Synthesis of new quinoline-2-pyrazoline-based thiazolinone derivatives as potential antimicrobial agents

Article abstract of DOI:10.1007/s00044-012-0377-3

A series of 2-(5-(2-chloro-6-methylquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H- pyrazol-1-yl)thiazol-4(5H)ones (4a-l) were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectra. All the synthesized compounds were tested for their in vitro antimicrobial activity against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Compounds 4e, 4f, 4g, 4i, 4j, and 4l were the most distinctive derivatives identified in present study because of their remarkable in vitro antimicrobial potency.

Full text of DOI:10.1007/s00044-012-0377-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3663–3674
DOI 10.1007/s00044-012-0377-3
ORIGINAL RESEARCH
Synthesis of new quinoline-2-pyrazoline-based thiazolinone
derivatives as potential antimicrobial agents
•
N. C. Desai V. V. Joshi K. M. Rajpara
•
Received: 19 September 2012 / Accepted: 15 November 2012 / Published online: 29 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of 2-(5-(2-chloro-6-methylquinolin-3-
yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)ones
(4a–l) were synthesized and characterized by IR, 1H NMR,
13C NMR, and mass spectra. All the synthesized compounds
were tested for their in vitro antimicrobial activity against
Escherichia coli (MTCC 443), Pseudomonas aeruginosa
(MTCC 1688), Staphylococcus aureus (MTCC 96), Strep-
tococcus pyogenes (MTCC 442), Candida albicans (MTCC
227), Aspergillus niger (MTCC 282), and Aspergillus clav-
atus (MTCC 1323) by serial broth dilution. Compounds 4e,
4f, 4g, 4i, 4j, and 4l were the most distinctive derivatives
identified in present study because of their remarkable
in vitro antimicrobial potency.
immunocompromised patients. As known, not only bio-
chemical similarity of the human cell and fungi forms a
handicap for selective activity but also the easily gained
resistance is the main problem encountered in developing
safe and efficient antifungal. Despite the development of
several new antimicrobial agents, their clinical value is
limited to treating an increasing array of life-threatening
systemic infections because of their relatively high toxic-
ity, emergence of drug resistant strains, pharmacokinetic
differences, and/or insufficiencies in their activity (Brad
et al., 2004). Fascinating pharmacological activities asso-
ciated with heterocyclic compounds (Krchnak and
Holladay, 2002) are increasingly important in designing
new class of structural entities of medicinal importance.
The current interest in the development of new antimi-
crobial agents can be partially ascribed both to the
increasing emergence of bacterial resistance to antibiotic
therapy and to newly emerging pathogens (Cohen 2000,
Barrett and Barrett 2003). Over the past few years, we have
been principally engrossed in the synthesis of quinoline
incorporating structures for antimicrobial evaluations
(Desai et al., 2011, 2012a) on the premise that quinoline
moiety is found in a large variety of naturally occurring
compounds. In fact, introducing chloroquine into treatment
of malaria more than 60 years ago triggered a new era of
quickly developing antimicrobial drugs. Quinoline ring
is endowed with various activities, such as antituberculosis
(Lilienkampf et al., 2009), antimalarial (Nasveld and
Kitchener, 2005), anti-inflammatory (Bekhit et al., 2004),
anticancer (Shi et al., 2008), antihypertensive (Muruga-
nantham et al., 2004), tyrokinase PDGF-RTK-inhibiting
agents (Maguire et al., 1994), and anti-HIV (Ahmed et al.,
2010).The design concepts have been drawn in Fig. 1,
which explains the structural similarity of our new target
compounds with renowned drug chloroquine. Moreover,
Keywords Quinoline Á 2-Pyrazoline Á
Vilsmeier–Haack reaction Á Thiazolinone Á
Cycloaddition reaction Á Antimicrobial activity Á
MIC
Introduction
Resistance of pathogenic bacteria toward available antibi-
otics is rapidly becoming a major worldwide problem.
Owing to this reason, the design of new compounds to deal
with resistant bacteria has become one of the most
important areas of antibacterial research today. In addition,
primary and opportunistic fungal infections continue to
increase rapidly because of the increased number of
N. C. Desai (&) Á V. V. Joshi Á K. M. Rajpara
Division of Medicinal Chemistry, Department of Chemistry,
Maharaja Krishnakumarsinhji Bhavnagar University,
Mahatma Gandhi Campus, Bhavnagar 364 002, India
e-mail: dnisheeth@rediffmail.com
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Med Chem Res (2013) 22:3663–3674
N
Cl
HN
S
O
O
O
S
S
N
N
N
N
H
N
O
NH
Cl
N
Cl
H2N
Chloroquine
Ibipinabant
Sulfathiazole
Fig. 1 Commercially available drugs containing quinoline, pyrazoline, and thiazole nucleus
2-pyrazoline derivatives have been reported to exhibit
various pharmacological activities such as antimicrobial
(Baraldi et al., 2003), anti-inflammatory (Barsoum et al.,
2006), and antihypertensive (Turan-Zitouni et al., 2000).
1-Unsubstituted-3,5-diaryl-2-pyrazolines are reported to
exhibit human Acyl CoA cholesterol acyltransferase
activity (Jeong et al., 2004a) as well as the activity of low-
density lipoprotein oxidation inhibitors (Jeong et al.,
2004b). In addition, 1,3,5-triaryl-2-pyrazolines are reported
to possess antidepressant properties (Palaska et al., 1996)
and monoamine oxidase (MAO) inhibitory activities (Soni
et al., 1987). Structurally relevant drug ibipinabantis CB1
antagonists are shown in Fig. 1. Thiazole is a versatile
bioactive heterocycle with biocidal S–C = N entity having
its wide presence in many synthetic drugs such as sulfat-
hiazole (antimicrobial), nizatidine (Antihistaminic), fane-
tizole (anti-inflammatory), ritonavir (anti-HIV), niridazole
(schistosomicidal), abafungin (antifungal) with trade name:
abasol cream, bleomycin (antineoplastic), and tiazofurin
(antineoplastic) have been explored previously. Several
physiologic activities of various thiazole derivatives have
proved the efficacy in combating various diseases and are
found to have good antitubercular activity (krainets et al.,
2002).
Results and discussion
Chemistry
The Vilsmeier-Haack reaction on acetanilide provided a
vital and efficient intermediate for the synthesis of several
newer substituted heterocyclic compounds. The reaction
was performed at 100 °C for 15–20 h using the typical
Vilsmeiere-Haack reagent derived from phosphorus oxy-
chloride-dimethylformamide yielded chloroquinoline alde-
hyde (Meth-Cohn, 1993). Although the reaction proceeded
uneventfully, the products formed were isolated by silica gel
column chromatography. The reaction sequences employed
for synthesis of the target compounds (4a–l) are illustrated
in Scheme 1. The key chalcone intermediates (2a–l) were
synthesized through the Claisen–Schmidt condensation of
equimolar amounts of acetophenone derivatives and chlo-
roquinoline aldehyde (1) through stirring the reactants in
aqueous ethanolic solution containing 20 % sodium
hydroxide at room temperature for 24 h in accordance with
the method described in the literature (Elgazwy, 2008).
The newly synthesized compounds 5-(2-chloro-6-
methylquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazole-1-
carbothioamides (3a–l) were obtained by heating at reflux
equimolar amounts of thiosemicarbazide and the corre-
sponding a,b-unsaturated ketones (2a–l) in hot ethanolic
sodium hydroxide solution for 8 h (Scheme 1). 1-Thioc-
arbamoyl pyrazole derivative (3a) was characterized by IR,
NMR, and mass spectra. IR spectra showed strong
absorption bands at 3440 and 3373 cm-1 due to primary
amine group. The characteristic signals in 1H NMR of
1-thiocarbamoyl pyrazole derivative (3a) of the three pyr-
azoline protons displayed doublet of doublet confirms the
presence of 1-thiocarbamoyl pyrazole. The methine proton
of pyrazolines displayed a signal at d = 6.02 ppm as a
doublet of doublet with coupling constants of nearly 11.12
and 3.08 Hz. The two methylene protons displayed two
signals; a doublet of doublet at d = 3.93 ppm with cou-
pling constants of nearly 17.45 and 11.13 Hz and a doublet
of doublet at d = 3.18 ppm with coupling constants of
nearly 17.44 and 3.08 Hz. Furthermore, 13C NMR spectra
Prompted by the above-mentioned results, it was plan-
ned to construct some new antimicrobial derivatives bear-
ing quinoline moiety attached to different substituted
2-thiazolyl-pyrazoline nucleus at 3rd position and study the
structure activity relationship due to substituent variations.
These combinations are suggested in an attempt to inves-
tigate the possible synergistic influence of such structure
hybridizations on the antimicrobial activity, hoping to
discover a new lead structure that would have a significant
activity at a very small concentration. In continuation of
our recent work aiming to synthesize heterocyclic systems
with remarkable biologic importance (Desai et al. 2012a,
2012b, 2012c, 2012d, 2012e, 2012f), we report herein the
utility of 2-(5-(2-chloro-6-methylquinolin-3-yl)-3-(aryl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)ones (4a–l) as
building blocks to get new compounds that could be opti-
mized as potent antimicrobial agents.
