Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones and their 2-pyrazoline derivatives

Article abstract of DOI:10.1007/s00044-011-9912-x

A series of 12 new pyrazoline derivatives was prepared from piperidyl chalcones, which in turn were synthesized by condensing 4-piperidin-1- ylbenzaldehyde with diverse acetylthiophenes. The target compounds were characterized by spectroscopic techniques

Full text of DOI:10.1007/s00044-011-9912-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3741–3749
DOI 10.1007/s00044-011-9912-x
ORIGINAL RESEARCH
Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones
and their 2-pyrazoline derivatives
•
Syed Umar Farooq Rizvi Hamid Latif Siddiqui
•
•
Melissa Johns Mervi Detorio Raymond F. Schinazi
•
Received: 22 May 2011 / Accepted: 16 November 2011 / Published online: 4 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 12 new pyrazoline derivatives was
prepared from piperidyl chalcones, which in turn were
synthesized by condensing 4-piperidin-1-ylbenzaldehyde
with diverse acetylthiophenes. The target compounds were
characterized by spectroscopic techniques (NMR, IR, MS)
and elemental analysis. All the compounds were screened
for cytotoxic and anti-HIV-1 activities. Compounds 1c, 1g,
1j, 2a, 2c, 2e, 2g, and 2k demonstrated potential anti-HIV
activity but were cytotoxic except for 2e and 2k, which
displayed no cytotoxicity in primary human cells. Bioassay
results show that the type and positions of the substituents
seem to be critical for their cytotoxic and anti-HIV-1
activities.
et al., 1995), antifungal (Nowakowska, 2007), antioxidant
(Mukherjee et al., 2001), antimalarial (Wu et al., 2002),
antituberculosis (Sivakumar et al., 2007), analgesic (Viana
et al., 2003), anti-HIV (Tiwari et al., 1989), antitumor
(Shibata, 1994), anticancer (Wattenbergetal., 1994), antiviral
(Trivedi et al., 2007), anti-AIDS (Wu et al., 2003), and an-
tileishmanial agents (Boeck et al., 2006).
Pyrazoline derivatives of chalcones have also been
reported to possess a widespread range of biological
activities including antibacterial (Nauduri and Reddy,
1998), antifungal (Azarifar and Shaebanzadeh, 2002),
antidepressant (Bilgin et al., 1993), antitumor (Taylor and
Patel, 1992), antimicrobial (Ramalingham et al., 1977),
anti-inflammatory, molluscicidal activity (Barsoum et al.,
2006), antiamoebic (Budakoti et al., 2006), and anticon-
vulsant (Ozdemir et al., 2007). Considerable attention has
been focused on the pyrazoline family in the last two
decades. Among various pyrazoline derivatives, 2-pyrazo-
lines seem to be the most frequently studied pyrazoline
Keywords Chalcones ꢀ Pyrazolines ꢀ Cytotoxic activity ꢀ
Anti-HIV-1 activity ꢀ Acetylthiophenes
Introduction
´
type compounds (Levai, 2005). After the pioneering work
¨
by Fischer and Knovenagel in the late nineteenth century,
1,3-Diaryl-2-propen-1-ones (commonly known as chalcones)
are one of the most important classes of natural products,
which are abundant in the plant kingdom. Chalcones, either
naturally or synthetically derived, possess a broad spectrum of
biological activities including anti-inflammatory (Ballesteros
the reaction of a,b-unsaturated aldehydes and ketones
with hydrazines became one of the most popular methods
´
for the preparation of 2-pyrazolines (Levai et al., 2004)
(Scheme 1).
In the present study, firstly the 4-piperidin-1-ylbenzal-
dehyde nucleus and chalcone functionality have been
incorporated in a single molecule (1a–1l). Then, each of
the prepared chalcones was refluxed with hydrazine
hydrate in ethanol to yield a series of novel 2-pyrazolines
(2a–2l) based on piperidyl–thienyl ring systems. Finally,
all the title compounds with variation of substituents at
different positions in the Ar ring were tested for their
cytotoxic and anti-HIV-1 activities in primary human
lymphocytes (Table 1).
S. U. F. Rizvi ꢀ H. L. Siddiqui (&)
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan
e-mail: drhamidlatif@yahoo.com
M. Johns ꢀ M. Detorio ꢀ R. F. Schinazi
Center for AIDS Research, Veterans Affairs Medical Center
and Department of Pediatrics, Emory University School
of Medicine, Decatur, GA 30033, USA
123

3742
Med Chem Res (2012) 21:3741–3749
Scheme 1 Reaction protocol
for the synthesis of 2-pyrazoline
derivatives (2a–2l): (i) K2CO3,
CTAB, DMF, 100°C; (ii)
O
O
H
(i)
N
NH
F
+
H
NaOH, rt, 2 h; (iii) EtOH, reflux
( )
1
O
O
O
(ii)
Ar
H
+
Ar
N
N
(
)
a-l
( )
1
(
)
1a-l
HN
N
O
(iii)
H2N NH2
+
Ar
Ar
N
N
(
)
1a-l
(
)
2a-l
Table 1 Aryl moiety (Ar) of aromatic ketones (a–l)
were precipitated out within the reaction flask, which were
then filtered washed with water and then with cold meth-
anol. The pure products were obtained after recrystalliza-
tion from methanol.
Ketones
Ar
a
b
c
d
e
f
Thien-2-yl
Thien-3-yl
Selected bands of the IR spectra of the chalcones (1a–1l)
showed relevant information about their structures. Two
typical stretching bands of chalcone moiety, due to ethyl-
enic group C=C and carbonyl group C=O were observed at
1,590–1,607 and 1,650–1,658 cm-1, respectively. The
characteristic band for thiophene (a–l derivatives) was
observed at 750–700 cm-1. In mass spectra of compounds
(1a–1l), the base peak was exhibited by M? itself. This
gives information about the stability of the piperidyl
chalcone nucleus. Molecular masses of compounds (1a–1l)
3-Methylthien-2-yl
4-Methylthien-2-yl
5-Methylthien-2-yl
2,5-Dimethylthien-3-yl
3-Chlorothien-2-yl
5-Chlorothien-2-yl
2,5-Dichlorothien-3-yl
3-Bromothien-2-yl
5-Bromothien-2-yl
5-Iodothien-2-yl
g
h
i
j
k
l
1
were also confirmed by their mass spectra. The H-NMR
spectra of the chalcones (1a–1l) show that the Ha and Hb
protons appear in the aromatic region (d 7.09–7.79). As a
result, two very sharp doublets around 7.10 ppm for Ha and
7.79 ppm for Hb, with a coupling constant 15.2–15.6 Hz
for the trans chalcones were observed. Here also, the sig-
nals of the Ha, for chalcones (1g and 1j) appeared relatively
in the downfield at d 7.55. This again was attributed to an
additional (-)I of the groups like Cl/Br in the vicinity, i.e.,
on the 30 position of thiophene ring (Fig. 1).
