Anti-oxidant, anti-fungal and anti-leishmanial activities of novel 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones

Article abstract of DOI:10.1016/j.ejmech.2009.06.038

A series of new 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones were synthesized by the condensation of various acetophenones with 4-(1H-imidazol-1-yl) benzaldehyde which was itself prepared by the N-arylation of imidazole using hexadecyltrimethylammonium

Full text of DOI:10.1016/j.ejmech.2009.06.038

European Journal of Medicinal Chemistry 44 (2009) 4654–4660
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Anti-oxidant, anti-fungal and anti-leishmanial activities of novel
3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones
,
b
Tanvir Hussain a, Hamid Latif Siddiqui a , Muhammad Zia-ur-Rehman ,
*
Muhammad Masoom Yasinzai c, Masood Parvez d
a Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan
b Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore 54600, Pakistan
c Institute of Biochemistry, University of Balochistan, Quetta, Pakistan
d Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones were synthesized by the condensation
of various acetophenones with 4-(1H-imidazol-1-yl) benzaldehyde which was itself prepared by the N-
arylation of imidazole using hexadecyltrimethylammonium bromide as catalyst for the first time. All the
synthesized compounds were subjected to preliminary evaluation for their anti-leishmanial, anti-oxidant
and anti-fungal activities. Few of the synthesized compounds showed significant activities.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Received 24 February 2009
Received in revised form
29 June 2009
Accepted 30 June 2009
Available online 4 July 2009
Keywords:
Imidazole
Chalcones
Anti-oxidant
Anti-fungal
Anti-leishmanial
1. Introduction
Besides, these have a wide range of applications such as in non-
linear optical [17] and electro-active fluorescent materials [18] such
Synthesis, reactions and biological properties of substituted
imidazoles constitute a significant part of modern heterocyclic
chemistry. Compounds possessing imidazoles ring system have
been found to exhibit a number of pharmacological properties such
anticancer [1], carboxypeptidase [2], anti-aging [3], anti-fungal [4],
anti-bacterial [5], anti-diabetic [6] and anti-malarial [7] while
others show anti-hypertensive [8], and anti-depressive [9] activi-
ties. Among these, few are well known as commercial products
such as MetronidazoleÒ (anti-amoebic), Imidazole SalicylateÒ
(anti-inflammatory, anti-pyretic and analgesic), 2-imidazolinone
(pesticidal), NizofenoneÒ (nootropic), TioconazoleÒ (fungicide)
[Fig. 1] and are being sold in the market.
as fluorescent dyes [19], light-emitting diodes, LEDs, [20] and
fluorescent probes [21].
As part of a research program synthesizing various bioactive
heterocyclic compounds [22,23], we herein report the synthesis of
novel 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones with
a perception that with the synergism of both the imidazole ring
system and chalcone moieties in a single nucleus, the newly
synthesized compounds would likely possess significant biological
activities.
2. Chemistry
On the other hand, 1,3-diaryl-2-propen-1-ones, also known as
chalcones, continue to attract the interest of chemists and micro-
biologists due to their remarkable biological activities, among
which anti-malarial [10], anti-protozoal [11], anti-inflammatory
[12], immunomodulatory [13], nitric oxide inhibition [14], tyronase
inhibition [15] and cytotoxic [16] activities are the most familiar.
N-Arylation of imidazole was carried out with different aryl
halides using hexadecyltrimethylammonium bromide as a catalyst;
para-fluorobenzaldehyde, para-chlorobenzaldehyde and para-bro-
mobenzaldehyde were tried as arylating agents among which para-
fluorobenzaldehyde gave the maximum yield [Table 1] due to the
strongest (ꢀ) IE of fluoro group among the series and appreciable
(ꢀ) RE of –CHO group that cumulatively cause electron deficiency at
C-4 and thereby, facilitate the nucleophilic attack of imidazole. 4-
(1H-Imidazol-1-yl) benzaldehyde thus synthesized was then
* Corresponding author. Tel.: þ92 425830503; fax: þ92 429231169.
E-mail address: drhamidlatif@yahoo.com (H.L. Siddiqui).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.038

T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
4655
O
analyses which were found in accordance with the calculated
values [Table 2]. Configuration of the title compounds across
the double bond (C-8–C9) is proposed as E on the basis of
single crystal X-ray crystallography of two of the representative
chalcones (4c, 4j) and is discussed in the following section in
detail.
H
H
O-
OH
O
N+
N
O2N
CH3
HN
NH
.
N
N
OH
Metronidazole
Imidazole Salicylate
2-Imidazolinone
Cl
CH3
N
N
N
4. Single crystal X-ray crystallography
N
CH3
S
O
Cl
Single crystals of the compounds 4c and 4j were grown in
methanol and studied In order to determine the stereochemistry (E
or Z configuration) of the compounds under investigation, single
crystals of the products (4c and 4j) were grown by dissolving the
compound in absolute methanol and studied by X-ray crystallog-
raphy. The crystal structures indicate that both the compounds
crystallize with Z ¼ 4 (in space group P21/n; monoclinic).
N
O
Cl
Cl
NO2
Nizofenone
Tioconazole
The molecular structure of 4c is presented in Fig. 1 and is not
planar. The crystallographic parameters (Table 3) and selected bond
length and bond angles (Table 4) indicate that the phenyl-prop-en-
one moiety [O(1)/C(7)–C(15)] forms a plane (plane 1) wherein C(8)
lies out of the plane. The mean-plane of the chlorophenyl ring
[Cl(1)/C(1)–C(6)] is oriented at 25.55(6)ꢁ with respect to the plane
1. The mean-plane of imidazole ring [N(1)/N(2)/C(16)–C(18)] forms
an angle 30.22(6)ꢁ with the plane 1. The structure is devoid of any
classical hydrogen bonds but non-classical hydrogen bonding
interactions are present (CCDC No. 718262).
Fig. 1. Structures of some well-known imidazoles containing bioactive molecules.
