1-[4 - (1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones - A potential pharmacophore bearing anti-leishmanial activity

Article abstract of DOI:10.3184/174751916X14569208466251

A series of new potentially anti-microbial 1-[4-(1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones was synthesised by condensation of various substituted benzaldehydes with 1-[4-(1H-imidazol-1-yl)phenyl]ethanone, which was itself prepared by N-arylation o

Full text of DOI:10.3184/174751916X14569208466251

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 APRIL, 199–204
RESEARCH PAPER 199
1-[4-(1H-Imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones – a potential
pharmacophore bearing anti-leishmanial activity
a
b
b
b
Tanvir Hussain , Muhammad Zia-ur-Rehman *, Muhammad Zaheer , Chouhdary Muhammad Ashraf
c
and Michael Bolte
a
Institute of Chemistry, University of the Punjab, Lahore-54590, Pakistan
Applied Chemistry Research Centre, PCSIR Laboratories Complex, Ferozpur Road, Lahore-54600, Pakistan
Institut für Anorganische Chemie, J. W. Goethe-Universität Frankfurt, Max-von-Laue-Str. 7, 60438-Frankfurt/ Main, Germany
b
c
A series of new potentially anti-microbial 1-[4-(1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones was synthesised by condensation of
various substituted benzaldehydes with 1-[4-(1H-imidazol-1-yl)phenyl]ethanone, which was itself prepared by N-arylation of imidazole
with p-haloacetophenones, using copper iodide and 1,3-di(pyridin-2-yl)propane-1,3-dione as a catalyst. All the synthesised compounds
were subjected to preliminary evaluation for their anti-leishmanial and anti-fungal activities. Some of the synthesised compounds showed
significant activities.
Keywords: imidazole, N-arylation, 1,3-di(pyridin-2-yl)propane-1,3-dione, anti-fungal activity, anti-leishmanial activity
1
0
Considerable work has been carried out during the past 20
years on the design, synthesis, characterisation and applications
of various imidazole derivatives in order to explore their
interesting physicochemical and biological properties. Some of
these compounds have been found to possess activity against
distribution in fruits, vegetables and other foodstuffs. Their
1
1
wide range of biological activities such as anti-bacterial, anti-
fungal, anti-oxidant, anti-malarial, anti-plasmodial and
anti-leishmanial activities are largely attributed to their α,β-
unsaturated ketone moieties.
The literature shows that the introduction of various
12
13
14
15
16
1
2
3
carboxypeptidase and show anti-aging, anti-microbial, anti-
4
5
cancer and anti-malarial activities while others show anti-
substituents to the aromatic rings of chalcones is of interest
6
7
8
17,18
hypertensive, anti-diabetic and anti-depressant activities.
Imidazole-based drugs such as ornidazole, metronidazole,
nimorazole, miconazole and butoconazole (Fig. 1) are well
known for their anti-microbial nature and are also used as
in obtaining pharmacologically active compounds.
Our
interest in the synthesis of biologically active heterocyclic
19,20
compounds
has led us to synthesise new imidazole-based
compounds bearing 1,3-diarylprop-2-en-1-one moieties with
different substituents at the aryl ring and to investigate their
anti-leishmanial and anti-fungal activities.
9
sensitisers of hypoxic tumours in conjunction with radiotherapy.
On the other hand, 1,3-diphenyl substituted prop-2-en-1-one
derivatives, commonly known as chalcones (Fig. 2), correspond
to one of the major classes of natural products with widespread
Results and discussion
Synthesis of N-aryl imidazoles has attracted significant
N
interest due to their frequent occurrence in biologically active
21
inhibitors. We have synthesised 1-(4-(1-H-imidazol-1-yl)
phenyl)ethanone (3) by a mild and cost effective N-arylation
of imidazole with p-fluoroacetophenone, using a combination
of copper iodide and 1,3-di(pyridin-2-yl)propane-1,3-dione as a
Cl
NO2
N
HO
HO
2
2
coupling catalyst. Various para-substituted haloacetophenones
were condensed to explore their structure–activity relationship
and it was found that the 4-fluoro analogue is more reactive
than the corresponding bromo and chloro analogues (Table
N
N
N
O
NO2
NO2
N
N
1). This may be attributed to the stronger (–) inductive effect
Ornidazole
Metronidazole
Cl
Nimorazole
of the fluoro group amongst the series, which causes electron
deficiency at C-4 and thereby facilitates the nucleophilic attack
of imidazole. We then reacted 1-[4-(1H-imidazol-1-yl)phenyl]
ethanone (3) with a number of substituted aromatic aldehydes in
the presence of 10% methanolic sodium hydroxide to obtain a
series of novel potentially biologically active 1-(4-1H-imidazol-
1-yl)-3-phenylprop-2-en-1-ones 4a–o in good overall yields
Cl
O
Cl
S
N
N
N
Cl
(
Scheme 1).
N
Structures of the newly synthesised compounds were
Cl
established on the basis of IR, NMR and mass spectrometry
along with their elemental analyses, which were found to be
in accordance with the calculated values. In the IR spectra,
–1
characteristic peaks around 1660 cm were noted, signals
Cl
Cl
Miconazole
13
around δ 189 were observed in C NMR for C=O, while proton
NMR showed characteristic signals of α,β olefinic protons with
Butoconazole
2
3
Fig. 1 Structures of some well-known imidazole-based drugs.
J = 14.0–16.7 Hz.
