displayed similar
level of activity and IIIn showed higher activity than standard
against T. viridae. Compounds IIIa, IIIc, IIIe, IIIj and IIIm were
showed moderate activity towards P. chrysogenum. Compounds
IIId, IIIn were showed equivalent activity and IIIo, IIIp were dis-
played stronger activity than standard antifungal drug against P.
chrysogenum. Compounds IIIa, IIIb, IIIc, IIId, IIIf, IIIi, IIIk, IIIm and
IIIn were more sensitive towards C. albicans. Compounds IIIn
showed similar level of activity and IIIo displayed higher activity
than standard drug against C. albicans. Compounds IIIa, IIIc, IIIf,
IIIg, IIIi, IIIm, IIIo and IIIp were exhibited good zone of inhibition
against F. moniliforme as compared with standard antibiotic. Only
the compound IIIn showed similar level of activity against F.
moniliforme. From the studies of antifungal activity, it was observed
that compounds IIIn, IIIo and IIIp were exhibited more potent
activity against all fungal strains than other compounds. Consid-
ering the results obtained from antifungal and antibacterial tests
together, it is noteworthy to mention that tested compounds are
more active towards fungi than bacteria.
2-hydrazino-thiazole with
a,b-unsaturated carbonyl compounds
(chalcones) using NaOH in PEG-400 under mild reaction condition.
Table 3
Antifungal activities of 1-thiazolyl-2-pyrazolines (IIIa–p).
Compound
An
Tv
Pc
Ca
Fm
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIm
IIIn
IIIo
IIIp
Nystatin
16 (25)
12 (50)
15 (25)
18 (25)
12 (50)
14 (25)
15 (25)
14 (25)
16 (25)
14 (25)
10 (50)
12 (50)
14 (25)
19 (25)
20 (25)
19 (25)
18 (25)
15 (25)
11 (50)
16 (25)
15 (25)
14 (25)
12 (25)
16 (50)
12 (50)
14 (25)
14 (25)
14 (25)
08 (50)
16 (25)
20 (25)
18 (25)
18 (25)
18 (25)
12 (25)
10 (50)
14 (25)
16 (25)
13 (25)
15 (25)
09 (50)
10 (50)
12 (50)
12 (25)
13 (50)
–
14 (25)
16 (25)
18 (25)
18 (25)
16 (25)
16 (25)
14 (25)
15 (25)
16 (25)
–
13 (25)
12 (50)
–
14 (25)
11 (50)
12 (25)
10 (50)
15 (25)
18 (25)
20 (25)
16 (25)
18 (25)
15 (25)
11 (50)
12 (25)
10 (50)
11(50)
14 (25)
15 (25)
–
12 (25)
10 (50)
09 (50)
11 (50)
13 (25)
16 (25)
14 (25)
15 (25)
16 (25)
5. Conclusion
Zone of inhibition measured in mm; MIC values (
mg/mL) are given in brackets.
An-Aspergillus niger; Tv-Trichoderma virdea; Ca-Candida albicans.
Pc-Penicillium chrysogenum; Fm-Fusarium moniliforme.
In summary, we have developed a novel, efficient and envi-
ronmentally benign methodology towards the synthesis of 1-(4-
(40-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-
‘‘–’’ Indicates the concentration > 100 mg/mL.

390
B.S. Dawane et al. / European Journal of Medicinal Chemistry 45 (2010) 387–392
imidazol-5yl)-2-pyrazolines by the reaction of chalcones with
2-hydrazino-thiazole in PEG-400 as an alternative reaction solvent.
Pyrazolines carrying 2-hydroxy-3-iodo-5-chloro-phenyl (IIIc),
2-hydroxy-3-bromo-5-chloro-phenyl (IIId), 2-hydroxy-3, 5-di-
iodo-phenyl (IIIn), 2-hydroxy-3, 5-dibromo-phenyl (IIIo), and
2-hydroxy-3, 5-dichloro-phenyl (IIIp) were exhibited stronger
antifungal and antibacterial activity. The substitution of hydroxyl
group in position 2 and presence of halo groups in 3 and 5 positions
emerged as active in both antibacterial and antifungal screening.
