Novel quinolyl-thienyl chalcones and their 2-pyrazoline derivatives with diverse substitution pattern as antileishmanial agents against Leishmania major

Article abstract of DOI:10.1007/s00044-011-9647-8

A series of twenty-two new pyrazoline derivatives was prepared from quinoline-based chalcones which in turn were synthesized by condensing formylquinolines with diverse acetylthiophenes. The titled compounds were characterized by spectroscopic techniques (NMR, IR and MS) and elemental analysis. All the compounds were screened for antileishmanial activities. Compounds 1e, 1f, 2a, 2c, 2d, 2g, 2k, and 4a were found potentially active antileishmanial agents. Bioassay results show that the type and positions of the substituents seem to be critical for their antileishmanial activities. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9647-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1322–1333
DOI 10.1007/s00044-011-9647-8
ORIGINAL RESEARCH
Novel quinolyl-thienyl chalcones and their 2-pyrazoline
derivatives with diverse substitution pattern as antileishmanial
agents against Leishmania major
•
Syed Umar Farooq Rizvi Hamid Latif Siddiqui
•
•
Muhammad Nisar Ahmad Matloob Ahmad
•
Mujahid Hussain Bukhari
Received: 5 February 2011 / Accepted: 12 April 2011 / Published online: 26 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of twenty-two new pyrazoline deriv-
atives was prepared from quinoline-based chalcones which
in turn were synthesized by condensing formylquinolines
with diverse acetylthiophenes. The titled compounds were
characterized by spectroscopic techniques (NMR, IR and
MS) and elemental analysis. All the compounds were
screened for antileishmanial activities. Compounds 1e, 1f,
2a, 2c, 2d, 2g, 2k, and 4a were found potentially active
antileishmanial agents. Bioassay results show that the type
and positions of the substituents seem to be critical for their
antileishmanial activities.
et al., 2007), analgesic (Viana et al., 2003), antitumor
(Shibata, 1994), anticancer (Wattenberg et al., 1994),
antiviral (Trivedi et al., 2007), anti-AIDS (Wu et al., 2003)
and antileishmanial agents (Boeck et al., 2006).
Pyrazoline derivatives of chalcones have been reported
to possess a widespread range of biological activities
like antibacterial (Nauduri and Reddy, 1998), antifungal
(Azarifar and Shaebanzadeh, 2002), antidepressant (Bilgin
et al., 1993), antitumor (Taylor and Patel, 1992), antimi-
crobial (Ramalingham et al., 1977), anti-inflammatory,
molluscicidal activity (Barsoum et al., 2006), antiamoebic
(Budakoti et al., 2006), anticonvulsant activities (Ozdemir
et al., 2007). One of the most famous pyrazole-based drugs
used as a non-steroidal anti-inflammatory drug (NSAID) is
celecoxib (Fig. 1) (Rezende, et al., 2010). Considerable
attention has been focused on the pyrazoline family in the
last two decades. Among various pyrazoline derivatives,
2-pyrazolines seem to be the most frequently studied pyr-
Keywords Chalcones ꢀ Pyrazolines ꢀ
Antileishmanial activity ꢀ Formylquinolines ꢀ
Acetylthiophenes
Introduction
´
azoline-type compounds (Levai, 2005). After the pioneer-
¨
ing work by Fischer and Knovenagel in the late nineteenth
1,3-Diaryl-2-propen-1-ones (chalcones) are one of the most
important classes of natural products, and are widespread
in the plant kingdom. Chalcones (natural or synthetic)
possess a broad spectrum of biological activities including
anti-inflammatory (Ballesteros et al.,1995), antifungal
(Nowakowska, 2007), antioxidant (Mukherjee et al., 2001),
antimalarial (Wu et al., 2002), antituberculosis (Sivakumar
century, 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).
Quinolines and their derivatives, which represent a
major class of heterocycles (Meth-Cohn and Narine, 1978)
and are widely found in natural products (Michael 2003,
2004) and drugs (Alhaider et al., 1985; Campbell et al.,
1988; Du, 2003), exhibit significant role in medicinal
chemistry. Several quinoline derivatives have been repor-
ted to exhibit bactericidal (Awad et al., 1991), antimalarial
(Ginsburg et al., 1999), antiallergenic (Althuis et al., 1980)
and anti-inflammatory (Dillard et al., 1973) properties.
Some of the famous antimalarial drugs, containing quino-
line ring system; available in the market are plasmoquine
S. U. F. Rizvi ꢀ H. L. Siddiqui (&) ꢀ M. Ahmad ꢀ
M. H. Bukhari
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan
e-mail: drhamidlatif@yahoo.com
M. N. Ahmad
Institute of Chemical Sciences, University of Peshawar,
Peshawar 25120, Pakistan
123

Med Chem Res (2012) 21:1322–1333
1323
NH
2
Table 1 Aryl moiety (Ar) in chalcones (1a–k) and (2a–k)
S
O
Ketones
Ar
O
a
b
c
d
e
f
C4H3S-3-yl
N
3-CH3C4H2S-2-yl
4-CH3C4H2S-2-yl
5-CH3C4H2S-2-yl
2,5-diCH3C4HS-3-yl
3-ClC4H2S-2-yl
5-ClC4H2S-2-yl
2,5-diClC4HS-3-yl
3-BrC4H2S-2-yl
5-BrC4H2S-2-yl
5-IC4H2S-2-yl
N
HN
N
F
F
Cl
N
F
g
h
i
Chloroquine
Celecoxib
(NSAID)
(Antimalarial)
j
Fig. 1 Structures of a quinoline and a pyrazole-based drugs
k
(Manske and Kulka, 1953), primaquine and chloroquine
(Singh et al., 1978). Many quinoline derivatives are found
to possess anticancer and antitumor activities (Loaiza et al.,
2004). Among the quinolines, 2-chloro-3-formylquinolines
find an important place in synthetic organic chemistry, as
these are key intermediates for further b-annelation of a
wide variety of ring systems and for the inter-conversions
of many functional groups (Meth-Cohn, 1993).
peaks were found due to starting material aldehydic func-
1
tionality as impurity. In the H-NMR spectra of the chal-
cones (1a–k except 1e, 1f and 1i) and (2a–k except 2e, 2f
and 2i), two very sharp doublets around d 7.40 ppm for Ha
and d 8.20 ppm for Hb, with J-value 15–16 Hz for the trans
chalcones were exhibited. Interestingly, in chalcones 1e
and 2e, Ha and Hb showed a doublet in the upfield at d
7.33–7.32 and 8.10–8.08 ppm, respectively. This may be
attributed to an additional ?I effect induced by CH3 group
present in the close vicinity. Similarly, in chalcones (1f, 1i,
2f and 2i), Ha revealed a doublet relatively in the downfield
at d 7.82–7.81 ppm. This may be attributed to an additional
-I effect due to Cl/Br in the vicinity. The molecular ion
observed in the mass spectra for all the chalcones con-
firmed their molecular masses. The base peak, in the mass
spectra of most of the chalcones, was obtained possibly by
the cleavage of HC–CO bond in the chalcone moiety.
While in bromo- and iodo-substituted chalcones (1i–1k and
2i–2k), the base peak is due to the cleavage of two bonds,
i.e. CO—thiophenyl and Br/I—thiophenyl bonds. The E-
configuration was confirmed by X-ray structure of two
similar structured chalcones which were already reported
(Rizvi et al., 2008).
In this study, the 2-chloro-7/8-methyl-3-formylquinoline
nucleus and chalcone functionality have been incorporated
in a single molecule (1a–k and 2a–k). Then each of the
prepared chalcones was refluxed with hydrazine hydrate in
ethanol to yield twenty-two novel 2-pyrazolines (3a–k and
4a–k) based on quinolyl-thienyl ring systems. Finally, all
the title compounds were tested for their antileishmanial
activities.
Results and discussion
Chemistry
The two precursors, 2-chloro-3-formyl-7- and 8-methyl-
quinoline were prepared by reported method (Meth-
Cohn et al., 1981). Synthesis of the chalconess (1a–k and
2a–k) was based on Claisen-Schmidt condensation (Li
et al., 1995). For this purpose, the prepared formyl quin-
olines were condensed with commercially available acetyl
thiophenes (Table 1), in the presence of sodium hydroxide.
Finally, chalcones thus prepared, on cyclization with
hydrazine hydrate, gave the corresponding 2-pyrazoline
derivatives (3a–k and 4a–k) in a reasonably good yield
(Scheme 1).