*
Correspondent. E-mail: rehman_pcsir@hotmail.com

2
00 JOURNAL OF CHEMICAL RESEARCH 2016
CH3
O
CH3
CH3
HOOC
O
O
OH
O
MCHP (Insulin mimetic chalcone)
CH3
OH
O
O
H C
3
HO
OCH3
OH
H C
3
Xanthohumol (Anticancer prenylflavonoid)
CH3
Sofalcone (Antiulcerative drug)
Fig. 2 Structures of some medicinally important 1,3-disubstituted prop-2-en-1-ones.
COCH3
COCH3
R4
C O
H
O
N
N
R1
L (10 mol %),
R1
N
R3 R2
MeOH; 10% NaOH
CuI (10 mol %)
NH +
0
K CO , DMF, 110 C
2
3
R4
R2
X
N
L = 1,3-di(pyridine-2-yl)propane-1,3-dione
X = F, Cl, Br 2 a-c
4 a-o
R3
N
3
Entry
R
1
R
2
R
H
H
3
R
H
H
H
H
4
Entry
R
1
R
2
R
H
H
F
3
R
H
H
H
H
H
4
Entry
4k
R
1
R
2
R
3
R
H
H
H
H
H
4
4a
4
b
4c
4
d
4e
Cl
H
H
4f
Br
H
H
H
H
H
OMe H
Cl
OMe H
H
Cl
H
H
H
4g
4h
4i
Br
H
4l
H
OMe
OMe
e
OMe OM OMe
H
Cl
Cl
H
4m
4n
Cl
Cl
NO2 Cl
NO2
Cl
4j
H
4o
H
H
*
*
imidazol-1-yl
Scheme 1 Synthesis of 1-[4-(1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones from imidazole.
Table 1 Reaction conditions for the reaction of acetophenones with
is twisted by 43.89(7)° with respect to the plane of the other
phenyl ring.
imidazole
Entry Acetophenone
Yield/%
94
92
Reaction time/h
CCDC 739320 contains the supplementary data for
this paper. The data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
https://summary.ccdc.cam.ac.uk/structure-summary-form.
Details of crystal data and structure refinement have been
provided in Table 2.
1
2
3
1-(4-Fluorophenyl)ethanone
1-(4-Chlorophenyl)ethanone
1-(4-Bromophenyl)ethanone
12
18
16
93
Stereochemistry and X-ray crystallography
In order to investigate the stereochemistry (E or Z configuration)
and for structural elucidation of the synthesised compounds,
single crystals of the product 4n were grown for X-ray
crystallographic studies.
The asymmetric unit consists of discrete molecules devoid
of any classical hydrogen bonds and it is stabilised by non-
classical (C–H…O) hydrogen bonding interactions which link
the molecules into a three dimensional network. In the crystal
structure of compound 4n (Fig. 3), the phenyl-prop-en-one
moiety is not planar as evident from the associated torsion angles
Anti-leishmanial activity
Leishmaniasis is a group of prevalent diseases caused by
protozoan parasites belonging to the genus Leishmania.
Leishmania cause a broad spectrum of diseases ranging from the
cutaneous healing skin lesions caused by Leishmania major to a
fatal visceral form called kala azar caused by L. donovani. The
synthesised compounds were tested for their anti-leishmanial
activity using L. major promastigotes as parasites for in vitro
screening and the results are shown in Table 4. The obtained
data are represented as mean ± S.D. The data were statistically
analysed by one-way ANOVA, followed by Tukey’s multiple
comparison test. The IC50 (minimum concentration necessary
for inhibition of 50% of microorganism growth) values were
calculated using sigmoid dose–response curves (Table 3). It
was found that compounds 4i and 4j showed significant activity
almost comparable to the standard drug, amphotericin, while
the compounds 4f, 4g and 4o exhibited moderate activity.
Compounds 4a, 4b, 4c, 4d, 4e were found to be weakly active
[
1
O(1)-C(1)-C(2)-C(3) = –17.4(3)° and C(1)-C(2)-C(3)-C(31) =
73.42(19)°]. The mean-planes formed by the trimethoxyphenyl
ring [C(31)–C(36)] and phenyl ring [C(11)–C(16)] subtend
dihedral angles of 27.69(13)° and 17.06(11)° with the propenone
moiety [O(1)/C(1)–C(3)] respectively. Moreover, the mean-
plane of the imidazole ring [N(1)/N(2)/C(22)–C(25)] forms
an angle of 7.91(15)° with the phenyl ring [C(11)–C(16)].
The mean-plane of the trimethoxyphenyl ring [C(31)–C(36)]

JOURNAL OF CHEMICAL RESEARCH 2016 201
Fig. 3 ORTEP3 diagram of compound 4n showing the numbering scheme. Displacement ellipsoids are drawn at the 50% probability level
and H atoms are represented by circles of arbitrary radius.
Table 2 Crystallographic parameters for compound 4n
3
Structural formula
C H N O
Cell volume
896.35(13) Å
2
1 20 2 4
Formula weight
364.39
Z
2
Crystal system
Space group
T/K
Monoclinic
Pc
173(2)
Absorption correction
Calculated density
Crystal size
None
1.350 mg m
0.48 × 0.45 × 0.44 mm
–
3
3
a/Å
b/Å
c/Å
14.4923(13)
7.9425(5)
7.7897(7)
3.66–25.56°
Reflections collected
Independent reflections
Goodness-of-fit on F2
F(000)
5783
1676 [R(int) = 0.0586]
1.047
384
θ range for data collection
Table 3 Anti-leishmanial activity of the compounds (IC )
Table 4 Anti-fungal activity of the compounds (IC50)
5
0
–1
–1
Compd.
