Synthesis, antimicrobial and antioxidant activities of 2-[1-{3,5-diaryl-4, 5-dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-thiazoles

Article abstract of DOI:10.1007/s00044-012-0154-3

In this study, various substituted chalcones, prepared by condensing substituted acetophenones with substituted aldehydes/arylfurfurals, were treated with thiosemicarbazide in basic media to produce 1-thiocarbonyl-3,5- disubstituted pyrazolines which on further reaction with substituted phenacyl bromides afforded the title compounds in good yield. Structures of the newly synthesized compounds were assigned on the basis of elemental analyses, IR, ¹H NMR, and mass spectral studies. The newly synthesized compounds were tested for their in vitro antibacterial and antifungal activities against a variety of microorganisms and antioxidant activities by diphenylpicrylhydrazyl radical scavenging assay. Among the derivatives, compounds 3b, 3e, 6a, and 6h were identified as potent antioxidants. Compounds 3d, 3e, and 6a-f have emerged as the most promising antimicrobial agents displaying the maximum activity against all the tested microorganisms.

Full text of DOI:10.1007/s00044-012-0154-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1689–1699
DOI 10.1007/s00044-012-0154-3
ORIGINAL RESEARCH
Synthesis, antimicrobial and antioxidant activities of 2-[1-{3,5-
diaryl-4,5-dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-
thiazoles
•
Prajwal Lourdes Lobo Boja Poojary Manjunatha Kumsi Vinaya Chandra
•
•
•
•
Nalilu Sucheta Kumari K. R. Chandrashekar
Received: 19 October 2011 / Accepted: 12 June 2012 / Published online: 7 July 2012
ꢀ Springer Science+Business Media, LLC 2012
Abstract In this study, various substituted chalcones,
prepared by condensing substituted acetophenones with
substituted aldehydes/arylfurfurals, were treated with thi-
osemicarbazide in basic media to produce 1-thiocarbonyl-
3,5-disubstituted pyrazolines which on further reaction
with substituted phenacyl bromides afforded the title
compounds in good yield. Structures of the newly synthe-
sized compounds were assigned on the basis of elemental
analyses, IR, 1H NMR, and mass spectral studies. The
newly synthesized compounds were tested for their in vitro
antibacterial and antifungal activities against a variety of
microorganisms and antioxidant activities by diph-
enylpicrylhydrazyl radical scavenging assay. Among the
derivatives, compounds 3b, 3e, 6a, and 6h were identified
as potent antioxidants. Compounds 3d, 3e, and 6a–f have
emerged as the most promising antimicrobial agents dis-
playing the maximum activity against all the tested
microorganisms.
Keywords Chalcones ꢀ [1,3]-Thiazole ꢀ Pyrazolenyl ꢀ
Antibacterial ꢀ Antifungal ꢀ Antioxidant
Introduction
Heterocyclic synthesis has emerged as powerful technique
for generating new molecules that are useful for drug dis-
covery. Heterocyclic compounds provide scaffolds on
which pharmacophores can arrange to yield potent and
selective drugs. Thiazoles are familiar group of heterocy-
clic compounds possessing a wide variety of biological
activities, and their utility as medicine is very firmly
established. Thiazole nucleus is also an integral part of all
the available penicillins which have revolutionized the
therapy of bacterial diseases (Onca et al., 2004). [1,3]-
Thiazoles have attracted continuing interest because of
their varied biological activities (Quiroga et al., 2002),
which have recently found applications in the development
of drugs used for the treatment of allergies (Hargrave et al.,
1983), hypertension (Patt et al., 1992), inflammation
(Manjunatha et al., 2010), schizophrenia (Jean et al.,
1990), microbial (Lobo et al., 2010) and human immuno-
deficiency virus (HIV) infections (Bell et al., 1995), and
more recently for the treatment of pain (Carter et al., 1999).
Pyrazole and their derivatives could be considered as
possible antimicrobial agents (Lee et al., 2003); antide-
pressants (Erhan et al., 2001); inhibitors of protein kinases;
antiaggregating, antiarthritic (Nugen and Megan, 1993),
and cerebroprotectors (Kawazura et al., 1997). Some aryl
pyrazoles were reported to have non-nucleoside HIV-I
reverse transcriptase inhibitory activity (Jamode et al.,
2003), COX-2 inhibitory activity (Sakya and Rast, 2003),
and soluble guanylate cyclase activity (David and Selwood,
2001).
P. L. Lobo ꢀ B. Poojary (&)
Department of Chemistry, Mangalore University,
Mangalagangothri 575199, Karnataka, India
e-mail: bojapoojary@gmail.com
M. Kumsi
Department of Chemistry, Nagarjuna College of Engineering
and Technology, Devanahalli, Bangalore 562110, Karnataka,
India
V. Chandra ꢀ K. R. Chandrashekar
Department of Applied Botany, Mangalore University,
Mangalagangothri 575199, Karnataka, India
N. S. Kumari
Department of Biochemistry, K. S. Hegde Medical Academy,
Deralakatte 574162, Karnataka, India
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Med Chem Res (2013) 22:1689–1699
Following the successful introduction of antimicrobial
commercially available acetophenones were treated with
various simple aryl aldehydes and aryl furfurals by Clais-
en–Schmidt reaction to obtain the 1,3-diaryl prop-2-en-1-
ones (chalcones) 1 and 4, respectively. Their further con-
densation with thiosemicarbazides in alcohol medium led
to the formation of intermediate 3,5-disubstituted-4,5-
dihydro-1H-pyrazole-1-carbothioamides 2 and 5 which
were further treated with 4-nitrophenacyl bromides in
alcohol medium to obtain the title compounds 3a–e and
6a–k.
agents, inspired by the biological profiles of thiazoles,
pyrazoles, and in the design of new drugs, the develop-
ment of hybrid molecules through the combination of
different pharmacophores in one frame may lead to com-
pounds with interesting biological profiles, it was thought
worthwhile to accommodate thiazole and pyrazole moie-
ties in a single molecular framework for enhancing bio-
logical activity. The present investigation deals with the
use of chalcones in the synthesis of 2-[1-{3,5-diaryl-4,
5-dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-thiazole
and studying their antioxidant, antibacterial, and antifungal
properties.
All new compounds were characterized on the basis of
complementary spectroscopic (1H NMR, IR and MS) and
analytical data. The physicochemical properties and spec-
tral data of synthesized compounds are presented in
Table 1.