Results and discussion
Chemistry
The precursor 4-piperidin-1-ylbenzaldehyde was prepared
by N-arylation of piperidine with 4-fluorobenzaldehyde in
the presence of K2CO3 and CTAB, in DMF as solvent. The
4-piperidin-1-yl-benzaldehyde was then condensed with
various thienyl ketones in alkaline medium with constant
stirring at room temperature. The title compounds (1a–1l)
The pyrazoline derivatives (2a–2l) of the synthesized
piperidyl chalcones (1a–1l) were prepared by refluxing
them with hydrazine hydrate in ethanolic solution. The
123

Med Chem Res (2012) 21:3741–3749
3743
Fig. 1 General structure of
chalcones and their pyrazoline
derivatives
Hβ
O
HN
5
N
H
8
8
S
S
1'
7
7
9
9
1'
2'
3'
2'
3'
5'
5'
Hb
Ha
2
5
2
5
10
10
Hα
12
12
4'
4'
3
3
1N
1N
11
11
4
4
6
6
products (2a–2l) were precipitated within the reaction
flask, which were filtered, washed (first with water and then
with cold ethanol), and recrystallized from ethanol.
In case of pyrazoline derivatives (2a–2l), the unsubsti-
tuted thiophenyl derivatives (2a and 2b) showed enhanced
activities (EC50 = 7.3 and 11.3 lM, respectively) as
compared with their chalcones analogs (1a and 1b, EC50 =
The formation of product (2a–2l) was confirmed by the
disappearance of C=O peak at 1,650–1,658 cm-1 and
appearance of characteristic ring stretching bands of C=N
at 1,610–1,580 cm-1. Moreover, an additional stretching
band of N–H at 3,305–3,317 cm-1 confirmed the ring
closure at chalcone moiety. The molecular ion M?,
observed in the mass spectra for all the pyrazolines, con-
firmed their molecular masses. Again, the base peak, in all
of the mass spectra (except for 2g, 2h, and 2k where the
M?–Cl and M?–Br gave the base peak, respectively), was
exhibited by M? itself. In 1NMR spectra, the disappearance
of signals between d 7.22–8.23 ppm for olefinic protons
and appearance of peaks at d 2.77–3.14, 3.55–4.02, and
5.24–5.39 for CH2 (Ha and Hb, respectively) and H-5 in
pyrazoline ring, further confirmed the formation of target
73.8 and 56.0 lM, respectively). The compounds 2c and 2g
also proved to be active anti-HIV-1 agents like their
starting analogs (1c and 1g), whereas the activity of 2j
(EC50 = 17.4 lM) decreased than that of 1j (EC50
=
5.8 2.8 lM). The compounds in which methyl and halo
groups are present at position 5 of thiophenyl ring (2e, 2h,
2k and 2l), only 2e and 2k displayed improved anti-HIV-1
activity (EC50 = 7.2 0.5 and 9.0 0.4 lM, respec-
tively) than their corresponding chalcones (1e and 1k,
EC50 = 17.9 and 46.5 lM, respectively). The rest of the
compounds (2d, 2f, and 2i) showed no or weak anti-HIV-1
activities as summarized in Table 2.
1
compounds (2a–2l). The H-NMR spectra of pyrazolines
Cytotoxic activity
show the presence of two doublets of doublet signals due to
CH2 protons, Ha (upfield H of CH2) at d 2.82–3.21 ppm
region and Hb at 3.64–4.10 ppm. The CH proton appeared
as a triplet at d 5.28–5.40 ppm region.
Among the compounds under investigation, the unsubsti-
tuted thiophenyl derivatives (1a and 1b) of chalcones (1a–
1l) showed no toxicity in human PBM cells. As in case of
anti-HIV-1 assays, here also the activity was enhanced by
the incorporation of methyl and halo groups at position 3 of
thiophenyl ring (1c, 1g, and 1j). These three compounds
(i.e., 1c, 1g, and 1j) were found to be toxic in PBM, CEM,
and Vero cells, except that of 1c, which showed no toxicity
in Vero cells only. Moreover, both the disubstituted
derivatives (1f and 1i) showed cytotoxicity in all three
types of cells (i.e., PBM, CEM, and Vero cells). The rest of
the compounds 1d, 1e, 1h, 1k, and 1l exhibited no toxicity
in PBM cells, 1k was non-toxic only in CEM cells, while
1d, 1e, 1k, and 1l displayed no toxicity in Vero cells.
In the case of pyrazoline derivatives (2a–2l), only the
compounds 2a, 2c, 2d, and 2g were cytotoxic in PBM cells.
All of the pyrazoline derivatives (2a–2l) were cytotoxic
except 2h, while four compounds (2e, 2f, 2h, and 2i)
showed no cytotoxic activity in Vero cells.
Anti-HIV-1 activity
According to the results obtained, it is evident that the un-
substituted thiophenyl derivatives (1a and 1b) of chalcones
(1a–1l) demonstrated no anti-HIV-1 activity (EC50
[
20 lM) while the activity was considerably enhanced by
the substitution of methyl and halo groups at position 3 of
the thiophenyl ring (1c, 1g, and 1j). However, incorporation
of these functionalities at position 5 of thiophenyl ring (1e,
1h, 1k, and 1l) instead of position 3, the chloro- and bromo-
derivatives (1h and 1k) displayed no anti-HIV-1 activity,
whereas methyl- and iodo-derivatives (1e and 1l) were
proven to be weakly active anti-HIV-1 agents. Incorpora-
tion of methyl group at position 4 of thiophenyl ring (1d)
also exhibited weak anti-HIV-1 activity. Moreover, the two
disubstituted derivatives (1f and 1i) also showed weak anti-
HIV-1 activity. In short, in the chalcones series (1a–1l),
only three compounds (1c, 1g, and 1j) proved to be potential
anti-HIV-1 agents although these compounds also displayed
toxicity in human PBM cells.