Hence, it is concluded that there is enough scope for further study
in the developing these as good lead compounds.
6.4. Typical procedure for the synthesis of 1-(4-(40-chlorophenyl)-
2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H- imidazol-5yl)-2-
pyrazolines (IIIa–p)
A mixture of chalcone II (5 mmol), 2-hydrazino thiazole I
(5 mmol), NaOH (10 mmol) and PEG-400 (20 mL) was stirred at
room temperature for 5 min and then temperature raised to 80 ꢀC
for the period as shown in Table 1. After completion of reaction
(TLC), the reaction mixture was cooled and poured in ice cold water
(25 mL). The obtained solid product was filtered and washed with
2 ꢃ 5 mL water and recrystallized by aqueous acetic acid to give
pure product III. PEG-400 was recovered from water by direct
distillation and reused for second run by charging the same
substrates.
6. Experimental
6.5. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(5-chloro-2-
hydroxyphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIa)
Melting points were determined by in an open capillary method
and are uncorrected. The chemicals and solvents used for labora-
tory grade and were purified. IR spectra were recorded (in KBr
pallets) on Shimadzu spectrophotometer. 1H NMR spectra were
recorded (in DMSO-d6) on Avance-300 MHz spectrometer using
TMS as an internal standard. The mass were recorded on EI-Shi-
madzu GC–MS spectrometer. Elemental analyses were performed
on a Carlo Erba 106 Perkin–Elmer model 240 analyzer.
IR (KBr, cmꢂ1): 1602 (–C]N), 3126 (–OH), 3336 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3),1.31 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–), 2.75 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.43 (dd, 1H,
J ¼ 17.7, 8.1 Hz), 4.04 (dd,1H, J ¼ 17.7, 12.0 Hz,), 5.54 (dd, 1H, J ¼ 12.0,
8.1 Hz, -Hx), 7.05 (s, 1H, -5H of thiazole), 7.28–8.16 (m, 7H, Ar–H),
8.21 (s, 1H, –NH, D2O exchangeable), 12.46 (s, 1H, –OH, D2O
exchangeable); EIMS (m/z): 546 (Mþ), 548 (M þ 2, 30), 550 (M þ 4,
12), 552 (M þ 6, 4); Anal. Calcd for C25H22ON5SCl3: C, 54.92; H, 4.02;
N, 12.80%. Found: C, 54.78; H, 4.14; N, 12.68%
6.1. General procedure for the synthesis of 4-(40-chlorophenyl)-2-
hydrazino-thiazole (I)
A mixture of 4-chloro-a-halo-ketone (5 mmol), thiosemicarbazide
(5 mmol), and was stirred in PEG-400 (10 mL) at 40 ꢀC for 20 min.
After completion (TLC), the reaction mixture was extracted with
diethyl ether (2 ꢃ 20 mL). The combined organic layers were dried
over anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The crude product was recrystallized from 20%
aqueous acetic acid to afford to the pure product.
6.6. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(4-chlorophenyl)-5-(2-
butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline (IIIb)
IR (KBr, cmꢂ1): 1595 (–C]N), 3333 (–NH); 1H NMR (DMSO-d6,
d
ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3), 1.32 (m, 2H, –CH2–), 1.65
(m, 2H, –CH2–), 2.76 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.41 (dd, 1H, J ¼ 17.7,
8.1 Hz), 4.08 (dd, 1H, J ¼ 17.7, 12.0 Hz), 5.51 (dd, 1H, J ¼ 12.3, 8.1 Hz),
7.02 (s, 1H, -5H of thiazole), 7.26–8.15 (m, 8H, Ar–H), 8.22 (s, 1H,
–NH, D2O exchangeable); EIMS (m/z): 531(Mþ), 287 (100%); Anal.