Similarly, in case of 2-pyrazolines (3a–k and 4a–k), IR
spectra of all the compounds did not show absorbance at
1650 cm-1 which confirmed the absence of the chalcone
moiety. A new peak with absorption band at 3280 cm-1
1
was revealed due to NH of 2-pyrazoline ring. H-NMR
spectra of the pyrazolines (3a–k and 4a–k) ascertained 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 (downfield H of CH2) at d 3.64–4.10 ppm,
respectively. The CH proton appeared as a triplet at d
5.28–5.40 ppm region. The molecular ion M?, observed in
the mass spectra for all the pyrazolines confirmed their
molecular masses. The base peak, in almost all the mass
spectra (except for 3f), was exhibited by M? itself.
1
Spectral data (IR, H-NMR and MS) of all the newly
synthesized compounds were found in good agreement
with the proposed structures. IR spectra of the compounds
1a–k and 2a–k showed an absorption band at 1650 cm-1
typical of the stretching vibrations of chalcone moiety. No
,
123

1324
Med Chem Res (2012) 21:1322–1333
O
Scheme 1 Reaction protocol
for the synthesis of 2-pyralozine
derivatives (3a–k) and
(4a–k) (i) AcOH, H3PO4, reflux,
4–6 h, (ii) POCl3, DMF, 80°C,
(iii) a–k, NaOH, rt, 2 h, (iv)
Hydrazine, EtOH, reflux
O
(ii)
(i)
NH
NH
CH
3
R
R
N
Cl
2
1
R
1
1
R
R
R
2
2
2
HN
N
O
Ar
Ar
(iii)
(iv)
R
1
N
Cl
N
Cl
R
1
R
R
2
2
(
) and (
)
4a - k
3a - k
(
) and (
)
1a - k
2a - k
= CH , R = H
1: R1
3
2
2: R1 = H, R2 = CH3
Antileishmanial activity
greater electronic effect of chloro group, while the steric
effect of bromo group overweighs the electronic effect at
position 3 of thiophenyl ring (1i and 2i). Moreover,
substituting the halogen atoms (Cl, Br and I) at position 5
of thiophenyl ring (1g, 1j, 1k, 2g, 2j and 2k) deactivates
these compounds due to the absence of electronic effect
stereochemically. Similarly, 2,5-disubstituted methyl
derivatives (1e and 2e) displayed more activity than their
dichloro analogs (1h and 2h). This may be attributed to the
possibility of existence of electronic effect which is due to
the dipolar repulsive forces as shown in Fig. 2d by curved
arrow (iii). While, there is no such electronic or steric
effect in dimethyl derivatives (1e and 2e).
According to the results obtained, structure–activity rela-
tionship among the two series of chalcones (1a–k and
2a–k) may be explained in terms of stereo- and electronic
and/or steric properties (see Fig. 2).
For example, the unsubstituted thiophenyl derivatives
(1a and 2a) have prominent difference in antileishmanial
activities, i.e. 2a is more active than 1a (IC50 = 0.88
0.20 lg/ml for 1a and IC50 = 0.61 0.81 lg/ml for 2a),
while the activity decreased considerably by the introduc-
tion of CH3 group at position 3 of thiophenyl ring (1b and
2b; Table 2) perhaps due to steric effect, whereas, the
activity is relatively increased on moving the methyl sub-
stituent to position 4 (1c and 2c) or 5 (1d and 2d) impairing
the steric effect. Conversely, replacing the methyl group by
chloro group at position 3 of thiophenyl ring (1f and 2f)
results in enhanced activity. This may be attributed to the
It is quite obvious from Table 2 that conversion of both
series of chalcones (1a–k and 2a–k) to their corresponding
2-pyrazoline derivatives (3a–k and 4a–k) results in an
overall decrease in the antileishmanial activity. This fact
clearly indicates the significance of chalcone moiety
(i)
Fig. 2 Proposed stereo-,
electronic and/or steric
(i)
δ
-
-
δ
O
O
H
S
properties (i) electronic effect
(attractive forces), (ii) steric
effect; (iii) electronic effect
(dipolar repulsive forces)
H
S
(i+ii)
(ii)
-
δ
H
H
Cl
H3C
(i)
(i)
-
-
δ
δ
Cl
R1
R1
N
N
Cl
R2
R2
(A)
(B)
(iii)
(i)
(i)
-
δ
-
δ
-
O
δ
Cl
O
H
CH3
S
H
H
S
H
-
δ
Cl
CH3
-
Cl
(i)
δ
R1
N
δ
-
(i)
R1
N
Cl
R2
R2
(C)
(D)
123

Med Chem Res (2012) 21:1322–1333
1325
towards antileishmanial activity in the titled compounds. In
Fig. 2, this is proposed to be due to electronic effect shown
by curved arrows, labelled as (i), which is vanished by the
ring-closure at chalcones moiety.
Table 2 Antileishmanial activity of series 1a–k, 2a–k, 3a–k and 4a–
k (IC50 values)
Compounds
IC50 (lg/ml)
1a
1b
1c
1d
1e
1f
0.88 0.20
0.92 0.11
0.83 0.05
0.74 0.31
0.62 0.24
0.59 0.20
0.81 0.09
0.78 0.14
0.71 0.18
0.91 0.31
0.84 0.22
0.61 0.81
0.94 0.10
0.59 0.09
0.61 1.25
0.73 0.08
0.78 0.15
0.65 0.14
0.85 0.18
0.93 0.99
0.78 0.032
0.67 0.23
0.94 0.02
0.76 0.05
0.87 0.08
0.89 0.03
0.76 0.19
0.78 0.07
0.83 0.50
0.71 0.45
0.85 0.18
0.93 0.62
0.88 0.27
0.67 0.09
0.78 0.23
0.74 0.09
0.89 0.10
0.93 0.16
0.84 0.07
0.75 0.02
0.79 0.03
0.94 0.20
0.93 0.20
0.77 0.02
0.56 0.20
Conclusion
It is evident from the above discussion that the chalcones
(1a–k and 2a–k) exhibited more activity than their corre-
sponding pyrazoline derivatives (3a–k and 4a–k). We
divided the compounds into four categories for their an-
tileishmanial activities and represrented in Table 3, i.e.
IC50 = 0.59–0.56 lg/ml or below as significantly active,
0.69–0.60 lg/ml as good activity, 0.79–0.70 lg/ml as
moderately active and 0.95–0.80 lg/ml as low activity.
The compounds 1e, 1f, 2a, 2c, 2d, 2g, 2k and 4a were
found potentially active antileishmanial agents.
1g
1h
1i
1j
1k
2a
2b
2c
2d
2e
2f
Experimental
2g
2h
2i
General
Melting points were taken on Gallenkamp melting point
apparatus and remained uncorrected. IR spectra were
recorded in KBr pellets on Perkin Elmer infrared spectro-
photometer. 1H NMR spectra were performed in CDCl3 on
Bru¨cker/XWIN NMR (400 MHz) and TMS was used as
internal standard (chemical shifts, d in ppm) unless other-
wise specified. Mass spectra were recorded on a Jeol
MSRoute instrument. Thin layer chromatography (TLC)
was performed with aluminium sheets-Silica gel 60 F254
purchased from Merck. Purification of synthesized com-
pounds was made by recrystallization from appropriate
solvents. Reagent grade chemiocals such as phosphoryl
chloride, acetyl thiophenes, o-toluidine, m-toluidine, N,N-
dimethylformamide and hydrazine hydrate (Aldrich and
Alpha Aesar) 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.
2j
2k
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
4a
4b
4c
4d
4e
4f
General procedure for the preparation of (2E)-3-(2-chloro-
7/8-methylquinolin-3-yl)-1-(Ary) prop-2-en-1-ones (1a–k)
and (2a–k)
4g
4h
4i
The two precursors, 7/8-methyl-substituted 2-chloro-3-
formylquinolines were synthesized following literature
method (Meth-Cohn et al., 1981). A mixture of formyl-
quinoline (10 mmol) and an aromatic ketone (10 mmol) in
methanol (50 ml) was stirred at room temperature,
4j
4k
Standard drug MIC(lg/ml SD)
(Amphotericin B)
123

1326
Med Chem Res (2012) 21:1322–1333
Table 3 Proposed categories of
antileishmanial agents
Category
Compounds
Significant
Good
1f, 2c
1e, 2a, 2d, 2g, 2k, 4a
Moderate
Low
1d, 1h, 1i, 2e, 2f, 2j, 3b, 3e, 3f, 3h, 4b, 4c, 4g, 4h, 4k
1a–1c, 1g, 1j, 1k, 2b, 2h, 2i, 3a, 3c, 3d, 3g, 3i–3k, 4d–4f, 4i, 4j
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-methylthien-
2-yl)prop-2-en-1-one (1d) Yield, 52%; pale yellow solid.
mp 173–175°C. IR (KBr, cm-1): 1652 (C=O), 1595 (C=C),
1563 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
followed by dropwise addition of aq. NaOH (4 ml, 10%).