Table 1
% Yield of para substituted benzaldehydes with imidazole.
Entry
Aryl halide
Yield, %
1
2
3
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
78.3
16.1
5.2
As evident from Fig. 2, phenyl-prop-en-one moiety in the
compound 4j is also not planar like 4c In this case, the mean-planes
formed by the phenyl ring [C(10)–C(15)] and the propenone group
atoms [O(1)/C(7)–C(9)] are inclined at 26.53(8)ꢁ with respect to
each other. Moreover, the mean-planes of the phenyl ring [C(10)–
C(15)] and the imidazole ring [N(1)/N(2)/C(16)–C(18)] form an
angle 30.72(8)ꢁ. The mean-plane of the fluorophenyl ring [F(1)/
C(1)–C(6)] is twisted by 56.41(5)ꢁ with respect to the plane of the
other phenyl ring. The structure of 4j is also devoid of any classical
hydrogen bonds and is stabilized by non-classical hydrogen
bonding interactions, C(8)–H(8)/O(1), C(17)–H(17)/F(1) and
C(18)–H(18)/N(2) which link the molecules into a three-dimen-
sional network (CCDC No. 718263).
reacted with a number of substituted aromatic acetophenones in
the presence of 10% methanolic sodium hydroxide to get the title
compounds in good overall yields (Scheme 1).
3. Results and discussion
The synthesis of N-arylimidazoles and other aryl amines has
attracted significant interest because of the frequent occurrence of
these structural units in biologically active inhibitors [24]. The
development of mild and cost effective catalytic procedures for N-
arylation of imidazoles still remains an active research area [25].
Herein, hexadecyltrimethylammonium bromide has been used as
a catalyst for the purpose for the first time. Different para
substituted benzaldehydes were condensed to check the structure–
activity relationship and was found that 4-fluorobenzaldehyde is
the most reactive than the corresponding bromo and chloro
analogues [Table 1]. 4-(1H-Imidazol-1-yl) benzaldehyde (3) thus
synthesized, is further reacted with twenty different substituted
acetophenones to get a series of novel biologically active 3-[4-(1H-
imidazol-1-yl) phenyl]prop-2-en-1-ones.
5. Biological activity
5.1. Anti-oxidant activity
Generation of reactive oxygen species (ROS) and free radicals in
vivo is involved in a wide range of human diseases [26]. ROS,
including superoxide anion, hydrogen peroxide and hydroxyl
radical are byproducts of a variety of pathways of aerobic metab-
olism [27]. These are unstable and react readily with a wide range
of biological substrates, such as lipids, DNA and protein molecules,
All of the newly synthesized compounds were characterized
through spectroscopic techniques along with their elemental
N
F
N
N
N
N
O
R
Ph COCH3
(ii)
DMF
(i)
R1
+
N
H
(i)- K2CO3/ C16H33(CH3)3N+Br; 100oC
(ii)- MeOH/ NaOH/ 25oC
R5
R2
CHO
CHO
1
3
4a- 4t
2
R4
R3
Scheme 1. Conversion of imidazole to 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones.

4656
T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
Table 2
Characterization of 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones.
Compound
R1
R2
R3
R4
R5
Molecular formula
Yield, %
mp, ꢁC
Analysis, %
Calculated (Found)
C
H
N
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Cl
H
Cl
H
Cl
Cl
Cl
F
H
F
H
F
Br
H
H
H
H
H
H
H
H
H
H
Cl
H
H
Cl
H
H
F
F
H
H
H
H
OCH3
H
OCH3
OH
H
H
Cl
Cl
Cl
H
H
Cl
H
F
H
F
H
H
Br
I
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
F
H
H
H
H
H
H
H
C18H14N2O
C18H13ClN2O
C18H13ClN2O
C18H12Cl2N2O
C18H12Cl2N2O
C18H12Cl2N2O
C18H12Cl2N2O
C18H11Cl3N2O
C18H13FN2O
83
58
76
75
65
95
93
93
54
72
68
65
59
97
79
80
72
58
93
65
150–151
116–117
163–164
124–125
168–170
166–167
150–152
168
120–122
142–143
124–126
176–178
142–143
118
163–164
192–194
120
148–150
134–135
238–239
78.81 (78.80)
70.02 (70.01)
70.02 (70.02)
62.99 (62.98)
62.99 (62.99)
62.99 (63.01)
62.99 (63.00)
57.25 (57.26)
73.96 (73.95)
73.96 (73.95)
69.67 (69.69)
69.67 (69.67)
69.67 (69.68)
61.21 (61.22)
61.21 (61.21)
54.02 (54.01)
74.98 (75.00)
74.98 (74.99)
71.84 (71.83)
74.47 (74.45)
5.14 (5.14)
4.24 (4.23)
4.24 (4.25)
3.52 (3.51)
3.52 (3.53)
3.52 (3.53)
3.52 (3.51)
2.94 (2.94)
4.48 (4.49)
4.48 (4.48)
3.90 (3.89)
3.90 (3.91)
3.90 (3.91)
3.71 (3.70)
3.71 (3.73)
3.27 (3.25)
5.30 (5.31)
5.30 (5.29)
5.43 (5.44)
4.86 (4.87)
10.21 (10.22)
9.07 (9.09)
9.07 (9.07)
8.16 (8.18)
8.16 (8.15)
8.16 (8.15)
8.16 (8.16)
7.42 (7.43)
9.58 (9.58)
9.58 (9.60)
9.03 (9.02)
9.03 (9.02)
9.03 (9.03)
7.93 (7.92)
7.93 (7.93)
7.00 (7.01)
9.20 (9.19)
9.20 (9.22)
8.38 (8.40)
9.65 (9.67)
4j
4k
4l
C18H13FN2O
C18H12F2N2O
C18H12F2N2O
C18H12F2N2O
C18H13BrN2O
C18H13BrN2O
C18H13IN2O
C19H16N2O2
C19H16N2O
4m
4n
4o
4p
4q
4r
4s
4t
H
OCH3
OCH3
H
C20H18N2O3
C18H14N2O2
Table 3
Crystal data and structure refinement for (4c) and (4j).