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Med Chem Res (2013) 22:3663–3674
3665
O
O
CH3
H3C
CHO
H3C
(a)
+
R
R
N
Cl
N
Cl
(2a-l)
(1)
(b)
S
S
O
H2N
N
N
N
N
N
H3C
H3C
(c)
R
R
N
(3a-l)
Cl
N
(4a-l)
Cl
R= -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl, -2-F, -3-F, -4-F, -2-NO2, -3-NO 2, -4-NO 2
(a) Ethanol, NaOH, stirring, 24 h (b) NH2CSNHNH2, Ethanol, Reflux 8 h (c) BrCH2COOC2H5, Ethanol, Reflux 1 h
Scheme 1 Synthetic route for compounds 4a–l
displayed a signal at 176.3 ppm assignable to thiocarba-
moyl carbon (C=S). The mass spectrum of (3a) showed a
molecular ion peak at m/z = 380 (M?) corresponding to a
molecular formula C20H17ClN4S. Moreover, the afore-
mentioned 1-thiocarbamoyl pyrazole derivatives (3a–l)
were cyclized to (4a–l) through their reaction with ethyl
bromoacetate in hot ethanol for 1 h. Compound (4a)
showed a strong absorption band at 1711 cm-1due to the
d = 42.2 ppm, d = 60.1 ppm, and 159.5 ppm due to the
presence of a pyrazoline ring. Compound showed signals
at 124.7–143.7 due to the presence of aromatic carbons.
Moreover, the mass spectrum of (4a) showed a molecular ion
peak at m/z = 420 (M?) corresponding to a molecular for-
mula C22H17ClN4OS.
Antimicrobial activity
1
carbonyl group in IR spectra. H NMR spectrum revealed
the appearance of a singlet peak at d = 4.01 ppm inte-
grating the two protons of the thiazolinone ring. 1H NMR of
1-thiocarbamoyl pyrazoline derivative (4a) of the three
pyrazoline protons displayed doublet of doublet confirms
the presence of 1-thiocarbamoyl pyrazole. The methine
proton of pyrazolines displayed a signal at d = 6.02 ppm as
a doublet of doublet with coupling constants of nearly 11.17
and 3.00 Hz. The two methylene protons displayed two
signals; a doublet of doublet at d = 3.88 ppm with coupling
constants of nearly 17.48 and 11.18 Hz and a doublet of
doublet at d = 3.17 ppm with coupling constants of nearly
17.48 Hz and 3.01 Hz. The two aromatic proton displayed a
triplet at d = 7.56 ppm with coupling constants of nearly
8.2 Hz. The two aromatic proton displayed a doublet at
d = 7.76 ppm with coupling constants of nearly 7.8 Hz. The
one aromatic proton displayed a triplet at d = 7.48 ppm with
coupling constants of nearly 8.2 Hz. 13C NMR spectrum of
4a displayed a signal at d = 187.5 ppm assignable to the
carbonyl carbon (C=O) and the appearance of a signal around
d = 39.0 ppm due to the presence of a methylene group of
the thiazolinone ring. Compound 4a displayed signals at
Compounds 4a–l were evaluated against Gram-positive,
Gram-negative bacteria, and fungi strains. The intermedi-
ate compounds 3a-l exhibited poor activity. The individual
minimum inhibitory concentration (MIC, lg/mL) obtained
for compounds 4a-l is presented in (Table 1). It was
observed that compounds 4e (2-Cl), 4f (4-Cl), 4g (2-F), 4i
(4-F), 4j (2-NO2), and 4l (4-NO2) were most active. On the
basis of antibacterial screening, it was observed that com-
pounds 4e (2-Cl), 4i (4-F) and 4l (4-NO2) possessed very
good activity against E. coli. When hydrogen of phenyl ring
in 4a was replaced by fluoro and nitro groups at 2nd posi-
tion, i.e., 4g (2-F) and 4j (2-NO2), activity increased and
compounds displayed excellent activity against E. coli.
Compounds 4e (2-Cl) and 4i (4-F) possessed very good
activity against P. aeruginosa. When we replaced hydrogen
of phenyl ring in 4a by nitro group at 2nd position, we get
compound 4j which underwent enhancement in activity and
possessed excellent activity against P. aeruginosa. Com-
pounds 4g (2-F), 4i (4-F), and 4l (4-NO2) showed very good
activity, while compound exhibiting chloro group sub-
stituent at 4th position of substituted benzene ring showed
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Med Chem Res (2013) 22:3663–3674
excellent activity against S. aureus. Compounds 4e (2-Cl),
4f (4-Cl), and 4l (4-NO2) displayed very good activity,
while compounds 4i (4-F) and 4j (2-NO2) possessed
excellent activity against S. pyogenes.
thiazol-4(5H)-one led to a significant increase in the anti-
microbial activity.
Structure–activity relationship
The intermediate compounds 3a-l exhibited poor activity.
Antifungal activity showed that compounds 4i (4-F) and 4j
(2-NO2) possessed very good activity against C. albicans.
When we replace hydrogen of phenyl ring in 4a by 2-Cl and
2-F groups, activity enhanced and showed excellent activity
against C. albicans. Compounds 4e (2-Cl), 4g (2-F), and 4j
(2-NO2) displayed very good activity against A. niger,
whereas compounds 4l bearing nitro group at the 4th position
showed excellent activity against A. niger. Compounds 4f (3-
Cl) and 4 k (3-NO2) possessed very good activity against A.
clavatus. When we have incorporated NO2 group on the 2nd
carbon of phenyl ring of compound 4a, the activity enhanced
and it displayed excellent activity against A. clavatus. The
MIC (minimum inhibitory concentration) values were
determined by comparison with ampicillin and griseofulvin
as reference drugs.
Results of the biologic testing revealed that the activity
was considerably affected by various substituents on the
aromatic ring. For antibacterial activity, it was observed
that the introduction of electron-withdrawing groups on the
benzene ring showed considerable increase in the anti-
bacterial potency of the compounds. It was observed from
the screening data that the compounds 4g and 4j containing
fluoro and nitro substituents showed significant potency
against bacteria E. coli. Compound containing nitro group at
2-position of the substituted benzene ring showed maximum
inhibition against P. aeruginosa at MIC 12.5 lg/mL. Chloro
substitution at the 4th position on benzene ring showed
excellent activity against S. aureus. Compounds 4i and 4j
containing 4-F and 2-NO2 groups on benzene ring showed
maximum inhibition against S. pyogenes at MIC 25 lg/mL.
On the basis of MIC results, it was clear that electron-
withdrawing groups substituting the benzene ring showed
higher potency than electron donating groups. All other
compounds showed good to moderate activity. According to
the MIC values of antifungal activity, compounds containing
chloro and fluoro atoms 4e and 4g showed excellent activity
Results clearly demonstrate in Table 1 that when com-
pounds 3a–l were converted to the corresponding final
compounds 4a–l, they exhibited significant antimicrobial
activity. Most of the synthesized compounds 3a–l exhibited
poor antibacterial and antifungal activity. On the basis of
MIC values, it is our observation that the presence of
Table 1 Results of antibacterial and antifungal screening of compounds 4a–l
Entry -R Minimum inhibitory concentration for bacteria (lg/mL) SD
Minimum inhibitory concentration for fungi
(lg/mL) SD
Gram-negative
Gram-positive
E. coli
MTCC 443
P. aeruginosa
MTCC 1688
S. aureus
MTCC 96
S. pyogenes
MTCC 442
C. albicans
MTCC 227
A. niger
MTCC 282
A. clavatus
MTCC 1323
4a
4b
4c
4d
4e
4f
-H
500 3.05**
500 1.00*
500 1.52**
500 1.00*
50 3.21**
250 1.00*
250 2.04*
500 3.46
1000 4.61*
500 3.70
500 4.50*
-2-OH
-4-OH
-4-OCH3
-2-Cl
500 1.50** 500 3.21
250 2.04 500 4.04*** 250 1.92*** 1000 4.06* 1000 3.16*** 1000 2.04*
500 1.60** 500 2.04*
250 3.60** 1000 2.88** 500 1.60** 1000 1.00**
500 2.05
50 1.69**
50 3.78*
500 3.78**
1000 2.64*
100 1.52
500 3.06
100 4.72*
500 1.60
500 2.05*
100 4.50
50 2.88*
250 4.60
50 2.05**
100 1.05*
50 1.16*
-4-Cl
250 1.20*** 100 4.04
100 1.20***
50 4.72***
4g
4h
4i
-2-F
25 1.78**
500 1.60*
50 3.60**
25 1.78*
250 4.16
50 1.04*** 500 3.78**
-3-F
100 2.04** 500 1.60*** 100 1.21*** 1000 1.52** 500 4.16*
500 3.46*
100 4.04*
12.5 2.52***
50 1.00
100 3.60*
–
-4-F
50 3.21*** 100 3.16*
25 4.16**
25 1.16*
250 2.18*
250 4.72**
500 3.52
500 2.32*
–
250 1.18*
50 1.60**
100 1.58***
25 1.60*
–
4j
-2-NO2
-3-NO2
-4-NO2
Ampicillin
Griseofulvin
12.5 3.78** 250 1.78**
4k
4l
250 3.61*
500 1.60
500 4.16*** 500 3.21**
50 1.40*** 250 3.26*
100 2.04**
250 1.52
–
50 1.61**
100 2.06
–
100 2.05
–
100 1.00
–
500 0.50
100 1.10
100 1.20
2 % DMSO used as control and its antibacterial activity is nil or zero
SD Standard deviation
*** P \ 0.001 extremely significant, ** P \ 0.01 moderately significant, * P \ 0.05 significant. All values are presented as mean of
6 experiments (n = 6). All significant differences are considered from control value (0.00)
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Med Chem Res (2013) 22:3663–3674
3667
against C. albicans, whereas compound 4j containing nitro
group showed excellent activity against A. niger. Compound
4j containing nitro group exhibited maximum potency at
MIC 12.5 lg/mL against A. clavatus. On the basis of SAR, it
has been observed that there was strong correlation between
antibacterial and antifungal activity.
on strain growth. The result of this was greatly affected by
the size of the inoculum. The test mixture should contain
106 CFU/mL organisms. DMSO and sterilized distilled
water was used as negative control, while ampicillin anti-
biotic (1 U strength) was used as positive control. Standard
drug used in the present study was ‘‘ampicillin’’ for evalu-
ating antibacterial activity which showed 100, 100, 250, and
100 lg/mL MIC against E. coli, P. aeruginosa, S. aureus,
and S. pyogenes, respectively.