The stirring was continued for 2 h and the reaction mixture
was then kept at 0°C for 24 h. Subsequently, it was poured
onto ice-cold water (200 ml). The precipitates were col-
lected by filtration, washed with cold water followed by
cold MeOH. The resulting chalcones were recrystallized
from CHCl3 and dried in vacuo.
0
2.56–2.57 (s, 29 Me), 6.86 (1H, d, H4 , J = 3.3 Hz), 7.42
(1H, d, Ha, J = 15.6 Hz), 7.43 (1H, dd, H5, J = 8.2 Hz,
0
1.2 Hz), 7.71 (1H, d, H3 , J = 3.7 Hz), 7.75 (1H, d, H6,
J = 8.3 Hz), 7.78 (1H, s, H8), 8.18 (1H, d, Hb,
J = 15.6 Hz), 8.40 (1H, s, H4). MS (m/z): 327 (M?,
3.61%), 125 (M?–C12H9NCl, 100%). Anal. Calcd for
C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27. Found: C,
65.89; H, 4.26; N, 4.25.
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-thien-3-ylprop-
2-en-1-one (1a) Yield, 65%; colourless solid. mp
180–182°C. IR (KBr, cm-1): 1649 (C=O), 1594 (C=C),
1
1565 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.57
0
(3H, s, Me), 7.39 (1H, dd, H4 , J = 5.1 Hz, 2.9 Hz), 7.42
(1H, dd, H5, J = 8.2 Hz, 1.2 Hz), 7.45 (1H, d, Ha,
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dimethylth-
ien-3-yl)prop-2-en-1-one (1e) Yield, 70%; yellow solid.
mp 183–185°C. IR (KBr, cm-1): 1648 (C=O), 1590 (C=C),
0
J = 15.7 Hz), 7.69 (1H, dd, H5 , J = 5.1 Hz, 1.0 Hz), 7.76
(1H, d, H6, J = 8.3 Hz), 7.79 (01H, s, H8), 8.19 (1H, d, Hb,
J = 15.6 Hz), 8.20 (1H, dd, H2 , J = 2.9 Hz, 1.0 Hz), 8.42
(1H, s, H4). MS (m/z): 313 (M?, 1.86%), 111
(M?–C12H9NCl, 100%). Anal. Calcd for C17H12ClNOS: C,
65.07; H, 3.85; N, 4.46. Found: C, 65.03; H, 3.76; N, 4.43.
1
1565 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.44–
0
2.72 (s, 39 Me), 7.10 (1H, s, H4 ), 7.32 (1H, d, Ha, J =
15.7 Hz), 7.41 (1H, dd, H5, J = 8.4 Hz, 1.2 Hz), 7.74 (1H, d,
H6, J = 8.3 Hz), 7.78 (1H, s, H8), 8.08 (1H, d, Hb, J =
15.7 Hz), 8.37 (1H, s, H4). MS (m/z): 341 (M?, 10.31%), 306
(M?–Cl, 100%). Anal. Calcd for C19H16ClNOS: C, 66.75; H,
4.72; N, 4.10. Found: C, 66.65; H, 4.68; N, 4.08.
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-methylthien-
2-yl) prop-2-en-1-one (1b) Yield, 51%; pale yellow solid.
mp 208–210°C. IR (KBr, cm-1): 1653 (C=O), 1594 (C=C),
1563 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-chlorothien-
2-yl)prop-2-en-1-one (1f) Yield, 66%; yellow solid. mp
160–162°C. IR (KBr, cm-1): 1650 (C=O), 1591 (C=C),
0
2.56–2.66 (s, 29 Me), 7.02 (1H, d, H4 , J = 4.9 Hz), 7.40
(1H, d, Ha, J = 15.4 Hz)0, 7.42 (1H, dd, H5, J = 8.2 Hz,
1.3 Hz), 7.49 (1H, d, H5 J = 4.9 Hz), 7.77 (1H, d, H6,
J = 8.6 Hz), 7.78 (1H, s, H8), 8.18 (1H, d, Hb,
J = 15.4 Hz), 8.40 (1H, s, H4). MS (m/z): 327 (M?, 10%),
125 (M?–C12H9NCl, 100%). Anal. Calcd for
C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27. Found: C,
65.92; H, 4.25; N, 4.25.
1
1569 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.56
0
(3H, s, Me), 7.07 (1H, d, H4 , J = 5.2 Hz)0, 7.28 (1H, dd,
H5, J = 8.3 Hz, 1.1 Hz), 7.60 (1H, d, H5 , J = 5.2 Hz),
7.77 (1H, d, H6, J = 8.6 Hz), 7.82 (1H, d, Ha,
J = 15.5 Hz), 7.96 (1H, s, H8), 8.23 (1H, d, Hb,
J = 15.5 Hz), 8.42 (1H, s, H4). MS (m/z): 347 (M?, 1.8%),
145 (M?–C12H9NCl, 100%). Anal. Calcd. for
C17H11Cl2NOS: C, 58.63; H, 3.18; N, 4.02. Found: C,
58.53; H, 3.16; N, 3.97.
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(4-methylthien-
2-yl)prop-2-en-1-one (1c) Yield, 56%; yellow solid. mp
173–174°C. IR (KBr, cm-1): 1655 (C=O), 1594 (C=C),
1564 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-chlorothien-
2-yl)prop-2-en-1-one (1g) Yield, 80%; pale yellow solid.
mp 170–171°C. IR (KBr, cm-1): 1656 (C=O), 1598 (C=C),
0
2.33–2.56 (s, 29 Me), 7.31 (1H, s, H5 ), 7.42 (1H, dd, H5,
J = 8.2 Hz, 1.3 Hz), 7.44 (1H, d, Ha, J = 15.5 Hz), 7.71
0
1
1570 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.52
(1H, s, H3 ), 7.76 (1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8),
0
(3H, s, Me), 6.92 (1H, d, H4 , J = 4.1 Hz), 7.35 (1H, dd,
H5, J = 8.3 Hz, 1.2 Hz), 7.39 (1H, d, Ha, J = 15.6 Hz),
8.21 (1H, d, Hb, J = 15.6 Hz), 8.42 (1H, s, H4). MS (m/z):
327 (M?, %), 125 (M?–C12H9NCl, 100%). Anal. Calcd for
C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27. Found: C,
65.85; H, 4.24; N, 4.23.
0
7.57 (1H, d, H3 , J = 4.1 Hz), 7.64 (1H, d, H6,
J = 8.3 Hz), 7.72 (1H, s, H8), 8.20 (1H, d, Hb,
123

Med Chem Res (2012) 21:1322–1333
1327
J = 15.6 Hz), 8.39 (1H, s, H4). MS (m/z): 347 (M?,
2.41%), 145 (M?–C12H9NCl, 100%). Anal. Calcd for
C17H11Cl2NOS: C, 58.63; H, 3.18; N, 4.02. Found: C,
58.57; H, 3.14; N, 3.96.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-thien-3-ylprop-
2-en-1-one (2a) Yield, 60%; pale yellow solid. mp
128–130°C. IR (KBr, cm-1): 1649 (C=O), 1591 (C=C),
1
1561 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
0
(3H, s, Me), 7.39 (1H, dd, H4 , J = 5.1 Hz, 2.9 Hz), 7.46
(1H, d, Ha, J = 15.6 Hz), 7.47 (1H, t, H6,0 J = 7.6 Hz),
7.60 (1H, d, H7, J = 7.0 Hz), 7.69 (1H, d, H5 , J = 4.7 Hz,
1.1 Hz), 7.70 (1H, d, H5, J = 6.7 Hz), 8.20 (1H, d, Hb,
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dichloroth-
ien-3-yl)prop-2-en-1-one (1h) Yield, 63%; off-white
solid. mp 163°C. IR (KBr, cm-1): 1662 (C=O), 1596
(C=C), 1572 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
0
J = 15.7 Hz), 8.20 (1H, dd, H2 , J = 2.8 Hz, 1.1 Hz), 8.42
(1H, s, H4). MS (m/z): 313 (M?, 1.9%), 111 (M?–
C12H9NCl, 100%). Anal. Calcd for C17H12ClNOS: C,
65.07; H, 3.85; N, 4.46. Found: C, 65.04; H, 3.78; N, 4.44.
