Synthesis, characterization and pharmacological study of 4,5-dihydropyrazolines carrying pyrimidine moiety

Article abstract of DOI:10.1016/j.ejmech.2012.07.002

A series of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)pyrimidine were prepared under conventional heating as well as microwave reaction condition. The newly synthesized compounds were characterized on the basis of elemental, spectral and single crystal X-ray studies. These new compounds were screened for their antioxidant, anti-inflammatory and analgesic activities. Some of these compounds exhibited potent biological activities compared to the standard drug.

Full text of DOI:10.1016/j.ejmech.2012.07.002

European Journal of Medicinal Chemistry 55 (2012) 467e474
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and pharmacological study of 4,5-dihydropyrazolines
carrying pyrimidine moiety
,
a
b
Adithya Adhikari a, Balakrishna Kalluraya a , Kizhakke Veedu Sujith , Kuluvar Gouthamchandra ,
*
Ravikumar Jairam c, Riaz Mahmood b, Ravish Sankolli d
a Department of Studies in Chemistry, Mangalore University, Mangalagangothri 574 199, Karnataka, India
b Department of P.G. Studies and Research in Biotechnology and Bioinformatics, Jnanasahyadri, Kuvempu University, Shankaraghatta 577 451, Karnataka, India
c Department of Pharmacology, NGSM Institute of Pharmaceutical Science, Deralakkatte 574160, Karnataka, India
d Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)pyrimidine were prepared under
Received 30 September 2011
Received in revised form
19 May 2012
Accepted 2 July 2012
Available online 20 July 2012
conventional heating as well as microwave reaction condition. The newly synthesized compounds were
characterized on the basis of elemental, spectral and single crystal X-ray studies. These new compounds
were screened for their antioxidant, anti-inflammatory and analgesic activities. Some of these
compounds exhibited potent biological activities compared to the standard drug.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
2-Pyrazolines
XRD studies
Antioxidant
Anti-inflammatory and analgesic activity
1. Introduction
2. Chemistry
Pyrimidines belong to an important class of heterocyclic
compounds due to their significant role in several biological
processes and also due to extensive chemical and pharmacological
properties [1e3]. Pyrimidine derivatives exhibit a broad spectrum
of biological activities such as anticancer [4e6], antiviral [7], anti-
bacterial [8], antioxidant [9,10], anti-inflammatory and analgesic
activities [11e14].
Moreover the pyrazoline derivatives have been reported to
exhibit various pharmacological activities such as antimicrobial
[15], anti-inflammatory [16,17] and antihypertensive [18]. In addi-
tion, 1-substituted-3,5-diaryl-2-pyrazolines were reported to
exhibit human acyl CoA cholesterol acyltransferase activity [19] as
well as activity of low-density lipoprotein oxidation inhibitors [20].
Promoted by these reports and as a continuation of our work on
biologically important heterocycles [21e24], in the current study
we planned to incorporate the two bioactive entities pyrimidine
and pyrazoline into one compact structure and evaluated their
biological potencies through antioxidant, anti-inflammatory and
analgesic studies.
The reaction of 1,1,3,3-tetramethoxypropane with urea in the
presence of Conc. HCl in methanol medium afforded 2-
hydroxypyrimidine; which on further reaction with bromine yiel-
ded 5-bromo-2-hydroxypyrimidine. The last one was then con-
verted to 5-bromo-2-chloropyrimidine (1) with POCl3 at
105e110 ꢀC [25]. 5-Bromo-2-chloropyrimidine by means of
hydrazinolysis resulted 5-bromo-2-pyrimidinylhydrazine (2)
(Scheme 1), which on reaction with 1,3-diaryl-2-propen-1-one
furnished
5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)
pyrimidine (Scheme 2). Structures of the newly synthesized pyr-
azolines were confirmed on the basis of analytical, spectral and
single crystal X-ray studies. These pyrazolines were screened for
their antioxidant, anti-inflammatory and analgesic activities.
3. Pharmacology
3.1. In vitro antioxidant studies
All the newly synthesized pyrazolines were screened for their
antioxidant property on DPPH, hydroxyl, superoxide anion and
nitric oxide radicals. The brief procedure is outlined below.
* Corresponding author. Tel.: þ91 9448824075; fax: þ91 824 2287367.
E-mail address: bkalluraya@gmail.com (B. Kalluraya).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.07.002

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A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
3.1.2. Hydroxyl radical, superoxide anion and nitric oxide radical
(NOꢁ) scavenging activity
The ability of pyrazolines to scavenge hydroxyl radical was
assessed according to the modified method of Chung et al. [27]. Using
the method of Nishikimi [28], the superoxide anion scavenging
activity was determined and Griess Illosvoy reaction [29,30] was used
to analyze the nitric oxide scavenging ability of the novel pyrazolines.
The percentage radical scavenging activity was calculated and
compared with the standard butylated hydroxytoluene (BHT).