Results and discussion
In the 1H NMR spectra of the compounds 3a–e and 6a–k
protons of CH2–CH fragment of pyrazolines ring showed
characteristic splitting patterns of an ABX system. The
chemical shifts of the protons HA, HB, and HX have been
assigned to about d * 3.40–3.80, d * 3.70–4.00, and
d * 5.20–6.40, respectively and appeared as three doublets
of doublets (dd) and indicate that the methylene protons
Chemistry
The synthetic pathway for compounds described was
achieved by a sequence of reactions starting from alde-
hydes and is illustrated in Scheme 1. In the first step,
NH
NH
2
O
R
R1
H N
2
Br
S
R1
R
O N
2
N
O
N
EtOH/OH-
R1
1
EtOH
R
N
S
N
N
S
H2N
2
R
O2N
3
NH
2
H N
NH
2
Br
S
R
EtOH/OH-
O N
R1
2
O
R
R1
O
O
N
O
N
R1
O
N
EtOH
N
S
H2N
S
N
5
4
O2N
6
Scheme 1 R = 4-SCH3; 2,4-Cl2; 3-Cl-4-F; 2,4,5-Cl3; 4-NO2; 2-CH3-4-NO2; 4-Cl; 2-CH3-6-NO2; 4-OCH3-2-NO2; 4-Br; 4-Cl-2-NO2. R0 = 4-
OCH3; 3,4-(OCH3)2; 4-NO2; 4-Cl; 2,4-Cl2; 3,4-(OCH3)2; H
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Med Chem Res (2013) 22:1689–1699
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Table 1 Characterization data of compounds (2a–e) and (5a–k)
Compounds
R
R0
Molecular formula
Melting point (ꢁC)
Yield (%)
2a
2b
2c
2d
2e
5a
5b
5c
5d
5e
5f
4-SCH3
4-OCH3
C18H19N3OS2
162–164
132–134
198–199
140–142
176–178
183–185
124–127
158–160
173–175
189–191
139–141
188–190
186–188
154–156
192–193
167–169
88
85
77
89
70
83
75
78
77
79
85
69
82
72
78
83
4-SCH3
3,4-(OCH3)2
4-NO2
C19H16N3O2S2
C17H16N4O2S2
C17H16N3S2Cl
C17H15N3S2Cl2
C22H19N3O3SCl2
C22H19N3O3SClF
C22H18N3O3SCl3
C22H20N4O5S
4-SCH3
4-SCH3
4-Cl
4-SCH3
2,4-Cl2
2,4-Cl2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
3,4-(OCH3)2
H
3-Cl,4-F
2,4,5-Cl3
4-NO2
2-CH3-4-NO2
4-Cl
C23H22N4O5S
C22H20N3O3SCl
C23H22N4O5S
5g
5h
5i
2-CH3-6-NO2
4-OCH3-2-NO2
4-Br
C23H22N4O6S
C22H20BrN3O3S
C22H19N4O5SCl
5j
4-Cl-2-NO2
4-Cl
5k
C20H16N3OSCl
adjacent to an asymmetric centered are magnetically non-
of 4-chloro, 4-bromo, or 4-nitro group attached to any of the
phenyl rings of pyrazolynyl moiety. However, the com-
pounds 6g–k exhibited moderate activity compared to the
activity of the standard drug. Compounds 3a, 3b, and 3c did
not show any significant activity.
equivalent. The large values of JAB (approximate coupling
=
constants of JAB = 17.0–18.0, JAx = 11.0–12.0, and JBx
3.0–4.0 Hz) were observed. The protons belonging to aryl
groups were observed at expected chemical shifts and inte-
gral values. The H5-proton of thiazole ring was observed as a
singlet between d 6.9 and 7.3 ppm. The LC mass of
the compounds was also in agreement with the assigned
structure.
More extensive study is in progress to determine addi-
tional physicochemical and biological parameters to have a
deeper insight into structure–activity relationship and to
optimize the effectiveness of this series of molecules.
In compound 3a, the –SMe protons appeared as a singlet
at d 3.30 and the –OMe protons appeared as a singlet at d
3.89. The thiazole ring proton appeared at d 7.3. The aro-
matic protons appeared in the region from 6.93 to 8.18. In
compound 6k, the two protons of furan ring appeared as
two doublets at d 6.82 and d 7.24 with the coupling con-
stant J = 3.3 Hz.
DPPH radical scavenging activity
Antioxidants are very interesting, particularly in terms of
prevention of the presumed deleterious effects of free
radicals in the human body and in fats or other constituents
of food stuffs. There is therefore a parallel increase in the
use of methods for estimating the efficiency of such sub-
stances as antioxidants.
The IR spectra of the compounds 3a–e and 6a–k showed
the absence of NH2 peak confirming their formation. In
compounds containing NO2 group, two characteristic
absorption maxima in the region 1,507–1,515 and
1,330–1,370 cm-1 reveal its presence.
One such method that is currently popular is based on
the use of the stable, free radical diphenylpicrylhydrazyl
(DPPH). The purpose of our study is to examine the per-
centage inhibition of DPPH, compared with ascorbic acid
as standard. When a solution of DPPH is mixed with that of
the substance that can donate a hydrogen atom, then this
gives rise to the reduced form along with the loss of its
violet color. Representing the DPPH radical by Z• and the
donor molecule by AH, the primary reaction is given by
Antimicrobial activity studies
The antibacterial and antifungal screening data of the newly
synthesized compounds revealed that the most of the
compounds synthesized were very active against all the
bacterial (listed in Table 2) and fungal strains (listed in
Table 3). The compounds 3d, 3e, and 6a–f showed the
maximum activity against all the bacterial and fungal
strains. The good activity may be attributed to the presence
Zꢁ þ AH ¼ ZH þ Aꢁ
where ZH is the reduced form, and A• is the free radical
produced in the first step. This latter radical will then
ð1Þ
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Med Chem Res (2013) 22:1689–1699
Table 2 Antibacterial activities
of the newly synthesized
compounds (3a–e) and
MIC (1.56–25 lg/mL) and zone of inhibition (mm)
Bacterial strain
S. aureus
E. coli
P. aeruginosa
K. pneumoniae
(6a–k), expressed as MIC
(1.56–25 lg/mL) and zone
of inhibition (mm)
Compounds
3a
25(\10)
25(\10)
25(\10)
25(\10)
3b
25(\10)
25(\10)
25(\10)
25(\10)
3c
25(\10)
25(\10)
25(\10)
25(\10)
3d
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
1.56(22–30)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(30–40)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(25–33)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(23–27)
3e
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
Standard (amphicillin)
Table 3 Antifungal activities
of the newly synthesized
compounds (3a–e) and (6a–k),
expressed as MIC
MIC (1.56–25 lg/mL) and zone of inhibition (mm)
Fungal strain
P. marneffei
T. mentagrophytes
A. flavus
A. fumigatus
(1.56–25 lg/mL) and zone
of inhibition (mm)
Compounds
3a
25(\10)
25(\10)
25(\10)
25(\10)
3b
25(\10)
25(\10)
25(\10)
25(\10)
3c
25(\10)
25(\10)
25(\10)
25(\10)
3d
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(25–33)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(23–27)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
1.56(22–30)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
6.25(16–20)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
12.5(11–15)
6.25(30–40)
3e
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
Standard (itraconazol)
undergo further reactions which control the overall
stoichiometry that is the number of molecules of DPPH
reduced by one molecule of the reductant. The DPPH
molecule Z• is thus intended to represent the free radicals
formed in the system, activity of which is to be suppressed
by the substance AH. The free radical A• evidently then
reacts with another molecule of the same kind that was
produced by a parallel reaction to (1)
Aꢁ þ Aꢁ ¼ A ꢂ A
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Med Chem Res (2013) 22:1689–1699
1693
However, further detailed study on activity and long-term
toxicity needs to be carried out before any final conclusion
can be drawn.