0
2.56 (3H, s, Me), 7.23 (1H, s, H4 ), 7.42 (1H, dd, H5,
J = 8.3 Hz, 1.0 Hz), 7.45 (1H, d, Ha, J = 15.7 Hz), 7.76
(1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8), 8.15 (1H, d, Hb,
J = 15.7 Hz), 8.39 (1H, s, H4). MS (m/z): 383 (M?, 1.7%),
346 (M?–Cl, 100%). Anal. Calcd for C17H10Cl3NOS: C,
53.35; H, 2.63; N, 3.66. Found: C, 53.26; H, 2.58; N, 3.67.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-methylthien-
2-yl)prop-2-en-1-one (2b) Yield, 56%; yellow solid. mp
174–175°C. IR (KBr, cm-1): 1654 (C=O), 1594 (C=C), 1563
(C=N of quinoline ring). 1H-NMR (CDCl3) d: 2.66–2.76 (s,
(2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (1i) Yield, 79%; yellow solid. mp
164–165°C. IR (KBr, cm-1): 1652 (C=O), 1592 (C=C),
0
29 Me), 7.02 (1H, d, H4 , J = 4.9 Hz), 7.41 (1H, d, Ha,
0
J = 15.4 Hz), 7.47 (1H, t, H6, J = 7.6 Hz), 7.49 (1H, d, H5 ,
J = 5.3 Hz), 7.59 (1H, d, H7, J = 7.0 Hz), 7.71 (1H, d, H5,
J = 8.0 Hz), 8.20(1H, d, Hb, J = 15.4 Hz), 8.40 (1H, s, H4).
MS (m/z): 327 (M?, 6.74%), 125 (M?–C12H9NCl, 100%).
Anal. Calcd for C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27.
Found: C, 65.90; H, 4.27; N, 4.27.
1
1568 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.57
0
(3H, s, Me), 7.16 (1H, d, H4 , J = 5.16 Hz), 7.42 (1H, dd,
0
H5, J = 8.3 Hz, 1.3 Hz), 7.58 (1H, d, H5 , J = 5.2 Hz),
7.78 (1H, d, H6, J = 8.6 Hz), 7.82 (1H, d, Ha,
J = 15.6 Hz), 7.79 (1H, s, H8), 8.23 (1H, d, Hb,
J = 15.5 Hz), 8.43 (1H, s, H4). MS (m/z): 393 (M?, 1.5%),
82 (M?–C13H9NOClBr, 100%). Anal. Calcd for
C17H11BrClNOS: C, 51.99; H, 2.82; N, 3.57. Found: C,
51.94; H, 2.76; N, 3.56.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(4-methylthien-
2-yl)prop-2-en-1-one (2c) Yield, 49%; yellow solid. mp
146–147°C. IR (KBr, cm-1): 1655 (C=O), 1593 (C=C),
1565 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
0
2.33–2.76 (s, 29 Me), 7.31 (1H, s, H5 ), 7.46 (1H, d, Ha,
(2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (1j) Yield, 75%; yellow solid. mp
162–164°C. IR (KBr, cm-1): 1653 (C=O), 1588 (C=C),
J = 15.5 Hz), 7.47 (1H, t, H6, J = 7.6 Hz), 7.60 (1H, d,
H7, J = 7.0 Hz), 7.70 (1H, d, H5, J = 7.0 Hz), 7.71 (1H, s,
0
H3 ), 8.23 (1H, d, Hb, J = 15.6 Hz), 8.42 (1H, s, H4). MS
1
1566 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.56
(m/z): 327 (M?, 5.02%), 292 (M?–Cl, 100%). Anal. Calcd
for C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27. Found: C,
65.85; H, 4.23; N, 4.22.
0
(3H, s, Me), 7.16 (1H, d, H4 , J = 4.0 Hz), 7.38 (1H, d, Ha,
J = 15.6 Hz), 7.42 (1H, dd, H5, J = 8.3 Hz, 1.0 Hz), 7.63
0
(1H, d, H3 , J = 4.0 Hz), 7.76 (1H, d, H6, J = 8.3 Hz),7.79
(1H, s, H8), 8.21 (1H, d, Hb, J = 15.6 Hz), 8.40 (1H, s,
H4). MS (m/z): 393 (M?, 1.5%), 82 (M?–C13H9NOClBr,
100%). Anal. Calcd for C17H11BrClNOS: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.95; H, 2.79; N, 3.56.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-methylthien-
2-yl)prop-2-en-1-one (2d) Yield, 55%; yellow solid. mp
180–181°C. IR (KBr, cm-1): 1652 (C=O), 1596 (C=C),
1563 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
0
2.57–2.75 (s, 29 Me), 6.86 (1H, d, H4 , J = 3.1 Hz), 7.43
(1H, d, Ha, J = 15.6 Hz), 7.46 (1H, t, H6, J = 7.7 Hz),
7.59 (1H, d, H7, J = 7.0 Hz), 7.69 (1H, d, H5, J = 8.2 Hz),
(2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (1k) Yield, 90%; deep yellow solid.
mp 164–165°C. IR (KBr, cm-1): 1650 (C=O), 1596 (C=C),
0
7.72 (1H, d, H3 , J = 3.8 Hz), 8.19 (1H, d, Hb,
1
1565 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.56
J = 15.6 Hz), 8.40 (1H, s, H4). MS (m/z): 327 (M?,
5.56%), 125 (M?–C12H9NCl, 100%). Anal. Calcd for
C18H14ClNOS: C, 65.95; H, 4.30; N, 4.27. Found: C,
65.86; H, 4.25; N, 4.25.
0
(3H, s, Me), 7.36 (1H, d, H4 , J = 4.0 Hz), 7.37 (1H, d, Ha,
J = 15.5 Hz), 7.42 (1H, dd, H5, J = 8.4 Hz, 1.2 Hz), 7.50
0
(1H, d, H3 , J = 4.0 Hz), 7.76 (1H, d, H6, J = 8.3 Hz),
7.79 (1H, s, H8), 8.21 (1H, d, Hb, J = 15.6 Hz), 8.40 (1H,
s, H4). MS (m/z): 439 (M?, 1.5%), 82 (M?–C13H9NOICl,
100%). Anal. Calcd for C17H11ClINOS: C, 46.44; H, 2.52;
N, 3.19. Found: C, 46.44; H, 2.43; N, 3.18.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dimethylth-
ien-3-yl)prop-2-en-1-one (2e) Yield, 67%; yellow solid.
mp 138–140°C. IR (KBr, cm-1): 1648 (C=O), 1585 (C=C),
123

1328
Med Chem Res (2012) 21:1322–1333
1565 (C=N of quinoline ring). 1H-NMR (CDCl3) d:
2.44–2.75 (s, 39 Me), 7.10 (1H, s, H4 ), 7.33 (1H, d, Ha,
Ha, J = 15.6 Hz), 8.25 (1H, d, Hb, J = 15.5 Hz), 8.44
(1H, s, H4). MS (m/z): 393 (M?, 1.0%), 82 (M?
–C13H9NOClBr, 100%). Anal. Calcd. for C17H11BrClNOS:
C, 51.99; H, 2.82; N, 3.57. Found: C, 51.98; H, 2.77; N,
3.59.
0
J = 15.7 Hz), 7.46 (1H, t, H6, J = 7.7 Hz), 7.59 (1H, d,
H7, J = 7.0 Hz), 7.68 (1H, d, H5, J = 8.1 Hz), 8.10 (1H, d,
Hb, J = 15.7 Hz), 8.37 (1H, s, H4). MS (m/z): 341 (M?,
7.71%), 139 (M?–C12H9NCl, 100%). Anal. Calcd for
C19H16ClNOS: C, 66.75; H, 4.72; N, 4.10. Found: C,
66.66; H, 4.62; N, 4.02.
(2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-
3-yl) prop-2-en-1-one (2j) Yield, 71%; off-white solid.
mp 204–206°C. IR (KBr, cm-1): 1653 (C=O), 1588 (C=C),
1
1566 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-chlorothien-
2-yl)prop-2-en-1-one (2f) Yield, 73%; yellow solid. mp
162–163°C. IR (KBr, cm-1): 1650 (C=O), 1592 (C=C),
0
(3H, s, Me), 7.17 (1H, d, H4 , J = 4.0 Hz), 7.39 (1H, d, Ha,
J = 15.6 Hz), 7.48 (1H, t, H6, J0 = 7.6 Hz), 7.61 (1H, d,
H7, J = 7.1 Hz), 7.63 (1H, d, H3 , J = 4.0 Hz), 7.70 (1H,
d, H5, J = 8.0 Hz), 8.23 (1H, d, Hb, J = 15.6 Hz), 8.41
(1H, s, H4). MS (m/z): 393 (M?, 2%), 82 (M?