Biologic screening
Antibacterial assay
Antifungal assay
The newly synthesized compounds (4a–l) were screened for
their antibacterial activity against Gram-positive bacteria
(Staphylococcus aureus (MTCC-96)—Streptococcus pyoge-
nes (MTCC-442)) and Gram-negative (Escherichia coli
(MTCC-443)—Pseudomonas aeruginosa (MTCC-1688)).
All MTCC cultures were collected from the Institute of
Microbial Technology, Chandigarh. The activity of com-
pounds was determined as per the National Committee for
Clinical Laboratory Standards (NCCLS) protocol using
Mueller–Hinton Broth (Becton–Dickinson, USA) (Al-
Bayati and Al-Mola, 2008, Finegold and Garrod, 1995).
Compounds were screened for their antibacterial activity as
primary screening in six sets against E. coli, S. aureus,
P. aeruginosa, and S. pyogenes at different concentrations
of 1000, 500, and 250 lg/mL. The compounds found to be
active in primary screening were similarly diluted to obtain
200, 125, 100, 62.5, 50, 25, and 12.5 lg/mL concentrations
for secondary screening to test in a second set of dilution
against all microorganisms. Inoculum size for test strain is
adjusted to 106 CFU/mL (Colony Forming Unit per milli-
liter) by comparing the turbidity (turbidimetric method).
Mueller–Hinton Broth is used as nutrient medium to grow
and dilute the compound suspension for test bacteria. 2 %
DMSO was used as a diluent/vehicle to obtain the desired
concentration of synthesized compounds and standard drugs
to test upon standard microbial strains. Synthesized com-
pounds were diluted to 1000 lg/mL concentration as a stock
solution. The control tube containing no antibiotic was
immediately subcultured [before inoculation] by spreading
a loopful evenly over a quarter of plate of medium suitable
for the growth of test organisms. The tubes were then put for
incubation at 37 °C for 24 h for bacteria. 10 lg/mL sus-
pensions were further inoculated on an appropriate media
and growth is noted after 24 and 48 h. The highest dilution
(lowest concentration) preventing appearance of turbidity
was considered as minimum inhibitory concentration (MIC,
lg/mL), i.e., the amount of growth from the control tube
before incubation (which represents the original inoculum)
was compared. A set of tubes containing only seeded broth
and solvent controls were maintained under identical con-
ditions so as to make sure that the solvent had no influence
The same compounds (4a–l) were tested for their antifungal
activity as primary screening in six sets against C.albicans,
A. niger, and A. clavatus at various concentrations of 1000,
500, 250 lg/mL, respectively. The compounds found to be
active in primary screening were similarly diluted to obtain
200, 125, 100, 62.5, 50, 25, and 12.5 lg/mL concentrations
for secondary screening to test in a second set of dilution
against all microorganisms. Griseofulvin was used as a
standard drug for the antifungal activity, which showed 500,
100, and 100 lg/mL MIC against C. albicans, A. niger, and
A. clavatus, respectively. DMSO and sterilized distilled
water was used as negative control, while Griseofulvin (1 U
strength) was used as positive control. For fungal growth, in
the present protocol, we have used Sabourauds dextrose
broth at 28 °C in an aerobic condition for 48 h.
Statistical analysis
Standard deviation value is expressed in terms of SD. On
the basis of calculated value by one-way ANOVA method
followed by independent two sample t test, it has been
observed that differences below 0.001 level are considered
as statistically significant.
Materials and methods
General
All reactions except those in aqueous media were carried
out by standard techniques for the exclusion of moisture.
Melting points were determined on an electro thermal
melting point apparatus and were reported uncorrected.
TLC on silica gel plates (Merck, 60, F254) was used for
purity checking and reaction monitoring. Column chroma-
tography on silica gel (Merck, 70–230 mesh and 230–400
mesh ASTH for flash chromatography) was applied when
necessary to isolate and purify the reaction products. Ele-
mental analysis (% C, H, N) was carried out using a Perkin-
Elmer 2400 CHN analyzer. IR spectra of all compounds
were recorded on a Perkin-Elmer FT-IR spectrophotometer
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1
in KBr. H NMR spectra were obtained on Varian Gemini
300 MHz and 13C NMR spectra on Varian Mercury-400
100 MHz in DMSO-d6 as a solvent and tetramethylsilane
(TMS) as an internal standard. Mass spectra were scanned
on a Shimadzu LCMS 2010 spectrometer. Anhydrous
reactions were carried out in oven-dried glassware in
nitrogen atmosphere.
(dd, 1H, J = 17.35 Hz, 11.04 Hz, C4–H pyrazoline), 6.11
(dd, 1H, J = 11.04 Hz, 3.01 Hz, C5–H pyrazoline), 6.92 (d,
1H, J = 8.4 Hz, Ar–H), 7.00(d, 1H, J = 7.8 Hz, Ar–H), 7.36
(d, 1H, J = 7.6 Hz, Ar–H), 7.43 (t, 1H, J = 8.0 Hz, Ar–H),
7.58 (d, 1H, J = 7.4 Hz, Ar–H), 7.67 (s, 1H, Ar–H), 7.94 (d,
1H, J = 8.2 Hz, Ar–H), 8.33 (s, 1H, Ar–H), 8.47 (s, 2H, NH2,
D2O exch.), 9.19 (s, 1H, OH, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.0 (CH3), 43.3 (C4 of pyr-
azoline), 62.9 (C5 of pyrazoline), 117.3–143.6 (Ar–C), 151.3
(C–Cl of quinoline), 156.4 (C=N of pyrazoline), 162.3 (C
–OH), 176.0 (C=S); LCMS (m/z): 396(M?), 398 (M??2);
Anal. Calcd. For C20H17ClN4OS: C-60.52, H-4.32, N-14.12;
Found: C-60.60, H-4.38, N-14.20 %.
Experimental
General procedure for the preparation of 5-(2-chloro-
6-methylquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-
pyrazole-1-carbothioamides (3a–l)
To a suspension of chalcones (0.01 mol) and sodium
hydroxide (0.025 mol) in ethanol (99.5 %) (50 mL), thio-
semicarbazide (0.01 mol) was added and the mixture was
refluxed for 8 h. The mixture was then poured onto crushed
ice and the solid mass which separated out was filtered,
dried, and crystallized from ethanol (95 %).
5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-hydroxyphenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3c)
Dark yellow crystals, yield: 74 %; m.p.: 192-194 °C; IR
(KBr) mmax/cm-1: 3442, 3366 (NH2), 3415 (OH), 3073 (C–H,
aromatic), 1575(C=N), 1525(C=C), 1327(C=S), 734 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.33 (s, 3H, –CH3),
3.14 (dd, 1H, J = 17.48 Hz, 3.07 Hz, C4–H pyrazoline), 3.83
(dd, 1H, J = 17.48 Hz, 11.12 Hz, C4-Hpyrazoline), 6.07(dd,
1H, J = 11.11 Hz, 3.07 Hz, C5–H pyrazoline), 6.81 (d, 2H,
J = 8.0 Hz, A2B2, p-chlorophenyl), 7.32 (d, 1H, J = 7.6 Hz,
Ar–H), 7.65 (s, 1H, Ar–H), 7.83 (d, 2H, J = 8.0 Hz, A2B2, p-
chlorophenyl), 7.95 (d, 1H, J = 8.0 Hz, Ar–H), 8.32 (s, 1H,
Ar–H), 8.52 (s, 2H, NH2, D2O exch.), 9.21 (s, 1H, OH, D2O
exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 21.1 (CH3),
43.3 (C4 of pyrazoline), 62.9 (C5 of pyrazoline), 115.9–143.2
(Ar–C), 151.3 (C–Cl of quinoline), 156.6 (C=N of pyrazo-
line), 160.7 (C–OH), 176.3 (C=S); LCMS (m/z): 396 (M?),
398 (M??2); Anal. Calcd. For C20H17ClN4OS: C-60.52,
H-4.32, N-14.12; Found: C-60.47, H-4.27, N-14.05 %.
Physical constants and characterization of synthesized
compounds (3a-l)
5-(2-Chloro-6-methylquinolin-3-yl)-3-phenyl-4,5-dihydro-
1H-pyrazole-1-carbothioamide (3a)
Light brown crystals, yield: 75 %; m.p.: 137–139 °C; IR
(KBr) mmax/cm-1: 3440, 3373 (NH2), 3067 (C–H, aromatic),
1576 (C=N), 1511 (C=C), 1330 (C=S), 728 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.35 (s, 3H, –CH3), 3.18 (dd,
1H, J = 17.44 Hz, 3.08 Hz, C4–H pyrazoline), 3.93 (dd, 1H,
J = 17.45 Hz, 11.13 Hz, C4-H pyrazoline), 6.02 (dd, 1H,
J = 11.12 Hz, 3.08 Hz, C5–H pyrazoline), 7.35 (d, 1H,
J = 7.8 Hz, Ar–H), 7.48 (t, 1H, J = 8.2 Hz, Ar–H), 7.56 (t,
2H, J = 7.8 Hz, Ar–H),7.62 (s, 1H, Ar–H), 7.69 (d, 2H,
J = 7.8 Hz, Ar–H), 7.90 (d, 1H, J = 8.0 Hz, Ar–H), 8.36 (s,
1H, Ar–H),8.52 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.4 (CH3), 43.2 (C4 of
pyrazoline), 63.1 (C5 of pyrazoline), 124.8–144.1 (Ar–C),
151.2 (C–Cl of quinoline), 156.7 (C=N of pyrazoline), 176.3
(C=S); LCMS (m/z): 380(M?), 382 (M??2); Anal. Calcd.