IC /µg mL
Compd.
IC /µg mL
Candida
albicans
39.84 ± 0.112 34.17 ± 0.318
37.76 ± 0.192 > 50
Aspergillus Trichoderma Aspergillus
5
0
50
Compound
fumigatus
viride
> 50
> 50
niger
> 50
> 50
4
4
4
4
4
4
4
4
a
b
c
d
e
f
0.81 ± 0.08
0.83 ± 0.14
0.85 ± 0.06
0.76 ± 0.21
0.72 ± 0.04
0.68 ± 0.01
0.62 ± 0.25
0.99 ± 1.12
4i
4j
4k
4l
4m
4n
4o
0.59 ± 0.03
0.58 ± 0.02
0.82 ± 0.02
0.97 ± 0.92
0.93 ± 0.40
0.91 ± 0.02
0.67 ± 0.10
0.56 ± 0.20
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
42.15 ± 0.189 38.72 ± 0.183 36.53 ± 0.174 44.27 ± 0.741
22.07 ± 0.221 38.79 ± 0.194 34.28 ± 0.183 28.65 ± 0.512
20.07 ± 0.241 34.29 ± 0.166 34.28 ± 0.183 31.98 ± 0.211
31.09 ± 0.231 41.98 ± 0.211 40.69 ± 0.062 44.61 ± 0.060
33.77 ± 0.123 42.07 ± 0.221 48.42 ± 0.123 43.94 ± 0.251
33.77 ± 0.143 40.07 ± 0.241 49.42 ± 0.113 46.24 ± 0.271
18.37 ± 0.999 21.09 ± 0.231 21.98 ± 0.136 24.34 ± 0.141
19.86 ± 0.132 23.77 ± 0.193 29.31 ± 0.182 28.87 ± 0.214
31.98 ± 0.136 23.77 ± 0.193 7.31 ± 0.082 24.87 ± 0.264
g
h
g
h
i
j
k
l
m
n
o
Amphotericin B
whilst the compounds 4h, 4k, 4l, 4m and 4n exhibited almost
no activity against L. major promastigotes. It is evident from
the results that compounds bearing nitro groups are the most
active ones while introduction of electron-donating methoxy
groups makes the pharmacophore almost inactive.
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
> 50
Anti-fungal activity
The in vitro antifungal activity of the synthesised compounds
against four strains of fungi i.e. Candida albicans, Aspergillus
fumigatus, Trichoderma viride and Aspergillus niger was
investigated. Most of the newly synthesised compounds
were found active against all the strains under evaluation to
a certain extent (Table 4). The data are represented as mean
of the triplicate ± S.D. An insight into the structure–activity
relationship shows that the compounds bearing nitro groups
i.e. 4i and 4j are moderately active along with the dichloro
derivatives (4d and 4e). It is also evident that the newly
synthesised compounds are comparatively more active against
Candida albicans than the rest of the strains. The compounds
bearing methoxy groups at the benzene ring were found almost
inactive with an IC greater than 50.
Clotrimazole 9.36 ±0.11
9.56 ± 0.129 11.07 ± 0.241 13.42 ± 0.113
1
a MAT 312 instrument. H NMR spectra were recorded on a Bruker
13
XWIN instrument at 400 MHz and C NMR spectra were recorded
at 100 MHz. Chemical shifts are reported in ppm referenced to the
residual solvent signal. IR spectra (in KBr disks) were recorded using a
Thermo Nicolet FTIR 200 spectrometer. Melting points were recorded
on a Stuart Scientific SMP3 apparatus and are uncorrected. Elemental
analyses were carried out using a PerkinElmer 2400-CHN Analyser.
1-[4-(1H-Imidazol-1-yl)phenyl]ethanone (3)
The compound was prepared according to a modified literature
2
2
procedure. A mixture of imidazole (1.021 g, 15 mmol), anhydrous
potassium carbonate (2.76 g, 20 mmol), copper iodide (0.119 g,
5
0
1
4
.0 mmol), 1,3-di(pyridin-2-yl)propane-1,3-dione (10.0 mmol),
-haloacetophenone (10.0 mmol) and DMF (15 mL) was stirred for
Experimental
Chemistry
30 min at room temperature under a nitrogen atmosphere. This was
followed by heating at 110 °C for 12–18 h. After the completion of the
reaction (as indicated by TLC), the contents were cooled to room
All the chemicals were purchased from Merck, BDH, Aldrich and
WAKO and were used without purification. EIMS was recorded on

2
02 JOURNAL OF CHEMICAL RESEARCH 2016
temperature and passed through a plug of Celite. The filtrate was diluted
with ethyl acetate (50 mL) and washed three times with saturated
brine (10 mL each time). Treatment of the organic layer with activated
charcoal and evaporation of the solvent under vacuum afforded the
(21.43), 307.1 (100.00), 275.0 (14.15), 171.1 (49.42), 116.0 (40.91);
1
H NMR (CDCl ): δ 8.15 (d, 2H, J = 7.6 Hz), 7.95 (s, 1H), 7.90 (d, 1H,
3
J = 16.1 Hz), 7.67 (d, 1H, J = 16.1 Hz), 7.54 (d, 2H, J = 7.7 Hz), 7.39
(d, 2H, J = 8.0 Hz), 7.35 (t, 1H, J = 1.8 Hz), 7.21 (d, 2H, J = 8.2 Hz);
2
2
°
13
product: Yield (see Table 1); m.p. 115–116 °C (lit. 114–116 C).