Conclusion
All the compounds (1a–1l and 2a–2l) were tested against
HIV-1LAI in primary human PBM cells for anti-viral and
123

3744
Med Chem Res (2012) 21:3741–3749
Experimental
Table 2 Anti-HIV-1 activity in human PBM cells (EC50) and cyto-
toxicity in PBM, CEM, and Vero cells (IC50) of the series 1a–1l and
2a–2l
General melting points were obtained on Gallenkamp
melting point apparatus and were uncorrected. IR spectra
were recorded in KBr pellets on Perkin Elmer infrared
spectrophotometer. 1H-NMR spectra were recorded in
CDCl3 on Bru¨cker/XWIN NMR (400 MHz) and TMS was
used as internal standard (chemical shifts, d in ppm). Mass
spectra were recorded on a Jeol MSRoute instrument.
Acetyl thiophenes (Alpha Aesar), piperidine (Wako),
p-fluorobenzaldehyde (Wako), cetyl trimethylammonium
bromide (Wako), dimethyl formamide (Aldrich), ethanol
(Aldrich), and hydrazine hydrate (Aldrich) were used as
received. Elemental analyses were performed by C.S.I.C.,
Madrid Spain and were within 0.4% of predicted values
for all compounds.
Anti-HIV-1 activity in human PBM cells Cytotoxicity (IC50, lM)
Code EC50 (lM)
EC90 (lM)
PBM
CEM
Vero
1a
1b
1c
1d
1e
1f
73.8
C100
[100
[100
11.6
65.5
56.0
C100
32.1
9.9
34.4
63.9
56.3
50.5
42.3
18.1
32.4
24.9
18.0
69.5
56.5
3.2
2.5 1.8
11.6
19.6 20.4
23.1
26.4
68.8
77.8
38.2
32.1
33.3
21.2
16.6
12.2
41.5
15.0
12.5
52.8
22.0
6.9
17.9
30.9
11.6 4.6
8.4 7.8
35.4
23.6 4.9
29.0 25.4
C100
1g
1h
1i
[100
11.8 2.9
5.8 2.8
46.5
24.7 1.8
27.8 16.8
C100
42.8
39.3
1j
1k
1l
[100
[100
20.8
[100
11.0
General method for the synthesis of piperidyl chalcones
11.6
C100
(1a–1l)
2a
2b
2c
2d
2e
2f
7.3
26.8
11.3
C100
27.0
2.3
29.5
11.4
31.6
52.0
83.4
31.6
A mixture of 4-piperidin-1-ylbenzaldehyde (1) (10 mmol)
and an aromatic ketone (a–l, 10 mmol) in methanol (50 ml)
was stirred at room temperature, followed by dropwise
addition of aq. NaOH (4 ml, 10%). The stirring was con-
tinued for 2 h and the reaction mixture was then kept at 0°C
(24 h). Subsequently, it was poured onto ice-cold water
(200 ml). The precipitates were collected by filtration,
washed with cold water followed by cold MeOH. The
resulting chalcones (1a–1l) were recrystallized from CHCl3.
5.1 3.9
13.0
15.5 11.1
24.9
24.4
86.4
77.5
34.2
16.3
15.3
20.1
10.2
7.2 0.5
16.9 11.7
2.4 1.4
75.3
52.9 11.9
29.8 12.9
13.1 7.8
[100
2g
2h
2i
[100 [100 [100
32.5
[100
30.4
59.0
57.0
80.0
37.7
31.6
21.5
36.5
14.3
53.9
24.8
25.8
15.9
56.0
2j
17.4
2k
2l
9.0 0.4
14.5
33.3 17.5
43.6
[100
(2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-
1-one (1a)
AZT 0.0029 0.0020 0.026 0.013 [100
80% Yield. mp. 141°C. IR (KBr) cm-1: 1652 (C=O), 1598
(C=C). 1H-NMR (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
3.29–3.30 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
cytotoxicity. Assays were conducted using at least two dif-
ferent donor cells in duplicate or triplicate. Eight compounds
(1c, 1g, 1j, 2a, 2c, 2e, 2g, and 2k) were found to be active
below 10 lM with no significant cytotoxicity at active
concentrations, especially at or above the anti-viral con-
centrations. Compounds 1c and 2g demonstrated the most
potent anti-HIV-1 activity (median effective concentration,
EC50 = 2.5 and 2.4 lM, respectively) with modest toxicity
above 20 lM in human PBM cells. None of the compounds
were more potent than the positive control AZT. Compounds
were also evaluated for cytotoxicity in CEM and Vero cells
to determine their spectrum of toxicity. CEM cells are a line
of lymphoblastic cells originally derived from a child with
acute lymphoblastic leukemia, whereas Vero cells are
derived from African Green monkey kidney cells. In general,
the eight compounds listed above were found to be more
toxic in CEM and Vero than PBM cells. Modification of the
chemical structure of compounds that were found to be
active against HIV-1 merits exploration to improve their
potency and reduce their cytotoxicity.
0
J = 8.8 Hz), 7.15 (1H, t, H4 , J = 4.2 Hz), 7.23 (1H, d, Ha,
J = 15.2 Hz), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.62 (1H,
0
d, H5 , J = 4.8 Hz), 7.79 (1H, d, Hb, J = 15.6 Hz), 7.82
?
0
(1H, d, H3 , J = 3.6 Hz). MS (m/z): 297 (M , 100%).
Anal. Calculated for C18H19NOS: C, 72.69; H, 6.44; N,
4.71. Found: C, 72.62; H, 6.48; N, 4.68.
(2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-
1-one (1b)
85% Yield. mp. 160°C. IR (KBr) cm-1: 1655 (C=O), 1596
(C=C). 1H-NMR (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
J = 8.8 Hz), 7.21 (1H, d, Ha, J = 15.2 Hz), 7.33 (1H, t,
0
H4 , J = 4.0 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.64
0
(1H, d, H5 , J = 4.8 Hz), 7.76 (1H, d, Hb, J = 15.6 Hz),
?
8.10 (1H, s, H2 ). MS (m/z): 297 (M , 100%). Anal.
0
123

Med Chem Res (2012) 21:3741–3749
3745
(2E)-1-(3-Chlorothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1g)
Calculated for C18H19NOS: C, 72.69; H, 6.44; N, 4.71.