3.2. In vivo anti-inflammatory activity
The anti-inflammatory activity of the pyrazolines was determined
by carrageenan induced paw edema method [31] using plethysmog-
raphy. Wister albino rats of either sex weighing 180e250 g were used
for the experiment. They were housed in the clean polypropylene
cages and kept under room temperature (25 ꢀC), relative humidity
(60e70%) in 12 h of light-dark cycle. The animals were given standard
laboratory diet and wateradlibitum. Foodwaswithdrawn12 h before
and duringexperimentalhours. Anti-inflammatoryactivityof the test
compounds was measured with respect to the control and compared
with respect to the standard drug diclofenac. Diclofenac at a dose of
20 mg/kg served as the standard drug for comparison. The test
compounds (20 mg/kg) were administered 30 min prior to adminis-
tration of carrageenan (0.1 mL of 1% w/v) in the plantar region of the
paw. The paw volumes were measured at 30, 60, 90, 120, 150 and
180 min after carrageenan administration. Percent of inhibition
compared to standard drug is calculated using the formula
Scheme 1.
3.1.1. DPPH scavenging assay
The procedure of Brand-Williams [26] was followed for evalu-
ation of newly synthesized pyrazolines for their free radical-
scavenging capacity. Briefly, 1 mL of the test sample at the
concentration of 25, 50 and 100
mg/mL was mixed with the
methanolic 2,2-diphenyl-1-picrylhydrazyl (DPPH) solution (2 mL,
0.2 mM). The absorbance was measured at 517 nm immediately
after standing at room temperature for 30 min. The percentage of
scavenging has been calculated as the ratio of the absorption of the
sample relative to the control DPPH (0.2 mM) solution without the
test samples. DPPH radical-scavenging activity was expressed as
the inhibition percentage.
ꢀ
ꢁ
Vt
Vc
% inhibition ¼ 1 ꢂ
ꢃ 100
Vt ¼ Average edema volume of test compounds
Vc ¼ Average edema volume of control
3.3. In vivo analgesic activity
Analgesic activities were evaluated on Swiss albino mice by tail
immersion method [32]. In this method heat is used as a source of
pain. Animals are grouped into 5, each containing 6 animals (n ¼ 6).
Group 1 animals were kept as control and group 2 animals received
standard drug, pentazocine and other group of animals received test
compounds (10 mg/kg) intraperitoneally. The basal reaction time to
thermal heat was noted by placing the tip of the tail in the thermo-
static organ bath inwhich water is maintained at 55 ꢀC. The responses
produced in the animal were observed for 30 min intervals.
Percentage increase in reaction timeðRTÞ
ꢂ
ꢃ
RTAT
RTBT
¼
ꢂ 1 ꢃ 100
RTAT ¼ Reaction time after treatment
RTBT ¼ Reaction time before treatment
4. Results and discussion
4.1. Synthetic protocols
In this work, 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-
yl)pyrimidine (4ael) were synthesized under conventional
Scheme 2.

A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
469
heating and microwave (MW) irradiation technique. The conven-
tional method requires use of solvent and the reaction was found to
be slow. As expected under microwave, the process was rapid and
it’s necessary to mention product was obtained in good yield in the
presence of few drops of acetic acid which is used as a catalyst.
Another positive advantage of microwave reaction was, simple
procedure and also avoids the lengthy workup procedure. The
compounds prepared using these procedures, time required for
their synthesis and yield obtained were presented in Table 1.
The structure of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyr-
azol-1-yl)pyrimidine (4ael) were established on the basis of
elemental analyses, IR, 1H NMR, 13C NMR, HSQC and Mass spectral
and single crystal XRD data.
In a typical example, in the 1H NMR spectrum of compound 4a,
the chiral proton of the pyrazoline ring appeared as doublet of
a doublet centered at
d
5.88 with a coupling constant J ¼ 12.08 Hz &
Fig. 1. Graph comparing the anti-inflammatory activity of pyrazolines at 20 mg/kg.
J ¼ 4.72 Hz integrating for one proton. The pro-chiral CH2 protons of
pyrazoline ring appeared as two distinct doublet of a doublet
Further the structure was confirmed by single crystal XRD
studies.
centered at
a coupling constant of 17.8 Hz & 12.12 Hz) and
d
4.01 (due to geminal & vicinal coupling and having
3.26 (with geminal
d
& vicinal coupling of 17.88 Hz & 4.72 Hz) each integrating for one
proton thereby indicating that the two pro-chiral protons are
magnetically non-equivalent. The signal due to protons of 4-
nitrophenyl moiety and aromatic protons of other phenyl group
4.2. Pharmacological screening
Newly synthesized pyrazolines 4ael were screened for their free
radical scavenging activity by DPPH method. Antioxidant reacts
with DPPH, which is a stable free radical and converts it to 1,1-
diphenyl-2-picrylhydrazine. The degree of discoloration indicates
the scavenging potentials of the antioxidant compounds. At the
appeared as multiplets in the region of
d 7.44e7.80 integrating for
nine protons and pyrimidine protons appeared as a sharp singlet at
d
8.53 integrating for two protons.