For C20H17ClN4S: C-63.07, H-4.50, N-14.71; Found:
C-63.13, H-4.57, N-14.77 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-methoxyphenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3d)
Light pink crystals, yield: 72 %; m.p.: 205–207 °C; IR (KBr)
m
(C=N), 1523 (C=C), 1324 (C=S), 1215 (C–O–C), 740 (C–
max/cm-1: 3454, 3368 (NH2), 3073 (C–H, aromatic), 1585
1
Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 2.36 (s, 3H,
–CH3), 3.18 (dd, 1H, J = 17.52 Hz, 3.02 Hz, C4–H pyraz-
oline), 3.67 (s, 3H, –OCH3), 3.87 (dd, 1H, J = 17.52 Hz,
11.16 Hz, C4–H pyrazoline), 6.04 (dd, 1H, J = 11.16 Hz,
3.03 Hz, C5–H pyrazoline), 7.03 (d, 2H, J = 8.2 Hz, A2B2,
p-methoxyphenyl), 7.36 (d, 1H, J = 8.2 Hz, Ar–H), 7.61 (s,
1H, Ar–H), 7.95 (d, 1H, J = 7.8 Hz, Ar–H), 8.03 (d, 2H,
J = 8.2 Hz, A2B2, p-methoxyphenyl), 8.38 (s, 1H, Ar–H),
8.44 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 21.2 (CH3), 43.5 (C4 of pyrazoline), 54.4
(OCH3), 62.7 (C5 of pyrazoline), 114.5–144.6 (Ar–C), 151.5
(C–Cl of quinoline), 156.2 (C=N of pyrazoline), 176.7
5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-hydroxyphenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3b)
Light yellow crystals, yield: 72 %; m.p.: 158–160 °C; IR
(KBr) mmax/cm-1: 3452, 3361 (NH2), 3414 (OH), 3067 (C–H,
aromatic), 1584(C=N), 1513(C=C), 1326(C=S), 722 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.31 (s, 3H, –CH3),
3.09 (dd, 1H, J = 17.34 Hz, 3.01 Hz, C4–H pyrazoline), 3.86
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Med Chem Res (2013) 22:3663–3674
3669
(C=S); LCMS (m/z): 410(M?), 412 (M??2); Anal. Calcd.
For C21H19ClN4OS: C-61.38, H-4.66, N-13.63; Found:
C-61.44, H-4.73, N-13.72 %.
1580 (C=N), 1528 (C=C), 1334 (C=S), 1145 (C–F), 738 (C–
1
Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 2.38 (s, 3H,
–CH3), 3.36 (dd, 1H, J = 17.40, 3.01 Hz, C4–H pyrazoline),
3.89 (dd, 1H, J = 17.41 Hz, 11.14 Hz, C4–H pyrazoline),
6.10 (dd, 1H, J = 11.14 Hz, 3.00 Hz, C5–H pyrazoline),7.29
(t, 1H, J = 8.0 Hz, Ar–H), 7.37 (d, 1H, J = 8.4 Hz, Ar–H),
7.42 (d, 1H, J = 8.2 Hz, Ar–H), 7.50 (t, 1H, J = 8.6 Hz,
Ar–H), 7.62 (s, 1H, Ar–H), 7.84 (d, 1H, J = 8.4 Hz, Ar–H),
7.93 (d, 1H, J = 8.4 Hz, Ar–H), 8.33 (s, 1H, Ar–H), 8.61 (s,
2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 21.4 (CH3), 43.6 (C4 of pyrazoline), 62.2 (C5 of pyr-
azoline), 118.3–144.7 (Ar–C), 151.6 (C–Cl of quinoline),
156.4 (C=N of pyrazoline), 160.1 (C–F of fluorophenyl),
176.4 (C=S); LCMS (m/z): 398(M?), 400 (M??2); Anal.
Calcd. For C20H16ClFN4S: C-60.22, H-4.04, N-14.05;
Found: C-60.30, H-4.10, N-14.11 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-chlorophenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3e)
Light gray crystals, yield: 75 %; m.p.: 182–184 °C; IR
(KBr) mmax/cm-1: 3454, 3373 (NH2), 3071 (C–H, aro-
matic), 1573 (C=N), 1515 (C=C), 1338 (C=S), 745 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.35 (s, 3H, –
CH3), 3.23 (dd, 1H, J = 17.44, 3.10 Hz, C4–H pyrazoline),
3.90 (dd, 1H, J = 17.44 Hz, 11.12 Hz, C4–H pyrazoline),
6.10 (dd, 1H, J = 11.12, 3.09 Hz, C5–H pyrazoline), 7.38
(d, 1H, J = 8.4 Hz, Ar–H), 7.42 (t, 1H, J = 8.2 Hz, Ar–H),
7.54 (t, 1H, J = 8.2 Hz, Ar–H), 7.59 (d, 1H, J = 8.4 Hz,
Ar–H), 7.62 (s, 1H, Ar–H), 7.79 (d, 1H, J = 8.4 Hz, Ar–H),
7.92 (d, 1H, J = 8.2 Hz, Ar–H), 8.34 (s, 1H, Ar–H), 8.51 (s,
2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 21.5 (CH3), 43.2 (C4 of pyrazoline), 62.6 (C5 of
pyrazoline), 128.8 (C–Cl of chlorophenyl), 124.6–143.8
(Ar–C), 151.5 (C–Cl of quinoline), 156.1 (C=N of pyraz-
oline), 176.5 (C=S); LCMS (m/z): 414(M?), 416 (M??2);
Anal. Calcd. For C20H16Cl2N4S: C-57.84, H-3.88, N-13.49;
Found: C-57.78, H-3.83, N-13.55 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(3-fluorophenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3h)
Light brown crystals, yield: 78 %; m.p.: 167–169 °C; IR
(KBr) mmax/cm-1: 3469, 3361 (NH2), 3075 (C–H, aro-
matic), 1585 (C=N), 1528 (C=C), 1330 (C=S), 1146 (C–
1
F), 748 (C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm):
2.36 (s, 3H, CH3), 3.43 (dd, 1H, J = 17.38, 3.06 Hz, C4–
H pyrazoline), 3.92 (dd, 1H, J = 17.39 Hz, 11.29 Hz,
C4–H pyrazoline), 6.09 (dd, 1H, J = 11.28 Hz, 3.06 Hz,
C5–H pyrazoline), 7.35(d, 1H, J = 7.8 Hz, Ar–H), 7.44
(d, 1H, J = 8.2 Hz, Ar–H), 7.62 (t, 1H, J = 8.2 Hz, Ar–
H), 7.67 (s, 1H, Ar–H), 7.75 (d, 1H, J = 8.4 Hz, Ar–H),
7.80 (s, 1H, Ar–H), 7.94 (d, 1H, J = 8.1 Hz, Ar–H), 8.34
(s, 1H, Ar–H), 8.62 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.5 (CH3), 43.8 (C4 of
pyrazoline), 62.1 (C5 of pyrazoline), 113.5–144.5 (Ar–C),
151.8 (C–Cl of quinoline), 156.3 (C=N of pyrazoline),
163.6 (C–F of fluorophenyl), 176.8 (C=S); LCMS (m/z):
398 (M?), 400 (M??2); Anal. Calcd. For C20H16ClFN4S:
C-60.22, H-4.04, N-14.05; Found: C-60.17, H-4.01,
N-14.00 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3f)
Dark gray crystals, yield: 71 %; m.p.: 177–179 °C; IR
(KBr) mmax/cm-1: 3448, 3380 (NH2), 3067 (C–H, aro-
matic), 1577 (C=N), 1514 (C=C), 1337 (C=S), 753 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.34 (s, 3H, –
CH3), 3.19 (dd, 1H, J = 17.48, 3.13 Hz, C4–H pyrazoline),
3.93 (dd, 1H, J = 17.47 Hz, 11.18 Hz, C4-H pyrazoline),
6.07 (dd, 1H, J = 11.18 Hz, 3.12 Hz, C5-H pyrazo-
line),7.35 (d, 1H, J = 7.8 Hz, Ar–H), 7.52 (d, 2H,
J = 8.2 Hz, A2B2, p-chlorophenyl), 7.67 (s, 1H, Ar–H),
7.95 (d, 1H, J = 8.4 Hz, Ar–H), 8.01 (2H, d, J = 8.2 Hz,
A2B2, p-chlorophenyl), 8.37 (s, 1H, Ar–H), 8.55 (s, 2H,
NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 21.7 (CH3), 43.5 (C4 of pyrazoline), 62.3 (C5 of
pyrazoline), 124.2–143.5 (Ar–C), 132.5 (C–Cl of chloro-
phenyl), 151.3 (C–Cl of quinoline), 156.7 (C=N of pyraz-
oline), 176.8 (C=S); LCMS (m/z): 414 (M?), 416 (M??2);
Anal. Calcd. For C20H16Cl2N4S: C-57.84, H-3.88, N-13.49;
Found: C-57.90, H-3.94, N-13.44 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-fluorophenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3i)
Light reddish brown crystals, yield: 72 %; m.p.: 208–210 °C;
IR (KBr) mmax/cm-1: 3471, 3384 (NH2), 3066 (C–H, aro-
matic), 1584 (C=N), 1527 (C=C), 1333 (C=S), 1154 (C–F),
733 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.34
(s, 3H, –CH3), 3.38 (dd, 1H, J = 17.40, 3.00 Hz, C4-H
pyrazoline), 3.88 (dd, 1H, J = 17.41, 11.20 Hz, C4–H pyr-
azoline), 6.09 (dd, 1H, J = 11.19 Hz, 3.00 Hz, C5–H pyr-
azoline), 7.32 (d, 1H, J = 8.4 Hz, Ar–H), 7.41 (d, 2H,
J = 8.4 Hz, A2B2, p-fluorophenyl), 7.66 (s, 1H, Ar–H), 7.81
(d, 2H, J = 8.4 Hz, A2B2, p-fluorophenyl), 7.95 (d, 1H,
5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-fluorophenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3g)
Light brown crystals, yield: 74 %; m.p.: 179–181 °C; IR
(KBr) mmax/cm-1: 3463, 3376 (NH2), 3061 (C–H, aromatic),
123

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Med Chem Res (2013) 22:3663–3674
5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-nitrophenyl)-4,5-
J = 8.4 Hz, Ar–H), 8.36 (s, 1H, Ar–H), 8.57 (s, 2H, NH2,
D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 21.5
(CH3), 43.8 (C4 of pyrazoline), 62.1 (C5 of pyrazoline),
113.5–144.5 (Ar–C), 151.7 (C–Cl of quinoline), 156.7 (C=N
of pyrazoline), 162.4 (C–F of fluorophenyl), 176.5 (C=S);
LCMS (m/z): 398 (M?), 400 (M??2); Anal. Calcd. For
C20H16ClFN4S: C-60.22, H-4.04, N-14.05; Found: C-60.28,
H-4.10, N-14.12 %.