Found: C, 72.60; H, 6.40; N, 4.64.
82% Yield. mp. 85°C. IR (KBr) cm-1: 1658 (C=O), 1600
(C=C). 1H-NMR (CDCl3) d: 1.64–1.68 (6H, m, H3/H4/H5),
3.30–3.32 (4H, m, H2/H6), 6.87 (2H, d, H8/H12,
(2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1c)
90% Yield. mp. 125°C. IR (KBr) cm-1: 1654 (C=O), 1590
(C=C). 1H-NMR: (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
2.56 (3H, s, Me), 3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d,
0
J = 8.8 Hz), 7.02 (1H, d, H5 , J = 5.2 Hz), 7.51 (1H, d,
0
H4 , J = 5.2 Hz), 7.52 (2H, d, H9/H11, J = 8.8 Hz), 7.55
(1H, d, Ha, J = 15.6 Hz), 7.80 (1H, d, Hb, J = 15.2 Hz).
MS (m/z): 331 (M?, 48%), 333 (M??2, 12%), 331 (M?-
1, 100%). Anal. Calculated for C18H18ClNOS: C, 65.15; H,
5.47; N, 4.22. Found: C, 65.18; H, 5.43; N, 4.19.
0
H9/H11, J = 8.4 Hz), 7.12 (1H, d, H5 , J = 5.2 Hz), 7.18
(1H, d, Ha, J = 15.2 Hz), 7.52 (2H, d, H8/H12,
0
J = 8.4 Hz), 7.60 (1H, d, H4 , J = 5.2 Hz), 7.78 (1H, d,
Hb, J = 15.2 Hz) MS (m/z): 311 (M?, 100%). Anal. Cal-
culated for C19H21NOS: C, 73.27; H, 6.80; N, 4.50. Found:
C, 73.22; H, 6.78; N, 4.44.
(2E)-1-(5-Chlorothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1h)
(2E)-1-(4-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1d)
76% Yield. mp. 162°C. IR (KBr) cm-1: 1656 (C=O), 1602
(C=C). 1H-NMR (CDCl3) d: 1.65–1.68 (6H, m, H3/H4/H5),
3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
82% Yield. mp. 110°C. IR (KBr) cm-1: 1652 (C=O), 1600
(C=C). 1H-NMR: (CDCl3) d: 1.63–1.68 (6H, m, H3/H4/H5),
2.30 (3H, s, Me), 3.29–3.31 (4H, m, H2/H6), 6.87 (2H, d,
H9/H11, J 0= 8.8 Hz), 7.20 (1H, d, Ha, J = 15.2 Hz), 7.21
(1H, s, H5 ), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.63 (1H, s,
0
J = 8.8 Hz), 6.97 (1H, d, H4 , J = 4.0 Hz), 7.12 (1H, d,
Ha, J = 15.2 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.58
0
(1H, d, H3 , J = 3.6 Hz), 7.77 (1H, d, Hb, J = 15.2 Hz).
MS (m/z): 331 (M?, 44%), 333 (M?-1, 100%). Anal.
Calculated for C18H18ClNOS: C, 65.15; H, 5.47; N, 4.22.
Found: C, 65.27; H, 5.42; N, 4.26.
0
H3 , J = 4.8 Hz), 7.77 (1H, d, Hb, J = 15.2 Hz). MS (m/z):
311 (M?, 100%). Anal. Calculated for C19H21NOS: C,
73.27; H, 6.80; N, 4.50. Found: C, 73.32; H, 6.83; N, 4.48.
(2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1i)
(2E)-1-(5-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1e)
62% Yield. mp. 84°C. IR (KBr) cm-1: 1654 (C=O), 1594
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
3.30–3.31 (4H, m, H2/H6), 6.85 (2H, d, H9/H11,
79% Yield. mp. 90°C. IR (KBr) cm-1: 1656 (C=O), 1606
(C=C). 1H-NMR: (CDCl3) d: 1.62–1.67 (6H, m, H3/H4/H5),
2.54 (3H, s, Me), 3.28–3.30 (4H, m, H2/H6), 6.81 (1H, d,
0
J = 8.8 Hz), 7.11 (1H, s, H4 ), 7.13 (1H, d, Ha,
J = 15.6 Hz), 7.48 (2H, d, H8/H12, J = 8.4 Hz), 7.67 (1H,
d, Hb, J = 15.6 Hz). MS (m/z): 367 (M??2, 24%),
364 (M?-1, 100%). Anal. Calculated for C18H17Cl2NOS:
C, 59.02; H, 4.68; N, 3.82. Found: C, 58.70; H, 4.70; N,
3.75.
0
H4 , J = 3.2 Hz), 6.87 (2H, d, H9/H11, J = 8.4 Hz), 7.19
(1H, d, Ha, J = 15.2 Hz), 7.51 (2H, d, H8/H12,
0
J = 8.4 Hz), 7.64 (1H, d, H3 , J = 3.2 Hz), 7.75 (1H, d,
Hb, J = 15.6 Hz). MS (m/z): 311 (M?, 100%). Anal.
Calculated for C19H21NOS: C, 73.27 H, 6.80; N, 4.50.
Found: C, 73.21; H, 6.76; N, 4.53.
(2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1j)
(2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1f)
69% Yield. mp. 93°C. IR (KBr) cm-1: 1655 (C=O), 1596
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
3.30–3.32 (4H, m, H2/H6), 6.87 (2H, d, H9/H11,
72% Yield. mp. 115–117°C. IR (KBr) cm-1: 1650 (C=O),
1607 (C=C). H-NMR (CDCl3) d: 1.63–1.67 (6H, m, H3/
H4/H5), 2.42–2.67 (3H, s, 2xMe), 3.30–3.31 (4H, m, H2/
1
0
J = 8.4 Hz), 7.10 (1H, d, H5 , J = 5.2 Hz), 7.48 (1H, d,
0
0
H4 , J = 5.2 Hz), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.55
H6), 6.86 (2H, d, H9/H11, J = 8.8 Hz), 7.10 (1H, s, H4 ),
(1H, d, Ha, J = 15.6 Hz), 7.79 (1H, d, Hb, J = 15.6 Hz).
MS (m/z): 375 (M?, 100%). Anal. Calculated for
C18H18BrNOS: C, 57.45; H, 4.82; N, 3.72. Found: C,
57.54; H, 4.76; N, 3.76.