C NMR (CDCl ): δ 188.4, 143.3, 138.0, 136.5, 136.2, 133.7, 132.9,
3
1
31.6, 130.5, 129.9, 129.6, 129.0, 128.4, 127.2, 124.0, 123.3, 122.8,
Synthesis of 1-[4-(1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-
ones 4a–o; general procedure
121.4. Anal. calcd for C H Cl N O: C, 62.99; H, 3.52; N, 8.16; found:
18
12
2
2
C, 65.01; H, 3.55; N, 8.11%.
-(2-Fluorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-
one (4f): Off-white powder; yield 60%; m.p. 140–141 °C; IR (KBr):
A methanolic sodium hydroxide solution (10%; 10.0 mL) was added
drop-wise to a mixture of 1-(4-(1H-imidazol-1-yl)phenyl)ethanone
3
(
(
3) (10.0 mmol, 1.86 g), aromatic aldehyde (10.0 mmol) and methanol
50 mL) over a period of 30–40 min with continuous stirring at room
–1
3114, 1662, 1510, 648 cm ; EIMS m/z (%): 293.0 (22.03), 292.0
(100.00), 291.1 (32.91), 225.0 (27.48), 171.1 (49.06), 116.0 (41.36),
temperature until completion of the reaction (as indicated by TLC).
The reaction flask was kept in the freezer overnight. The obtained
precipitates were filtered off and washed with a cold methanol–
water mixture (1:10). Finally the product was purified by column
1
102.1 (10.89), 101.0 (63.08); H NMR (CDCl ): δ 8.15 (d, 2H, J = 7.8
3
Hz), 7.95 (s, 1H), 7.93 (d, 1H, J = 15.8 Hz), 7.65 (d, 1H, J = 15.8 Hz),
7.62 (d, 1H, J = 6.7 Hz), 7.53 (d, 2H, J = 8.6 Hz), 7.40 (m, 2H), 7.20
13
(m, 3H); C NMR (CDCl ): δ 189.3, 142.8, 140.1, 136.2, 133.8, 132.9,
3
chromatography using CHCl :MeOH (97:3) as a solvent.
3
131.2, 129.4, 128.0, 124.8, 124.2, 123.8, 123.6, 122.8, 122.4, 119.8,
18.2, 116.1. Anal. calcd for C H BrN O: C, 61.21; H, 3.71; N, 7.93;
3
-(2-Chlorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-
1
18
13
2
one (4a): Light yellow powder; yield 57%; m.p. 136–137 °C; IR (KBr):
found: C, 61.29; H, 3.73; N, 7.98%.
3-(3-Bromophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-
one (4g): Yellow powder; yield 89%; m.p. 171 °C; IR (KBr): 3106, 1652,
–1 1
3
106, 1662, 1509, 642 cm ; H NMR (CDCl ): δ 8.15 (d, 2H, J = 7.8
3
Hz), 7.95 (s, 1H), 7.78 (d, 1H, J = 15.6 Hz), 7.63 (t, 1H, J = 6.9 Hz),
13
7
.54 (m, 5H), 7.40 (m, 3H); C NMR (CDCl ): δ 188.5, 143.9, 140.8,
–1
3
1510, 643 cm ; EIMS m/z (%): 354.9 (8.71), 353.9 (38.63), 353.0 (20.25),
136.7, 136.6, 135.2, 131.3, 131.0, 130.5, 129.2, 128.1, 127.1, 126.5,
3
52.0 (37.82), 273.1 (44.46), 171.1 (39.21), 116.1 (45.79), 102.1 (100.00);
124.0, 123.0, 122.6 , 121.5, 121.0; EIMS m/z (%): 310.9 (7.98), 310.0
1
H NMR (CDCl ): δ 8.15 (dd, 2H, J = 1.7 Hz, 8.8 Hz), 7.95 (s, 1H), 7.80
3
(34.72), 309.0 (33.30), 308.0 (100.00), 307.0 (41.52), 273.1 (48.26),
(t, 1H, J = 1.5 Hz), 7.77 (d, 1H, J = 15.7 Hz), 7.55 (m, 5H), 7.36 (t, 1H,
2
41.0 (26.71), 171.1 (56.79), 143.1 (27.88), 137.0 (29.56), 116.0 (52.79),
13
J = 1.2 Hz), 7.31 (t, 2H, J = 7.8 Hz); C NMR (CDCl ): δ 189.4, 144.3,
143.8, 137.4, 137.0, 136.3, 131.7, 131.2, 130.8, 130.6, 130.4, 129.2, 128.6,
3
1
02.1 (52.30). Anal. calcd for C H ClN O: C, 70.02; H, 4.24; N, 9.07;
18
13
2
found: C, 70.01; H, 4.29; N, 9.16%.
-(3-Chlorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-
one (4b): Yellow powder; yield 64%; m.p. 138–139 °C; IR (KBr): 3125,
1
25.8, 123.6, 123.0, 121.6, 120.8. Anal. calcd for C H BrN O: C, 61.21;
18
13
2
3
H, 3.71; N, 7.93; found: C, 61.13, H, 3.76, N, 7.96%.