Table 4 DPPH radical scavenging activities of compounds 3a–e and
6a–k, tested in dose 4,000 lg/mL and expressed as percent of
inhibition
Compounds
Percentage
inhibition
The antibacterial and antifungal screening data of the
newly synthesized compounds revealed that the most of the
compounds synthesized were very active against all the bac-
terial and fungal strains. Compounds 3d, 3e, and 6a–f showed
maximum activity against all the tested microorganisms.
3a
79
86
75
38
88
86
74
57
62
14
35
66
86
69
82
45
96
3b
3c
3d
3e
Experimental part
6a
6b
Materials and methods
6c
6d
Melting points were determined by an open capillary method
and are uncorrected (melting point apparatus: Sewell
instruments inc., India).The purity of the compounds was
checked by thin layer chromatography on a silica-coated
aluminum sheet (silica gel F254) using n-hexane and ethyl
acetate (4:1, v/v). The IR spectra (in KBr pellets) were
recorded on a Shimadzu FT-IR 157 spectrophotometer. The
1H NMR spectra were recorded on a BRUKER AVANCE II-
400 (400 MHz) spectrometer using TMS as an internal
standard. Mass spectra were recorded in Finnigan MAT8230
mass spectrometer. Elemental analysis was carried out using
CHNS elemental analyzer. Solvents and reagents were pur-
chased in the appropriate grade from commercial vendors
and were used without purification. 5-Aryl-furan-2-carbox-
aldehydes were prepared through Meerwein reaction (Holla
et al., 2005). Chalcones were prepared from substituted
aldehydes and substituted acetophenones according to the
procedure in the literature (Rai et al., 2008).
6e
6f
6g
6h
6i
6j
6k
Ascorbic acid
This therefore leads to the observed reduction of two
molecules of DPPH by two molecules of the reductant, that
is, a 1:1 stoichiometry.
The DPPH radical scavenging activity in terms of per-
centage inhibition exhibited by the title compounds are
summarized in Table 4.
In this assay 3a, 3b, 3c, 3e, 6a, 6b, 6h, and 6j are the
best DPPH radical scavengers. They showed significant
radical scavenging activity, compared with ascorbic acid as
standard. Among these compounds 3b, 3e, 6a, and 6h were
as active as ascorbic acid, while other tested compounds
expressed lower scavenging effect. Except compound 3e,
the other three compounds have O–CH3 function.
General procedure for the synthesis of 3,5-
disubstituted-4,5-dihydro-1H-pyrazole-1-
carbothioamides (2a–e) and (5a–k)
To a suspension of chalcones (0.01 mol) and sodium hydroxide
(0.025 mol) in ethanol, thiosemicarbazide (0.01) was added.
The mixture was refluxed, and after completion of the reaction,
the solution was poured into ice water. The resulting precipitate
was filtered off and recrystallized from ethanol.
Conclusion
In conclusion, we have reported a convenient protocol
for the synthesis of novel 2-[1-{3,5-diaryl-4,5-dihydro-
1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-thiazole in good
yield. The antioxidant properties of the new compounds
were evaluated using DPPH radical scavenging assay.
Compounds 3b, 3e, 6a, and 6h were identified as potent
antioxidants. They have OCH3 substitution in one of the
phenyl ring attached to pyrazole moiety. Antioxidant
activities of these compounds against the stable, free rad-
ical DPPH showed that these species could help in
increasing the overall antioxidant capacity of an organism.
3-(4-Methoxyphenyl)-5-(4-methylthiophenyl)-4,5-dihydro-
1H-pyrazole-1-carbothio-amide (2a)
Light yellow solid (yield 88 %) mp 162–164 ꢁC. IR (KBr,
m in cm-1): 3414 (N–H), 3243 (N–H), 3023 (ArC–H), 2943
(C–H), 1593 (C=N), 1249 (C–O), 1155 (C=S); H NMR
1
(CDCl3, d): 2.48 (s, 3H, SCH3), 3.87 (s, 3H, OCH3), 3.15
(dd, 1H, J1 = 17.6 Hz, J2 = 3.5 Hz, pyrazole–CH2), 3.82
(dd, 1H, J1 = 17.6 Hz, J2 = 11.3 Hz, pyrazole–CH2), 4.68
(bs, 2H, NH2), 6.01 (dd, 1H, J = 11.3, 3.5 Hz, pyrazole–CH),
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Med Chem Res (2013) 22:1689–1699
6.97 (d, 2H, J = 7.4 Hz, 4-methoxyphenyl), 7.19
(d, 2H, J = 8.3 Hz, 4-methylthiophenyl), 7.22 (d, 2H,
J = 8.3 Hz, 4-methylthiophenyl), 7.69 (d, 2H, J = 7.4 Hz,
4-methoxyphenyl); LC–MS (m/z, %): 358 (M?1, 92); anal.
calcd. for C18H19N3OS2: C, 60.47; H, 5.36; N, 11.75; S,
17.94 %; found: C, 60.47; H, 5.36; N, 11.75; S, 17.9 %.
J1 = 17.5 Hz, J2 = 6.3 Hz, pyrazole–CH2), 4.70 (bs, 2H,
NH2), 3.85 (dd, 1H, J1 = 17.5 Hz, J2 = 11.3 Hz, pyra-
zole–CH2), 5.74 (m, 1H, pyrazole–CH), 7.06 (s, 1H, thia-
zole), 7.45 (m, 5H, phenyl), 6.52 (s, 1H, J = 3.4 Hz,
furan), 6.63 (s, 1H, J = 3.4 Hz, furan), 7.21 (d, 2H,
J = 7.2 Hz, 4-chlorophenyl), 7.68 (d, 2H, J = 7.2 Hz,
4-chlorophenyl); LC–MS (m/z, %): 382 (M?1, 92); anal.
calcd. for C20H16ClN3OS: C, 62.90; H, 4.22; N, 11.00; S,
8.40 %; found: C, 62.93; H, 4.25; N, 11.04; S, 8.43 %.
5-(4-Methylthiophenyl)-3-(4-nitrophenyl)-4,5-dihydro-1H-
pyrazole-1-carbothioamide (2c)
Light yellow solid (yield 85 %) mp 132–134 ꢁC. IR (KBr,
m in cm-1): 3387 (N–H), 3246 (N–H), 3023 (ArC–H), 2943
(C–H), 1593 (C=N), 1592.4 (C=C), 1550 (NO2asym), 1362
(NO2sym), 1237 (C–O), 1153 (C=S); 1H NMR (CDCl3, d):
2.48 (s, 3H, SCH3), 3.87 (s, 3H, OCH3), 3.15 (dd, 1H,
J1 = 17.6 Hz, J2 = 3.5 Hz, pyrazole–CH2), 3.82 (dd, 1H,
J1 = 17.6 Hz, J2 = 11.3 Hz, pyrazole–CH2), 4.66 (bs, 2H,
NH2), 6.01 (dd, 1H, J1 = 11.3 Hz, J2 = 3.5 Hz, pyrazole–
CH), 7.17 (d, 2H, J = 8.3 Hz, 4-thiomethylphenyl), 7.22
(d, 2H, J = 8.3 Hz, 4-thiomethylphenyl), 7.83 (d, 2H,
J = 7.4 Hz, 4-nitrophenyl), 8.1 (d, 2H, J = 7.4 Hz,
4-nitrophenyl); LC–MS (m/z, %): 373 (M?1, 95); anal.
calcd. for C19H21N3O2S2: C, 54.82; H, 4.33; N, 15.04; S,
17.22 %; found: C, 54.85; H, 4.37; N, 15.07; S, 17.24 %.