–C13H9NOClBr, 100%). Anal. Calcd for C17H11BrClNOS:
C, 51.99; H, 2.82; N, 3.57. Found: C, 51.93; H, 2.75; N,
3.55.
1
1570 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
0
(3H, s, Me), 7.07 (1H, d, H4 , J = 5.3 Hz), 7.47 (1H, t, H6,
J = 7.7 Hz), 7.59 (1H, d, H7, J = 7.0 Hz), 7.60 (1H, d,
0
H5 , J = 5.3 Hz), 7.71 (1H, d, H5, J = 8.1 Hz), 7.82 (1H,
d, Ha, J = 15.5 Hz), 8.24 (1H, d, Hb, J = 15.6 Hz), 8.42
(1H, s, H4). MS (m/z): 347 (M?, 1.18%), 145 (M?
–C12H9NCl, 100%). Anal. Calcd. for C17H11Cl2NOS: C,
58.63; H, 3.18; N, 4.02. Found: C, 58.59; H, 3.12; N, 3.98.
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (2k) Yield, 86%; yellow solid. mp
196–198°C. IR (KBr, cm-1): 1649 (C=O), 1596 (C=C),
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-chlorothien-
2-yl) prop-2-en-1-one (2g) Yield, 85%; pale yellow solid.
mp 166–168°C. IR (KBr, cm-1): 1656 (C=O), 1598 (C=C),
1
1565 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
0
(3H, s, Me), 7.36 (1H, d, H4 , J = 3.8 Hz), 7.38 (1H, d, Ha,
J = 15.6 Hz), 7.47 (1H, t, H6, J = 7.6 Hz), 7.51 (1H, d,
1
1572 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
0
H3 , J = 3.9 Hz), 7.61 (1H, d, H7, J = 7.0 Hz), 7.70 (1H,
0
(3H, s, Me), 7.02 (1H, d, H4 , J = 4.0 Hz), 7.39 (1H, d, Ha,
d, H5, J = 8.1 Hz), 8.23 (1H, d, Hb, J = 15.6 Hz), 8.41
(1H, s, H4). MS (m/z): 439 (M?, 1%), 82 (M?
–C13H9NOICl, 100%). Anal. Calcd for C17H11ClINOS: C,
46.44; H, 2.52; N, 3.19. Found: C, 46.39; H, 2.42; N, 3.13.
J = 15.5 Hz), 7.48 (1H, t, H6, J0 = 7.6 Hz), 7.61 (1H, d,
H7, J = 7.0 Hz), 7.68 (1H, d, H3 , J = 4.2 Hz), 7.70 (1H,
d, H5, J = 8.1 Hz), 8.23 (1H, d, Hb, J = 15.6 Hz), 8.41
(1H, s, H4). MS (m/z): 347 (M?–Cl, 1.24%), 145 (M?
–C12H9NCl, 100%). Anal. Calcd for C17H11Cl2NOS: C,
58.63; H, 3.18; N, 4.02. Found: C, 58.55; H, 3.13; N, 3.97.
General procedure for the preparation of 2-chloro-3-[3-
(aryl)-4,5-dihydro-1H-pyrazol-5-yl]-7/8-methylquinoline
(3a–k) and (4a–k)
(2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dichloroth-
ien-3-yl)prop-2-en-1-one (2h) Yield, 69%; colourless
solid. mp 120–121°C. IR (KBr, cm-1): 1664 (C=O), 1596
(C=C), 1570 (C=N of quinoline ring).01H-NMR (CDCl3) d:
2.76 (3H, s, Me), 7.15 (1H, s, H4 ), 7.45 (1H, d, Ha,
J = 15.7 Hz), 7.47 (1H, t, H6, J = 7.7 Hz), 7.61 (1H, d,
H7, J = 6.8 Hz), 7.70 (1H, d, H5, J = 8.1 Hz), 8.17 (1H, d,
Hb, J = 15.7 Hz), 8.39 (1H, s, H4). MS (m/z): 383 (M?,
1.8%), 179 (M?–C12H9NCl, 100%). Anal. Calcd for
C17H10Cl3NOS: C, 53.35; H, 2.63; N, 3.66. Found: C,
53.24; H, 2.55; N, 3.60.
A mixture of chalcone (1a–k or 2a–k, 1.0 mmol) and
hydrazine hydrate (3.0 mmol) in ethanol (10 ml) was
refluxed. The crude product got precipitated within
8–15 min which 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 recrystallised from EtOH (95%) to obtain pure
compounds (3a–k and 4a–k).
2-Chloro-7-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyr-
azol-5-yl)quinoline (3a) Yield, 80%; colourless solid. mp
180–181°C. IR (KBr, cm-1): 3275 (NH), 1596 (C=N of
(2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-
3-yl) prop-2-en-1-one (2i) Yield, 86%; yellow solid. mp
210–212°C. IR (KBr, cm-1): 1652 (C=O), 1592 (C=C),
1
pyrazoline ring), 1555 (C=N of quinoline ring). H-NMR
(CDCl3) d: 2.50 (3H, s, CH3), 2.95 (1H, dd, J = 16.3,
9.4 Hz, 4-Ha), 3.74 (1H, dd, J = 16.4, 10.6 Hz, 4-Hb), 5.38
1
1568 (C=N of quinoline ring). H-NMR (CDCl3) d: 2.76
0
0
(3H, s, Me), 7.16 (1H, d, H4 , J = 5.2 Hz), 7.47 (1H, t, H6,
0
(1H, t, J = 9.9 Hz, 5-H), 7.31 (1H, dd, H4 , J = 5.0 Hz,
0
J = 7.6 Hz), 7.58 (1H, d, H5 , J = 5.2 Hz), 7.60 (1H, d,
H7, J = 7.1 Hz), 7.71 (1H, d, H5, J = 8.0 Hz), 7.81 (1H, d,
2.8 Hz), 7.40 (1H, d, H5, J = 8.1 Hz), 7.62 (1H, dd, H5 ,
J = 4.9 Hz, 0.9 Hz), 7.73 (1H, d, H6, J = 8.3 Hz), 7.75
123

Med Chem Res (2012) 21:1322–1333
1329
0
(1H, s, H8), 8.08 (1H, dd, H2 , J = 2.8 Hz, 1.0 Hz), 8.40
J = 8.3 Hz), 7.76 (1H, s, H8), 8.34 (1H, s, H4). MS (m/z):
355 (M?, 100%). Anal. Calcd. for C19H18ClN3S: C, 64.12;
H, 5.10; N, 11.81. Found: C, 64.08; H, 5.05; N, 11.76.
(1H, s, H4). MS (m/z): 327 (M?, 78.53%). Anal. Calcd for
C17H14ClN3S: C, 62.28; H, 4.30; N, 12.82. Found: C,
62.24; H, 4.25; N, 12.80.
2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (3f) Yield, 79%; col-
ourless solid. mp 166167°C. IR (KBr, cm-1): 3288 (NH),
1608 (C=N of pyrazoline ring), 1560 (C=N of quinoline
ring). 1H-NMR (CDCl3) d: 2.52 (3H, s, CH3), 3.15 (1H, dd,
J = 16.9, 10.1 Hz, 4-Ha), 4.00 (1H, dd, J = 16.9, 10.8 Hz,
2-Chloro-7-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (3b) Yield, 78%; yellow solid.
mp 160–161°C. IR (KBr, cm-1): 3285 (NH), 1602 (C=N of
1
pyrazoline ring), 1559 (C=N of quinoline ring). H-NMR
(CDCl3) d: 2.53–2.62 (s, 29 CH3), 2.84 (1H, dd, J = 16.3,
9.4 Hz, 4-Ha), 3.64 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 5.29
0
4-Hb), 5.39 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4 ,
J = 5.2 Hz), 7.21 (1H, d, H5, J = 8.3 Hz), 7.32 (1H, d,
0
(1H, t, J = 9.9 Hz, 5-H), 6.82 (1H, d, H4 , J = 5.0 Hz),
0
0
7.35 (1H, d, H5, J = 8.1 Hz), 7.35 (1H, d, H5 ,
H5 , J = 5.2 Hz), 7.76 (1H, d, H6, J = 8.6 Hz), 7.89 (1H,
J = 4.9 Hz), 7.74 (1H, d, H6, J = 8.5 Hz), 7.76 (1H, s,
H8), 8.39 (1H, s, H4). MS (m/z): 341 (M?, 84.01%). Anal.