Parameter
4c
4j
Structural formula
Formula weight
Crystal system
Space group
T, K
C18H13ClN2O
308.75
Monoclinic
P21/n
C18H13FN2O
292.30
Monoclinic
P21/n
173(2)
173(2)
a, Å
b, Å
c, Å
6.987(6)
22.490(9)
9.270(3)
1430.1(8)
4
14.923(3)
10.876(5)
8.512(4)
1373.8(9)
4
Cell volume, Å3
Z
Calculated density, mg/m3
Crystal size, mm3
Reflections collected
1.434
1.413
0.16 ꢂ 0.08 ꢂ 0.07
0.20 ꢂ 0.16 ꢂ 0.04
4934
5701
s
min;
s
max
2.7–27.5ꢁ
1.04
3.0–27.5ꢁ
1.04
Goodness-of-fit on F2
F(000)
640
608
Table 4
Selected bond lengths [Å] and angles [ꢁ] for (4c) and (4j).
Fig. 2.
Bond length
4c
1.747(2)
1.227(2)
1.366(2)
4j
Cl/F(1)–C(4)
O(1)–C(7)
N(1)–C(16)
1.359(2)
1.225(2)
1.365(2)
Table 5
% Age superoxide anion radical scavenging activity at 0.5 mM conc.
N(1)–C(13)
1.428(2)
1.423(2)
Compound
% RSA
Compound
% RSA
N(2)–C(16)
N(2)–C(17)
C(16)–N(1)–C(18)
C(16)–N(1)–C(13)
C(18)–N(1)–C(13)
C(16)–N(2)–C(17)
1.317(2)
1.380(2)
106.15(15)
127.39(15)
126.27(15)
104.73(16)
1.313(2)
1.382(2)
106.48(14)
127.05(14)
126.38(15)
104.38(14)
4a
4b
4c
4d
4e
4f
4g
4h
4i
81.94
70.40
90.06
3.30
4l
4m
4n
4o
4p
4q
4r
4s
8.30
69.47
76.02
42.10
40.43
83.90
66.02
50.95
8.65
0.40
18.80
47.70
2.40
79.25
64.50
16.70
4t
4j
4k
N-Propyl gallate
91.3
consequently resulting in the cell damage [28,16]. All the synthe-
sized compounds were assessed for their superoxide anion radical
scavenging activity. All the synthesized compounds were subjected
to anti-oxidant studies.
The synthesized compounds were assessed for their superoxide
anion radical scavenging activity. The compounds 4a–4c, 4i, 4n
and 4q showed potent activity. From the results (Table 5), it is
evident that substitution of Cl at para position in benzene ring
belonging to acetophenone moiety has maximum activity, almost
equal to the standard (n-propyl gallate). It is obvious from
the results that substitution of methoxy group at meta position
increases the activity compared to the unsubstituted acetophenones

T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
4657
Table 6
6. Conclusion
Anti-fungal activity expressed in size (mm/100 m
g mlꢀ1) of inhibition zone.
In our experiments, we used a new catalyst for N-arylation of
imidazole and synthesized a new series of imidazole based chal-
cones. Some of these showed significant anti-oxidant, anti-leish-
manial and anti-fungal activities, especially against A. fumigatus
which causes aspergillosis, a significant threat to human health in
the form of allergic and life threatening invasive infections.
Sample
Aspergillus
fumigatus
Trichoderma
vivide
Candida
lipolytica
Aspergillus
niger
4a
4b
4c
4d
4e
18
19
20
15
10
19
20
10
17
01
19
18
15
18
18
10
16
17
10
05
22
03
05
09
02
06
10
06
06
05
01
04
03
05
02
09
02
08
06
04
06
17
04
05
10
04
07
10
07
06
05
01
03
04
07
03
08
03
07
06
04
05
16
04
05
08
01
02
06
04
01
03
02
04
04
04
04
04
02
03
03
03
05
10
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
7. Experimental
All the chemicals were purchased from Merck, BDH and WAKO
and used without purification. EIMS were recorded on MAT 312
instrument. 1H NMR spectra were recorded on a Bruker XWIN-
300 MHz and 13C NMR on 100 MHz. Chemical shifts are reported in
ppm referenced to the residual solvent signal. IR spectra (KBr) were
recorded with an IR-spectrophotometer. Melting points were
measured on a Stuart scientific SMP3 apparatus and are uncor-
rected. Elemental analysis was carried out using a Perkin Elmer
2400-CHN Analyzer. The purity of products was checked by TLC
(Silica gel Merck). Visualization was achieved with UV light and
Iodine vapor staining.
4s
4t
Nystatin
7.1. Procedure for synthesis of 4-(1H-imidazol-1-yl)
benzaldehyde (3)
ring; also it is found that incorporation of halo (bromo and fluoro)
groups at ortho and meta positions leads to more active compounds
than that at para position. Introduction of substituents at adjacent
position reduces the activity significantly even at 2,4-positions
(4e, 4d, 4h).
A mixture of imidazole (6.80 g, 100 mmol), anhydrous potas-
sium carbonate (13.80 g, 100 mmol), 4-fluorobenzaldehyde
(12.40 g, 100 mmol), hexadecyltrimethylammonium bromide
(20 mg) and dimethylformamide (50.0 ml) was stirred for a period
of 18 hours at 100 ꢁC and after cooling to room temperature, was
poured onto crushed ice (200 ml). Pale yellow precipitates obtained
were filtered, dried and crystallized from methanol. Yield: 78.3%;
mp 150–152 ꢁC.