dihydro-1H-pyrazole-1-carbothioamide (3l)
Orange crystals, yield: 76 %; m.p.: 220–222 °C; IR (KBr,
cm-1): IR (KBr) mmax/cm-1: 3466, 3362 (NH2), 3077 (C–H,
aromatic), 1585 (C=N), 1511 (C=C), 1480, 1349 (NO2), 1326
(C=S), 739 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm):
2.35(s, 3H,–CH3), 3.42(dd, 1H, J = 17.50 Hz, 3.08 Hz, C4–
H pyrazoline), 3.88 (dd, 1H, J = 17.50 Hz, 11.18 Hz, C4–H
pyrazoline), 6.11 (dd, 1H, J = 11.18 Hz,3.08 Hz, C5–H
pyrazoline), 7.35 (d, 1H, J = 8.4 Hz, Ar–H), 7.66 (s, 1H, Ar–
H), 7.95 (d, 1H, J = 8.1 Hz, Ar–H), 8.04 (d, 2H, J = 8.2 Hz,
A2B2, p-nitrophenyl), 8.28 (2H, d, J = 8.2 Hz, A2B2, p-
nitrophenyl), 8.37 (s, 1H, Ar–H), 8.58 (s, 2H, NH2, D2O
exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 21.6 (CH3),
43.5 (C4 of pyrazoline), 62.6 (C5 of pyrazoline), 124.8–145.4
(Ar–C), 150.3 (C–NO2), 151.8 (C–Cl of quinoline),156.9
(C=N of pyrazoline), 176.2 (C=S); LCMS (m/z): 425 (M?),
427 (M??2); Anal. Calcd. For C20H16ClN5O2S: C-56.40,
H-3.79, N-16.44; Found: C-56.34, H-3.84, N-16.50 %.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-nitrophenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (3j)
Light orange yellow crystals, yield: 79 %; m.p.: 169–
171 °C; IR (KBr) mmax/cm-1: 3452, 3364 (NH2), 3053 (C–H,
aromatic), 1584 (C=N), 1520 (C=C), 1485, 1354 (NO2),
1333 (C=S), 730 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 2.38 (s, 3H, CH3), 3.45 (dd, 1H, J = 17.36, 3.13 Hz,
C4–H pyrazoline), 3.97 (dd, 1H, J = 17.36, 11.17 Hz, C4-H
pyrazoline), 6.08 (dd, 1H, J = 11.16 Hz, 3.12 Hz, C5–H
pyrazoline), 7.36 (d, 1H, J = 8.2 Hz, Ar–H), 7.53 (t, 1H,
J = 8.2 Hz, Ar–H), 7.62 (s, 1H, Ar–H), 7.84 (t, 1H,
J = 7.8 Hz, Ar–H), 7.92 (d, 1H, J = 7.4 Hz, Ar–H), 7.98 (d,
1H, J = 7.6 Hz, Ar–H), 8.09 (d, 1H, J = 7.6 Hz, Ar–H),
8.35 (s, 1H, Ar–H), 8.68 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.6 (CH3), 43.6 (C4 of
pyrazoline), 62.3 (C5 of pyrazoline), 125.2–143.3 (Ar–C),
134.6 (C–NO2), 151.8 (C–Cl of quinoline), 156.6 (C=N of
pyrazoline), 176.7 (C=S); LCMS (m/z): 425(M?), 427
(M??2); Anal. Calcd. For C20H16ClN5O2S: C-56.40,
H-3.79, N-16.44; Found: C-56.47, H-3.73, N-16.52 %.
General procedure for the preparation of 2-(5-(2-
chloro-6-methylquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-
pyrazol-1-yl)thiazol-4(5H)ones (4a–l)
To a suspension of compounds (3a–l) (0.01 mol) in ethanol
(99.9 %), ethyl bromoacetate (0.01 mol) was added and
heated at reflux for 1 h. After cooling, the separated
product was filtered and washed. The product was crys-
tallized from DMF.
5-(2-Chloro-6-methylquinolin-3-yl)-3-(3-nitrophenyl)-4,5-
Physical constants and characterization of synthesized
dihydro-1H-pyrazole-1-carbothioamide (3k)
compounds (4a–l)
Dark yellow crystals, yield: 74 %; m.p.: 201–203 °C; IR
(KBr) mmax/cm-1: 3475, 3353 (NH2), 3068 (C–H, aro-
matic), 1583 (C=N), 1526 (C=C), 1484, 1348 (NO2), 1327
(C=S), 750 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 2.36 (s, 3H, –CH3), 3.39 (dd, 1H, J = 17.45,
3.10 Hz, C4–H pyrazoline), 3.80 (dd, 1H, J = 17.45 Hz,
11.16 Hz, C4-H pyrazoline), 6.05 (dd, 1H, J = 11.15 Hz,
3.10 Hz, C5-H pyrazoline), 7.32 (d, 1H, J = 8.0 Hz, Ar–
H), 7.62 (s, 1H, Ar–H), 7.76 (t, 1H, J = 8.0 Hz, Ar–H),
7.93 (d, 1H, J = 7.6 Hz, Ar–H), 8.14 (d, 1H, J = 8.2 Hz,
Ar–H), 8.28 (d, 1H, J = 7.6 Hz, Ar–H), 8.34 (s, 1H, Ar–
H),8.53 (s, 1H, Ar–H), 8.62 (s, 2H, NH2, D2O exch.); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 21.4 (CH3), 43.9 (C4
of pyrazoline), 62.1 (C5 of pyrazoline), 124.8–144.9 (Ar–
C), 132.7 (C–NO2), 151.6 (C–Cl of quinoline), 156.7 (C=N
of pyrazoline), 176.5 (C=S); LCMS (m/z): 425 (M?), 427
(M??2);Anal. Calcd. For C20H16ClN5O2S: C-56.40,
H-3.79, N-16.44; Found: C-56.48, H-3.75, N-16.36 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-phenyl-4,5-
dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4a)
Light brown crystals, yield: 60 %; m.p.: 188-190 °C; IR
(KBr) mmax/cm-1: 3076 (C–H, aromatic), 1711 (C=O), 1578
(C=N), 1535 (C=C), 748 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.35 (s, 3H, –CH3), 3.17 (dd, 1H,
J = 17.48 Hz, 3.01 Hz, C4–H pyrazoline), 3.88 (dd, 1H,
J = 17.48 Hz, 11.18 Hz, C4–H pyrazoline), 4.01 (s, 2H, C5–
H thiazolinone), 6.02 (dd, 1H, J = 11.17 Hz, 3.00 Hz, C5–H
pyrazoline), 7.37 (d, 1H, J = 8.4 Hz, Ar–H), 7.48 (t, 1H,
J = 8.2 Hz, Ar–H), 7.56 (t, 2H, J = 7.8 Hz, Ar–H),7.67 (s,
1H, Ar–H), 7.76 (d, 2H, J = 7.8 Hz, Ar–H), 7.92 (d, 1H,
J = 7.8 Hz, Ar–H), 8.35 (s, 1H, Ar–H);13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.3 (CH3), 39.0 (C5 of thiazolinone),
42.2 (C4 of pyrazoline), 60.1 (C5 of pyrazoline), 124.7–143.7
(Ar–C), 151.4 (C–Cl of quinoline), 159.5 (C=N of pyrazo-
line), 178.1 (C=N of thiazolinone), 187.5 (C=O of
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Med Chem Res (2013) 22:3663–3674
3671
thiazolinone); LCMS (m/z): 420(M?), 422 (M??2); Anal.