General procedure for the synthesis of 2-[1-{3,5-diaryl-
4,5-dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-
thiazoles (3a–e) and (6a–k)
To a suspension of the compound 2 or 5 (0.01 mol) in eth-
anol, 4-nitrophenacyl bromide (0.01 mol) was added and
heated to reflux for 1 h. After completion of the reaction, the
reaction mixture was cooled, and the solid separated was
collected by suction filtration. The crude product was puri-
fied by recrystallization from suitable solvents.
2-[1-{3-(4-Methoxyphenyl)-5-(4-methylthiophenyl)-4,5-
dihydro-1H-pyrazolyl}]-4-(4-nitro-phenyl)-[1,3]-thiazole
(3a)
5-(3,4-Dimethoxylthiophenyl)-3-(5-(4-chlorophenyl)-
furan-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide
(5f)
Yellow solid (yield 73 %) mp 153–154 ꢁC. IR (KBr, m in
cm-1): 3053 (ArC–H), 2949 (C–H), 1594 (C=N), 1512
(NO2asym), 1327 (NO2sym), 1262 (C–O); 1H NMR
(CDCl3, d): 2.46 (s, 3H, SCH3), 3.85 (s, 3H, OCH3), 3.30
(dd, 1H, J1 = 17.6 Hz, J2 = 6.6 Hz, pyrazole–CH2), 3.91
(dd, 1H, J1 = 17.6 Hz, J2 = 11.8 Hz, pyrazole–CH2), 5.59
(dd, 1H, J1 = 11.8 Hz, J2 = 6.6 Hz, pyrazole–CH), 7.01
(s, 1H, –CH, thiazole), 6.95 (d, 2H, J = 8.8 Hz,
4-methoxyphenyl), 7.23 (d, 2H, J = 8.4 Hz, 4-thiometh-
ylphenyl), 7.34 (d, 2H, J = 8.4 Hz, 4-thiomethylphenyl),
7.70 (d, 2H, J = 8.8 Hz, 4-methoxyphenyl), 7.80 (d, 2H,
J = 8.9 Hz, 4-nitrophenyl), 8.17 (d, 2H, J = 8.9 Hz,
4-nitrophenyl); LC–MS (m/z, %): 503 (M?1, 96); anal.
calcd. for C26H22N4O3S: C, 66.38; H, 4.68; N, 11.91 %;
found: C, 66.41; H, 4.72; N, 11.94 %.
Yellow solid (yield 85 %) mp 139–141 ꢁC. IR (KBr, m in
cm-1): 3394 (N–H), 3248 (N–H), 3024 (ArC–H), 2945 (C–
H), 1640 (C=N), 1237 (C–O), 1250 (C–O), 1299 (C–O),
1162 (C=S), 755 (C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 3.71 (dd, 1H, J1 = 17.5 Hz,
J2 = 6.3 Hz, pyrazole–CH2), 4.70 (bs, 2H, NH2) 3.85 (dd,
1H, J1 = 17.5 Hz, J2 = 11.3 Hz, pyrazole–CH2), 5.85 (m,
1H, pyrazole–CH), 7.23 (d, 1H, J = 7.9 Hz, 3,4-dime-
thoxyphenyl), 7.49 (dd, 1H, J1 = 7.9 Hz, J2 = 1.9 Hz,
3,4-dimethoxyphenyl), 7.53 (d, 1H, J = 2.0 Hz, 3,4-
dimethoxyphenyl), 6.62 (s, 1H, J = 3.3 Hz, furan), 6.92 (s,
1H, J = 3.3 Hz, furan), 8.16 (d, 2H, J = 7.2 Hz, 4-chlo-
rophenyl), 8.35 (d, 2H, J = 7.2 Hz, 4-chlorophenyl); LC–
MS (m/z, %): 442 (M?1, 96); anal. calcd. for
C22H20ClN3O3S: C, 59.79; H, 4.56; N, 9.51; S, 7.26 %;
found: C, 59.63; H, 4.57; N, 9.54; S, 7.28 %.
2-[1-{3-(3,4-Dimethoxyphenyl)-5-(4-methylthiophenyl)-
4,5-dihydro-1H-pyrazolyl}]-4-(4-nitrophenyl)-[1,3]-
thiazole (3b)
Yellow solid (yield 78 %) mp 159–161 ꢁC. IR (KBr, m in
cm-1): 3053 (ArC–H), 2943 (C–H), 1592 (C=N), 1507
(NO2asym), 1330 (NO2sym), 1297 (C–O), 1262 (C–O), 1239
(C–O); 1H NMR (CDCl3, d): 2.45 (s, 3H, SCH3), 3.96 (s, 3H,
OCH3), 4.01 (s, 3H, OCH3), 3.33 (dd, 1H, J1 = 17.4 Hz,
J2 = 6.2 Hz, pyrazole–CH2), 3.75 (dd, 1H, J1 = 17.4 Hz,
J2 = 11.2 Hz, pyrazole–CH2), 5.75 (m, 1H, pyrazole–CH),
7.01 (s, 1H, –CH, thiazole), 6.89 (d, 1H, J = 8.4 Hz,
3-(5-(4-Chlorophenyl)-furan-2-yl)-5-phenyl-4,5-dihydro-
1H-pyrazole-1-carbothioamide (5k)
Yellow solid (yield 83 %) mp 167–169 ꢁC. IR (KBr, m in
cm-1): 3391 (N–H), 3246 (N–H), 3030 (ArC–H), 2957 (C–
H), 1592 (C=C), 1167 (C=S), 752 (C–Cl), 1589 (C=N),
1299 (C–O); 1H NMR (CDCl3, d): 3.66 (dd, 1H,
123

Med Chem Res (2013) 22:1689–1699
1695
3,4-dimethoxyphenyl), 7.15 (dd, 1H, J1 = 8.4 Hz,
J2 = 2.0 Hz, 3,4-dimethoxyphenyl), 7.47 (d, 1H,
J = 2.0 Hz, 3,4-dimethoxyphenyl), 7.24 (d, 2H, J = 8.4 Hz,
4-thiomethylphenyl), 7.36 (d, 2H, J = 8.4 Hz, 4-thiometh-
ylphenyl), 7.83 (d, 2H, J = 8.9 Hz, 4-nitrophenyl), 8.19 (d,
2H, J = 8.9 Hz, 4-nitrophenyl); LC–MS (m/z, %): 533
(M?1, 95); anal. calcd. for C26H22ClN3OS: C, 67.97; H, 4.79;
N, 9.14 %; found: C, 67.99; H, 4.77; N, 9.17 %.