5.2. Anti-fungal activity
The in vitro antimicrobial activity of the synthesized compounds
against four strains of fungi i.e. Aspergillus fumigatus, Trichoderma
viride, Candida lipolytica, Aspergillus niger was investigated and all
the newly synthesized compounds were found active against all the
strains under evaluation to certain extent (Table 6). The compounds
4a–4c, 4g, 4f, 4i, and 4k are strongly active against A. fumigatus and
moderately active against other strains.
7.2. 3-[4-(1H-Imidazol-1-yl) phenyl]prop-2-en-1-ones
A methanolic sodium hydroxide solution (40%; 10.0 ml) was
added dropwise to a mixture of 4-(1H-imidazol-I-yl)benzaldehyde
(10.0 mmol, 1.72 g), acetophenone (10.0 mmol) and methanol
(50 ml) over a period of 30–40 minutes with continuous stirring at
room temperature till completion of the reaction (as indicated by
TLC). Precipitates obtained, were filtered, washed with cold
methanol–water mixture (1:10). Finally the product was recrys-
tallized from methanol.
5.3. Anti-leishmanial activity
All the compounds were tested for their anti-leishmanial
activity using Leishmania major promastigotes as parasites for in
vitro screening. The results are shown in Table 7. Compounds 4d, 4j
and 4g showed significant activity while the compounds 4o, 4n and
4k exhibited moderate activity.
7.2.1. 3-[4-(1H-Imidazol-1-yl)phenyl]-1-phenyl-prop-2-en-1-one
(4a)
Yellowish solid. IR (KBr, cmꢀ1) 3099, 1662, 1521, 653; 1H NMR
Table 7
(CDCl3):
d
8.02 (d, 2H, J ¼ 7.1 Hz), 7.90 (s, 1H), 7.83 (d, 1H,
Anti-leishmanial activity of the compound IC50
.
J ¼ 15.7 Hz), 7.76 (t, 2H, J ¼ 8.5 Hz), 7.61 (m, 1H), 7.57 (d, 1H,
J ¼ 15.7 Hz), 7.53 (m, 4H), 7.31 (t, 1H, J ¼ 1.2 Hz), 7.22 (s, 1H); 13C
NMR: 190.3, 143.2, 138.7, 138.1, 135.5, 133.2, 131.0, 130.2, 128.9,
128.7, 122.8, 121.6, 118.0. EIMS (m/z, %) 275.2 (15.27), 274.2 (Mþ,
75.12), 197.1 (27.80), 169.0 (9.49) 144.1 (7.53), 105.0 (36.48), 77
(100).
Compound
IC50
,
m
g/ml
Compound
IC50, mg/ml
4a
4b
4c
4d
4e
4f
4g
4h
4i
0.91 ꢃ 0.04
0.93 ꢃ 0.50
0.92 ꢃ 0.02
0.72 ꢃ 0.62
0.99 ꢃ 0.06
0.99 ꢃ 0.03
0.67 ꢃ 0.10
0.63 ꢃ 0.06
0.98 ꢃ 0.22
0.71 ꢃ 0.03
083 ꢃ 0.04
4l
0.89 ꢃ 0.03
0.97 ꢃ 0.02
0.86 ꢃ 0.08
0.86 ꢃ 0.19
0.92 ꢃ 0.19
0.98 ꢃ 0.02
0.98 ꢃ 0.04
0.82 ꢃ 0.20
0.96 ꢃ 0.05
0.56 ꢃ 0.20
4m
4n
4o
4p
4q
4r
7.2.2. 3-(2-Chlorophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
en-1-one (4b)
4s
4t
Yellowish solid. IR (KBr, cmꢀ1) 3119, 1640, 1525, 653; 1H NMR
4j
4k
Standard drug (Amphotericin B)
(CDCl3):
d
7.89 (s, 1H), 7.68 (d, 2H, J ¼ 8.5 Hz), 7.50 (m, 7H), 7.29 (t,
1H, J ¼ 7.8 Hz), 7.21 (d, 1H, J ¼ 7.8 Hz), 7.17 (d, 1H, J ¼ 16.6 Hz); 13C

4658
T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
NMR: 188.5, 143.8, 136.9, 136.7 (2C), 133.7 (2C), 131.0 (2C), 130.7
(4C), 127.6 (2C), 123.3, 122.6, 121.0. EIMS (m/z, %) 310.2 (Mþ þ 2,
31.03), 309.2 (35.69), 308.2 (Mþ, 100), 273.2 (30.28), 241.1 (26.55),
197.1 (58.56), 139.0 (94.87), 111.0 (15.20), 102.0 (35.0).
7.2.8. 3-[4-(1H-Imidazol-1-yl)phenyl]-1-(2,3,4-
trichlorophenyl)prop-2-en-1-one (4h)
Yellow solid. IR (KBr, cmꢀ1) 3108, 1640, 1520, 658; 1H NMR
(CDCl3):
d
7.89 (s, 1H), 7.67 (d, 2H, J ¼ 8.4 Hz), 7.50 (d, 1H,
J ¼ 16.0 Hz), 7.42 (m, 3H), 7.30 (d, 1H, J ¼ 8.2 Hz), 7.27 (t, 2H,
J ¼ 6.8 Hz), 7.08 (d, 1H, J ¼ 16.0 Hz); 13C NMR: 191.0, 144.8, 143.1,
138.3, 137.1, 136.9, 135.8, 135.0, 131.8, 131.2, 131.0, 130.9, 130.7, 124.6,
123.8, 123.6, 122.1, 118.5; EIMS (m/z, %) 380.1 (Mþ þ 2, 11.78), 378
(Mþ, 26.14), 377 (48.05), 376 (31.44), 341.2 (13.55), 309.1 (13.60),
197.1 (82.99), 141.0 (100), 102.0 (64.80), 76 (36.96).