Calcd. for C18H16ClN3S: C, 63.24; H, 4.72; N, 12.29.
Found: C, 63.14; H, 4.65; N, 12.29.
s, H8), 8.37 (1H, s, H4). MS (m/z): 361 (M?, 96.20%) 185
(M?–C10H7NCl, 100%). Anal. Calcd. for C17H13Cl2N3S:
C, 56.36; H, 3.62; N, 11.60. Found: C, 56.32; H, 3.61; N,
11.58.
2-Chloro-7-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (3c) Yield, 83%; colourless
solid. mp 200°C. IR (KBr, cm-1): 3280 (NH), 1599 (C=N
of pyrazoline ring), 1555 (C=N of quinoline ring). 1H-
NMR (CDCl3) d: 2.30–2.50 (s, 29 CH3), 2.85 (1H, dd,
J = 16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz,
2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyr-
azol-5-yl]-7-methylquinoline (3g) Yield, 83%; off-white
solid. mp 205–207°C. IR (KBr, cm-1): 3284 (NH), 1605
(C=N of pyrazoline ring), 1560 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.50 (3H, s, CH3), 2.87 (1H, dd,
J = 16.2, 10.0 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz,
0
0
4-Hb), 5.30 (1H, t, J = 9.9 Hz, 5-H), 7.11 (1H, s, H5 ), 7.37
0
4-Hb), 5.36 (1H, t, J = 10.3 Hz, 5-H), 6.82 (1H, d, H4 ,
J = 4.3 Hz), 7.28 (1H, d, H5, J = 8.3 Hz), 7.47 (1H, d,
(1H, d, H5, J = 8.1 Hz), 7.51 (1H, s, H3 ), 7.74 (1H, d, H6,
0
J = 8.3 Hz), 7.76 (1H, s, H8), 8.41 (1H, s, H4). MS (m/z):
341 (M?, 84.02%). Anal. Calcd. for C18H16ClN3S: C,
63.24; H, 4.72; N, 12.29. Found: C, 63.21; H, 4.69; N,
12.25.
H3 , J = 4.3 Hz), 7.65 (1H, d, H6, J = 8.3 Hz), 7.69 (1H,
s, H8), 8.34 (1H, s, H4). MS (m/z): 361 (M?, 100%). Anal.
Calcd for C17H13Cl2N3S: C, 56.36; H, 3.62; N, 11.60.
Found: C, 56.34 H, 3.59; N, 11.52.
2-Chloro-7-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihy-
dro-1H-pyrazol-5-yl]quinoline (3d) Yield, 87%; pale
yellow solid. mp 198°C. IR (KBr, cm-1): 3275 (NH), 1595
(C=N of pyrazoline ring), 1558 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.52–2.54 (s, 29 CH3), 2.85 (1H, dd,
J = 16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz,
2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (3h) Yield, 75%; off-
white solid. mp 178–179°C. IR (KBr, cm-1): 3282 (NH),
1612 (C=N of pyrazoline ring), 1561 (C=N of quinoline
ring). 1H-NMR (CDCl3) d: 2.52 (3H, s, CH3), 3.11 (1H, dd,
J = 16.7, 9.9 Hz, 4-Ha), 3.98 (1H, dd, J = 16.7, 10.5 Hz,
0
0
4-Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.66 (1H, d, H4 ,
0
4-Hb), 5.39 (1H, t, J = 10.2 Hz, 5-H), 6.97 (1H, s, H4 ),
J = 3.2 Hz), 6.85 (1H, d, H3 , J = 3.5 Hz), 7.37 (1H, d,
7.35 (1H, d, H5, J = 8.3 Hz), 7.72 (1H, d, H6, J = 8.2 Hz),
7.75 (1H, s, H8), 8.33 (1H, s, H4). MS (m/z): 397 (M?,
100%). Anal. Calcd. for C17H12Cl3N3S: C, 51.47; H, 3.05;
N, 10.59. Found: C, 51.45; H, 3.02; N, 10.54.
H5, J = 8.1 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.76 (1H, s,
H8), 8.40 (1H, s, H4). MS (m/z): 341 (M?, 84.04%). Anal.
Calcd. for C18H16ClN3S: C, 63.24; H, 4.72; N, 12.29.
Found: C, 63.23; H, 4.69; N, 12.31.
3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-
2-chloro-7-methylquinoline (3i) Yield, 92%; colourless
solid. mp 170–171°C; IR (KBr, cm-1): 3279 (NH), 1608
(C=N of pyrazoline ring), 1556 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.53 (3H, s, CH3), 3.19 (1H, dd,
J = 16.8, 10.1 Hz, 4-Ha), 4.06 (1H, dd, J = 16.8, 10.8 Hz,
2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (3e) Yield, 86%; off-
white solid. mp 116–117°C. IR (KBr, cm-1): 3279 (NH),
1610 (C=N of pyrazoline ring), 1556 (C=N of quinoline
1
ring). H-NMR (CDCl3) d: 2.36–2.65 (s, 39 CH3), 2.82
(1H, dd, J = 16.2, 9.7 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3,
0
4-Hb), 5.39 (1H, t, J = 10.4 Hz, 5-H), 6.95 (1H, d, H4 ,
J = 5.5 Hz), 7.35 (1H, d, H5, J = 8.2 Hz), 7.21 (1H, d,
10.5 Hz, 4-Hb), 5.28 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H,
0
0
s, H4 ), 7.41 (1H, d, H5, J = 8.3 Hz), 7.72 (1H, d, H6,
H5 , J = 5.5 Hz), 7.72 (1H, d, H6, J = 8.6 Hz), 7.74 (1H,
123

1330
Med Chem Res (2012) 21:1322–1333
s, H8), 8.38 (1H, s, H4). MS (m/z): 407 (M?, 100%). Anal.
Calcd. for C17H13BrClN3S: C, 50.20; H, 3.22; N, 10.33.
Found: C, 50.12; H, 3.14; N, 10.30.
J = 5.1 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.69 (1H, d, H5,
J = 7.9 Hz), 8.38 (1H, s, H4). MS (m/z): 341 (M?,
59.47%). Anal. Calcd. for C18H16ClN3S: C, 63.24; H, 4.72;
N, 12.29. Found: C, 63.22; H, 4.75; N, 12.23.
3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-
2-chloro-7-methylquinoline (3j) Yield, 76%; colourless
solid. mp 195°C. IR (KBr, cm-1): 3282 (NH), 1600 (C=N
of pyrazoline ring), 1552 (C=N of quinoline ring). 1H-
NMR (CDCl3) d: 2.52 (3H, s, CH3), 2.88 (1H, dd,
J = 16.2, 9.9 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz,
2-Chloro-8-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihy-
dro-1H-pyrazol-5-yl]quinoline (4c) Yield, 71%; colour-
less solid. mp 182°C. IR (KBr, cm-1): 3281 (NH), 1595
(C=N of pyrazoline ring), 1555 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.30–2.72 (s, 29 CH3), 2.87 (1H, dd,
J = 16.3, 9.3 Hz, 4-Ha), 3.69 (1H, dd, J = 16.3, 10.5 Hz,
0
4-Hb), 5.36 (1H, t, J = 10.3 Hz, 5-H), 6.86 (1H, d, H4 ,
J = 4.2 Hz), 7.36 (1H, d, H5, J = 8.3 Hz), 7.43 (1H, d,
0
4-Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H) 7.11 (1H, s, H5 ), 7.44
(1H, t, H6, J = 7.5 Hz), 7.55 (1H, d, H7, J = 7.0 Hz), 7.69
0
H3 , J = 4.2 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H,
s, H8), 8.35 (1H, s, H4). MS (m/z): 407 (M?, 100%). Anal.
Calcd. for C17H13BrClN3S: C, 50.20; H, 3.22; N, 10.33.
Found: C, 50.15; H, 3.19; N, 10.25.
(1H, d, H5, J = 7.0 Hz), 7.52 (1H, s, H3 ), 8.37 (1H, s, H4).
0
MS (m/z): 341 (M?, 60.02%). Anal. Calcd. for C18H16
ClN3S: C, 63.24; H, 4.72; N, 12.29. Found: C, 63.20; H,
4.69; N, 12.25.