In the 13C NMR spectrum of pyrazoline 4a, the C-4 carbon of
pyrazoline ring appeared at
61.37. The C-2 carbon of pyrimidine ring appeared at
the C-5 carbon appeared at 108.47. The C-4 and C-6 carbons
appeared at 156.27. The other carbon atoms appeared in the
region 124.10e153.20. Further, the carbon proton correlation of
d
41.97 and C-5 carbon appeared at
concentration of 100 mg, pyrazolines 4b, 4c, 4d, 4i and 4j exhibited
d
d
158.31 and
94.11, 93.51, 93.44, 89.79 and 90.51% free radical scavenging activity
respectively, it is interesting to note that the inhibition showed by
pyrazolines 4b, 4c and 4d is greater than that of standard BHT
d
d
d
(93.16% at 100 mg/mL), where as other pyrazolines 4i and 4j showed
pyrazoline 4a has been confirmed by HSQC experiment (Fig. 4).
In the mass spectrum of the pyrazolines, the molecular ion
peaks were in consistent with the assigned molecular formulas. For
compound 4b the (Mþ þ 1) and (Mþ þ 3) peaks were observed at
m/z, 393/395 in agreement with the molecular formula C20H17BrN4.
For compound 4c, the (Mþ þ 1) peak was observed at m/z, 413 in
consistent with the molecular formula C19H14BrClN4. The cluster of
isotope peaks was observed at m/z, 415 and 417. Similarly for
compound 4h, the (Mþ þ 1) peak was observed at m/z, 427 in
agreement with the molecular formula C20H16BrClN4. The cluster of
isotope peaks was observed at m/z, 429 and 431.
inhibition comparable to the standard BHT. The activity exhibited
by the remaining pyrazolines 4a, 4e, 4f, 4g, 4h and 4k is lesser than
that of standard BHT. The results are shown in Table 2.
The scavenging effect of hydroxyl radical was investigated using
the Fenton reaction and the results are shown as an inhibition rate
in Table 3. Pyrazolines 4b, 4c and 4d exhibited the highest inhibi-
tion of 89.12, 87.91 and 86.81% which is higher than the standard
BHT (86.98% at 100 mg/mL), where as pyrazolines 4i and 4j showed
lower effect than that of standard BHT. Among superoxide anion
radical scavenging studies, pyrazolines 4b, 4c, 4d, 4i and 4j
exhibited significant activity comparable with that of standard BHT.
Further potent nitric oxide anion scavenging activity was exhibited
by pyrazolines 4b, 4c, 4d and 4i. All the results are shown together
in Table 3. In conclusion among the pyrazolines tested, compounds
4b, 4c, 4d, 4i and 4j exhibited potent antioxidant property. This
result was taken as a basis for the further experiments.
Table 1
Characterization data of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)
pyrimidine (4ael).
Compda
R
R1
M.P ꢀ
C
Yield %
Mol formula
(Mol. Wt.)avg
MW (Time
[min])
D (Time
[hour])
4ac
4bb
4cc
4db
4eb
4fb
4gb
4hb
4ib
H
H
H
H
NO2
CH3
Cl
220
196
194
187
192
184
204
175
89 (5)
88 (4.5)
83 (4)
84 (5)
88 (5)
84 (4.5)
86 (5)
85 (5)
82 (5)
87 (4.5)
84 (5.5)
86 (5)
60 (6)
67 (7)
52 (8)
64 (7)
64(7)
69 (7)
65 (8)
58 (7)
63 (7)
65 (7)
70 (8)
65 (8)
C19H14BrN5O2 (423)
C20H17BrN4 (393)
C19H14BrClN4 (413.5)
C19H14Br2N4 (458)
C19H13Br3N4 (537)
C20H16Br2N4 (472)
C19H13Br2ClN4 (492.5)
C20H16BrClN4 (427.5)
C20H16BrClN4O (492.5)
C19H14BrClN4 (413.5)
C19H13BrCl2N4 (448)
C19H13Br2ClN4 (492.5)
Br
Br Br
Br CH3
Br Cl
Cl CH3
Cl OCH3 155
Cl
Cl Cl
Cl Br
4jc
H
189
202
217
4kc
4lc
a
Solvent for recrystallization.
Ethanol.
Ethanol þ DMF.
b
c
Fig. 2. Bar diagram comparing analgesic activity of test pyrazolines at 30, 60 and
90 min.

470
A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
Further these pyrazolines were also evaluated for analgesic
activity using tail flick method in mice. Table 5 displays the anal-
gesic activity of pyrazolines 4b, 4c, 4d, 4i and 4j. Among the
compounds tested all of the tested compounds showed significant
analgesic activity comparable to pentazocine as illustrated in
Table 4. A graph was plotted to understand the potency of the test
compounds (Fig. 2). From the graph we can clearly say that the
pyrazolines 4c and 4j exhibited highest activity and pyrazolines 4b,
4d and 4i exhibited better activity when compared with the stan-
dard. In conclusion, among the pyrazolines selected based on the
excellent antioxidant results displayed potent anti-inflammatory
and analgesic activity.