Calcd.ForC22H17ClN4OS:C-62.78,H-4.07,N-13.31;Found:
C-62.84, H-4.16, N-13.22 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-
4(5H)-one (4d)
Light pink crystals, yield: 55 %; m.p.: 198–200 °C; IR
(KBr) mmax/cm-1: 3073 (C–H, aromatic), 1698 (C=O), 1580
(C=N), 1525 (C=C), 1234 (C–O–C), 748 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.33 (s, 3H, –CH3), 3.14
(dd, 1H, J = 17.45 Hz, 3.11 Hz, C4–H pyrazoline), 3.66 (s,
3H, –OCH3), 3.88 (dd, 1H, J = 17.46 Hz, 11.13 Hz, C4–H
pyrazoline), 4.03 (s, 2H, C5–H thiazolinone), 6.04 (dd, 1H,
J = 11.14, 3.10 Hz, C5–H pyrazoline), 7.02 (d, 2H,
J = 8.0 Hz, A2B2, p-methoxyphenyl), 7.34 (d, 1H,
J = 8.2 Hz, Ar–H), 7.64 (s, 1H, Ar–H), 7.95 (d, 1H,
J = 8.4 Hz, Ar–H), 8.03 (d, 2H, J = 8.0 Hz, A2B2, p-
methoxyphenyl), 8.32 (s, 1H, Ar–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.5 (CH3), 39.7 (C5 of thiazolinone),
42.2 (C4 of pyrazoline), 54.8 (OCH3), 62.0 (C5 of pyrazo-
line), 114.7–143.7 (Ar–C), 151.5 (C–Cl of quinoline), 159.7
(C=N of pyrazoline), 178.3 (C=N of thiazolinone), 187.4
(C=O of thiazolinone); LCMS (m/z): 450(M?), 452
(M??2); Anal. Calcd. For C23H19ClN4O2S: C-61.26,
H-4.25, N-12.42; Found: C-61.20, H-4.31, N-12.35 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-
hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-
4(5H)-one (4b)
Light yellow crystals, yield: 58 %; m.p.: 175–177 °C; IR
(KBr) mmax/cm-1: 3414 (OH, Ar-OH), 3068 (C–H, aro-
matic), 1701 (C=O), 1573 (C=N), 1530 (C=C), 748 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.30 (s, 3H,
–CH3), 3.06 (dd, 1H, J = 17.44 Hz, 3.09 Hz, C4–H pyr-
azoline), 3.84 (dd, 1H, J = 17.44 Hz, 11.12 Hz, C4–H
pyrazoline), 3.98 (s, 2H, C5–H thiazolinone), 6.11 (dd, 1H,
J = 11.12 Hz, 3.08 Hz, C5–H pyrazoline), 6.92 (d, 1H,
J = 8.2 Hz, Ar–H), 7.00 (d, 1H, J = 8.1 Hz, Ar–H), 7.38
(d, 1H, J = 8.0 Hz, Ar–H), 7.43 (t, 1H, J = 7.8 Hz, Ar–H),
7.58 (t, 1H, J = 7.4 Hz, Ar–H), 7.66 (s, 1H, Ar–H), 7.97 (d,
1H, J = 8.0 Hz, Ar–H), 8.38 (s, 1H, Ar–H), 9.19 (s, 1H,
OH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
21.1 (CH3), 39.4 (C5 of thiazolinone), 42.4 (C4 of pyrazo-
line), 60.2 (C5 of pyrazoline), 117.3–143.8 (Ar–C), 151.6
(C–Cl of quinoline), 159.1 (C=N of pyrazoline), 162.3 (C–
OH), 178.6 (C=N of thiazolinone), 187.4 (C=O of thiaz-
olinone); LCMS (m/z): 436(M?), 438 (M??2); Anal. Calcd.
For C22H17ClN4O2S: C-60.48, H-3.92, N-12.82; Found:
C-60.55, H-3.85, N-12.89 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-chlorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4e)
Light yellow crystals, yield: 59 %; m.p.: 226–228 °C; IR
(KBr) mmax/cm-1: 3065 (C–H, aromatic), 1695 (C=O), 1573
(C=N), 1529 (C=C), 745 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.35 (s, 3H, –CH3), 3.24 (dd, 1H,
J = 17.48 Hz, 3.10 Hz, C4–H pyrazoline), 3.94 (dd, 1H,
J = 17.48 Hz, 11.18 Hz, C4–H pyrazoline), 4.04 (s, 2H,
C5–H thiazolinone), 6.08 (dd, 1H, J = 11.17 Hz, 3.09 Hz,
C5–H pyrazoline),7.37 (d, 1H, J = 7.8 Hz, Ar–H), 7.42 (t,
1H, J = 7.4 Hz, Ar–H), 7.54 (t, 1H, J = 8.2 Hz, Ar–H),
7.59 (d, 1H, J = 8.4 Hz, Ar–H), 7.61 (s, 1H, Ar–H), 7.79
(d, 1H, J = 8.4 Hz, Ar–H), 7.94 (d, 1H, J = 8.4 Hz, Ar–
H), 8.36 (s, 1H, Ar–H);13C NMR (100 MHz, DMSO-d6, d,
ppm): 21.6 (CH3), 39.6 (C5 of thiazolinone), 42.2 (C4 of
pyrazoline), 62.8 (C5 of pyrazoline), 128.4 (C–Cl of chlo-
rophenyl), 124.3–143.4 (Ar–C), 151.6 (C–Cl of quinoline),
159.5 (C=N of pyrazoline), 178.5 (C=N of thiazolinone),
187.3 (C=O of thiazolinone); LCMS (m/z): 454(M?), 456
(M??2); Anal. Calcd. For C22H16Cl2N4OS: C-58.03,
H-3.54, N-12.30; Found: C-58.11, H-3.61, N-12.37 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-
hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-
4(5H)-one (4c)
Light brown crystals, yield: 58 %; m.p.: 185–187 °C; IR
(KBr) mmax/cm-1: 3413 (OH), 3065 (C–H, aromatic), 1705
(C=O), 1572 (C=N), 1524 (C=C), 737 (C–Cl); H NMR
1
(300 MHz, DMSO-d6, d, ppm): 2.35 (s, 3H, –CH3), 3.17
(dd, 1H, J = 17.52, 3.12 Hz, C4–H pyrazoline), 3.81 (dd,
1H, J = 17.51, 11.18 Hz, C4–H pyrazoline), 4.00 (s, 2H,
C5–H thiazolinone), 6.11 (dd, 1H, J = 11.18, 3.12 Hz, C5–
H pyrazoline), 6.82 (d, 2H, J = 8.0 Hz, Ar–H),7.31 (d, 1H,
J = 8.0 Hz, Ar–H), 7.62 (s, 1H, Ar–H), 7.82 (d, 2H,
J = 7.8 Hz, Ar–H), 7.93 (d, 1H, J = 8.2 Hz, Ar–H), 8.36
(s, 1H, Ar–H), 9.21 (s, 1H, OH, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.4 (CH3), 39.6 (C5 of
thiazolinone), 42.1 (C4 of pyrazoline), 60.7 (C5 of pyraz-
oline), 115.7–143.6 (Ar–C), 151.6 (C–Cl of quinoline),
159.3 (C=N of pyrazoline), 160.4 (C–OH), 178.2 (C=N of
thiazolinone), 187.7 (C=O of thiazolinone); LCMS (m/z):
436 (M?), 438 (M??2); Anal. Calcd. For C22H17ClN4O2S:
C-60.48, H-3.92, N-12.82; Found: C-60.55, H-3.85, N-
12.89 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4f)
Light brown crystals, yield: 55 %; m.p.: 164–166 °C; IR
(KBr) mmax/cm-1: 3061 (C–H, aromatic), 1690 (C=O),
123

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Med Chem Res (2013) 22:3663–3674
1582 (C=N), 1527 (C=C), 738 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.34 (s, 3H, –CH3), 3.17
(dd, 1H, J = 17.36, 3.02 Hz, C4–H pyrazoline), 3.97 (dd,
1H, J = 17.36 Hz, 11.17 Hz, C4–H pyrazoline), 4.08 (s,
2H, C5–H thiazolinone), 6.10 (dd, 1H, J = 11.16, 3.01 Hz,
C5–H pyrazoline), 7.33 (d, 1H, J = 7.6 Hz, Ar–H), 7.54 (d,
2H, J = 8.0 Hz, A2B2, p-chlorophenyl), 7.63 (s, 1H, Ar–
H), 7.91 (d, 1H, J = 8.1 Hz, Ar–H), 8.01 (d, 2H,
J = 8.0 Hz, A2B2, p-chlorophenyl), 8.38 (s, 1H, Ar–H);
13C NMR (100 MHz, DMSO-d6, d, ppm): 21.6 (CH3), 39.7
(C5 of thiazolinone), 42.4 (C4 of pyrazoline), 62.5 (C5 of
pyrazoline), 132.3 (C–Cl of chlorophenyl), 124.6–143.8
(Ar–C), 151.6 (C–Cl of quinoline), 159.4 (C=N of pyraz-
oline), 178.4 (C=N of thiazolinone), 187.8 (C=O of thiaz-
olinone); LCMS (m/z): 454 (M?), 456 (M??2); Anal.
Calcd. For C22H16Cl2N4OS: C-58.03, H-3.54, N-12.30;
Found: C-57.96, H-3.49, N-12.23 %.