7.09 (1H, d, Ha, J = 15.6 Hz), 7.48 (2H, d, H8/H12,
J = 8.4 Hz), 7.67 (1H, d, Hb, J = 15.6 Hz). MS (m/z): 325
(M?, 100%). Anal. Calculated for C20H23NOS: C, 73.86;
H, 7.97; N, 4.10. Found: C, 73.82; H, 7.10; N, 4.12.
123

3746
Med Chem Res (2012) 21:3741–3749
(2E)-1-(5-Bromothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1k)
1-[4-(3-Thiophen-3-yl-4,5-dihydro-1H-pyrazol-5-
yl)phenyl]piperidine (2b)
88% Yield. mp. 162°C. IR (KBr) cm-1: 1650 (C=O), 1595
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
3.29–3.31 (4H, m, H2/H6), 6.86 (2H, d, H9/H11,
69% Yield. mp. 125°C. IR (KBr) cm-1: 3312 (N–H) 1596
(C=N). 1H-NMR (CDCl3) d: 1.61–1.65 (6H, m, H3/H4/H5),
2.94 (1H, dd, J = 16.4, 9.4 Hz, 4-Ha), 3.27–3.29 (4H, m,
H2/H6), 3.71 (1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.39 (1H,
t, J = 9.80Hz, 5-H), 6.81 (2H, d, H9/H11, J = 8.7 Hz), 7.23
(1H, t, H4 , J =0 4.0 Hz), 7.42 (2H, d, H8/H12, J = 8.4 Hz),
311 (M?, 100%). Anal. Calculated for C18H21N3S: C,
69.42; H, 6.80; N, 13.49. Found: C, 69.47; H, 6.72; N,
13.44.
0
J = 8.4 Hz), 7.11 (1H, d, H4 , J = 4.0 Hz), 7.12 (1H, d,
Ha, J = 15.2 Hz), 7.50 (2H, d, H8/H12, J = 8.4 Hz), 7.54
0
(1H, d, H3 , J = 3.6 Hz), 7.78 (1H, d, Hb, J = 15.2 Hz).
MS (m/z): 374 (M?-1, 100%) 375 (M?, 67%). Anal.
Calculated for C18H18BrNOS: C, 57.45; H, 4.82; N, 3.72.
Found: C, 57.38; H, 4.16; N, 3.61.
7.51 (1H, d, H5 , J = 4.8 Hz), 8.02 (1H, s, H2 ). MS (m/z):
0
(2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (1l)
1-{4-[3-(3-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2c)
92% Yield. mp. 142°C. IR (KBr) cm-1: 1652 (C=O), 1602
(C=C). 1H-NMR (CDCl3) d: 1.64–1.67 (6H, m, H3/H4/H5),
3.30–3.32 (4H, m, H2/H6), 6.86 (2H, d, H9/H11,
61% Yield. mp. 119–120°C. IR (KBr) cm-1: 3307 (N–H)
1610 (C=N). H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/
1
0
J = 8.4 Hz), 7.31 (1H, d, H4 , J = 3.6 Hz), 7.11 (1H, d,
Ha, J = 15.2 Hz), 7.50 (2H, d, H8/H12, J = 8.8 Hz), 7.43
H4/H5), 2.51 (3H, s, Me), 2.81 (1H, dd, J = 16.1, 9.3 Hz,
4-Ha), 3.30–3.31 (4H, m, H2/H6), 3.62 (1H, dd, J = 16.1,
10.2 Hz, 4-Hb), 5.28 (1H, t, J = 9.8 Hz0 , 5-H), 6.81 (2H, d,
H9/H11, J = 8.4 Hz), 7.04 (1H, d, H5 , J = 5.2 Hz), 7.42
0
(1H, d, H3 , J = 4.0 Hz), 7.77 (1H, d, Hb, J 15.2 Hz). MS
(m/z): 423 (M?, 100%). Anal. Calculated for C18H16INOS:
C, 51.94; H, 5.05, N, 3.19. Found: C, 52.04; H, 5.12; N,
3.26.
0
(2H, d, H8/H12, J = 8.4 Hz), 7.48 (1H, d, H4 , J = 5.2 Hz).
MS (m/z): 325 (M?, 100%). Anal. Calculated for
C19H23N3S: C, 70.11; H, 7.12; N, 12.91. Found: C, 70.09;
H, 7.07; N, 12.84.
General method for the synthesis of 2-pyrazolines of 4-
piperidin-1-ylbenzaldehyde (2a–2l)
1-{4-[3-(4-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2d)
A mixture of Chalcone (1a–1l, 1.0 mmol) and hydrazine
hydrate (3.0 mmol) in ethanol (10 ml) was refluxed. After
completion of the reaction (4–6 h, TLC monitoring), the
crude product was precipitated out when the reaction
mixture was poured onto ice-cold water (50 ml). The
precipitates were collected by filtration, washed with cold
water followed by cold EtOH to obtain 2-pyrazolines
which were recrystallized from EtOH (95%) to obtain pure
compounds 2a–2l.
74% Yield. mp. 145°C. IR (KBr) cm-1: 3315 (N–H) 1602
(C=N). 1H-NMR (CDCl3) d: 1.62-1.66 (6H, m, H3/H4/H5),
2.26 (3H, s, Me), 2.84 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha),
3.30-3.32 (4H, m, H2/H6), 3.60 (1H, dd, J = 16.3, 10.4 Hz,
4-Hb), 5.28 (1H, t, J = 9.9 Hz, 5-H), 6.77 (2H, d, H9/H11,
0
J = 8.5 Hz), 7.21 (1H, s, H5 ), 7.43 (2H, d, H8/H12,
0
J = 8.6 Hz), 7.54 (1H, s, H3 , J = 4.8 Hz). MS (m/z): 325
(M?, 100%). Anal. Calculated C19H23N3S: C, 70.11; H,
1-[4-(3-Thiophen-2-yl-4,5-dihydro-1H-pyrazol-5-
yl)phenyl]piperidine (2a)
7.12; N, 12.91. Found: C, 70.14; H, 7.07; N, 12.88.