7.2.3. 3-(4-Chlorophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
en-1-one (4c)
Yellow crystalline solid. IR (KBr, cmꢀ1) 3107, 1659, 1518, 656; 1H
NMR (400 MHz, CDCl3):
d
7.97 (d, 2H, J ¼ 8.5 Hz), 7.90 (s, 1H), 7.83
(d,1H, H
b
, J ¼ 15.7 Hz), 7.75 (t, 2H, J ¼ 7.5 Hz), 7.51 (d,1H, J ¼ 8.2 Hz),
7.49 (d, 1H, J ¼ 14.8 Hz), 7.46 (t, 2H, J ¼ 8.5 Hz), 7.43 (d, 1H,
J ¼ 8.5 Hz), 7.31 (t, 1H), 7.22 (s, 1H); 13C NMR (100 MHz, CDCl3):
189.9, 143.7, 143.7, 139.7, 138.8, 136.4, 134.0, 131.2, 130.9, 130.5,
130.3, 130.1, 129.9, 129.2, 129.4, 122.3, 121.7, 118.0; EIMS (m/z, %)
310.2 (Mþ þ 2, 34.08), 308.2 (Mþ, 100), 273.2 (99.45), 241.1 (21.34),
197.1 (42.76), 142.0 (53.72), 113.0 (75.5), 111.0 (61.23).
7.2.9. 1-(2-Fluorophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
en-1-one (4i)
Yellow solid. IR (KBr, cmꢀ1) 3113, 1659, 1515, 659; 1H NMR
(CDCl3):
d
7.89 (s, 1H), 7.85 (d, 1H, J ¼ 15.1 Hz), 7.79 (dd, 2H,
J ¼ 1.7 Hz, 8.5 Hz), 7.73 (d, 1H, J ¼ 8.3 Hz), 7.57 (m, 1H), 7.44 (d, 1H,
J ¼ 14.8 Hz), 7.41 (t, 1H, J ¼ 6.0 Hz), 7.38 (d, 1H, J ¼ 2.8 Hz), 7.30 (t,
1H, J ¼ 7.5 Hz), 7.29 (t, 1H, J ¼ 7.5 Hz), 7.21 (s, 1H), 7.17 (dd, 1H,
J ¼ 1.9 Hz, 7.6 Hz); 13C NMR: 189.8, 162.5, 144.3, 138.0, 137.6, 135.8,
135.0, 130.7, 129.9, 129.7, 129.5, 123.9 (2C), 123.3, 122.1, 121.8, 117.6,
114.5; EIMS (m/z, %) 292.2 (Mþ, 43.48), 225.1 (12.74), 197.1 (16.40),
169.1 (6.72), 144.1 (23.31), 123.1 (100), 95 (27.82).
7.2.4. 3-(2,4-Dichlorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4d)
Off white solid. IR (KBr, cmꢀ1) 3133, 1663, 1523, 648; 1H NMR
(CDCl3): 7.89 (s, 1H), 7.68 (d, 2H, J ¼ 8.5 Hz), 7.51 (d, 1H, J ¼ 15.7 Hz),
7.48 (m, 4H), 7.36 (dd, 1H, J ¼ 6.3 Hz), 7.30 (s, 1H), 7.21 (s, 1H), 7.15
(d, 1H, J ¼ 16.0 Hz); 13C NMR: 192.3, 144.6, 138.5, 137.4, 136.2, 135.6,
133.1, 130.7, 130.4 (3C), 127.6, 126.6, 121.6 (2C), 118.0; EIMS (m/z, %)
344.2 (20.71), 343.2 (Mþ, 11.14), 342.2 (35.8), 307.2 (16.27), 197.1
(40.98), 172.9 (61.00), 145.0 (27.31) 116.1 (100), 102 (92.60), 76.0
(53.45), 75.0 (58.76).
7.2.10. 1-(4-Fluorophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
en-1-one (4j)
Yellow crystalline solid. IR (KBr, cmꢀ1) 3097, 1660, 1515, 656; 1H
NMR (CDCl3):
d
8.08 (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz), 7.90 (s, 1H), 7.83 (d,
1H, J ¼ 15.7 Hz), 7.75 (d, 2H, J ¼ 8.5 Hz), 7.53 (d, 1H, J ¼ 15.7 Hz), 7.46
(t, 2H, J ¼ 8.5), 7.31 (t, 1H, J ¼ 7.5 Hz), 7.20 (m, 3H); 13C NMR: 188.6,
167.1, 143.4, 138.8, 135.5, 134.5, 134.0, 131.4, 131.2, 131.0, 130.2, 130.4,
122.3, 122.1, 121.6, 118.0, 116.2, 115.9; EIMS (m/z, %) 292.2 (Mþ,
57.36), 291.2 (22.56), 225.1 (14.25), 197.1 (18.80), 169.1 (7.64), 144.1
(75.25), 123.1 (100), 95 (34.04).
7.2.5. 3-(3,4-Dichlorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4e)
White amorphous solid. IR (KBr, cmꢀ1) 3110, 1661, 1521, 659; 1H
NMR (CDCl3):
d
8.09 (d, 1H, J ¼ 1.9 Hz), 7.91 (s, 1H), 7.86 (d, 1H, H
b,
J ¼ 15.7 Hz), 7.85 (dd, 1H, J ¼ 7.7 Hz, 2.0 Hz), 7.76 (t, 2H, J ¼ 8.5 Hz);
7.60 (d, 1H, J ¼ 8.3 Hz), 7.46 (d, 1H, J ¼ 15.9 Hz), 7.43 (d, 2H,
J ¼ 7.7 Hz), 7.31 (t, 1H), 7.22 (s, 1H); 13C NMR: 188.8, 142.9, 138.8,
136.9, 136.0, 133.2, 132.9, 132.8, 130.9, 129.9, 129.8, 129.6, 129.2,
126.2, 124.3, 124.1, 119.8, 117.8; EIMS (m/z, %) 344.1 (M þ 2, 54.93),
343.2 (33.26), 342.3 (Mþ, 100), 307.2 (46.83), 275.1 (17.79), 197.1
(52.57), 145.0 (28.64), 115.0 (38.26), 102.1 (32.86).