7.68 (s, 1H, Ar–H), 7.75 (d, 1H, J = 8.4 Hz, Ar–H), 7.80
(s, 1H, Ar–H), 7.91 (d, 1H, J = 8.0 Hz, Ar–H), 8.36 (s, 1H,
Ar–H);13C NMR (100 MHz, DMSO-d6, d, ppm): 21.7
(CH3), 39.8 (C5 of thiazolinone), 42.2 (C4 of pyrazoline),
62.4 (C5 of pyrazoline), 113.8–144.2 (Ar–C), 151.7 (C–Cl
of quinoline), 159.6 (C=N of pyrazoline), 162.4 (C–F),
178.7 (C=N of thiazolinone), 187.5 (C=O of thiazolinone);
LCMS (m/z): 438 (M?), 440 (M??2); Anal. Calcd. For
C22H16ClFN4OS: C-60.20, H-3.67, N-12.77; Found:
C-60.13, H-3.60, N-12.84 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-fluorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4i)
Light reddish brown crystals, yield: 59 %; m.p.: 180–182 °C;
IR (KBr) mmax/cm-1: 3071 (C–H, aromatic), 1696 (C=O),
1582 (C=N), 1521 (C=C), 1148 (C–F); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.37 (s, 3H, –CH3), 3.35 (dd, 1H,
J = 17.52 Hz, 3.10 Hz, C4–H pyrazoline), 3.87 (dd, 1H,
J = 17.51 Hz, 11.12 Hz, C4–H pyrazoline), 4.07 (s, 2H, C5–
H thiazolinone), 6.14 (dd, 1H, J = 11.12 Hz, 3.11 Hz, C5–H
pyrazoline), 7.32 (d, 1H, J = 7.8, Ar–H), 7.40 (d, 2H,
J = 8.4 Hz, A2B2, p-fluorophenyl), 7.67 (s, 1H, Ar–H), 7.81
(d, 2H, J = 8.4 Hz, A2B2, p-fluorophenyl), 7.90 (d, 1H,
J = 8.2 Hz, Ar–H), 8.32 (s, 1H, Ar–H);13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.4 (CH3), 39.3 (C5 of thiazolinone),
42.1 (C4 of pyrazoline), 62.6 (C5 of pyrazoline), 115.1–143.7
(Ar–C), 151.5 (C–Cl of quinoline), 159.8 (C=N of pyrazo-
line), 164.3 (C–F), 178.4 (C=N of thiazolinone), 187.9 (C=O
of thiazolinone); LCMS (m/z): 438 (M?), 440 (M??2); Anal.
Calcd. For C22H16ClFN4OS: C-60.20, H-3.67, N-12.77;
Found: C-60.28, H-3.73, N-12.82 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-fluorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4g)
Light yellow crystals, yield: 53 %; m.p.: 173–175 °C; IR
(KBr) mmax/cm-1: 3072 (C–H, aromatic), 1698 (C=O),
1583 (C=N), 1524 (C=C), 1147 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.37 (s, 3H, –CH3), 3.33
(dd, 1H, J = 17.42 Hz, 3.10 Hz, C4–H pyrazoline), 3.89
(dd, 1H, J = 17.41 Hz, 11.29 Hz, C4–H pyrazoline), 4.02
(s, 2H, C5–H thiazolinone), 6.11 (dd, 1H, J = 11.28 Hz,
3.10 Hz, C5–H pyrazoline),7.29 (t, 1H, J = 8.0, Ar–H),
7.35 (d, 1H, J = 8.4, Ar–H), 7.42 (d, 1H, J = 8.2, Ar–H),
7.50 (t, 1H, J = 8.4, Ar–H), 7.62 (s, 1H, Ar–H), 7.84 (d,
1H, J = 8.6, Ar–H), 7.94 (d, 1H, J = 8.3 Hz, Ar–H), 8.33
(s, 1H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm):
21.8 (CH3), 39.8 (C5 of thiazolinone), 42.5 (C4 of pyraz-
oline), 62.2 (C5 of pyrazoline), 114.7–144.1 (Ar–C), 151.9
(C–Cl of quinoline), 159.4 (C=N of pyrazoline), 159.8 (C–
F), 178.3 (C=N of thiazolinone), 187.4 (C=O of thiazoli-
none); LCMS (m/z): 438(M?), 440 (M??2); Anal. Calcd.
For C22H16ClFN4OS: C-60.20, H-3.67, N-12.77; Found:
C-60.28, H-3.73, N-12.70 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(2-nitrophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4j)
Dark yellow crystals, yield: 53 %; m.p.: 194–196 °C; IR
(KBr) mmax/cm-1: 3060 (C–H, aromatic), 1700 (C=O), 1582
(C=N), 1528 (C=C), 1486, 1357 (NO2); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.38 (s, 3H, –CH3), 3.40
(dd, 1H, J = 17.34 Hz, 3.03 Hz, C4–H pyrazoline), 3.95
(dd, 1H, J = 17.34 Hz, 11.19 Hz, C4–H pyrazoline), 4.05
(s, 2H, C5–H thiazolinone), 6.02 (dd, 1H, J = 11.18 Hz,
3.03 Hz, C5–H pyrazoline), 7.36 (d, 1H, J = 8.2, Ar–
H),7.53 (t, 1H, J = 8.2 Hz, Ar–H), 7.64 (s, 1H, Ar–H), 7.84
(t, 1H, J = 8.4 Hz, Ar–H), 7.93 (d, 1H,J = 7.8 Hz, Ar–H),
7.98 (d, 1H, J = 7.8 Hz, Ar–H), 8.07 (d, 1H, J = 7.8 Hz,
Ar–H), 8.35 (s, 1H, Ar–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 21.8 (CH3), 39.2 (C5 of thiazolinone), 42.3 (C4
of pyrazoline), 62.8 (C5 of pyrazoline), 124.4–143.6 (Ar–
C), 134.8 (C-NO2), 151.6 (C–Cl of quinoline), 159.2 (C=N
of pyrazoline), 178.4 (C=N of thiazolinone), 187.7 (C=O of
thiazolinone); LCMS (m/z): 465(M?), 467 (M??2); Anal.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(3-fluorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4h)
Light brown crystals, yield: 61 %; m.p.: 163–165 °C; IR
(KBr) mmax/cm-1: 3070 (C–H, aromatic), 1704 (C=O),
1572 (C=N), 1501 (C=C), 1152 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.35 (s, 3H, –CH3), 3.46
(dd, 1H, J = 17.45, 3.18 Hz, C4–H pyrazoline), 3.90 (dd,
1H, J = 17.44 Hz, 11.19 Hz, C4–H pyrazoline), 4.10 (s,
2H, C5–H thiazolinone), 6.03 (dd, 1H, J = 11.18, 3.18 Hz,
C5–H pyrazoline),7.34 (d, 1H, J = 8.2 Hz, Ar–H), 7.44 (d,
1H, J = 7.8 Hz, Ar–H), 7.63 (t, 1H, J = 8.2 Hz, Ar–H),
123

Med Chem Res (2013) 22:3663–3674
3673
Calcd. For C22H16ClN5O3S: C-56.71, H-3.46, N-15.03;
Found: C-56.78, H-3.52, N-15.11 %.
thiazolinone derivatives exhibited remarkable antimicro-
bial potency. Results of antimicrobial activity clearly
demonstrated that the presence of thiazolinone heterocycle
is essential for enhancing biologic activity along with the
variation on different groups/atom on the phenyl ring at 3rd
position of pyrazoline heterocycle. It is a very well-known
fact that halogen atom (chloro/fluoro) is hydrophobic in
nature; due to this reason, it will influence as substituent
group’s physicochemical properties on the activity of
compounds. This property is useful to a compound to dif-
fuse through the biologic membranes and reach to its site of
action. Owing to this reason, hydrophobicity was found to
be directly related to the antimicrobial activity. The pres-
ence of hydrophobic substituent at 2nd position of phenyl
ring provides a positive influence on antimicrobial activity.
The presence of chloro, fluoro, and nitro substituents
conjugated to the aromatic ring has increased the activity
of the compounds compared to those with electron donat-
ing substituents. It may be considered as a promising lead
for further design and development of new lead molecules.
SAR studies have encouraged us to make further modifi-
cations on basic structures of the synthesized compounds to
achieve more selective and more potential antimicrobial
derivatives in ongoing program. In addition, further
investigations of these findings can have good effects on
medicinal chemists to synthesize similar compounds
selectively bearing chloro, fluoro, and nitro substituents.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(3-nitrophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4k)
Light yellowish brown crystals, yield: 54 %; m.p.:
158–160 °C; IR (KBr) mmax/cm-1: 3078 (C–H, aromatic),
1697 (C=O), 1579 (C=N), 1518 (C=C), 1488, 1359 (NO2);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.36 (s, 3H, –CH3),
3.44 (dd, 1H, J = 17.48 Hz, 3.13 Hz, C4–H pyrazoline),
3.89 (dd, 1H, J = 17.48 Hz, 11.04 Hz, C4–H pyrazoline),
4.11 (s, 2H, C5–H thiazolinone), 6.18 (dd, 1H,
J = 11.04 Hz, 3.12 Hz, C5–H pyrazoline), 7.34 (d, 1H,
J = 7.8, Ar–H), 7.63 (s, 1H, Ar–H), 7.74 (t, 1H, J = 8.0 Hz,
Ar–H), 7.89 (d, 1H, J = 8.0 Hz, Ar–H), 8.14 (d, 1H,
J = 8.4 Hz, Ar–H), 8.28 (d, 1H, J = 8.2 Hz, Ar–H), 8.34 (s,
1H, Ar–H), 8.52 (s, 1H, Ar–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.6 (CH3), 39.7 (C5 of thiazolinone),
42.8 (C4 of pyrazoline), 62.4 (C5 of pyrazoline), 124.5–144.1
(Ar–C), 132.3 (C-NO2),151.8 (C–Cl of quinoline), 159.6
(C=N of pyrazoline), 178.3 (C=N of thiazolinone), 187.6
(C=O of thiazolinone); LCMS (m/z): 465 (M?), 467
(M??2); Anal. Calcd. For C22H16ClN5O3S: C-56.71,
H-3.46, N-15.03; Found: C-56.66, H-3.40, N-14.95 %.
2-(5-(2-Chloro-6-methylquinolin-3-yl)-3-(4-nitrophenyl)-
4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4l)
Acknowledgments The authors are thankful to the Head, Department
of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji
Bhavnagar University, Bhavnagar, for providing laboratory facilities.