Calcd. For C25H22N5SCl3: C, 56.58; H, 4.14; N, 13.19%. Found: C,
56.68; H, 4.21; N, 13.05%
(I): M.P. 158 ꢀC; Yield, 88%; IR (KBr, cmꢂ1): 1586, 1610; 1H NMR
(DMSO-d6,
d ppm): 6.95 (s, 1H, -5H of thiazole), 7.22 (s, 2H, NH2),
7.52 (d, 1H, J ¼ 9 Hz), 7.71 (d, 1H, J ¼ 9 Hz), 8.26 (s, 1H, NH); EIMS
(m/z): 224 (Mþ).
6.2. General procedure for synthesis of 1-(Substituted phenyl)-3-(2-
butyl-4-chloro-1H-imidazol-5yl)-2-propen-1-ones (IIa–p)
6.7. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(5-chloro-2-hydroxy-3-
iodophenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIc)
An equimolar mixture of substituted acetophenone (1 mmol),
2-butyl-4-chloro-5-formyl-imidazole (1 mmol) and KOH (2 mmol)
was stirred in PEG-400 (15 mL) at 40 ꢀC for 1 h. After completion of
the reaction (monitored by TLC), the crude mixture was worked up
in ice cold water (100 mL). Product separated out was filtered and
processed out. Filtrate was evaporated to remove water leaving
PEG behind. The same PEG was utilized to synthesize further
chalcones.
IR (KBr, cmꢂ1): 1605 (–C]N), 3158 (–OH), 3331 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.93 (t, J ¼ 7.2 Hz, 3H, –CH3), 1.31 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–),
d
2.74 (t, J ¼ 7.8 Hz, 2H, –CH2), 3.48 (dd, 1H,
J ¼ 18.0, 8.1 Hz), 4.10 (dd, 1H, J ¼ 18.0, 12.0 Hz), 5.58 (dd, 1H, J ¼ 12.0,
8.1 Hz), 7.05 (s, 1H, -5H of thiazole), 7.23–8.16 (m, 6H, Ar–H), 8.20
d
(s, 1H, –NH, D2O exchangeable), 12.51 (s, 1H, –OH, D2O exchange-
able); EIMS (m/z): 672 (Mþ), 674 (M þ 2, 44), 676 (M þ 4, 16), 678
(M þ 6, 5); Anal. Calcd. For C25H21ON5SCl3I: C, 44.64; H, 3.12; N,
10.40%. Found: C, 44.55; H, 3.15; N, 10.29%
6.3. 1-(4-chlorophenyl)-3-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
propen-1-one (IIb)
6.8. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(3-bromo-5-chloro-2-
hydroxyphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIId)
M.P. 115 ꢀC; Yield, 91%; IR (KBr, cmꢂ1): 1598 (–C ¼ N), 1651
(>C ¼ O), 3335 (–NH); 1H NMR (DMSO-d6,
d ppm): 0.93
(t, J ¼ 7.2 Hz, 3H, –CH3), 1.32 (m, 2H, –CH2–), 1.64 (m, 2H, –CH2–),
2.72 (t, J ¼ 7.5 Hz, 2H, –CH2), 7.12–7.98 (m, 6H, Ar–H þ CH ¼ CH),
IR (KBr, cmꢂ1): 1604 (–C]N), 3142 (–OH), 3330 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.5 Hz, 3H, –CH3),1.30 (m, 2H, –CH2–),
8.19 (s, 1H, –NH, D2O exchangeable); 13C NMR (DMSO-d6,
d ppm):
14, 22, 29, 30, 117, 122, 128, 129 (2 ꢃ C), 130 (2 ꢃ C) 134, 136, 138,
152, 187; EIMS (m/z): 322 [Mþ], 324 [M þ 2] (14), 326 [M þ 4] (8),
287 [100%]; Anal. Calcd. For C16H16ON2Cl2: C, 59.62; H, 4.96; N,
8.69%. Found: C, 59.54; H, 4.81; N, 8.74%
1.65 (m, 2H, –CH2–),
d
2.75 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.46 (dd, 1H,
J ¼ 18.3, 8.4 Hz), 4.08 (dd,1H, J ¼ 18.3,12.3 Hz), 5.51 (dd,1H, J ¼ 12.3,
8.4 Hz), 7.08 (s, 1H, -5H of thiazole), 7.26–8.18 (m, 6H, Ar–H), 8.21 (s,
1H, –NH, D2O exchangeable), 12.38 (s, 1H, –OH, D2O exchangeable);

B.S. Dawane et al. / European Journal of Medicinal Chemistry 45 (2010) 387–392
391
EIMS (m/z): 625 (Mþ), 627 (M þ 2, 22), 629 (M þ 4, 12), 631 (M þ 6,
3); Anal. Calcd. For C25H21ON5SCl3Br: C, 47.99; H, 3.35; N, 11.19%.