3
-(4-Fluorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-
–1
1662, 1529 cm ; EIMS m/z (%): 311.0 (7.34), 310.0 (34.89), 309.0
1-one (4h): Colourless solid; yield 51%; m.p. 149 °C; IR (KBr): 3116,
(
1
34.62), 308.0 (100.00), 273.1 (47.95), 241.0 (22.44), 171.1 (57.20),
–1
1659, 1526, 644 cm ; EIMS m/z (%): 293.9 (3.73), 293.0 (19.79), 292.0
1
37.0 (26.93), 116.0 (46.90), 102.1 (50.58); H NMR (CDCl ): δ 8.13
3
(100.00), 291.0 (36.10), 225.0 (33.71), 196.0 (11.87), 171.1 (38.30),
(d, 2H, J = 8.6 Hz), 8.02 (d, 1H, J = 15.8 Hz), 7.94 (s, 1H), 7.56 (d,
1
116.0 (38.10), 102.1 (10.83), 101.0 (56.74); H NMR (CDCl ): δ 8.14
3
1H, J = 15.8 Hz), 7.52 (t, 2H, J = 8.7 Hz), 7.38 (d, 1H, J = 8.7 Hz),
(dd, 2H, J = 6.8 Hz, 1.8 Hz), 7.95 (s, 1H), 7.82 (d, 1H, J = 15.6 Hz),
7
.35 (t, 1H, J = 1.8 Hz), 6.73 (d, 1H, J = 8.8 Hz), 3.94 (s, 3H), 3.90
7.66 (dd, 2H, J = 9.2 Hz, 1.9 Hz), 7.54 (d, 2H, J = 7.7 Hz), 7.46 (d, 1H,
13
(s, 3H), 3.88 (s, 3H); C NMR (CDCl ): δ 188.3, 143.6, 143.1, 138.6,
13
3
J = 15.6 Hz), 7.35 (t, 1H, J = 1.9 Hz), 7.13 (t, 3H, J = 7.7 Hz); C NMR
CDCl ): δ 189.0, 142.2, 140.0, 136.1, 134.0, 132.8, 131.0, 129.2, 128.0,
134.7, 131.2, 129.5, 129.1, 128.0, 127.1, 125.3, 123.3, 123.1, 122.0, 121.5,
(
3
1
20.2, 119.8, 117.3. Anal. calcd for C H ClN O: C, 70.02; H, 4.24; N,
18
13
2
125.0, 124.4, 123.7, 123.3, 122.6, 122.2, 119.6, 118.0, 116.0. Anal. calcd
for C H FN O: C, 73.96; H, 4.48; N, 9.58; found: C, 73.93, H, 4.57, N,
9
.07; found: C, 69.91; H, 4.31; N, 9.01%.
-(4-Chlorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-
-one (4c): Colourless solid; yield 58%; m.p. 135–136 °C; IR (KBr):
18
13
2
3
9
.59%.
-[4-(1H-Imidazol-1-yl)phenyl]-3-(3-nitrophenyl)prop-2-en-1-one
4i): Off-white powder; yield 86%; m.p. 159–160 °C; IR (KBr): 3128,
1
1
–1
3
(
1
124, 1660, 1519, 650 cm ; EIMS m/z (%): 310.0 (34.93), 308.0
100.00), 307.0 (44.78), 273.1 (29.82), 241.0 (28.83), 186.1 (6.99),
71.1 (59.40), 143.1 (29.62), 137.1 (35.29), 116.0 (56.08), 102.1 (49.54);
(
–1
1661, 1512, 640 cm ; EIMS m/z (%): 321.0 (3.44), 320.0 (23.12), 319.0
(100.00), 291.0 (14.65), 252.0 (16.07), 171.1 (79.77), 143.1 (28.07),
1
1
H NMR (CDCl ): δ 8.14 (d, 2H, J = 7.0 Hz), 7.95 (s, 1H), 7.80 (d, 1H,
116.1 (45.05), 102.1 (41.04); H NMR (CDCl ): δ 8.52 (t, J = 1.5 Hz),
3
3
J = 15.6 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.53 (d, 2H, J = 8.6 Hz), 7.50 (d,
8.27 (dd, 1H, J = 1.3 Hz, 8.1 Hz), 8.18 (d, 2H, J = 8.5 Hz), 8.08 (d, 1H,
J = 8.6 Hz), 7.96 (d, 1H, J = 15.5 Hz), 7.91 (t, 2H, J = 7.5 Hz), 7.85 (s,
1H), 7.66 (d, 1H, J = 15.3 Hz), 7.62 (d, 1H, J = 7.4 Hz), 7.55 (d, 1H, J
= 6.8 Hz), 7.37 (t, 1H, J = 1.3 Hz); C NMR (CDCl ): δ 188.2, 149.0,
142.5, 141.8, 136.6, 136.4, 134.7, 132.6, 130.9, 130.4, 127.2, 125.0,
1
H, J = 15.6 Hz), 7.40 (d, 2H, J = 8.5 Hz), 7.35 (t, 1H, J = 7.2 Hz), 7.24
13
(s, 1H); C NMR (CDCl ): δ 189.7, 144.2, 143.0, 136.9, 136.8, 133.3,
3
13
132.5, 130.7, 130.3, 129.5, 128.6, 128.4, 127.1, 126.8, 124.0, 123.1,
3
1
22.7, 121.0. Anal. calcd for C H ClN O: C, 70.02; H, 4.24; N, 9.07;
18
13
2
found: C, 70.15; H, 4.30; N, 9.02%.