2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-7-methylquinoline (3k) Yield, 85%; colourless solid.
mp 212°C. IR (KBr, cm-1): 3281 (NH), 1610 (C=N of
2-Chloro-8-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (4d) Yield, 80%; pale yellow
solid. mp 209–210°C. IR (KBr, cm-1): 3278 (NH), 1592
(C=N of pyrazoline ring), 1550 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.53–2.72 (s, 29 CH3), 2.86 (1H, dd,
J = 16.3, 9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.3, 10.5 Hz,
1
pyrazoline ring), 1550 (C=N of quinoline ring). H-NMR
(CDCl3) d: 2.52 (3H, s, CH3), 2.87 (1H, dd, J = 16.2,
9.9 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 5.36
0
(1H, t, J = 10.3 Hz, 5-H), 6.71 (1H, d, H4 , J = 4.2 Hz),
0
0
7.15 (1H, d, H3 , J = 4.2 Hz), 7.34 (1H, d, H5,
4-Hb), 5.31 (1H, t, J = 9.90 Hz, 5-H), 6.66 (1H, d, H4 ,
J = 8.4 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H, s,
H8), 8.35 (1H, s, H4). MS (m/z): 453 (M?, 100%). Anal.
Calcd. for C17H13ClIN3S: C, 45.00; H, 2.89; N, 9.26.
Found: C, 44.95; H, 2.85; N, 9.23.
J = 3.0 Hz), 6.86 (1H, d, H3 J = 3.4 Hz), 7.44 (1H, t, H6,
J = 7.6 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.62 (1H, d, H5,
J = 8.1 Hz), 8.33 (1H, s, H4). MS (m/z): 341 (M?,
59.81%). Anal. Calcd. for C18H16ClN3S: C, 63.24; H, 4.72;
N, 12.29. Found: C, 63.23; H, 4.70; N, 12.27.
2-Chloro-8-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyr-
azol-5-yl)quinoline (4a) Yield, 72%; colourless solid. mp
195–196°C. IR (KBr, cm-1): 3274 (NH), 1595 (C=N of
2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (4e) Yield, 88%; brown
solid. mp 126–127°C. IR (KBr, cm-1): 3282 (NH), 1609
(C=N of pyrazoline ring), 1553 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.42–2.73 (s, 39 Me), 2.84 (1H, dd,
J = 16.3, 9.7 Hz, 4-Ha), 3.68 (1H, dd, J = 16.3, 10.6 Hz,
1
pyrazoline ring), 1550 (C=N of quinoline ring). H-NMR
(CDCl3) d: 2.70 (3H, s, CH3), 2.97 (1H, dd, J = 16.4,
9.4 Hz, 4-Ha), 3.75 (1H, dd, J = 16.4, 10.7 Hz, 4-Hb), 5.39
0
(1H, t, J = 9.9 Hz, 5-H), 7.32 (1H, dd, H4 , J = 5.0 Hz,
2.8 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7,
0
4-Hb), 5.30 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H, s, H4 ),
0
J = 7.0 Hz), 7.60 (1H, d, H5 , J = 4.6 Hz,0 1.0 Hz), 7.67
7.42 (1H, t, H6, J = 7.7 Hz), 7.54 (1H, d, H7, J = 7.0 Hz),
7.68 (1H, d, H5, J = 8.1 Hz), 8.34 (1H, s, H4). MS (m/z):
355 (M?, 100%). Anal. Calcd. for C19H18ClN3S: C, 64.12;
H, 5.10; N, 11.81. Found: C, 64.10; H, 5.08; N, 11.79.
(1H, d, H5, J = 6.6 Hz), 8.08 (1H, dd, H2 , J = 2.7 Hz,
1.0 Hz), 8.39 (1H, s, H4). MS (m/z): 327 (M?, 70.30%).
Anal. Calcd. for C17H14ClN3S: C, 62.28; H, 4.30; N, 12.82.
Found: C, 62.22; H, 4.22; N, 12.78.
2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyr-
azol-5-yl]-8-methylquinoline (4f) Yield, 81%; yellowish
brown solid. mp 152°C. IR (KBr, cm-1): 3277 (NH), 1610
(C=N of pyrazoline ring), 1559 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.72 (3H, s, CH3), 3.16 (1H, dd,
J = 16.9, 10.2 Hz, 4-Ha), 4.01 (1H, dd, J = 16.9, 10.8 Hz,
2-Chloro-8-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (4b) Yield, 67%; colourless
solid. mp 130–131°C. IR (KBr, cm-1): 3277 (NH), 1605
(C=N of pyrazoline ring), 1552 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.63–2.73 (s, 29 CH3), 2.85 (1H, dd,
J = 16.3, 9.4 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz,
0
4-Hb), 5.39 (1H, t, J = 10.4 Hz, 5-H), 6.87 (1H, d, H4 ,
J = 5.4 Hz), 7.41 (1H, t, H6, J = 7.6 Hz), 7.54 (1H, d, H7,
0
4-Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H),6.82 (1H, d, H4 ,
J = 5.1 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.33 (1H, d, H5 ,
0
0
J = 7.0 Hz), 7.32 (1H, d, H5 , J = 5.4 Hz), 7.65 (1H, d,
123

Med Chem Res (2012) 21:1322–1333
1331
H5, J = 8.1 Hz), 8.37 (1H, s, H4). MS (m/z): 361 (M?,
100%). Anal. Calcd. for C17H13Cl2N3S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.34; H, 3.58; N, 11.54.
H5, J = 8.0 Hz), 8.36 (1H, s, H4). MS (m/z): 407 (M?,
100%). Anal. Calcd. for C17H13BrClN3S: C, 50.20; H,
3.22; N, 10.33. Found: C, 50.19 H, 3.17; N, 10.28.
2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyr-
azol-5-yl]-8-methylquinoline (4g) Yield, 80%; pale yel-
low solid. mp 230–232°C. IR (KBr, cm-1): 3285 (NH),
1603 (C=N of pyrazoline ring), 1560 (C=N of quinoline
ring). 1H-NMR (CDCl3) d: 2.72 (3H, s, CH3), 2.89 (1H, dd,
J = 16.3, 10.1 Hz, 4-Ha), 3.71 (1H, dd, J = 16.3, 10.7 Hz,
2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (4k) Yield, 82%; pale yellow
solid. mp 178°C. IR (KBr, cm-1): 3280 (NH), 1605 (C=N
of pyrazoline ring), 1550 (C=N of quinoline ring). 1H-
NMR (CDCl3) d: 2.72 (3H, s, CH3), 2.90 (1H, dd,
J = 16.3, 9.9 Hz, 4-Ha), 3.73 (1H, dd, J = 16.3, 10.6 Hz,
0
0
4-Hb), 5.39 (1H, t, J = 10.3 Hz, 5-H), 6.85 (1H, d, H4 ,
J = 4.2 Hz), 7.42 (1H, t, H6, J = 7.6 Hz), 7.56 (1H, d, H7,
4-Hb), 5.37 (1H, t, J = 10.2 Hz, 5-H), 6.71 (1H, d, H4 ,
J = 4.0 Hz), 7.42 (1H, t, H6, J = 7.6 Hz), 7.16 (1H, d, H3 ,
0
0
J = 7.0 Hz), 7.48 (1H, d, H3 , J = 4.4 Hz), 7.63 (1H, d,
J = 4.1 Hz), 7.56 (1H, d, H7, J = 7.0 Hz), 7.63 (1H, d, H5,
J = 8.1 Hz), 8.36 (1H, s, H4). MS (m/z): 453 (M?, 100%).
Anal. Calcd. for C17H13ClIN3S: C, 45.00; H, 2.89; N, 9.26.
Found: C, 44.98; H, 2.81; N, 9.25.
H5, J = 8.0 Hz), 8.35 (1H, s, H4). MS (m/z): 361 (M?,
100%). Anal. Calcd. for C17H13Cl2N3S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.31; H, 3.56; N, 11.55.
2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (4h) Yield, 75%; yel-
lowish brown solid. mp 153°C. IR (KBr, cm-1): 3280
(NH), 1615 (C=N of pyrazoline ring), 1560 (C=N of
In vitro antileishmanial assay
The title compounds (1a–k and 2a–k) and (3a–k and
4a–k) were tested for the antileishmanial activity using
L. major promastigotes as parasites for in vitro screening.
Parasites were cultured at 24°C in shaking incubator on M
199 medium containing foetal bovine serum (10%);
HEPES (25 mM), and penicillin and streptomycin (0.22 lg
each) (Ali et al., 1997).
1
quinoline ring). H-NMR (CDCl3) d: 2.72 (3H, s, CH3),
3.15 (1H, dd, J = 16.8, 10.0 Hz, 4-Ha), 4.00 (1H, dd,
J = 16.8, 10.50Hz, 4-Hb), 5.40 (1H, t, J = 10.3 Hz, 5-H),
6.96 (1H, s, H4 ), 7.41 (1H, t, H6, J = 7.6 Hz), 7.56 (1H, d,
H7, J = 6.8 Hz), 7.62 (1H, d, H5, J = 8.1 Hz), 8.35 (1H, s,
H4). MS (m/z): 397 (M?, 100%). Anal. Calcd. for
C17H12Cl3N3S: C, 51.47; H, 3.05; N, 10.59. Found: C,
51.41; H, 3.00; N, 10.56.