Found: C, 47.86; H, 3.41; N, 11.28%
1.61 (m, 2H, –CH2–), 2.41 (s, 3H, CH3), 2.76 (t, J ¼ 7.8 Hz, 2H, –CH2),
3.54 (dd,1H, J ¼ 17.7, 8.4 Hz), 4.13 (dd,1H, J ¼ 17.7,12.3 Hz), 5.61 (dd,
1H, J ¼ 12.3, 8.4 Hz), 7.06 (s, 1H, -5H of thiazole), 7.23–8.18 (m, 6H,
Ar–H), 8.21 (s, 1H, –NH, D2O exchangeable), 12.48 (s, 1H, –OH, D2O
exchangeable); EIMS (m/z): 652 (Mþ), 654 (M þ 2, 26), 656 (M þ 4,
5); Anal. Calcd. For C26H24ON5SCl2I: C, 47.87; H, 3.73; N, 10.72%.
Found: C, 47.76; H, 3.78; N, 10.65%
6.9. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(5-chloro-2-hydroxy-4-
methylphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIe)
IR (KBr, cmꢂ1): 1597 (–C]N), 3118 (–OH), 3335 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.92 (t, J ¼ 7.5 Hz, 3H, –CH3),1.32 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–), 2.34 (s, 3H, CH3), 2.76 (t, J ¼ 7.8 Hz, 2H, –CH2),
3.42 (dd, 1H, J ¼ 18.3, 8.1 Hz), 4.05 (dd, 1H, J ¼ 18.3, 12.3 Hz), 5.56
(dd, 1H, J ¼ 12.3, 8.1 Hz), 7.06 (s, 1H, -5H of thiazole), 7.24–8.16 (m,
6H, Ar–H), 8.21 (s, 1H, –NH, D2O exchangeable), 12.31 (s, 1H, –OH,
D2O exchangeable); 13C NMR (DMSO-d6, d ppm): 14, 16, 22, 28, 30,
43, 66, 113, 116, 122, 123, 124, 126, 128 (2 ꢃ C), 129 (2 ꢃ C), 130, 131,
132, 133, 138, 140, 142, 154, 168; EIMS (m/z): 559 (Mþ), 561 (M þ 2,
89), 563 (M þ 4, 86), 565 (M þ 6, 8), 317 (100); Anal. Calcd. For
C26H24ON5SCl3: C, 55.69; H, 4.28; N,12.48%. Found: C, 55.65; H, 4.18;
N, 12.55%
6.14. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(2-hydroxy-5-
methylphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIl)
IR (KBr, cmꢂ1): 1599 (–C]N), 3136 (–OH), 3335 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.5 Hz, 3H, –CH3), 1.33 (m, 2H, –CH2–
),1.64 (m, 2H, –CH2–), 2.34 (s, 3H, CH3), 2.75 (t, J ¼ 7.8 Hz, 2H, –CH2),
3.51 (dd, 1H, J ¼ 18.0, 8.1 Hz), 4.09 (dd, 1H, J ¼ 18.0, 12.0 Hz), 5.58