-(2,4-Dichlorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-
-en-1-one (4d): Yellow powder; yield 76%; m.p. 169–170 °C; IR
124.0, 123.8, 122.6, 122.1, 121.0, 120.9. Anal. calcd for C H N O : C,
67.71; H, 4.10; N, 13.16; found: C, 67.70, H, 4.14, N, 13.10%.
18
13
3
3
3
2
1-[4-(1H-Imidazol-1-yl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one
(4j): Colourless solid; yield 47%; m.p. 202–204 °C; IR (KBr): 3112,
–1
(
KBr): 3116, 1656, 1508, 648 cm ; EIMS m/z (%): 342.0 (6.26), 308.0
–1
(
(
100.00), 273.1 (29.82), 241.0 (28.83), 186.1 (6.99), 171.1 (59.46), 143.1
1648, 1521, 644 cm ; EIMS m/z (%): 321.0 (3.48), 320.0 (22.79), 319.0
1
29.62), 137.1 (35.29), 116.0 (56.08), 102.1 (49.54); H NMR (CDCl ): δ
(100.00), 318.0 (10.48), 272.0 (20.03), 252.0 (18.94), 171.1 (72.29),
3
1
8
.14 (d, 2H, J = 8.8 Hz), 8.10 (d, 1H, J = 15.1 Hz), 7.95 (s, 1H), 7.69 (d,
116.0 (57.52), 102.1 (52.32); H NMR (CDCl ): δ 8.29 (d, 2H, J = 8.7
3
1H, J = 8.5 Hz), 7.54 (d, 2H, J = 8.9 Hz), 7.51 (d, 1H, J = 6.9 Hz), 7.47
Hz), 8.17 (d, 2H, J = 8.6 Hz), 7.96 (s, 1H), 7.87 (d, 1H, J = 15.7 Hz),
(
8
d, 1H, J = 15.6 Hz), 7.36 (t, 1H, J = 6.9 Hz), 7.31 (dd, 2H, J = 1.9 Hz,
7.80 (d, 3H, J = 8.7 Hz), 7.64 (d, 1H, J = 15.7 Hz), 7.56 (d, 2H, J =
13
13
.4 Hz); C NMR (CDCl ): δ 188.6, 140.2, 137.0, 136.5, 136.3, 133.8,
5.6 Hz), 7.36 (t, 1H, J = 4.9 Hz); C NMR (CDCl ): δ 189.0, 146.7,
3
3
132.4, 131.7, 130.4, 129.8, 129.2, 128.8, 127.8, 124.5, 123.3, 123.0,
143.0, 142.8, 139.5, 137.0, 135.7, 131.4, 131.0, 129.0, 125.6, 125.4, 123.0,
1
21.4, 121.1. Anal. calcd for C H Cl N O: C, 62.99; H, 3.52; N, 8.16;
122.5, 122.1, 121.8, 121.5, 121.2. Anal. calcd for C H N O : C, 67.71;
18
12
2
2
18 13
3
3
found: C, 63.06; H, 3.62; N, 8.09%.
-(2,6-Dichlorophenyl)-1-[4-(1H-imidazol-1-yl)phenyl]prop-
-en-1-one (4e): Light brown powder; yield 76%; m.p. 162–163 °C.
H, 4.10; N, 13.16; found: C, 67.78, H, 4.16, N, 13.12%.
3
1-[4-(1H-Imidazol-1-yl)phenyl]-3-(2-methoxyphenyl)prop-2-en-1-
one (4k): Light yellow powder; yield 67%; m.p. 127–128 °C; IR (KBr):
2
–1
–1
IR (KBr): 3106, 1665, 1508 cm ; EIMS m/z (%): 346.0 (5.10), 345.0
6.33), 344.0 (30.63), 343.0 (10.72), 342.0 (45.15), 309.0 (34.45), 308.0
3110, 1648, 1510, 641 cm ; EIMS m/z (%): 304.1 (6.66), 274.0 (21.50),
1
(
273.0 (100.00), 171.1 (10.94), 116.0 (21.85), 102.1 (5.80); H NMR

JOURNAL OF CHEMICAL RESEARCH 2016 203
(
CDCl ): δ 8.14 (dd, 3H, J = 1.9 Hz, 8.6 Hz), 7.94 (s, 1H), 7.63 (d, 2H,
Anti-leishmanial activity
3
J = 7.4 Hz), 7.61 (d, 1H, J = 14.0 Hz), 7.52 (d, 2H, J = 8.5 Hz), 7.40 (dd,
H, J = 1.5 Hz, 7.8 Hz), 7.36 (d, 1H, J = 13.6 Hz), 6.95 (m, 2H), 3.91
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 mg of penicillin and streptomycin respectively in a shaking
1
13
(
s, 3H); C NMR (CDCl ): δ 189.0, 162.0, 145.6, 145.0, 137.8, 137.2,
3
130.2, 130.0, 127.4, 124.5, 123.6, 123.4, 121.8, 121.5, 120.9, 119.8,
21
1
19.2, 114.7, 55.6. Anal. calcd for C H N O : C, 74.98; H, 5.30; N,
incubator. Each compound (1 mg) 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 1 g phase were centrifuged at 3000 rpm
for 3 min. Parasites were diluted in fresh culture medium to a final
19
16
2
2
9
.20; found: C, 75.05, H, 5.35, N, 9.15%.