Fig. 3. ORTEP diagram obtained for pyrazoline 4e.
4.3. X-Ray crystallographic analysis of compound 4e
Based on antioxidant results pyrazolines 4b, 4c, 4d, 4i and 4j
were selected for anti-inflammatory and analgesic activity. The
anti-inflammatory activity of the pyrazolines was evaluated by
applying the carrageenan-induced rat paw edema bioassay in rats.
Diclofenac was used as a reference substance in the assay. All the
tested pyrazolines showed significant activity. In comparison to
diclofenac, pyrazolines 4b, 4c, 4d and 4j showed potent anti-
inflammatory activity (Table 4). Pyrazoline 4i displayed equiva-
lent performance as standard diclofenac. A graph was plotted to
understand the significant anti-inflammatory activity displayed by
the pyrazolines with standard (Fig. 1). The graph clearly indicates
the significant anti-inflammatory activity displayed by pyrazolines
4b, 4c, 4d and 4j.
The X-ray crystallographic analysis of pyrazoline 4e was deter-
mined on a pale yellow crystal, with approximate dimensions of
0.31 mm ꢃ 0.25 mm ꢃ 0.15 mm, grown from the slow evaporation
of an ethanol DMF mixture at room temperature. The data of 15
frames were collected in Oxford diffraction Xcalibur Mova, a four
circled single crystal diffractometer equipped with CCD detector
using 1ꢀ scan width. The data was reduced using CrysAlisRED
(special programs available with the diffractometer) and an
analytical absorption correction (after Clark and Reid) was applied.
Structure solution and refinements were performed by the
SHELX97 using the WinGX suite [33,34]. All the atoms were located
in different Fourier maps and refined isotropically, using a riding
Fig. 4. HSQC spectrum of pyrazoline 4a.

A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
471
Table 2
them showed scavenging capacity much higher than that of stan-
dard BHT. Anti-inflammatory studies of pyrazolines exhibited
promising results as they displayed significant activity compared to
the standard drug. Analgesic studies on the pyrazolines are highly
encouraging as few molecules displayed excellent activity. So the
idea of combining two bioactive groups namely, pyrimidine and
pyrazoline resulted in the formation of new series of biologically
potent molecules.
Percentage inhibition of pyrazolines 4ael on DPPH radical.
Compound No
Percentage inhibition of compounds at various
concentration on DPPH radicala
25
mg
50
m
g
100 mg
4a
4b
4c
4d
4e
4f
4g
4h
4i
54.51
67.45
60.11
65.39
51.45
55.34
56.77
54.35
68.45
62.70
54.54
52.18
65.91
64.68
79.24
78.11
79.61
69.71
66.31
68.22
71.81
79.42
76.45
69.16
67.35
79.41
75.56
94.11
93.51
93.44
78.25
69.29
78.91
80.01
89.79
90.51
78.35
78.46
93.16
6. Experimental protocols
Melting points were determined in open capillary tubes and are
uncorrected. Elemental analysis was carried out in Vario EL III
Elementar model. IR spectra were recorded by dispersing the
compounds in KBr pellets on a Schimadzu FT-IR 157 spectropho-
tometer. 1H NMR spectra were recorded on a Bruker Avance II
4j
4k
4l
BHT
a
400 MHz NMR spectrometer and chemical shift (d) values are
Results are expressed as their mean values (n ¼ 3).
given in parts per million (ppm) and coupling constants (J) in
Hertz. Splitting patterns are designated as s, singlet; d, doublet; t,
triplet; q, quartet; dd, doublet of doublet; m, multiple. 13C NMR
spectra were recorded on a Bruker Avance II 100 MHz NMR
spectrometer. HSQC experiment was conducted on Bruker Avance
400 MHz NMR spectrometer. Mass spectra were recorded on
a LCMS (Agilent 6320 ion trap). Microwave reactions were carried
out in Godrej (GMC 20E 08 SSGX) microwave oven. Purity of the
newly synthesized compounds was checked by TLC on silica gel
plates (Merck, Silica gel 60F254). Compounds are prepared as
shown in Schemes 1 and 2. Synthesis of 2-hydroxypyrimidine,
5-bromo-2-hydroxypyrimidine and 5-bromo-2-chloropyrimidine
was done as per literature method [25].
Table 3
Percentage radical scavenging activity of pyrazolines 4ael for hydroxyl, superoxide
anion and nitric oxide radicals.