(dd, 1H, J ¼ 12.0, 8.1 Hz), 7.05 (s, 1H, -5H of thiazole), 7.25–8.16
(m, 7H, Ar–H), 8.19 (s, 1H, –NH, D2O exchangeable), 12.32 (s, 1H,
–OH, D2O exchangeable); EIMS (m/z): 526 (Mþ), 528 (M þ 2, 30),
530 (M þ 4, 9); Anal. Calcd. For C26H25ON5SCl2: C, 59.34; H, 4.75; N,
13.30%. Found: C, 59.42; H, 4.78; N, 13.41%
6.10. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(3-bromo-5-chloro-2-
hydroxy-4-methylphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIg)
6.15. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(2-hydroxyphenyl)-5-
(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline (IIIm)
IR (KBr, cmꢂ1): 1599 (–C]N), 3138 (–OH), 3338 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3),1.31 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–), 2.36 (s, 3H, CH3), 2.75 (t, J ¼ 7.5 Hz, 2H, –CH2),
3.51 (dd,1H, J ¼ 18.0, 8.1 Hz), 4.12 (dd,1H, J ¼ 18.0,12.0 Hz), 5.58 (dd,
1H, J ¼ 12.0, 8.1 Hz), 7.08 (s, 1H, -5H of thiazole), 7.23–8.15 (m, 5H,
Ar–H), 8.21 (s, 1H, –NH, D2O exchangeable), 12.48 (s, 1H, –OH, D2O
exchangeable); EIMS (m/z): 639 (Mþ), 641 (M þ 2, 25), 643 (M þ 4,
18), 645 (M þ 6, 5) Anal. Calcd. For C26H23ON5SCl3Br: C, 48.82; H,
3.59; N, 10.94%. Found: C, 48.74; H, 3.68; N, 10.82%
IR (KBr, cmꢂ1): 1601 (–C]N), 3128 (–OH), 3335 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.93 (t, J ¼ 7.2 Hz, 3H, –CH3),1.32 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–), 2.76 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.46 (dd, 1H,
J ¼ 18.3, 8.4 Hz ꢂ HA), 4.08 (dd, 1H, J ¼ 18.3, 12.3 Hz), 5.52 (dd, 1H,
J ¼ 12.3, 8.4 Hz), 7.05 (s, 1H, -5H of thiazole), 7.23–8.16 (m, 8H, Ar–
H), 8.21 (s, 1H, –NH, D2O exchangeable), 12.43 (s, 1H, –OH, D2O
exchangeable); EIMS (m/z): 512 (Mþ), 514 (M þ 2, 20), 516 (M þ 4,
5); Anal. Calcd. For C25H23ON5SCl2: C, 58.62; H, 4.49; N, 13.66%.