1-{4-[3-(5-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2e)
65% Yield. mp. 132°C. IR (KBr) cm-1: 3313 (N–H) 1585
(C=N). 1H-NMR (CDCl3) d: 1.60–1.65 (6H, m, H3/H4/H5),
2.87 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha), 3.30–3.31 (4H, m,
H2/H6), 3.68 (1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.33 (1H,
t, J = 9.80Hz, 5-H), 6.85 (2H, d, H9/H11, J = 8.8 Hz), 7.10
(1H, t, H4 , J = 4.20Hz), 7.49 (2H, d, H8/H12, J = 8.8 Hz),
J = 3.6 Hz). MS (m/z): 311 (M?, 100%). Anal. Calculated
for C18H21N3S: C, 69.42; H, 6.80; N, 13.49. Found: C,
69.35; H, 6.86; N, 13.56.
75% Yield. mp. 157°C. IR (KBr) cm-1: 3310 (N–H) 1589
1
(C=N). H-NMR: (CDCl3) d: 1.62–1.67 (6H, m, H3/H4/
H5), 2.53 (3H, s, Me), 2.84 (1H, dd, J = 16.2, 9.1 Hz,
4-Ha), 3.30–3.32 (4H, m, H2/H6), 3.57 (1H, dd, J = 16.2,
10.0 Hz, 4-Hb), 5.23 (1H, t, J = 9.8 Hz, 5-H), 6.72 (1H, d,
0
7.55 (1H, d, H5 , J = 4.8 Hz), 7.75 (1H, d, H3 ,
0
H4 , J = 3.2 Hz), 6.77 (2H, d, H9/H11, J = 8.4 Hz),
0
7.41 (2H, d, H8/H12, J = 8.4 Hz), 7.51 (1H, d, H3 ,
J = 3.2 Hz). MS (m/z): 325 (M?, 100%). Anal. Calculated
123

Med Chem Res (2012) 21:3741–3749
3747
for C19H23N3S : C, 70.11; H, 7.12; N, 12.91. Found: C,
70.03; H, 7.18; N, 12.97.
379 (M?, 100%). Anal. Calculated for C18H19Cl2N3S: C,
56.84; H, 5.04; N, 11.05. Found: C, 56.74; H, 5.14; N,
11.09.
1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]phenyl}piperidine (2f)
1-{4-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2j)
73% Yield. mp. 144°C. IR (KBr) cm-1: 3316 (N–H) 1582
1
(C=N). H-NMR: (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/
77% Yield. mp. 180°C. IR (KBr) cm-1: 3317 (N–H) 1600
(C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5),
3.14 (1H, dd, J = 16.5, 10.2 Hz, 4-Ha), 3.25-3.28 (4H, m,
H2/H6), 4.02 (1H, dd, J = 16.5, 10.6 Hz, 4-Hb), 5.35 (1H,
t, J = 10.4 Hz, 5-H), 6.78 (2H, d, H9/H11, J = 8.4 Hz),
H5), 2.39–2.60 (3H, s, 2xMe), 2.77 (1H, dd, J = 16.3,
9.5 Hz, 4-Ha), 3.30–3.32 (4H, m, H2/H6), 3.55 (1H, dd,
J = 16.3, 10.2 Hz, 4-Hb), 5.24 (1H, t, J = 10.0 Hz, 5-H),
0
6.78 (2H, d, H9/H11, J = 8.7 Hz), 7.02 (1H, s, H4 ), 7.45
(2H, d, H8/H12, J = 8.4 Hz). MS (m/z): 339 (M?, 100%).
Anal. Calculated for C20H25N3S: C, 70.76; H, 7.42; N,
12.38. Found: C, 70.69; H, 7.37; N, 12.37.
7.05 (1H, d, H5 , J = 5.2 Hz), 7.46 (1H, d, H4 ,
J = 5.2 Hz), 7.49 (2H, d, H8/H12, J = 8.6 Hz). MS (m/z):
389 (M?, 100%). Anal. Calculated for C18H20BrN3S: C,
55.39; H, 5.16; N, 10.76. Found: C, 55.30; H, 5.20; N,
10.72.
0
0
1-{4-[3-(3-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2g)
1-{4-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2k)
65% Yield. mp. 151°C. IR (KBr) cm-1: 3308 (N–H) 1597
(C=N). 1H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/H5),
3.12 (1H, dd, J = 16.6, 10.2 Hz, 4-Ha), 3.30–3.32 (4H, m,
H2/H6), 3.96 (1H, dd, J = 16.7, 10.2 Hz, 4-Hb), 5.37 (1H,
t, J = 10.2 Hz, 5-H), 6.80 (2H, d, H8/H12, J = 8.7 Hz),
78% Yield. mp. 140°C. IR (KBr) cm-1: 3305 (N–H) 1586
(C=N). 1H-NMR (CDCl3) d: 1.62–1.66 (6H, m, H3/H4/H5),
2.85 (1H, dd, J = 16.2, 9.6 Hz, 4-Ha), 3.30–3.32 (4H, m,
H2/H6), 3.65 (1H, dd, J = 16.2, 9.6 Hz, 4-Hb), 5.32 (1H, t,
J = 10.3 Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.4 Hz), 7.05
0
0
7.02 (1H, d, H5 , J = 5.2 Hz), 7.47 (1H, d, H4 ,
J = 5.2 Hz), 7.49 (2H, d, H9/H11, J = 8.8 Hz). MS (m/z):
345 (M?, 12%), 310 (M?-Cl, 100%). Anal. Calculated for
C18H20ClN3S : C, 62.50; H, 5.83; N, 12.15. Found: C,
62.48; H, 5.76; N, 12.21.
0
(1H, d, H4 , J = 4.0 Hz), 7.49 (2H, d, H8/H12, J = 8.4 Hz),
?
0
7.39 1H, d, H3 , J = 3.6 Hz). MS (m/z): 389 (M , 8%), 310
(M?-Br, 100%). Anal. Calculated for C18H20BrN3S: C,
55.39; H, 5.16; N, 10.76. Found: C, 55.34; H, 5.14; N,
10.71.