(NO2asym), 1330 (NO2sym), 1262 (C–O); 1H NMR
(CDCl3, d): 2.46 (s, 3H, SCH3), 3.34 (dd, 1H,
J1 = 17.7 Hz, J2 = 6.4 Hz, pyrazole–CH2), 3.90 (dd, 1H,
J1 = 17.7 Hz, J2 = 11.3 Hz, pyrazole–CH2), 5.72 (dd,
1H, J1 = 11.3 Hz, J2 = 6.4 Hz, pyrazole–CH), 7.04 (s, 1H,
–CH, thiazole), 7.32 (d, 2H, J = 8.4 Hz, 4-thiomethyl-
phenyl), 7.45 (d, 2H, J = 8.4 Hz, 4-thiomethylphenyl),
7.67–7.70 (m, 3H, 2, 4-dichlorophenyl), 7.83 (d, 2H,
J = 8.8 Hz, 4-nitrophenyl), 8.12 (d, 2H, J = 8.8 Hz,
4-nitrophenyl); LC–MS (m/z, %): 543 (M?1, 82); anal.
calcd. for C25H18N4O2S2Cl2: C, 55.45; H, 3.35; N,
11.05 %; found: C, 55.48; H, 3.32; N, 11.04 %.
2[1-{5-(4-(Methylthio)phenyl)-3-(4-nitrophenyl)-4,5-
dihydro-1H-pyrazolyl}]-4-(4-nitro-phenyl)-[1,3]-thiazole
(3c)
Yellow solid (yield 75 %) mp 172–175 ꢁC. IR (KBr, m in
cm-1): 3054 (ArC–H), 2952 (C–H), 1594 (C=N), 1512
(NO2asym), 1327 (NO2sym), 1262 (C–O); 1H NMR
(CDCl3, d): 2.46 (s, 3H, SCH3), 3.30 (dd, 1H,
J1 = 17.6 Hz, J2 = 6.7 Hz, pyrazole–CH2), 3.88 (dd, 1H,
J1 = 17.6 Hz, J2 = 12.1 Hz, pyrazole–CH2), 5.60 (dd,
1H, J1 = 12.1 Hz, J2 = 6.7 Hz, pyrazole–CH), 7.04 (s, 1H,
–CH, thiazole), 7.92 (d, 2H, J = 8.8 Hz, 4-nitrophenyl),
7.23 (d, 2H, J = 8.2 Hz, 4-thiomethylphenyl), 7.34 (d, 2H,
J = 8.2 Hz, 4-thiomethylphenyl), 7.84 (d, 2H, J = 8.8 Hz,
4-nitrophenyl), 7.88 (d, 2H, J = 8.9 Hz, 4-nitrophenyl),
8.21 (d, 2H, J = 8.9 Hz, 4-nitrophenyl); LC–MS (m/z, %):
519 (M?1, 90); anal. calcd. for C25H19N5O4S2: C, 58.01;
H, 3.72; N, 13.53 %; found: C, 58.03; H, 3.75; N, 13.56 %.
2-[1-{5-(5-(2,4-Dichlorophenyl)furan-2-yl)-3-(2,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6a)
Yellow solid (yield 82 %) mp 155–157 ꢁC. IR (KBr, m in
cm-1): 3051 (ArC–H), 2948 (C–H), 1592 (C=N), 1557
(NO2asym), 1380 (NO2sym), 1307 (C–O), 1262 (C–O),
1239 (C–O), 743 (C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 3.71 (dd, 1H, J1 = 17.5 Hz,
J2 = 6.3 Hz, pyrazole–CH2), 3.85 (dd, 1H, J1 = 17.5 Hz,
J2 = 11.3 Hz, pyrazole–CH2), 5.85 (m, 1H, pyrazole–CH),
7.06 (s, 1H, thiazole), 6.89 (d, 1H, J = 7.9 Hz, 3,4-dime-
thoxyphenyl), 7.20 (dd, 1H, J1 = 7.9 Hz, J2 = 1.9 Hz,
3,4-dimethoxyphenyl), 7.49 (d, 1H, J = 2.0 Hz, 3,4-
dimethoxyphenyl), 7.31 (s, 1H, J = 3.3 Hz, furan), 7.54 (s,
1H, J = 3.3 Hz, furan), 7.91 (d, 2H, J = 8.6 Hz, 4-nitro-
phenyl), 8.17 (d, 2H, J = 8.6 Hz, 4-nitrophenyl),
7.72–7.87 (m, 3H, 4-chlorophenyl); LC–MS (m/z, %): 623
(M??1, 89); anal. calcd. for C30H22Cl2N4O5S: C, 57.98;
H, 3.57; N, 9.01 %; found: C, 57.94; H, 3.60; N, 9.04 %.
2-[1-{3-(4-Chlorophenyl)-5-(4-(methylthio)phenyl)-4,5-
dihydro-1H-pyrazolyl}]-4-(4-nitro-phenyl-[1,3]-)thiazole
(3d)
Light red solid (yield 87 %) mp 157–159 ꢁC. IR (KBr, m in
cm-1): 3057 (ArC–H), 2950 (C–H), 1594 (C=N), 1512
1
(NO2asym), 1327 (NO2sym), 1262 (C–O), 758 (C–Cl); H
NMR (CDCl3, d): 2.46 (s, 3H, SCH3), 3.32 (dd, 1H,
J1 = 18.2 Hz, J2 = 7.1 Hz, pyrazole–CH2), 3.95 (dd, 1H,
J1 = 18.2 Hz, J2 = 11.8 Hz, pyrazole–CH2), 5.63 (dd,
1H, J1 = 11.8 Hz, J2 = 7.1 Hz, pyrazole–CH), 7.02 (s, 1H,
–CH, thiazole), 7.42 (d, 2H, J = 8.3 Hz, 4-chlorophenyl),
7.27 (d, 2H, J = 8.4 Hz, 4-thiomethylphenyl), 7.48 (d, 2H,
J = 8.4 Hz, 4-thiomethylphenyl), 7.67 (d, 2H, J = 8.3 Hz,
4-chlorophenyl), 7.80 (d, 2H, J = 8.8 Hz, 4-nitrophenyl),
8.17 (d, 2H, J = 8.8 Hz, 4-nitrophenyl); LC–MS (m/z, %):
508 (M?1, 96); anal. calcd. for C25H19N4O2S2Cl: C, 59.22;
H, 3.78; N, 11.05 %; found: C, 59.26; H, 3.80; N, 11.08 %.