-[4-(1H-Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)prop-2-en-
-one (4l): Colourless solid; yield 77%; m.p. 158 °C; IR (KBr): 3103,
1
1
–1
6
1658, 1510 cm ; EIMS m/z (%): 305.9 (4.01), 305.1 (22.17), 304.1
density of 2 × 10 cells/mL. In 96-well plates, 180 mL of medium was
(
(
100.00), 303.1 (36.12), 289.1 (16.30), 273.1 (13.18), 196.0 (4.04), 116.0
added in different wells. The experimental compound (20 mL) was
added to the medium and serially diluted. Parasite culture (100 mL)
was added to 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 h at 24 °C. The culture was examined
microscopically on an improved Neubaur counting chamber and
IC50 values of compounds possessing anti-leishmanial activity were
calculated. All the assays were run in duplicate and the data obtained
are represented as mean ± S.D. The data were statistically analysed
by one-way ANOVA, followed by Tukey’s multiple comparison test.
The IC50 (minimum concentration necessary for inhibition of 50% of
microorganism growth) values were calculated using sigmoid dose–
response curves.
1
23.67), 102.1 (7.78); H NMR (CDCl ): δ 8.13 (dd, 2H, J = 1.7 Hz,
3
6
.8 Hz), 7.94 (s, 1H), 7.83 (d, 1H, J = 15.6 Hz), 7.61 (d, 2H, J = 8.7
Hz), 7.52 (d, 2H, J = 7.0 Hz), 7.41 (d, 1H, J = 15.5 Hz), 7.35 (t, 1H,
13
J = 1.7 Hz), 6.94 (d, 2H, J = 8.7 Hz), 3.85 (s, 3H); C NMR (CDCl ):
3
δ 188.9, 161.8, 145.2, 144.8, 137.5, 137.0, 130.1, 130.2, 127.2, 124.3,
123.3, 123.2, 121.8, 121.2, 121.0, 120.0, 119.4, 114.9, 55.4. Anal. calcd
for C H N O : C, 74.98; H, 5.30; N, 9.20; found: C, 75.03, H, 5.33, N,
19
16
2
2
9
.26%.
-[4-(1H-Imidazol-1-yl)phenyl]-3-(2,4-dimethoxyphenyl)prop-2-
en-1-one (4m): Yellow crystalline solid; yield 63%; m.p. 158–159 °C;
1
–1
IR (KBr): 3126, 1658, 1519, 650 cm ; EIMS m/z (%): 334.1 (22.88),
04.1 (22.97), 303.1 (100.00), 171.1 (10.59), 116.0 (17.86), 102.1 (4.13);
3
1
H NMR (CDCl ): δ 8.13 (d, 2H, J = 8.7 Hz), 8.08 (d, 1H, J = 15.7
3
Hz), 7.94 (s, 1H), 7.57 (t, 2H, J = 8.6 Hz), 7.54 (d, 1H, J = 15.0 Hz),
Anti-fungal activity
7
8
.51 (d, 2H, J = 8.2 Hz), 7.35 (t, 1H, J = 6.8 Hz), 6.55 (dd, 1H, J = 2.2,
.5 Hz), 6.47 (d, 1H, J = 2.3 Hz), 3.90 (s, 3H), 3.85 (s, 3H); C NMR
13
The assay for anti-fungal activity was performed in sterile 96-well
microplates according to the reported method,
2
5,26
which is based on
(
CDCl ): δ 189.7, 163.5, 160.7, 141.5, 137.8, 136.5, 130.6, 130.4, 128.3,
3
the principle that the microbial cell number is directly proportional
to the microbial growth. This proceeds in the log phase resulting in
increased absorbance of broth medium. The fungal strains used for the
experiments were obtained from the Department of Pathology, Quaid-
e-Azam Medical College Bahawalpur. The organisms were maintained
on stock sabroud dextrose agar culture before use. The test sample
solutions, standard drug (clotrimazole) and their dilutions were pipetted
into the wells (20 µg/well) along with the overnight maintained fresh
fungal culture (180 µL). The initial absorbance of the culture was strictly
maintained between 0.12–0.19 at 405 nm. The total volume in each well
was kept to 200 µL, while incubation was carried out at 28 °C for 72 h
with lids on the microplates. The absorbance was measured at 405 nm
using a Synergy HT BioTek USA microplate reader before and after
incubation and the difference was noted as an index of fungal growth.
The percent inhibition was calculated using the formula:
1
24.4, 123.2, 122.9, 119.9, 119.8, 113.2, 105.7, 98.6, 55.8, 55.7. Anal.
calcd for C H N O : C, 71.84; H, 5.43; N, 8.38; found: C, 71.89, H,
2
0
18
2
3
5.49, N, 8.44%.