Compound
Percentage radical scavenging activity at 100
m
ga
Nitric oxide
Hydroxyl radical
Superoxide anion
4a
4b
4c
4d
4e
4f
4g
4h
4i
79.22
89.12
87.91
86.81
71.39
71.48
66.26
63.24
81.56
82.56
69.42
70.62
86.98
42.19
59.11
60.01
62.09
52.46
50.18
38.91
43.81
58.67
42.58
38.64
24.58
64.02
32.13
56.14
43.29
47.61
23.81
33.71
40.19
38.11
46.17
39.14
31.41
38.10
43.18
6.1. Procedure for the synthesis of 5-bromo-2-hydrazinylpyrimidine (2)
4j
4k
4l
To a solution of 5-bromo-2-chloropyrimidine (1) (0.01 mol) in
methanol (100 mL), added hydrazine hydrate (80%, 0.03 mol) drop
wise with external cooling. The reaction mixture was stirred at
room temperature. Completion of the reaction was confirmed by
thin layer chromatography (TLC). The solid separated was filtered,
washed well with water, dried and recrystallized from ethyl
acetate [35].
BHT
a
Results are expressed as their mean values (n ¼ 3).
model and all the projections were generated using ORTEP.
Parameters obtained during the XRD study is given in Table 6 and
ORTEP image is given in Fig. 3.
5. Conclusion
6.2. Synthesis of 1,3-diaryl-2-propen-1-one or chalcones (3)
The present study reports a successful green protocol along with
conventional synthesis of novel series of pyrazoline derivatives
carrying pyrimidine. Our report on the synthesis of the novel
molecules under solvent free conditions using microwave is
convenient and rapid over conventional heating method.
Suitably substituted acetophenone (0.1 mol) and substituted
aromatic aldehyde (0.1 mol) were dissolved in ethanol (30 mL). To
the clear reaction mixture 10% NaOH was added drop wise. The
reaction mixture was agitated and allowed to stand at room
temperature for 24 h. The precipitated crystals of 1,3-diaryl-2-
propen-1-one were collected by filtration, washed and recrystal-
lized from ethanol [36,37].
Also newly synthesized pyrazolines displayed significant anti-
oxidant property comparable with that of standard and some of
Table 4
Anti-inflammatory activity data of pyrazolines 4b, 4c, 4d, 4i and 4j.
Compounds
% inhibition ꢄ SEMa
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4b
4c
4d
4i
63 ꢄ 1.23c
61 ꢄ 4.01b
64 ꢄ 2.27c
58 ꢄ 3.24b
60 ꢄ 2.40b
61 ꢄ 0.89c
68 ꢄ 2.15b
70 ꢄ 2.52c
68 ꢄ 2.74b
62 ꢄ 3.01b
71 ꢄ 1.29b
69 ꢄ 1.11b
71 ꢄ 1.39b
71 ꢄ 3.17b
74 ꢄ 1.53b
64 ꢄ 2.69b
71 ꢄ 1.65b
67 ꢄ 1.90c
69 ꢄ 3.44c
76 ꢄ 3.05c
74 ꢄ 2.10c
70 ꢄ 1.45b
73 ꢄ 1.43b
78 ꢄ 3.71c
72 ꢄ 2.81c
72 ꢄ 2.69b
78 ꢄ 1.76b
69 ꢄ 2.05b
70 ꢄ 1.54b
71 ꢄ 0.78b
79 ꢄ 1.53c
78 ꢄ 2.08b
76 ꢄ 2.06c
73 ꢄ 1.43c
75 ꢄ 0.14c
80 ꢄ 1.87b
4j
Diclofenac
a
Results are expressed as their mean values (n ¼ 6).
b
c
P < 0.05.
P < 0.01; significant from the control.

472
A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
Table 5
Analgesic activity data of pyrazolines 4b, 4c, 4d, 4i and 4j.
Compounds
Before Treatment ꢄ SEM
After Treatment ꢄ SEMa (% increase in reaction time)
30 min
60 min
90 min
4b
4c
4d
4i
2.24 ꢄ 0.53
2.12 ꢄ 0.45
2.29 ꢄ 0.22
2.14 ꢄ 0.44
2.02 ꢄ 0.14
2.14 ꢄ 0.33
2.61 ꢄ 0.45b (16.51)
2.75 ꢄ 0.48c (29.71)
2.88 ꢄ 0.51c (25.76)
2.76 ꢄ 0.48b (28.97)
2.78 ꢄ 0.18c (37.62)
2.69 ꢄ 0.37b (25.70)
3.89 ꢄ 0.27c (73.66)
3.65 ꢄ 0.26c (72.16)
3.71 ꢄ 0.09 (62.01)
2.98 ꢄ 0.38c (39.25)
3.45 ꢄ 0.29b (70.79)
3.12 ꢄ 0.44c (45.79)
3.71 ꢄ 0.52b (65.63)
3.78 ꢄ 0.18c (78.31)
3.65 ꢄ 0.54c (59.39)
3.68 ꢄ 0.41c (71.96)
3.73 ꢄ 0.05c (84.65)
3.58 ꢄ 0.24b (67.28)
4j
Pentazocine
a
Results are expressed as their mean values (n ¼ 6).
b
c
P < 0.05.
P < 0.01; significant from the control.