Found: C, 58.71; H, 4.58; N, 13.58%
6.11. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(4-aminophenyl)-5-(2-
butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline (IIIh)
6.16. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(3,5-dibromo-2-
hydroxyphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIo)
IR (KBr, cmꢂ1): 1602 (–C]N), 3331 (–NH); 1H NMR (DMSO-d6,
d
ppm): 0.91 (t, J ¼ 7.5 Hz, 3H, –CH3), 1.31 (m, 2H, –CH2–), 1.65 (m,
2H, –CH2–), 2.75 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.46 (dd, 1H, J ¼ 17.7,
8.1 Hz), 4.11 (dd, 1H, J ¼ 17.7, 8.1 Hz), 5.56 (dd, 1H, J ¼ 12.0, 8.1 Hz),
7.05 (s, 1H, -5H of thiazole), 7.23–8.15 (m, 8H, Ar–H), 8.20 (s, 1H,
–NH, D2O exchangeable); EIMS (m/z): 511 (Mþ), 513 (M þ 2, 16), 515
(M þ 4, 6); Anal. Calcd. For C25H24N6SCl2: C, 58.73; H, 4.69; N,
16.43%. Found: C, 58.85; H, 4.62; N, 16.38%
IR (KBr, cmꢂ1): 1605 (–C]N), 3142 (–OH), 3331 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3),1.31 (m, 2H, –CH2–),
1.62 (m, 2H, –CH2–), 2.75 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.52 (dd, 1H,
J ¼ 18.0, 8.1 Hz), 4.11 (dd, 1H, J ¼ 18.0, 12.3 Hz), 5.56 (dd, 1H, J ¼ 12.3,
8.1 Hz), 7.08 (s, 1H, -5H of thiazole), 7.23–8.18 (m, 6H, Ar–H), 8.20
(s, 1H, –NH, D2O exchangeable), 12.38 (s, 1H, –OH, D2O exchange-
able); EIMS (m/z): 670 (Mþ), 672 (M þ 2, 32), 674 (M þ 4, 18), 676
(M þ 6, 4); Anal. Calcd. For C25H21ON5SCl2Br2: C, 44.81; H, 3.13; N,
10.44%. Found: C, 44.72; H, 3.25; N, 10.36%
6.12. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(4-methoxyphenyl)-5-
(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazoline (IIIi)
IR (KBr, cmꢂ1): 1599 (–C]N), 3333 (–NH); 1H NMR (DMSO-d6,
d
ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3), 1.32 (m, 2H, –CH2–), 1.65
(m, 2H, –CH2–), 3.41 (s, 3H, OCH3), 2.76 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.48
(dd, 1H, J ¼ 18.3, 8.1 Hz), 4.11 (dd, 1H, J ¼ 18.3, 12.0 Hz), 5.62 (dd, 1H,
J ¼ 12.0, 8.1 Hz), 7.08 (s, 1H, -5H of thiazole), 7.21–8.15 (m, 8H, Ar–
H), 8.19 (s, 1H, –NH, D2O exchangeable); EIMS (m/z): 526 (Mþ), 528
(M þ 2, 38), 530 (M þ 4, 8); Anal. Calcd. For C26H25ON5SCl2: C,
59.34; H, 4.75; N, 13.30%. Found: C, 59.21; H, 4.82; N, 13.16%
6.17. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(3,5-dichloro-2-
hydroxyphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIp)
IR (KBr, cmꢂ1): 1600 (–C]N), 3151 (–OH), 3338 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.5 Hz, 3H, –CH3),1.32 (m, 2H, –CH2–),
1.65 (m, 2H, –CH2–), 2.76 (t, J ¼ 7.5 Hz, 2H, –CH2), 3.63 (dd, 1H,
J ¼ 17.7, 8.1 Hz), 4.16 (dd, 1H, J ¼ 17.7, 12.3 Hz), 5.66 (dd, 1H, J ¼ 12.3,
8.1 Hz), 7.10 (s, 1H, -5H of thiazole), 7.25–8.18 (m, 6H, Ar–H), 8.21
(s, 1H, –NH, D2O exchangeable), 12.52 (s, 1H, –OH, D2O exchange-
able); EIMS (m/z): 581 (Mþ), 583 (M þ 2, 46), 585 (M þ 4, 25), 587
(M þ 6, 8), 589 (M þ 8, 2); Anal. Calcd. For C25H21ON5SCl4: C, 51.66;
H, 3.61; N, 12.04%. Found: C, 51.78; H, 3.68; N, 12.11%
6.13. 1-(4-(40-chlorophenyl)-2-thiazolyl)-3-(2-hydroxy-3-iodo-5-
methylphenyl)-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-
pyrazoline (IIIj)
IR (KBr, cmꢂ1): 1601 (–C]N), 3154 (–OH), 3331 (–NH); 1H NMR
(DMSO-d6, d ppm): 0.91 (t, J ¼ 7.2 Hz, 3H, –CH3),1.31 (m, 2H, –CH2–),

392
B.S. Dawane et al. / European Journal of Medicinal Chemistry 45 (2010) 387–392
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