7.2.11. 1-(2,3-Difluorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4k)
White solid. IR (KBr, cmꢀ1) 3126, 1661, 1523, 659; 1H NMR
(CDCl3):
d
7.90 (s, 1H), 7.76 (d, 1H, J ¼ 13.2 Hz), 7.73 (d, 2H,
J ¼ 8.2 Hz), 7.57 (m, 1H), 7.45 (d, 1H, J ¼ 8.4 Hz), 7.43 (d, 1H,
J ¼ 13.3 Hz), 7.37 (m, 2H), 7.31 (t, 1H), 7.22 (s, 1H), 7.18 (d, 1H,
J ¼ 6.8 Hz); 13C NMR: 188.2, 160.2, 154.6, 143.1, 138.3, 135.1, 135.0,
131.9, 131.3, 131.1, 126.6, 126.0, 123.7, 121.7, 120.9, 120.7, 119.3, 117.5;
EIMS (m/z, %) 311.0 (19.52), 310.0 (Mþ, 100), 309 (37.61), 243.0
(33.57), 199.1 (45.71), 167.1 (26.31), 141.0 (46.45), 113.0 (38.57).
7.2.6. 3-(2,5-Dichlorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4f)
Yellow solid. IR (KBr, cmꢀ1) 3115, 1661, 1523, 651; 1H NMR
7.2.12. 1-(3,4-Difluorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4l)
(CDCl3):
d
7.89 (s, 1H), 7.69 (d, 2H, J ¼ 8.5 Hz), 7.51 (d, 1H,
J ¼ 16.7 Hz), 7.45 (d, 2H, J ¼ 1.8 Hz), 7.42 (t, 1H, J ¼ 7.8 Hz), 7.39 (d,
2H, J ¼ 1.3 Hz), 7.30 (t, 1H, J ¼ 7.2 Hz), 7.21 (s, 1H), 7.13 (d, 1H,
J ¼ 16.1 Hz); 13C NMR: 192.0, 145.0, 140.3, 139.2, 135.5, 133.5, 133.3,
132.1, 131.8, 131.1, 130.5, 129.8, 129.4, 126.7, 126.4, 121.6, 118.0;
EIMS (m/z, %) 346.2 (2.62), 343.1 (15.6), 342.2 (Mþ, 50.19), 307.2
(14.11), 275.0 (20.38), 197.1 (100), 169.1 (39.10), 116.0 (68.10), 102
(74.70).
White solid. IR (KBr, cmꢀ1) 3124, 1665, 1520, 657; 1H NMR
(CDCl3):
d
7.90 (s, 1H), 7.86 (d, 1H, J ¼ 5.7 Hz), 7.85 (t, 1H, J ¼ 6.8 Hz),
7.84 (d, 1H, J ¼ 15.7 Hz), 7.75 (d, 2H, J ¼ 8.5 Hz), 7.47 (d, 1H,
J ¼ 15.8 Hz), 7.44 (d, 1H, J ¼ 8.5 Hz), 7.31 (t, 1H, J ¼ 1.9 Hz), 7.27 (m,
2H), 7.22 (s, 1H); 13C NMR: 188.8, 158.6, 156.1, 143.8, 138.2, 136.1,
135.6,134.0,130.6,129.4,129.2,123.3,123.0,122.7,122.0,117.0,114.2;
EIMS (m/z, %) 311 (20.50), 310 (Mþ, 100), 309 (34.87), 243 (23.40),
197.1 (25.55), 169 (16.31), 141 (49.80), 113 (57.82), 102.1 (18.02).
7.2.7. 3-(2,6-Dichlorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4g)
7.2.13. 1-(2,6-Difluorophenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4m)
Off white solid. IR (KBr, cmꢀ1) 3102, 1646, 1522, 654; 1H NMR
White amorphous solid. IR (KBr, cmꢀ1) 3108, 1658, 1523; 1H
(CDCl3):
d
7.88 (s, 1H), 7.65 (d, 2H, J ¼ 8.4 Hz), 7.43 (d, 1H, J ¼ 8.4 Hz),
7.40 (m, 5H), 7.29 (d, 1H, J ¼ 16.3 Hz), 7.21 (s, 1H), 6.97 (d, 1H,
J ¼ 16.2 Hz); 13C NMR: 188.4, 144.1, 138.5, 138.2, 138.0, 136.9, 136.0,
135.0, 130.7, 129.5, 129.3, 129.0, 126.5, 126.1, 124.6, 124.4, 122.5,
118.6; EIMS (m/z, %), 344.1 (Mþ þ 2, 40.17), 343.2 (30.12), 342.1 (Mþ,
63.89), 307.2 (8.94), 275.1 (32.86), 197.1 (100), 115 (24.25), 102
(41.23).
NMR (CDCl3):
d
7.89 (s, 1H), 7.68 (d, 2H, J ¼ 8.5 Hz), 7.53 (d, 1H, H
b,
J ¼ 16.1 Hz), 7.47 (m, 3H), 7.30 (t, 1H, J ¼ 7.8 Hz), 7.21 (s, 1H), 7.08 (d,
1H, J ¼ 16.1), 7.02 (dd, 2H, J ¼ 7.8, 2.8 Hz); 13C NMR: 189.3, 160.5,
160.3, 143.8, 136.6, 135.3, 135.1, 134.0, 130.8, 129.8, 129.6, 124.9,
121.1, 116.5, 109.8, 109.5, 106.3; EIMS (m/z, %), 311.2 (8.61), 310.2
(Mþ, 48.70), 243.2 (40.47), 197.2 (28.23), 169.1 (12.51), 141.0 (100).