6.3. Synthesis of 5-bromo-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)
pyrimidine (4ael)
7.44e8.19 (m, 9H, AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H); 13C
NMR (100 MHz, DMSO-d6, ppm): 41.97 (C-4, Pyrazoline), 61.37
d
(C-5, Pyrazoline), 108.47 (C-5, Pyrimidine), 124.10, 126.54, 126.91,
128.78, 130.01, 131.30, 146.64, 150.12, 153.20 (C-3, Pyrazoline and
Aromatic Carbons), 156.29 (C-4 & C-6, Pyrimidine), 158.30 (C-2,
Pyrimidine); MS (m/z): 424/426 (M þ 1/M þ 3); Anal. Calcd. (%) for
C19H14BrN5O2: C, 53.79; H, 3.33; N, 16.51. Found: C, 53.68; H, 3.32;
N, 16.43.
6.3.1. Conventional method
1,3-Diaryl-2-propen-1-one (3) (0.001 mol) and 5-bromo-2-
hydrazinylpyrimidine (2) (0.001 mol) was dissolved in 20 mL of
glacial acetic acid. Catalytic amount of Conc. H2SO4 was added.
Contents were then heated under reflux on an oil-bath at
100e110 ꢀC. Completion of the reaction was confirmed by TLC.
Excess of solvent was removed under reduced pressure. Filtered the
solid precipitated, washed with ethanol, dried and recrystallized
using suitable solvent mixture to give pyrazolines 4ael.
6.3.2.2. 5-Bromo-2-(3-phenyl-5-p-tolyl-4,5-dihydro-1H-pyrazol-1-
yl)pyrimidine (4b). IR (KBr, gmax, cmꢂ1): 3019 (CeH), 1566 (C]N);
1H NMR (400 MHz, DMSO-d6,
d ppm): 2.22 (s, 3H, CH3), 3.15 (dd,1H,
J ¼ 4.32, 17.76 Hz, pyrazoline 4H), 3.91 (dd, 1H, J ¼ 11.88, 17.92 Hz,
pyrazoline 4H), 5.70 (dd, 1H, J ¼ 4.36, 11.92 Hz, pyrazoline 5H),
7.05e7.79 (m, 9H, AreH), 8.50 (s, 2H, Pyrimidine 4H and 6H); MS
(m/z): 393/395 (M þ 1/M þ 3); Anal. Calcd. (%) for C20H17BrN4:
C, 61.08; H, 4.36; N, 14.25. Found: C, 60.97; H, 4.32; N, 14.12.
6.3.2. Microwave irradiation method
Substituted chalcones (3) (0.001 mol), 5-bromo-2-
hydrazinylpyrimidine (2) (0.001 mol) and 5 drops of glacial acetic
acid was ground together in a mortar using a pestle for uniform
mixing. This was taken in a 50 mL beaker and subjected to micro-
wave irradiation (90 W). The completion of the reaction was
confirmed by TLC. The product obtained was poured to crushed ice,
filtered, dried and recrystallized from suitable solvent mixture to
give pyrazolines 4ael.
6.3.2.3. 5-Bromo-2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-
pyrazol-1-yl)pyrimidine (4c). IR (KBr, gmax, cmꢂ1): 2928 (CeH), 1569
(C]N); 1H NMR (400 MHz, DMSO-d6,
17.84 Hz, pyrazoline 4H), 3.92 (dd, 1H, J ¼ 11.92, 17.84 Hz, pyrazoline
4H),5.74(dd,1H, J¼4.4,11.84, pyrazoline5H), 7.20e7.8(m, 9H, AreH),
8.53 (s, 2H, Pyrimidine 4H and 6H); 13C NMR (100 MHz, DMSO-d6,
d
ppm): 3.19 (dd, 1H, J ¼ 4.44,
6.3.2.1. 5-Bromo-2-(5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1H-
pyrazol-1-yl)pyrimidine (4a). IR (KBr, gmax, cmꢂ1): 3026 (CeH),
d ppm): 42.11 (C-4, Pyrazoline), 61.15 (C-5, Pyrazoline), 108.23 (C-5,
1566 (C]N); 1H NMR (400 MHz, DMSO-d6,
d
ppm): 3.26 (dd, 1H,
Pyrimidine), 126.48, 127.44, 128.72, 128.76, 129.91, 131.46, 131.64,
141.49, 153.19 (C-3, Pyrazoline and Aromatic Carbons), 156.29 (C-4 &
C-6, Pyrimidine), 158.30 (C-2, Pyrimidine); MS (m/z): 413/415/417
(M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for C19H14BrClN4: C, 55.16; H,
3.41; N, 13.54. Found: C, 55.09; H, 3.32; N, 13.12.
J ¼ 4.72, 17.88 Hz, pyrazoline 4H), 4.01 (dd, 1H, J ¼ 12.12, 17.8 Hz,
pyrazoline 4H), 5.88 (dd, 1H, J ¼ 4.72, 12.08 Hz, pyrazoline 5H),
Table 6
XRD data obtained for pyrazoline 4e.