2-[1-{5-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-3-(2,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6b)
Yellow solid (yield 82 %) mp 155–157 ꢁC. IR (KBr, m in
cm-1): 3051 (ArC–H), 2948 (C–H), 1592 (C=N), 1557
(NO2asym), 1380 (NO2sym), 1307 (C–O), 1262 (C–O), 1239
(C–O), 743 (C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00(s, 3H, OCH3),3.71(dd,1H, J1 = 17.5 Hz, J2 = 6.3 Hz,
pyrazole–CH2), 3.85 (dd, 1H, J1 = 17.5 Hz, J2 = 11.3 Hz,
pyrazole–CH2), 5.85 (m, 1H, pyrazole–CH), 7.06 (s, 1H,
thiazole), 6.89 (d, 1H, J = 7.9 Hz, 3,4-dimethoxyphenyl),
7.20(dd, 1H, J = 7.9, 1.9 Hz, 3,4-dimethoxyphenyl), 7.49(d,
1H, J = 2.0 Hz, 3,4-dimethoxyphenyl), 7.31 (s, 1H,
J = 3.3 Hz, furan), 7.54 (s, 1H, J = 3.3 Hz, furan), 7.91 (d,
2H, J = 8.6 Hz, 4-nitrophenyl), 8.17 (d, 2H, J = 8.6 Hz,
4-nitrophenyl), 7.72–7.87 (m, 3H, 4-chlorophenyl); LC–MS
(m/z, %): 623 (M??1, 89); anal. calcd. for C20H16ClN3OS: C,
2-[1-{3-(2,4-Dichlorophenyl)-5-(4-(methylthio)phenyl)-
4,5-dihydro-1H-pyrazolyl)}]-4-(4-nitrophenyl)-[1,3]-
thiazole (3e)
Light red solid (yield 78 %) mp 162–164 ꢁC. IR (KBr, m in
cm-1): 3053 (ArC–H), 2950 (C–H), 1597 (C=N), 1517
123

1696
Med Chem Res (2013) 22:1689–1699
57.98; H, 3.57; N, 9.01 %; found: C, 57.94; H, 3.60; N,
9.04 %.
(NO2asym), 1380 (NO2sym), 1307 (C–O), 1262 (C–O),
1
1239 (C–O); H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 2.42 (s, 3H, CH3), 3.74 (dd, 1H,
J1 = 17.2 Hz, J2 = 6.6 Hz, pyrazole–H2), 3.85 (dd, 1H,
J1 = 17.2 Hz, J2 = 11.3 Hz, pyrazole–CH2), 5.88 (m,
1H, pyrazole–CH), 7.06 (s, 1H, thiazole), 6.95 (d, 1H, J =
7.8 Hz, 3,4-dimethoxyphenyl), 7.27 (dd, 1H, J1 = 7.8,
J2 = 1.9 Hz, 3,4-dimethoxyphenyl), 7.49 (d, 1H, J =
1.9 Hz, 3,4-dimethoxyphenyl), 7.23 (s, 1H, J = 3.3 Hz,
furan),7.38 (s, 1H, J = 3.3 Hz, furan), 7.83 (d, 2H,
J = 8.6 Hz, 4-nitrophenyl), 8.09 (d, 2H, J = 8.6 Hz,
4-nitrophenyl), 7.72–7.74 (m, 3H, 2-methyl-4-nitrophenyl);
LC–MS (m/z, %): 613 (M??1, 91); anal. calcd. for
C31H25N5O7S: C, 60.88; H, 4.12; N, 11.45 %; found: C,
60.71; H, 4.16; N, 11.48 %.
2-[1-{3-(2,4-Dimethoxyphenyl)-5-(5-(2,4,5-
trichlorophenyl)furan-2-yl)-4,5-dihydro-1H-pyrazole)}]-4-
(4-nitrophenyl)-[1, 3]-thiazole (6c)
Yellow solid (yield 65 %) mp 167–169 ꢁC. IR (KBr, m in
cm-1): 3051 (ArC–H), 2953 (C–H), 1592 (C=N), 1560
(NO2asym), 1389 (NO2sym), 1308 (C–O), 1268 (C–O),
1242 (C–O), 760 (C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 3.73 (dd, 1H, J1 = 17.7 Hz,
J2 = 6.3 Hz, pyrazole–CH2), 3.87 (dd, 1H, J1 = 17.7 Hz,
J2 = 11.5 Hz, pyrazole–CH2), 5.85 (m, 1H, pyrazole–CH),
7.04 (s, 1H, thiazole), 6.73 (d, 1H, J = 8.1 Hz, 3,4-dime-
thoxyphenyl), 7.20 (dd, 1H, J1 = 8.1, J2 = 1.9 Hz, 3,4-
dimethoxyphenyl), 7.53 (d, 1H, J = 1.9 Hz, 3,4-dime-
thoxyphenyl), 7.33 (s, 1H, J = 3.4 Hz, furan), 7.47 (s, 1H,
J = 3.4 Hz, furan), 7.89 (d, 2H, J = 8.4 Hz, 4-nitro-
phenyl), 8.21 (d, 2H, J = 8.4 Hz, 4-nitrophenyl), 7.78 (s,
1H, 2,4,5-trichlorophenyl), 7.93 (s, 1H, 2,4,5-trichlor-
ophenyl); LC–MS (m/z, %): 657 (M??1, 82); anal. calcd.
for C30H21Cl3N4O5S: C, 54.93; H, 3.23; N, 8.54 %; found:
C, 54.98; H, 3.27; N, 8.57 %.
2-[1-{2-(5-(4-Chlorophenyl)-furan-2-yl)-5-[1-{3-(3,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazolenyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6f)
Yellow red solid (yield 83 %) mp 167–169 ꢁC. IR (KBr, m
in cm-1): 3051 (ArC–H), 2948 (C–H), 1592 (C=N), 1557
(NO2asym), 1380 (NO2sym), 1302 (C–O), 1262 (C–O),
1239 (C–O), 743 (C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 3.71 (dd, 1H, J1 = 17.5 Hz,
J2 = 6.3 Hz, pyrazole–CH2), 3.85 (dd, 1H, J1 = 17.5 Hz,
J2 = 11.3 Hz, pyrazole–CH2), 5.85 (m, 1H, pyrazole–CH),
7.06 (s, 1H, thiazole), 6.89 (d, 1H, J = 7.9 Hz, 3,4-dime-
thoxyphenyl), 7.20 (dd, 1H, J1 = 7.9 Hz, J2 = 1.9 Hz,
3,4-dimethoxyphenyl), 7.49 (d, 1H, J = 2.0 Hz, 3,4-
dimethoxyphenyl), 7.31 (s, 1H, J = 3.3 Hz, furan), 7.54 (s,
1H, J = 3.3 Hz, furan), 7.93 (d, 2H, J = 8.8 Hz, 4-nitro-
phenyl), 8.19 (d, 2H, J = 8.8 Hz, 4-nitrophenyl), 8.16 (d,
2H, J = 7.2 Hz, 4-chlorophenyl), 8.35 (d, 2H, J = 7.2 Hz,
4-chlorophenyl); LC–MS (m/z, %): 587(M??1, 89); anal.
calcd. for C30H23ClN4O5S: C, 61.38; H, 3.95; N, 9.54 %;
found: C, 61.31; H, 3.97; N, 9.58 %.