1-{4-[3-(5-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]phenyl}piperidine (2h)
1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (2l)
80% Yield. mp. 147°C. IR (KBr) cm-1: 3314 (N–H) 1606
(C=N). 1H-NMR (CDCl3) d: 1.64–1.68 (6H, m, H3/H4/H5),
2.86 (1H, dd, J = 16.3, 10.1 Hz, 4-Ha), 3.29–3.30 (4H, m,
H2/H6), 3.65 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 5.35 (1H,
t, J = 10.3 Hz, 5-H), 6.86 (2H, d, H9/H11, J = 8.7 Hz),
72% Yield. mp. 167°C. IR (KBr) cm-1: 3312 (N–H), 1608
(C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5),
2.86 (1H, dd, J = 16.3, 9.7 Hz, 4-Ha), 3.30–3.32 (4H, m,
H2/H6), 3.64 (1H, dd, J = 16.2, 10.1 Hz, 4-Hb), 5.29 (1H,
t, J = 10.2 Hz, 5-H), 6.79 (2H, d, H9/H11, J = 8.4 Hz),
0
6.92 (1H, d, H4 , J = 4.00Hz), 7.47 (2H, d, H8/H12,
J = 8.4 Hz), 7.53 (1H, d, H3 , J = 3.6 Hz). MS (m/z): 345
(M?, 18%), 310 (M?-Cl, 100%). Anal. Calculated for
C18H20ClN3S: C, 62.50; H, 5.83; N, 12.15. Found: C,
62.42; H, 5.91; N, 12.09.
0
7.15 (1H, d, H4 , J = 3.60Hz), 7.50 (2H, d, H8/H12,
J = 8.5 Hz), 7.32 (1H, d, H3 , J = 4.0 Hz). MS (m/z): 437
(M?, 100%). Anal. Calculated for C18H20IN3S: C, 49.43;
H, 4.61; N, 9.61. Found: C, 49.47; H, 4.55; N, 9.56.
1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]phenyl}piperidine (2i)
Anti-HIV-1 assay
65% Yield. mp. 175°C. IR (KBr) cm-1: 3311 (N–H) 1605
(C=N). 1H-NMR (CDCl3) d: 1.63–1.66 (6H, m, H3/H4/H5),
3.14 (1H, dd, J = 16.3, 10.0 Hz, 4-Ha), 3.30–3.32 (4H, m,
H2/H6), 3.95 (1H, dd, J = 16.4, 9.5 Hz, 4-Hb), 5.35 (1H, t,
J = 10.3 Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.5 Hz), 7.09
The assay was performed as described by Schinazi et al.
(1990) with modifications. Primary human PBM cells
obtained from LifeSouth Community Blood Centers
(Atlanta, GA), were isolated by Histopaque (Sigma-Aldrich,
St.Louis, MO) and discontinuous gradient centrifugation
0
(1H, s, H4 ), 7.46 (2H, d, H8/H12, J = 8.4 Hz). MS (m/z):
123

3748
Med Chem Res (2012) 21:3741–3749
from healthy seronegative donors. Cells were activated with
6 lg/ml phytohemagglutinin A (Associates of Cape Cod,
Inc., East Falmouth, MA) in 500 ml of RPMI-1640
(Mediatech Inc., Herndon, VA) containing 100 ml heat-
inactivated fetal bovine serum (Hyclone, Logan, Utah),
83.3 IU/ml penicillin, 83.3 lg/ml, streptomycin (Mediatech
Inc., Herndon, VA), 1.6 mM L-glutamine (Mediatech Inc.,
Herndon, VA), for 2–3 days prior to use. HIV-1LAI obtained
from the Centers for Disease Control and Prevention was
used as the standard reference virus for the anti-viral assays.
A multiplicity of infection (MOI) of 0.1, as determined by a
limiting dilution method in PBM cells, was selected for the
assays. This represented about 50% tissue culture infectious
doses per 24-well plate per 2 9 106 cells per 2 ml. Using
this MOI, peak reverse transcriptase (RT) levels occurred
within 5–7 days. Cells were exposed to virus for 1 h prior to
addition of the compound. RPMI-1640 medium (500 ml)
supplemented with 100 ml heat-inactivated fetal bovine
serum, 1.6 mM L-glutamine, 83.3 IU/ml penicillin, 83.3 lg/
ml streptomycin, 0.0008% DEAE–Dextran (Sigma-Aldrich,
St. Louis, MO), 0.047% sodium bicarbonate, and 26 IU/ml
recombinant interleukin-2 (Chiron Corporation, Emeryville,
CA) were used. The compounds were added in assay med-
ium at concentrations of 0.1, 1.0, 10, and 100 lM in dupli-
cate. 30-Azido-30-deoxythymidine (AZT) was used as a
positive control for the assay.
Cytotoxic assay
Human PBM, CEM, and VERO cells were cultured in
96-well plates (5 9 104 cells per well) along with increasing
concentrations of the test compound (Stuyver et al., 2002).
Cell viability was measured after 5-day incubation period
using the Cell Titer 96 Aqueous One Solution cell prolif-
eration assay (Promega, Madison, WI) by incubating in an
incubator at 37°C with 5% CO2 for human PBM cells. The
results are summarized in Table 2.
Acknowledgments The author is grateful to Higher Education
Commission, Pakistan and Institute of Chemistry, University of the
Punjab, Lahore, for financial assistance. We are also thankful to Inter-
national Centre for Chemical and Biological Sciences, HEJ Research
Institute of Chemistry, University of Karachi, Karachi, for spectral
measurements. This work was also supported in part by NIH grant
2P30-AI-050409 and the Department of Veterans Affairs (to RFS).
References
Azarifar D, Shaebanzadeh M (2002) Synthesis and characterization of
new 3,5-dinaphthyl substituted 2-pyrazolines and study of their
antimicrobial activity. Molecules 7:885–895
Ballesteros JF, Sanz MJ, Ubeda A, Miranda MA, Iborra S, Paya M,
Alcaraz M (1995) Synthesis and pharmacological evaluation of
20-hydroxychalcones and flavones as inhibitors of inflammatory
mediators generation. J Med Chem 38:2794–2797
The cells were kept for 5 days in a humidified 5% CO2 air
incubator, and then one ml of supernatant was harvested
from each plate, and centrifuged at 11,000 rpm (9,7409g) at
4°C for 2 h to pellet the virus (Jouan MR23i, Br4i, Sigma
3k30). The pellet was solubilized by vortexing in the pres-
ence of 100 ll virus solubilization buffer containing 0.5%
Triton X-100, 0.8 M NaCl, 0.5 mM phenylmethylsulfonyl
fluoride, 20% glycerol, and 0.05 M Tris. Ten microlitres of
each sample were added to 75 ll RT reaction mixture
(0.06 M Tris, pH 7.8, 0.012 M MgCl2, 0.006 M dithiothre-
itol, 0.006 mg/ml poly rAoligo dT(12–18) (The Midland
Certified Reagent Co. Inc. Midland, TX), 96 lg/ml dATP
(Sigma-Aldrich, St. Louis, MO), and 1 lM of 0.08 mCi/ml
3H-thymidine-50-triphosphate 87.0 Ci/mmol (Moravek
Biochemicals, Brea, CA) and incubated at 37°C for 2–3 h.