6.3.2.4. 5-Bromo-2-(5-(4-bromophenyl)-3-phenyl-4,5-dihydro-1H-
Parameters
4e
pyrazol-1-yl)pyrimidine (4d). IR (KBr, gmax, cmꢂ1): 2946 (CeH), 1579
Empirical formula
MW
Color, Habit
Crystal system
Space group
Z
a (Å)
b (Å)
c (Å)
C19H13Br3N4
1074.1
Yellow, Block
Monoclinic
P 21/n
(C]N); 1H NMR (400 MHz, DMSO-d6,
d
ppm): 3.19 (dd, 1H, J ¼ 4.64,
17.72 Hz, pyrazoline 4H), 3.93 (dd, 1H, J ¼ 11.68, 17.61 Hz, pyrazoline
4H), 5.75 (dd, 1H, J ¼ 4.74, 11.71 Hz, pyrazoline 5H), 7.32e7.9 (m, 9H,
AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H); MS (m/z): 457/459/461
(M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for C19H14Br2N4: C, 49.81; H,
3.08; N, 12.23. Found: C, 49.76; H, 3.01; N, 12.12.
4
11.0970(50)
20.5920(50)
16.8780(50)
90
104.392(5)
90
3735.75(54)
1.91
296(2)
a
b
g
(deg)
(deg)
(deg)
6.3.2.5. 2-(3,5-Bis(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-5-
bromopyrimidine(4e). IR (KBr, gmax, cmꢂ1): 2928 (CeH), 1562
V (Å3)
(C]N); 1H NMR (400 MHz, DMSO-d6,
17.92 Hz, pyrazoline 4H), 3.92 (dd,1H, J ¼ 11.72,17.81 Hz, pyrazoline
4H), 5.72 (dd, 1H, J ¼ 4.43, 11.66 Hz, pyrazoline 5H), 7.14e7.73 (m,
8H, AreH), 8.52 (s, 2H, Pyrimidine 4H and 6H); 13C NMR (100 MHz,
d
ppm): 3.20 (dd, 1H, J ¼ 4.53,
Density (g/cm3)
T (K)
X-ray wavelength
0.71073
6.49
m
(mmꢂ1
)
DMSO-d6,
d ppm): 42.52 (C-4, Pyrazoline), 62.06 (C-5, Pyrazoline),
qmin (deg)
qmax (deg)
No. of reflns collected
R1 (obsd)
wR2 (all)
2.14
27.00
8121
0.040
109.12 (C-5, Pyrimidine), 120.84, 123.82, 128.44, 129.04, 131.34,
132.28, 132.38, 142.41, 152.88 (C-3, Pyrazoline and Aromatic
Carbons), 156.86 (C-4 & C-6, Pyrimidine), 158.96 (C-2, Pyrimidine);
MS (m/z): 535/537/539/541 (M þ 1/M þ 3/M þ 5/M þ 7); Anal.
0.068

A. Adhikari et al. / European Journal of Medicinal Chemistry 55 (2012) 467e474
473
Calcd. (%) for C19H13Br3N4: C, 42.49; H, 2.44; N, 10.43. Found: C,
42.36; H, 2.31; N, 10.22.
413/415/417 (M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for C19H14BrClN4:
C, 55.16; H, 3.41; N, 13.54. Found: C, 55.1; H, 3.32; N, 13.44.
6.3.2.6. 5-Bromo-2-(3-(4-bromophenyl)-5-p-tolyl-4,5-dihydro-1H-
6.3.2.11. 2-(3,5-Bis(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-
pyrazol-1-yl)pyrimidine (4f). IR (KBr, gmax, cmꢂ1): 2858 (CeH), 1571
5-bromopyrimidine (4k). IR (KBr, gmax, cmꢂ1): 2985 (CeH), 1572
(C]N); 1H NMR (400 MHz, DMSO-d6,
d
ppm): 2.24 (s, 3H, CH3), 3.15
(C]N); 1H NMR (400 MHz, DMSO-d6,
17.8 Hz, pyrazoline 4H), 3.92 (dd, 1H, J ¼ 11.52, 17.57 Hz, pyrazoline
4H), 5.74 (dd, 1H, J ¼ 4.74, 11.61 Hz, pyrazoline 5H), 7.2e7.8 (m, 8H,
AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H); 13C NMR (100 MHz,
d
ppm): 3.19 (dd, 1H, J ¼ 4.85,
(dd, 1H, J ¼ 4.78, 17.61 Hz, pyrazoline 4H), 3.90 (dd, 1H, J ¼ 11.69,
17.27 Hz, pyrazoline 4H), 5.71 (dd, 1H, J ¼ 4.66, 11.58 Hz, pyrazoline
5H), 7.04e7.83 (m, 8H, AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H);
MS (m/z): 471/473/475 (M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for
C20H16Br2N4: C, 50.87; H, 3.42; N, 11.87. Found: C, 50.78; H, 3.31;
N, 11.72.