Orange crystals, yield: 52 %; m.p.: 170–172 °C; IR (KBr)
m
max/cm-1: 3073 (C–H, aromatic), 1705 (C=O), 1580 (C=N),
1513 (C=C), 1487, 1354 (NO2); 1H NMR (300 MHz, DMSO-
d6, d, ppm): 2.38 (s, 3H, –CH3), 3.47 (dd, 1H, J = 17.42 Hz,
3.10 Hz, C4–H pyrazoline), 3.88 (dd, 1H, J = 17.43,
11.14 Hz, C4–H pyrazoline), 4.07 (s, 2H, C5–H thiazolinone),
6.14 (dd, 1H, J = 11.15, 3.10 Hz, C5–H pyrazoline), 7.32 (d,
1H, J = 7.8, Ar–H), 7.60 (s, 1H, Ar–H), 7.92 (d, 1H, Ar–H),
8.06 (d, 2H, J = 8.6 Hz, A2B2, p-nitrophenyl), 8.29 (d, 2H,
J = 8.6 Hz, A2B2, p-nitrophenyl), 8.37(s, 1H, Ar–H), 8.32(s,
1H, Ar–H), 8.58 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.8 (CH3), 39.8 (C5 of
thiazolinone), 42.3(C4 ofpyrazoline), 62.1(C5 ofpyrazoline),
124.1–145.1 (Ar–C), 150.1 (C–NO2),151.6 (C–Cl of quino-
line), 159.3 (C=N of pyrazoline), 178.4 (C=N of thiazoli-
none), 187.4 (C=O of thiazolinone); LCMS (m/z): 465 (M?),
467 (M??2);Anal. Calcd. For C22H16ClN5O3S: C-56.71,
H-3.46, N-15.03; Found: C-56.76, H-3.52, N-15.08 %.
References
Ahmed N, Brahmbhatt KG, Sabde S, Mitra D, Singh IP, Bhutani KK
(2010) Synthesis and anti-HIV activity of alkylated quinoline
2,4-diols. Bioorg Med Chem 18:2872–2879. doi:10.1016/
j.bmc.2010.03.015
Al-Bayati FA, Al-Mola HF (2008) Antibacterial and antifungal
activities of different parts of Tribulus terrestris L. growing in
Iraq. J Zhenjiang 9:154–159. doi:10.1631/jzus.B0720251
Baraldi PG, Bovero A, Fruttarolo F, Romagnoli R, Tabrizi MA, Preti
D, Varani K, Borea PA, Moorman AR (2003) New strategies for
the synthesis of A3 adenosine receptor antagonists. Bioorg Med
Chem 11:4161–4169. doi:10.1016/S0968-0896(03)00484-X
Barrett CT, Barrett JF (2003) Antibacterials: are the new entries
enough to deal with the emerging resistance problems? Curr
Opin Biotechnol 14:621–626. doi:10.1016/j.copbio.2003.10.003
Barsoum FF, Hosni HM, Girgis AS (2006) Novel bis(1-acyl-2-
pyrazolines) of potential anti-inflammatory and molluscicidal
properties. Bioorg Med Chem 14:3929–3937. doi:10.1016/
j.bmc.2006.01.042
Conclusion
Bekhit AA, El-Sayed OA, Aboulmagd E, Young PJI (2004)
Tetrazolo[1,5-a]quinoline as a potential promising new scaffold
for the synthesis of novel anti-inflammatory and antibacterial
The preliminary in vitro antibacterial and antifungal
screening results of novel quinoline-2-pyrazoline-based
123

3674
Med Chem Res (2013) 22:3663–3674
agents. Eur J Med Chem 39:249–255. doi:10.1016/j.ejmech.
2003.12.005
Brad S, John HP, Eric PB, Loren GM, John EE (2004) Trends in
antimicrobial drug development: implications for the future. Clin
Infect Dis 38:1279–1286. doi:10.1086/420937
Cohen ML (2000) Changing patterns of infectious disease. Nature
406:762–767. doi:10.1038/35021206
Desai NC, Maheta AS, Rajpara KM, Joshi VV, Vaghani HV, Satodiya
HM (2011) Green synthesis of novel quinoline based imidazole
derivatives and evaluation of their antimicrobial activity. J Saudi
Chem Soc. doi:10.1016/j.jscs.2011.11.021
Jeong TS, Kim KS, Kim JR, Cho KH, Lee S, Lee WS (2004b) Novel
3,5-diaryl pyrazolines and pyrazole as low-density lipoprotein
(LDL) oxidation inhibitor. Bioorg Med Chem Lett 14:2719–
2723. doi:10.1016/j.bmcl.2004.03.072
Krainets IV, Amer M, Bezuglyi PA, Gorokhova OV, Sidorenko LV,
Turov AV (2002) 4-Hydroxy-2-quinolones. 56. 4-(Adamant-1-
yl)thiazolyl-2-amides of 1-R-4-hydroxy-2-oxoquinoline-3-car-
boxylic acids as potential antitubercular agents. Chem Hetero-
cycl Compd 38:571–575
Krchnak V, Holladay MW (2002) Solid phase heterocyclic chemistry.
Chem Rev 102:61–92. doi:10.1021/cr010123h
Desai NC, Rajpara KM, Joshi VV (2012a) Synthesis and character-
ization of some new quinoline based derivatives endowed with
broad spectrum antimicrobial potency. Bioorg Med Chem Lett
15:6871–6875. doi:10.1016/j.bmcl.2012.09.039
Desai NC, Joshi VV, Rajpara KM, Vaghani HV, Satodiya HM
(2012b) Microwave assisted synthesis and antimicrobial screen-
ing of new imidazole derivatives bearing 4-thiazolidinone
nucleus. Med Chem Res. doi:10.1007/s00044-012-0190-z
Desai NC, Rajpara KM, Joshi VV, Vaghani HV, Satodiya HM
(2012c) Synthesis of promising antimicrobial agents—a novel
series of N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-
yl)-2-morpholinoacetamides. Med Chem Res. doi:10.1007/
s00044-012-0121-z
Desai NC, Rajpara KM, Joshi VV, Vaghani HV, Satodiya HM
(2012d) Synthesis and characterization of some new thiazole
based thiazolidinone derivatives as potent antimicrobial and
antimycobacterial agents. Anti-Infective Agents 10:75–86
Desai NC, Joshi VV, Rajpara KM, Vaghani HV, Satodiya HM
(2012e) Facile synthesis of novel fluorine containing pyrazole
based thiazole derivatives and evaluation of antimicrobial
activity. J Fluor Chem 142:67–78. doi:10.1016/j.jfluchem.2012.
06.021
Desai NC, Rajpara KM, Joshi VV (2012f) Microwave induced
synthesis of fluorobenzamides containing thiazole and thiazol-
idine as promising antimicrobial analogs. J Fluor Chem. doi:
10.1016/j.jfluchem.2012.10.012
Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski
AP (2009) Structure—activity relationships for a series of
quinoline-based compounds active against replicating and non-
replicating Mycobacterium tuberculosis. J Med Chem 52:
2109–2118. doi:10.1021/jm900003c
Maguire MP, Sheets KR, McVety K, Spada AP, Zilberstein A (1994)
A new series of PDGF receptor Tyrosine Kinase inhibitors:
3-substituted quinoline derivatives. J Med Chem 37:2129–2137.
doi:10.1021/jm00040a003
Meth-Cohn O (1993) The synthesis of pyridines, quinolines and other
related systems by the Vilsmeier and the reverse Vilsmeier
method. Heterocycles 35:539–557
Muruganantham N, Sivakumar R, Anbalagan N, Gunasekaran V,
Leonard JT (2004) Synthesis, anticonvulsant and antihyperten-
sive activities of 8-substituted quinoline derivatives. Biol Pharm
Bull 27:1683–1687. doi:10.1248/bpb.27.1683
Nasveld P, Kitchener S (2005) Treatment of acute vivax malaria with
tafenoquine. Trans R Soc Trop Med Hyg 99:2–5. doi:10.1016/
j.trstmh.2004.01.013
Palaska E, Erol D, Demirdamar R (1996) Synthesis and antidepres-
sant activities of some 1,3,5-triphenyl-2-pyrazolines. Eur J Med
Chem 31:43–47. doi:10.1016/S0223-5234(96)80005-5
Shi A, Nguyen TA, Battina SK, Rana S, Takemoto DJ, Chiang PK,
Hua DH (2008) Synthesis and anti-breast cancer activities of
substituted quinolines. Bioorg Med Chem Lett 18:3364–3368.
doi:10.1016/j.bmcl.2008.04.024
Elgazwy ASH (2008) Synthesis and characterization of pyrido[1,2-
a]quinoline palladacycles. Monatsh Chem 139:1285–1297. doi:
10.1007/s00706-008-0932-2
Finegold SM, Garrod L (1995) Bailey and Scott’s diagnostic micro-
biology, 8th edn., chap 13C.V. Mosby, Toronto, pp 171–193
Jeong TS, Kim KS, An SJ, Cho KH, Lee S, Lee WS (2004a) Novel
3,5-diaryl pyrazolines as human acyl-CoA: cholesterol acyl-
transferase inhibitors. Bioorg Med Chem Lett 14:2715–2717.
doi:10.1016/j.bmcl.2004.03.079
Soni N, Pande K, Kalsi R, Gupta TK, Parmer SS, Barthwal JP (1987)
Inhibition of rat brain monoamine oxidase and succinic dehy-
drogenase by anticonvulsant pyrazolines. Res Commun Chem
Pathol Pharmacol 56:129–132
Turan-Zitouni G, Chevallet P, Kilic¸ FS, Erol K (2000) Synthesis of
some thiazolyl-pyrazoline derivatives and preliminary investi-
gation of their hypotensive activity. Eur J Med Chem 35:
635–641. doi:10.1016/S0223-5234(00)00152-5
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