2-[1-{3-(2,4-Dimethoxyphenyl)-5-(5-(4-nitrophenyl)furan-
2-yl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-nitrophenyl)-[1,3]-
thiazole (6d)
Yellow solid (yield 73 %) mp 182–184 ꢁC. IR (KBr, m in
cm-1): 3055 (ArC–H), 2957 (C–H), 1594 (C=N), 1558
(NO2asym), 1392 (NO2sym), 1309 (C–O), 1267 (C–O),
1
1247 (C–O); H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 3.70 (dd, 1H, J1 = 17.6 Hz,
J2 = 6.3 Hz, pyrazole–CH2), 3.81 (dd, 1H, J1 = 17.6 Hz,
J2 = 11.5 Hz, pyrazole–CH2), 5.88 (m, 1H, pyrazole–CH),
7.04 (s, 1H, thiazole), 6.74 (d, 1H, J = 8.2 Hz, 3,4-dime-
thoxyphenyl), 7.20 (dd, 1H, J1 = 8.2 Hz, J2 = 2.0 Hz,
3,4-dimethoxyphenyl), 7.53 (d, 1H, J = 2.0 Hz, 3,4-
dimethoxyphenyl), 7.33 (s, 1H, J = 3.4 Hz, furan), 7.47 (s,
1H, J = 3.4 Hz, furan), 7.84 (d, 2H, J = 8.4 Hz, 4-nitro-
phenyl), 8.11 (d, 2H, J = 8.4 Hz, 4-nitrophenyl), 7.92 (d,
2H, 4-nitrophenyl), 8.08 (d, 2H, 4-nitrophenyl); LC–MS
(m/z, %): 599 (M??1, 84); anal. calcd. for C30H23N5O7S:
C, 60.29; H, 3.88; N, 11.72 %; found: C, 60.32; H, 3.91; N,
11.75 %.
2-[1-{3-(2,4-Dimethoxyphenyl)-5-(5-(2-methyl-6-
nitrophenyl)furan-2-yl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6g)
Light red solid (yield 70 %) mp 169–171 ꢁC. IR (KBr, m in
cm-1): 3051 (ArC–H), 2948 (C–H), 1592 (C=N), 1557
(NO2asym), 1380 (NO2sym), 1307 (C–O), 1262 (C–O),
1
1239 (C–O); H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 2.42 (s, 3H, CH3), 3.74 (dd, 1H,
J1 = 17.2 Hz, J2 = 6.6 Hz, pyrazole–CH2), 3.85 (dd, 1H,
J1 = 17.2 Hz, J2 = 11.3 Hz, pyrazole–CH2), 5.88 (m, 1H,
pyrazole–CH), 7.06 (s, 1H, thiazole), 6.95 (d, 1H, J =
7.8 Hz, 3,4-dimethoxyphenyl), 7.27 (dd, 1H, J1 = 7.8,
J2 = 1.9 Hz, 3,4-dimethoxyphenyl), 7.49 (d, 1H, J =
1.9 Hz, 3,4-dimethoxyphenyl), 7.23 (s, 1H, J = 3.3 Hz,
2-[1-{3-(2,4-Dimethoxyphenyl)-5-(5-(2-methyl-4-
nitrophenyl)furan-2-yl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6e)
Light red solid (yield 73 %) mp 173–175 ꢁC. IR (KBr, m in
cm-1): 3051 (ArC–H), 2948 (C–H), 1592 (C=N), 1557
123

Med Chem Res (2013) 22:1689–1699
1697
2-[1-{5-(5-(4-Chloro-2-nitrophenyl)furan-2-yl)-3-(2,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6j)
furan), 7.38 (s, 1H, J = 3.3 Hz, furan), 7.83 (d, 2H,
J = 8.6 Hz, 4-nitrophenyl), 8.09 (d, 2H, J = 8.6 Hz,
4-nitrophenyl), 7.72–7.74 (m, 3H, 2-methyl-6-nitrophenyl);
LC–MS (m/z, %): 613 (M??1, 91); anal. calcd. for
C31H25N5O7S: C, 60.88; H, 4.12; N, 11.45 %; found: C,
60.71; H, 4.16; N, 11.48 %.
Yellow solid (yield 75 %) mp 153–155 ꢁC. IR (KBr, m in
cm-1): 3053 (ArC–H), 2948 (C–H), 1597 (C=N), 1563
(NO2asym), 1384 (NO2sym), 1307 (C–O), 1262 (C–O),
1240 (C–O), 762(C–Cl); 1H NMR (CDCl3, d): 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 3.73 (dd, 1H, J1 = 17.4 Hz,
J2 = 6.6 Hz, pyrazole–CH2), 3.89 (dd, 1H, J1 = 17.4 Hz,
J2 = 11.4 Hz, pyrazole–CH2), 6.12 (m, 1H, pyrazole–CH),
7.05 (s, 1H, thiazole), 6.93 (d, 1H, J = 7.4 Hz, 3,4-dime-
thoxyphenyl), 7.27 (dd, 1H, J = 7.4, 2.0 Hz, 3,4-dime-
2-[1-{3-(2,4-Dimethoxyphenyl)-5-(5-(4-methoxy-2-
nitrophenyl)furan-2-yl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitrophenyl)-[1,3]-thiazole (6h)
Light yellow solid (yield 81 %) mp 175–177 ꢁC. IR (KBr,
m in cm-1): 3053(ArC–H), 2948 (C–H), 1592 (C=N), 1557
(NO2asym), 1380 (NO2sym), 1307 (C–O), 1262 (C–O),
thoxyphenyl),
7.39
(d, 1H,
J = 2.0 Hz,
3,4-
dimethoxyphenyl), 7.32 (s, 1H, J = 3.3 Hz, furan),7.42 (s,
1H, J = 3.3 Hz, furan), 7.67 (d, 2H, J = 8.8 Hz, 4-nitro-
phenyl), 8.11 (d, 2H, J = 8.8 Hz, 4-nitrophenyl), 7.92 (s,
1H, 4-chloro-2-nitrophenyl), 7.57 (d, 1H, J = 8.3 Hz,
4-chloro-2-nitrophenyl), 7.62 (d, 1H, J = 8.3 Hz, 4-chloro-
2-nitrophenyl); LC–MS (m/z, %): 678 (M??1, 83); anal.
calcd. for C30H22N5O7SCl: C, 63.81; H, 3.63; N, 10.63 %;
found: C, 63.84; H, 3.67; N, 10.67 %.
1
1239 (C–O); H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.82 (dd, 1H,
J1 = 17.4 Hz, J2 = 7.0 Hz, pyrazole–CH2), 3.85 (dd, 1H,
J1 = 17.4 Hz, J2 = 11.4 Hz, pyrazole–CH2), 5.88 (m,
1H, pyrazole–CH), 7.06 (s, 1H, thiazole), 6.99 (d, 1H, J =
7.8 Hz, 3,4-dimethoxyphenyl), 7.27 (dd, 1H, J1 = 7.8 Hz,
J2 = 1.9 Hz, 3,4-dimethoxyphenyl), 7.49 (d, 1H, J =
1.9 Hz, 3,4-dimethoxyphenyl), 7.23 (s, 1H, J = 3.3 Hz,
furan), 7.41 (s, 1H, J = 3.3 Hz, furan), 7.77 (d, 2H,
J = 8.6 Hz, 4-nitrophenyl), 8.13 (d, 2H, J = 8.6 Hz,
4-nitrophenyl), 7.97 (s, 1H, 4-methoxy-2-nitrophenyl),
7.82 (d, 1H, 2-methyl-4-nitrophenyl),7.88 (d, 1H,
2-methyl-4-nitrophenyl); LC–MS (m/z, %): 629 (M??1,
91); anal. calcd. for C31H25N5O8S: C, 59.32; H, 4.01; N,
11.16 %; found: C, 59.35; H, 4.04; N, 11.18 %.