DMSO-d6,
d ppm): 42.03 (C-4, Pyrazoline), 61.39 (C-5, Pyrazoline),
108.48 (C-5, Pyrimidine), 127.48, 128.23, 128.76, 128.87, 130.40,
131.72,134.43,141.40,152.21 (Aromatic Carbons),156.27 (C-4 & C-6,
Pyrimidine), 158.35 (C-2, Pyrimidine); MS (m/z): 447/449/451
(M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for C19H13BrCl2N4: C, 50.92;
H, 2.92; N, 12.5. Found: C, 50.81; H, 2.82; N, 12.41.
6.3.2.7. 5-Bromo-2-(3-(4-bromophenyl)-5-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazol-1-yl)pyrimidine (4g). IR (KBr, gmax, cmꢂ1): 2949
(CeH), 1586 (C]N); 1H NMR (400 MHz, DMSO-d6,
d ppm): 3.19 (dd,
1H, J ¼ 4.42, 17.52 Hz, pyrazoline 4H), 3.92 (dd, 1H, J ¼ 11.21,
17.13 Hz, pyrazoline 4H), 5.74 (dd, 1H, J ¼ 4.57, 11.31 Hz, pyrazoline
5H), 7.34e7.78 (m, 8H, AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H);
6.3.2.12. 5-Bromo-2-(5-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazol-1-yl)pyrimidine (4l). IR (KBr, gmax, cmꢂ1): 2953
(CeH), 1569 (C]N); 1H NMR (400 MHz, DMSO-d6,
d ppm): 3.2
13C NMR (100 MHz, DMSO-d6,
d
ppm): 41.94 (C-4, Pyrazoline), 61.38
(dd, 1H, J ¼ 4.86, 17.35 Hz, pyrazoline 4H), 3.97 (dd, 1H, J ¼ 11.73,
17.52 Hz, pyrazoline 4H), 5.81 (dd, 1H, J ¼ 4.78, 11.64 Hz, pyrazoline
5H), 7.22e7.90 (m, 8H, AreH), 8.53 (s, 2H, Pyrimidine 4H and 6H);
MS (m/z): 491/493/495 (M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for
C19H13Br2ClN4: C, 46.33; H, 2.66; N, 11.37. Found: C, 46.24; H, 2.52;
N, 11.31.
(C-5, Pyrazoline), 108.47 (C-5, Pyrimidine), 123.18, 127.46, 128.40,
128.72, 130.71, 131.74, 141.34, 152.24 (C-3, Pyrazoline and Aromatic
Carbons), 156.24 (C-4 & C-6, Pyrimidine), 158.31 (C-2, Pyrimidine);
MS (m/z): 491/493/495 (M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for
C19H13Br2ClN4: C, 46.33; H, 2.66; N, 11.37. Found: C, 46.26; H, 2.51;
N, 11.32.
The carbon proton correlation spectrum of pyrazoline 4a is
given in Fig. 4.
6.3.2.8. 5-Bromo-2-(3-(4-chlorophenyl)-5-p-tolyl-4,5-dihydro-1H-
pyrazol-1-yl)pyrimidine (4h). IR (KBr, gmax, cmꢂ1): 3026 (CeH),
Acknowledgments
1556 (C]N); 1H NMR (400 MHz, DMSO-d6,
d ppm): 2.23 (s, 3H,
CH3), 3.15 (dd, 1H, J ¼ 4.2, 17.88 Hz, pyrazoline 4H), 3.90 (dd, 1H,
J ¼ 11.88, 17.84 Hz, pyrazoline 4H), 5.70 (dd, 1H, J ¼ 4.28, 11.92 Hz,
pyrazoline 5H), 7.04e7.80 (m, 8H, AreH), 8.52 (s, 2H, Pyrimidine 4H
Authors are grateful to Prof. T. N. Guru Row, Solid State and
Structural Chemistry Unit (SSCU), I.I.Sc., Bangalore, India, for the
single crystal X-Ray diffraction studies.
and 6H); 13C NMR (100 MHz, DMSO-d6,
d ppm): 20.65 (CH3), 42.22
(C-4, Pyrazoline), 61.75 (C-5, Pyrazoline), 108.27 (C-5, Pyrimidine),
125.38, 128.19, 128.88, 129.32, 130.58, 134.35, 136.38, 139.45, 152.18
(C-3, Pyrazoline and Aromatic Carbons), 156.38 (C-4 & C-6, Pyrim-
idine), 158.31 (C-2, Pyrimidine); MS (m/z): 427/429/431
(M þ 1/M þ 3/M þ 5); Anal. Calcd. (%) for C20H16BrClN4: C, 56.16;
H, 3.77; N, 13.10. Found: C, 56.10; H, 3.62; N, 12.9.
Appendix A. Supplementary material
Supplementary material associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.ejmech.
2012.07.002.
References
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(CeH), 1566 (C]N); 1H NMR (400 MHz, DMSO-d6,
d ppm): 3.15 (dd,
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