T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
4659
7.2.14. 1-(2-Bromophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
7.2.20. 1-(3-Hydroxyphenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-
2-en-1-one (4t)
White amorphous solid. IR (KBr, cmꢀ1) 3432, 3115, 1664, 1518,
658; 1H NMR (CDCl3):
8.23 (s, 1H), 7.92 (d, 2H, J ¼ 8.6 Hz), 7.83 (d,
1H, H , J ¼ 15.7 Hz),
, J ¼ 15.7 Hz), 7.77 (d, 2H, J ¼ 7.2), 7.70 (d, 1H, H
en-1-one (4n)
Yellow solid. IR (KBr, cmꢀ1) 3128, 1663, 1522, 648; 1H NMR
(CDCl3):
d
7.89 (s, 1H), 7.67 (m, 3H), 7.46 (d, 1H, J ¼ 15.8 Hz), 7.43 (d,
d
4H, J ¼ 7.2 Hz), 7.38 (m, 2H), 7.29 (t, 1H, J ¼ 8.2 Hz), 7.21 (s, 1H), 7.13
(d, 1H, J ¼ 16.0 Hz); 13C NMR: 188.7, 143.8, 137.1, 136.0, 135.6, 134.0,
132.9, 132.8, 132.6, 128.8, 128.6, 128.4, 123.5, 123.4, 123.2, 121.4,
119.2, 116.8; EIMS (m/z, %) 354.1 (70.49), 353.1 (Mþ, 30.25), 273.2
(55.25), 197.1 (100), 155 (39.41); 115.0 (19.94), 102.0 (38.41).
b
a
7.65 (t, 2H, J ¼ 8.9 Hz), 7.58 (d, 1H, J ¼ 7.6 Hz), 7.44 (t, 1H, J ¼ 2.1 Hz),
7.36 (t, 1H, J ¼ 7.9 Hz), 7.06 (dd, 1H, J ¼ 1.74 Hz, 9.7 Hz); 13C NMR:
190.0, 159.2, 143.4, 139.0, 138.0, 136.0, 131.5, 131.4, 130.8, 124.8,
123.1, 122.5, 122.3, 122.0, 121.2, 120.0, 116.8; EIMS (m/z, %) 291.3
(45.27), 290.2 (Mþ, 31.36), 223.2 (4.90), 197.1 (12.05), 169.1 (7.29),
121.1 (100), 93 (34.01).
7.2.15. 1-(4-Bromophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-
en-1-one (4o)
White amorphous solid. IR (KBr, cmꢀ1) 3109, 1658, 1525, 649; 1H
7.3. Antimicrobial testing
NMR (CDCl3):
d
7.90 (d, 2H, J ¼ 8.7), 7.83 (s, 1H), 7.78 (d, 1H, H
b,
J ¼ 15.7 Hz), 7.75 (t, 2H, J ¼ 8.4 Hz), 7.66 (d, 2H, J ¼ 8.5 Hz), 7.50 (d,
1H, J ¼ 15.7 Hz), 7.46 (t, 2H, J ¼ 8.5 Hz), 7.31 (t, 1H, J ¼ 8.3 Hz), 7.22
(s, 1H); 13C NMR: 189.0, 143.6, 138.8, 136.7, 133.8, 132.0 (3C), 130.1,
130.0 (4C), 128.2 (3C), 121.5, 117.8; EIMS (m/z, %) 354.2 (Mþ þ 2,
42.48), 353.1 (Mþ, 29.36), 352.2 (47.17), 273.2 (100), 197.1 (44.67),
157.0 (51.25), 141.1 (60.49), 102.0 (27.41).
All the synthesized compounds (dissolved in DMSO) were
subjected to anti-fungal screening for determining the zone of
inhibition by cup diffusion method. The Petri plates were inocu-
lated in cultures of fungus on potato dextrose agar medium. Plates
were incubated at 37 ꢁC for 24 hours for bacteria, at 30 ꢁC for
fungus species and at 45 ꢁC for A. fumigatus. After inoculation, the
diameter of clear zone of inhibition surrounding the sample was
taken as a measure of the inhibitory power of the sample against
the particular test organism [29].
7.2.16. 3-[4-(1H-Imidazol-1-yl)phenyl]-1-(4-iodophenyl)prop-2-
en-1-one (4p)
Yellow crystalline solid. IR (KBr, cmꢀ1) 3116, 1656, 1521, 652; 1H
NMR (CDCl3):
d
7.90 (d, 2H, J ¼ 6.2 Hz), 7.85 (s, 1H), 7.82 (d, 1H,
7.4. Superoxide scavenging assay
J ¼ 15.7 Hz), 7.72 (m, 4H), 7.48 (d, 1H, J ¼ 15.8 Hz), 7.43 (d, 2H,
J ¼ 7.6 Hz), 7.31 (t,1H, J ¼ 8.5 Hz), 7.22 (s, 1H); 13C NMR: 189.0, 143.7,
138.2, 138.0, 137.1, 136.8, 135.7, 132.2, 130.4, 130.3, 130.2, 130.1,
129.8, 122.2, 122.0, 121.7, 117.6, 101.1; EIMS (m/z, %) 401.1 (23.10),
400.2 (Mþ, 100), 333.1 (11.66), 273.2 (96.34), 231 (51.78), 197.1
(46.88), 169.1 (20.29), 102 (32.83).