2-[1-{3-(5-(4-Chlorophenyl)-furan-2-yl)-5-phenyl-4,5-
dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-thiazole
(6k)
Yellow solid (yield 83 %) mp 167–169 ꢁC. IR (KBr, m in
cm-1): 3058 (ArC–H), 2952 (C–H), 1594 (C=N), 1552
1
(NO2asym), 1374 (NO2sym), 1297 (C–O), 747 (C–Cl); H
NMR (CDCl3, d): 3.66 (dd, 1H, J1 = 17.6 Hz, J2 =
6.8 Hz, pyrazole–CH2), 3.85 (dd, 1H, J1 = 17.6 Hz,
J2 = 12.0 Hz, pyrazole–CH2), 5.74 (m, 1H, pyrazole–CH),
6.89 (d, 1H, J = 3.4 Hz, furan), 7.09 (d, 1H, J = 3.4 Hz,
furan), 7.19 (m, 2H, phenyl), 7.06 (s, 1H, thiazole), 7.26 (d,
2H, J = 8.1 Hz, 4-chlorophenyl), 7.44 (m, 3H, phenyl),
7.50 (d, 2H, J = 8.1 Hz, 4-chlorophenyl), 7.68 (d, 2H,
J = 7.8 Hz, 4-nitrophenyl), 7.90 (d, 2H, J = 7.8 Hz,
4-nitrophenyl); LC–MS (m/z): 527 (M??1, 94); anal.
calcd. for C20H16ClN3OS: C, 62.90; H, 4.22; N, 11.00; S,
8.40 %; found: C, 62.93; H, 4.25; N, 11.04; S, 8.43 %.
2-[1-{5-(5-(4-Bromophenyl)furan-2-yl)-3-(2,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazolyl}]-4-(4-
nitropenyl)-[1,3]-thiazole (6i)
Light yellow solid (yield 76 %) mp 163–165 ꢁC. IR (KBr,
m in cm-1): 3053(ArC–H), 2948 (C–H), 1592 (C=N), 1560
(NO2asym), 1382 (NO2sym), 1307 (C–O), 1262 (C–O),
1
1239 (C–O); H NMR (CDCl3, d): 3.99 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.82 (dd, 1H,
J1 = 17.4 Hz, J2 = 7.0 Hz, pyrazole–CH2), 3.87 (dd, 1H,
J1 = 17.4 Hz, J2 = 11.4 Hz, pyrazole–CH2), 5.93 (m,
1H, pyrazole–CH), 7.05 (s, 1H, thiazole), 6.99 (d, 1H,
J = 7.8 Hz, 3,4-dimethoxyphenyl), 7.27 (dd, 1H,
J1 = 7.8 Hz, J2 = 1.9 Hz, 3,4-dimethoxyphenyl), 7.39 (d,
1H, J = 1.9 Hz, 3,4-dimethoxyphenyl), 7.23 (s, 1H,
J = 3.3 Hz, furan), 7.42 (s, 1H, J = 3.3 Hz, furan), 7.67
(d, 2H, J = 8.6 Hz, 4-nitrophenyl), 8.13 (d, 2H,
J = 8.6 Hz, 4-nitrophenyl), 7.52 (d, 2H, J = 8.3 Hz,
4-bromophenyl), 7.46 (d, 2H, J = 8.6 Hz, 4-bromophe-
nyl); LC–MS (m/z, %): 633 (M??1, 87); anal. calcd. for
C30H23BrN4O5S: C, 57.06; H, 3.67; N, 8.87 %; found: C,
57.09; H, 3.70; N, 8.88 %.
Antibacterial activity
The newly synthesized compounds were screened for their
antibacterial activities against Escherichia coli (ATTC-
25922), Staphylococcus aureus (ATTC-25923), Pseudo-
monas aeruginosa (ATTC-27853), and Klebsiella pneu-
moniae (recultured) bacterial strains by the serial plate
dilution method. The minimum inhibitory concentration
(MIC) was noted by observing the lowest concentration of
the tested compound at which there was no visible growth.
Antibacterial activity was determined by measuring the
123

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Med Chem Res (2013) 22:1689–1699
committee for clinical laboratory standards M27-A broth mic-
rodilution methods for antifungal drug susceptibility testing of
yeasts. J Clin Microbiol 38:2254–2255
diameter of inhibition zone. Activity of each compound
was compared with ciprofloxacin as standard (Davis and
Marham, 1996). Zone of inhibition was determined for all
the tested compounds (3a–e) and (6a–k) The results are
summarized in Table 3.
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The newly prepared compounds were also screened for their
antifungal activities against Aspergilus flavus (NCIM No.
524), Aspergilus fumigatus (NCIM No. 902), Penicillium
maneffei (recultured), and Trichophyton mentagrophytes
(recultured) in DMSO by the serial plate dilution method
(Arthington-Skaggs et al., 2000). Antifungal activity was
determined by measuring the diameter of inhibition zone.
Activity of each compound was compared with cyclo-
piroxolamine as standard. Zones of inhibition were deter-
mined for the tested compounds (3a–e) and (6a–k). The
results are summarized in Table 4.
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TheDPPH assay was based onthe methodreportedbyKokura
et al. (2005). In brief, the DMSO solutions containing
4,000 lg/mL of the tested compounds were made. Then, they
were diluted to 5 mL using acetone. To these solutions,
0.1 mL of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) solution
(10 mg/10 mL acetone) in acetone was added.. The mixed
solutions were incubated at room temperature for 15 min. The
absorbanceofstable DPPH was read at517 nmusingUV–Vis
spectrophotometer, and the remaining DPPH was calculated.
Decrease in the absorbance of DPPH solution indicated an
increaseintheradicalscavengingactivity.TheDPPHsolution
withoutsamplewas usedascontrol. Ascorbicacidwas usedas
standard. The experiments were carried out in triplicate. The
activity was expressed as percentage DPPH radical scaveng-
ing that was calculated from the following equation:
½Ac ꢂ Asꢃ
DPPH scavenging activity ð%Þ ¼
ꢄ 100
½Ac ꢂ Abꢃ
where Ac was the absorbance of the control, As for the sample
and Ab for the blank (MeOH). Each sample was assayed at
4,000 lg/mL, and all the experiments were carried out in
triplicate, and the % RSC is shown in Table 4.
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Acknowledgments The authors are thankful to the Director, IISc
1
Bangalore and CDRI Lucknow for H NMR and mass spectral data.
The authors are also grateful to UGC-SAP for the financial assistance.
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novel anti-inflammatory and anti arthritic agents. J Med Chem
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