Each compound (1 mg) was dissolved in DMSO (1 ml)
and Amphotericin B (1 mg) taken in DMSO (1 ml) was
used as a positive control. Parasites were taken from lag
phase of their growth and were centrifuged at 3000 rpm for
3 min. The parasite density was maintained at 2 9 106
cells/ml by diluting with fresh culture medium. In 96-well
plates, 180 ll of medium was added in different wells. The
experimental compound (20 ll) was added in medium and
serially diluted. Parasite culture (100 ll) was added in all
wells. In negative controls, DMSO was serially diluted in
medium; while the positive control, contained varying
concentrations of standard antileishmanial compound, i.e.
Amphotercin B. The plates were incubated for 72 h at
24°C. The culture was examined microscopically on an
improved neubaur counting chamber and IC50 values of
compounds possessing antileishmanial activity were cal-
culated. All assays were run in duplicate. The results are
summarized in Table 2. IC50 values of compounds were
determined using prism windows-based software.
3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-
2-chloro-8-methylquinoline (4i) Yield, 77%; pale yellow
solid. mp 166–168°C. IR (KBr, cm-1): 3279 (NH), 1607
(C=N of pyrazoline ring), 1555 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.72 (3H, s, CH3), 3.21 (1H, dd,
J = 16.9, 10.2 Hz, 4-Ha), 4.10 (1H, dd, J = 16.8, 10.8 Hz,
0
0
4-Hb), 5.40 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4 ,
J = 5.5 Hz), 7.43 (1H, t, H6, J = 7.6 Hz), 7.21 (1H, d, H5 ,
J = 5.5 Hz), 7.54 (1H, d, H7, J = 7.1 Hz), 7.65 (1H, d, H5,
J = 8.0 Hz), 8.39 (1H, s, H4). MS (m/z): 407 (M?, 100%).
Anal. Calcd. for C17H13BrClN3S: C, 50.20; H, 3.22; N,
10.33. Found: C, 50.14; H, 3.18; N, 10.29.
3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-
2-chloro-8-methylquinoline (4j) Yield, 80%; pale yellow
solid. mp 215–216°C. IR (KBr, cm-1): 3282 (NH), 1597
(C=N of pyrazoline ring), 1552 (C=N of quinoline ring).
1H-NMR (CDCl3) d: 2.72 (3H, s, CH3), 2.89 (1H, dd,
J = 16.2, 9.9 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.6 Hz,
After running the samples, % of inhibition is calculated
in serial dilution methods. It depends on the activity of the
compounds; some of them show in 4-6-7 or 10 dilution the
inhibitory concentration. Subsequently, we count the
number of parasite in neubauer chamber (0.0025 mm2) and
implement the result manually in the prism windows-based
software.
0
4-Hb), 5.36 (1H, t, J = 10.3 Hz, 5-H), 6.87 (1H, d, H4 ,
J = 4.2 Hz), 7.42 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7,
0
J = 7.1 Hz), 7.43 (1H, d, H3 , J = 4.2 Hz), 7.63 (1H, d,
123

1332
Med Chem Res (2012) 21:1322–1333
Acknowledgments The author is grateful to Higher Education
Commission, Pakistan and Institute of Chemistry, University of the
Punjab, Lahore, for financial support. 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 and Dr. M. Masoom Yasinzai, Institute of Biochem-
istry, University of Balochistan, Quetta, Pakistan for evaluation of
antileishmanial activities.
Li R, Kenyon GL, Cohen FE, Chen X, Gong B, Dominguez JN,
Davidson E, Kurzban G, Miller RE, Nuzum EO, Rosenthal PJ,
McKerrow JH (1995) In vitro antimalarial activity of chalcones
and their derivatives. J Med Chem 38:5031–5037
´
Loaiza PR, Quintero A, Rodrıguez-Sotres R, Solano JD, Rocha AL
(2004) Synthesis and evaluation of 9-anilinothiazolo[5,4-b]quin-
oline derivatives as potential antitumorals. Eur J Med Chem
39:5–10
Manske RHF, Kulka M (1953) The skraup synthesis of quinolines.
Org React 7:59–98
Meth-Cohn O (1993) The synthesis of pyridines, quinolines and other
related systems by the Vilsmeier and reverse Vilsmeier method.
Heterocycles 35:539–557
Meth-Cohn O, Narine B (1978) A versatile new synthesis of
quinolines, thiopyrimidines and related fused pyridines. Tetra-
hedron Lett 23:2045–2048
Meth-Cohn O, Narine B, Tarnowski B (1981) A versatile new
synthesis of quinolines and related fused pyridines, Part 5. The
synthesis of 2-chloroquinoline-3-carbaldehydes. J Chem Soc
Perkin Trans I 1520–1530
Michael JP (2003) Quinoline, quinazoline and acridone alkaloids. Nat
Prod Rep 20:476–493
Michael JP (2004) Quinoline, quinazoline and acridone alkaloids. Nat
Prod Rep 21:650–668
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
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
References
Alhaider AA, Abdelkader MA, Lien EJ (1985) Design, synthesis, and
pharmacological activities of 2-substituted 4-phenyl quinolines
as potential antidepressant drugs. J Med Chem 28:1394–1398
Ali SA, Iqbal J, Yasinzai MM (1997) In vitro maintenance of
Leishmania promastigote in an egg based biphasic culture
medium. Methods Cell Sci 19:107–110
Althuis TH, Khadin SB, Czuba LJ, Moore PF, Hess HJ (1980)
Structure-activity relationships in a series of novel 3,4-dihydro-
4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid antiallergy
agents. J Med Chem 23:262–269
Awad IMA, Abdel-Rehman AE, Bakhite EA (1991) Synthesis and
application of some new S-(substituted) thio- and thienoquino-
line derivatives as antimicrobial agents. Collect Czech Chem
Commun 56:1749–1760
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
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
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
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-
Boeck P, Falca˜o CAB, Leal PC, Yunes RA, Filho VC, Santos ECT,
Bergmann BR(2006)Synthesisof chalcone analogueswithincreased
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
Campbell SF, Hardstone JD, Palmer MJ (1988) 2,4-Diamino-6,7-
dimethoxyquinoline derivatives as alpha1-adrenoceptor antago-
nists and antihypertensive agents. J Med Chem 31:1031–1035
Dillard RD, Pavey DE, Benslay DN (1973) Synthesis and antiin-
flammatory activity of some 2,2-dimethyl-1,2-dihydroquino-
lines. J Med Chem 16:251–253
roman-4-one and tetrahydrothiapyran-4-one.
20:847–850
J Med Chem
ˆ
Rezende RM, Paiva-Lima P, Reis WGPD, Camelo VM, Bakhle YS,
de Francischi JN (2010) Celecoxib induces tolerance in a model
of peripheral inflammatory pain in rats. Neuropharmacology
59:551–557
Rizvi UF, Siddiqui HL, Ahmad S, Ahmad M, Parvez M (2008) Novel
chalcones derived from 2-chloro-6-methylquinoline. Acta Crys-
tallogr C 64:547–549
Shibata S (1994) Anti-tumorigenic chalcones. Stem Cells 12:44–52
Singh SP, Parmar SS, Stenberg VI (1978) Carbon-13 nuclear
magnetic resonance spectra of potent antimalarials: primaquine
and chloroquine. J Heterocycl Chem 15:9–11
Du W (2003) Towards new anticancer drugs: a decade of advances in
synthesis of camptothecins and related alkaloids. Tetrahedron
59:8649–8687
Ginsburg H, Ward SA, Bray PG (1999) An integrated model of
chloroquine action. Parasitol Today 15:357–360
´
Levai A (2005) Synthesis of chlorinated 3,5-diaryl-2-pyrazolines by
Sivakumar PM, Geetha BabuSK, 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
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
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
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
123

Med Chem Res (2012) 21:1322–1333
1333
Viana GS, Bandeira MA, Matos F (2003) Analgesic and antiinfla-
matory effects of chalcones isolated from Myracrodrum urun-
deiva. J Phytomedicine 10:189–195
Wattenberg LW, Coccia JB, Galbraith AR (1994) Inhibition of
carcinogen-induced pulmonary and mammarycarcinogenesis by
chalcone administered subsequent to carcinogen exposure. Can-
cer 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