The reaction was stopped and the nucleic acid precipitated
by the addition of 10% trichloroacetic acid (100 ll) con-
taining sodium pyrophosphate (0.05%) for 20 min to over-
night at 4°C. The acid insoluble product was harvested onto
filter paper (catalog # 6005422, Perkin Elmer, Waltham,
MA) using a Perkin Elmer Harvester (Filter Mate Har-
vester), and the activity was read on a Perkin Elmer Top-
Count NXT (Microplate Scintillation & Luminescence
Counter). The percent of control was calculated and then the
median effective concentration (EC50) was determined
using the method of Belen’kii and Schinazi (1994). The
results are expressed in Table 2.
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
Belen’kii MS, Schinazi RF (1994) Multiple drug effect analysis with
confidence interval. Antiviral Res 25:1–11
Bilgin AA, Palaska E, Sunal R (1993) Studies on the synthesis and
antidepressant activity of some 1-thiocarbamoyl-3,5-diphenyl-2-
pyrazolines. Arzneimforsch Drug Res 43:1041–1044
Boeck P, Falca˜o CAB, Leal PC, Yunes RA, Filho VC, Santos ECT,
Bergmann BR (2006) Synthesis of chalcone analogues with
increased antileishmanial activity. Bioorg Med Chem 14:
1538–1545
Budakoti A, Abid M, Azam A (2006) Synthesis and antiamoebic
activity of New 1-N-substituted thiocarbamoyl-3,5-diphenyl-
pyrazoline derivatives and their Pd(ll) complexes. Eur J Med
Chem 41:63–70
´
Levai A (2005) Synthesis of chlorinated 3,5-diaryl-2-pyrazolines by
the reaction of chlorochalcones with hydrazines. ARKIVOC
9:344–352
Levai A, Silva AMS, Pinto DCGA, Cavaleiro JAS, Alkorta I, Elguero J,
´
}
Jeko J (2004) Synthesis of pyrazolyl-2-pyrazolines by treatment
of 3-(3-aryl-3-oxopropenyl)-chromen-4-ones with hydrazine
and their oxidation to bis(pyrazoles). Eur J Org Chem 2004:
4672–4679
Mukherjee S, Kumar V, Prasad AK, Raj HG, Brakhe ME, Olsen CE,
Jain SC, Parmar VP (2001) Synthetic and biological activity
evaluation studies on novel 1,3-diarylpropenones. Bioorg Med
Chem 9:337–339
Nauduri D, Reddy GB (1998) Antibacterial and antimycotics Part 1:
synthesis and activity of 2-pyrazoline derivatives. Chem Pharm
Bull Tokyo 46:1254–1260
Nowakowska Z (2007) A review of anti-infective and anti-inflam-
matory chalcones. Eur J Med Chem 42:125–137
123

Med Chem Res (2012) 21:3741–3749
3749
Ozdemir Z, Kandilici HB, Gumusel B, Calis U, Bilgin AA (2007)
Synthesis and studies on antidepressant and anticonvulsant
activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med
Chem 42:373–379
Ramalingham K, Thyvekikakath GX, Berlin KD, Chesnut RW,
Brown RA, Durham NN, Ealick SE, Van der Helm D (1977)
Synthesis and biological activity of some derivatives of thioch-
roman-4-one and tetrahydrothiapyran-4-one. J Med Chem 20:
847–850
Schinazi RF, Sommadossi PJ, Cannon DL, Xie MY, Hart GC, Smith
JA, Hahan EF (1990) Activities of 30-azido-30-deoxythymidine
nucleotide dimers in primary lymphocytes infected with human
Immunodeficiency virus type 1. Antimicrobial Agents Chemo-
ther 34:1061–1067
Taylor EC, Patel HH (1992) Synthesis of pyrazolo[3,4,-d]pyrimidine
analogues of the potent antitumor agent N-{4-[2-(2-amino-
4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-
glutamic acid (LY231514). Tetrahedron 48:8089–8100
Tiwari N, Dwivedi B, Nizamuddin (1989) Synthesis of some
pyrazoline and isooxazolin derivatives as possible fungicides.
Boll Chim Farm 128:332–335
Trivedi JC, Bariwal JB, Upadhyay KD, Naliapara YT, Joshi SK,
Pannecouque CC, Clercq ED, Shah AK (2007) Improved and
rapid synthesis of new coumarinyl chalcone derivatives and their
antiviral activity. Tetrahedron Lett 48:8472–8474
Viana GS, Bandeira MA, Matos F (2003) Analgesic and antiinfla-
matory effects of chalcones isolated from Myracrodrum Urun-
deiva. J Phytomedicine 10:189–195
Shibata S (1994) Anti-tumorigenic chalcones. Stem Cells 12:44–52
Sivakumar PM, Geetha Babu SK, Mukesh D (2007) QSAR studies on
chalcones and flavonoids as anti-tuberculosis agents using
genetic function approximation (GFA) method. Chem Pharm
Bull 55:44–49
Stuyver LJ, Lostia S, Adams M, Mathew SJ, Pai SB, Grier J, Tharnish
MP, Choi Y, Chong Y, Choo H, Chu KC, Otto JM, Schinazi FR
(2002) Antiviral activities and cellular toxicities of modified 20,30-
dideoxy-20,30-didehydrocytidine analogues. Antimicrob Agents
Chemother 46:3854–3860
Wattenberg LW, Coccia JB, Galbraith AR (1994) Inhibition of
carcinogen-induced pulmonary and mammarycarcinogenesis by
chalcone administered subsequent to carcinogen exposure.
Cancer Lett 83:165–169
Wu X, Wilairat P, Go M (2002) Antimalarial activity of ferrocenyl
chalcones. Bioorg Med Chem Lett 12:2299–2302
Wu JH, Wang XH, Yi YH, Lee KH (2003) Anti-AIDS agents 54. A
potent anti-HIV chalcone and flavonoids from genus Desmos.
Bioorg Med Chem Lett 13:1813–1815
123