Compounds were assessed by the literature method [30] The
reaction mixture comprises 40
dinucleotide reduced form (NADH), 40
zolium (NBT), 20 l of 8 M phenazine methosulphate (PMS) 10
1 mM sample and 90 l of 0.1 M phosphate buffer (pH 7.4). The
m
l of 280
m
M
b
-nicotinamide adenine
l of 80 M nitro blue tetra-
l of
m
m
m
m
m
m
reagents were prepared in buffer and sample in DMSO. The reaction
was performed in 96-well microtitre plate at room temperature and
absorbance was measured at 560 nm. The formation of superoxide
was monitored by measuring the formation of water soluble blue
formazan dye. A lower absorbance of reaction mixture indicates
a higher scavenging activity of sample. Percent Radical Scavenging
Activity was determined in comparison with control as:
7.2.17. 3-[4-(1H-Imidazol-1-yl)phenyl-1-(3-methoxyphenyl)]prop-
2-en-1-one (4q)
Yellow solid. IR (KBr, cmꢀ1) 3120, 1655, 1520, 654; 1H NMR
(CDCl3):
d
7.90 (s, 1H), 7.82 (d, 1H, J ¼ 15.6 Hz), 7.75 (t, 2H,
J ¼ 8.5 Hz), 7.60 (d, 1H, J ¼ 7.5 Hz), 7.53 (d, 1H, J ¼ 15.6 Hz), 7.48
(m, 5H), 7.31 (t, 1H, J ¼ 8.3 Hz), 7.12 (dd, 1H, J ¼ 5.7 Hz, 2.3 Hz), 3.87
(s, 3H, OCH3); 13C NMR: 190.0, 160.1, 143.2, 138.8, 137.1, 135.2, 131.0,
130.2 (3C), 129.9, 122.8, 121.6, 121.4, 121.2, 119.6, 118.0, 113.1, 55.7;
EIMS (m/z, %) 305.2 (21.61), 304.2 (Mþ, 100), 273.1 (9.20), 237.1
(9.37), 197.1 (38.51), 144.0 (25.76), 102.0 (23.83).
% RSA ¼ 100 ꢀ fðOD test compound=OD controlÞ ꢂ 100g
7.5. Anti-leishmanial activity
7.2.18. 3-[4-(1H-Imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)prop-
2-en-1-one (4r)
Anti-leishmanial activity of the title compounds was carried out
on the pre-established culture of L. major. Parasites were cultured in
medium M 199 with 10% foetal bovine serum; 25 mM of HEPES, and
0.22 m
g of penicillin and streptomycin respectively at 24 ꢁC in
White solid. IR (KBr, cmꢀ1) 3101, 1659, 1523, 658; 1H NMR
(CDCl3):
d
8.03 (d, 2H, J ¼ 8.8 Hz), 7.88 (s, 1H), 7.79 (d, 1H, H
b,
J ¼ 15.7 Hz), 7.74 (t, 2H, J ¼ 8.5 Hz), 7.55 (d, 1H, J ¼ 15.6 Hz), 7.42 (d,
2H, J ¼ 8.4 Hz), 7.29 (t, 1H, J ¼ 8.0 Hz), 7.20 (d, 1H, J ¼ 10.5 Hz), 6.97
(d, 2H, J ¼ 8.8 Hz), 3.86 (s, 3H, –OCH3); 13C NMR: 188.4, 163.8, 142.3,
139.0, 135.5, 134.3, 130.9, 130.8, 130.0 (3C), 128.6, 121.7, 121.6, 121.5,
118.0, 114.1, 113.9; EIMS (m/z, %) 304.2 (Mþ, 32.57), 289.2 (4.35),
237.1 (2.06), 197.1 (3.30) 135.1 (100), 107 (7.07), 77 (23.11), 76 (5.60).
a shaking incubator [30].
1 mg of each compound was dissolved in 1 ml of DMSO and as
a positive control 1 mg of Amphotericin B was also dissolved in 1 ml
of DMSO.
Parasites at log phase were centrifuged at 3000 rpm for
3 minutes. Parasites were diluted in fresh culture medium to a final
density of 2 ꢂ 106 cells/ml. In 96-well plates, 180
ml of medium was
7.2.19. 1-(3,4-Dimethoxyphenyl)-3-[4-(1H-imidazol-1-
yl)phenyl]prop-2-en-1-one (4s)
added in different wells. 20 ml of the experimental compound was
Yellow solid. IR (KBr, cmꢀ1) 3110, 1655, 1516, 659; 1H NMR
added in medium and serially diluted. 100 ml of parasite culture
(CDCl3):
d
7.90 (s, 1H), 7.82 (d, 1H, J ¼ 15 .6 Hz), 7.76 (t, 2H,
was added in all wells. In negative controls, DMSO was serially
diluted in medium while the positive control contained varying
concentrations of standard anti-leishmanial compound i.e.
Amphotericin B. The plates were incubated for 72 hours at 24 ꢁC.
The culture was examined microscopically on an improved Neu-
bauer counting chamber and IC50 values of compounds possessing
anti-leishmanial activity were calculated. All the assays were run in
duplicate.
J ¼ 8.5 Hz), 7.66 (dd, 1H, J ¼ 6.5 Hz), 7.61 (d, 2H, J ¼ 10.5), 7.58 (d, 1H,
J ¼ 15.6 Hz), 7.45 (d, 2H, J ¼ 8.4 Hz), 7.31 (t, 1H, J ¼ 7.6 Hz), 7.22 (s,
1H), 6.94 (d, 1H, J ¼ 8.4 Hz), 3.96 (s, 6H, 2 (OCH3)); 13C NMR: 188.3,
153.6, 149.5, 142.3, 138.6, 135.2, 134.3, 131.2, 131.0, 130.0 (3C), 123.3,
122.4, 121.6, 118.0, 110.8, 110.1, 56.3, 56.2; EIMS (m/z, %) 335.2
(23.43), 334.2 (Mþ, 100), 303 (31.98), 197.1 (16.71), 165.1 (59.67),
115.0 (17.85), 102.0 (26.91).

4660
T. Hussain et al. / European Journal of Medicinal Chemistry 44 (2009) 4654–4660
[13] L. Barford, K. Kemp, M. Hansen, A. Kharazmi, Int. Immunopharmacol. 2 (2002)
Acknowledgements
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[15] O. Nerya, R. Musa, S. Khatib, S. Tamir, O. Jacob, Phytochemistry 65 (2004)
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This work was supported by grants from the Higher Education
Commission, Pakistan and University of the Punjab, Lahore. We also
acknowledge International Centre for Chemical and Biological
Sciences, HEJ, Research Institute of chemistry, University of Karachi
for spectral analyses and biological testing.
[17] P.S. Patil, S.M. Dharmaprakash, H.K. Fun, M.S. Karthikeyan, J. Cryst. Growth 297
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