1-[4-(1H-Imidazol-1-yl)phenyl]-3-(2,3,4-trimethoxyphenyl)prop-
2
-en-1-one (4n): Pale yellow powder; yield 80%; m.p. 134–135 °C;
–1
IR (KBr): 3101, 1658, 1520 cm ; EIMS m/z (%): 364.1 (4.40), 334.0
1
(
22.66), 333.0 (100.00), 171.1 (8.82), 116.0 (11.29); H NMR (CDCl ):
3
δ 8.13 (d, 2H, J = 8.6 Hz), 8.02 (d, 1H, J = 15.8 Hz), 7.94 (s, 1H), 7.56
d, 1H, J = 15.8 Hz), 7.52 (t, 2H, J = 8.7 Hz), 7.38 (d, 1H, J = 8.7 Hz),
.35 (s, 1H), 6.73 (d, 1H, J = 8.8 Hz), 3.94 (s, 3H), 3.90 (s, 3H), 3.88
(
7
13
(s, 3H); C NMR (CDCl ): δ 189.4, 156.3, 153.9, 142.7, 142.5, 137.6,
3
136.0, 134.4, 133.8, 133.6, 124.0, 123.8, 122.9, 120.9, 120.8, 112.9,
107.8, 61.6, 61.1, 56.4. Anal. calcd for C H N O : C, 69.22; H, 5.53; N,
21
21
2
4
7
.69; found: C, 69.42, H, 5.63, N, 7.76%.
,3-Bis[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-one (4o): Off
white powder; yield 76%; m.p. 202–203 °C; IR (KBr): 3109, 1663,
1
Inhibition (%) = 100 (X – Y) / X
–1
1518 cm ; EIMS m/z (%): 342.0 (5.29), 341.1 (24.78), 340.1 (100.00),
2
73.1 (31.37), 197.1 (22.50), 171.0 (42.09), 116.1 (51.26), 102.1
where X is the absorbance in the control with fungal culture and Y is
the absorbance in the test sample.
1
(
(
29.07); H NMR (CDCl ): δ 8.16 (dd, 2H, J = 7.0 Hz, 1.6 Hz), 7.95
s, 1H), 7.86 (d, 1H, J = 15.7 Hz), 7.77 (d, 2H, J = 8.5 Hz), 7.55 (d, 2H,
3
All the results were calculated as the mean of triplicate
measurements (n = 3, ± SD) and the minimum inhibitory concentration
(MIC) was measured with suitable dilutions (10–30 µg/well). Results
were calculated using EZ-Fit5 (Perrella Scientific Inc. Amherst USA)
software and data expressed as IC .
J = 2.1 Hz), 7.52 (d, 1H, J = 13.6 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.36
13
(
(
s, 1H), 7.32 (t, 1H, J = 1.2 Hz), 7.22 (d, 2H, J = 4.8 Hz); C NMR
CDCl ): δ 189.4, 141.1, 139.9, 138.2, 138.0, 136.8, 135.9, 134.0, 131.3,
3
131.4, 126.9, 126.7, 124.6, 124.3, 123.2, 122.9, 122.7, 121.6, 121.4,
5
0
1
20.8, 120.6. Anal. calcd for C H N O: C, 74.10; H, 4.74; N, 16.46;
21
16
4
found: C, 74.18, H, 4.78, N, 16.54%.
Conclusion
Prompted by the well-established anti-leishmanial and anti-
fungal properties of imidazoles and chalcones, a series of novel
X-ray crystallography
Crystals of the compound 1-[4-(1H-imidazol-1-yl)phenyl]-3-
2,3,4-trimethoxyphenyl)prop-2-en-1-one (4n) were grown by
1-[4-(1H-imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones
(
4
a–o were synthesised emphasising, in particular, the strategy
slow evaporation from methanol solution at room temperature. The
colourless crystal was mounted in a random orientation on a glass fibre
in a Stoe IPDS-II two circle diffractometer equipped with graphite
monochromated MoKα radiation (λ = 0.71073 Å). The data were
corrected for Lorentz and polarisation effects and for absorption using
the multi-scan method. The structure was solved by direct methods
using SHELXS-97 and was refined using full-matrix least-squares
of combining two chemically different but pharmacologically
compatible pharmacophores in one frame. The title compounds
weresynthesisedbythecondensationofaseriesofbenzaldehydes
with 1-[4-(1H-imidazol-1-yl)phenyl]ethanone and were assayed
for their anti-leishmanial and anti-fungal activities. Biological
evaluation revealed that some of the compounds obtained were
found to be active and could be useful as a template for further
development through modification or derivatisation to design
more potent biologically active compounds.
2
24
methods on F with SHELXL-97. All non-hydrogen atoms were
refined anisotropically, while hydrogen atoms were located with a
difference map and refined using a riding model.

2
04 JOURNAL OF CHEMICAL RESEARCH 2016
1
1
2
3
D. Bhakuni and R. Chaturvedi, J. Nat. Prod., 1984, 47, 585.
J. Vaya, P.A. Belinky and M. Aviram, Free Radical Biol. Med., 1997, 23,
This work was supported by grants from the Higher Education
Commission, Pakistan and the University of the Punjab, Lahore.
We also acknowledge the International Centre for Chemical
and Biological Sciences, HEJ, Research Institute of chemistry,
University of Karachi for spectral analyses and biological
testing.
3
02.
14
M. Chen, T.G. Theander, S. Christensen, L. Hviid, L. Zhai and A.
Kharazmi, Antimicrob. Agents Chemother., 1994, 38, 1470.
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15
16
T. Hussain, H.L. Siddiqui, M. Zia-ur-Rehman, M.M. Yasinzai and M.
Parvez, Eur. J. Med. Chem., 2009, 44, 4654.
Received 18 December 2015; accepted 2 February 2016
Paper 1503785 doi: 10.3184/174751916X14569208466251
Published online: 18 March 2016
1
7
E.M. Guantai, K. Ncokazi, T.J. Egan, J. Gut, P.J. Rosenthal, R.
Bhampidipati, A. Kopinathan, P.J. Smith and K. Chibale, J. Med. Chem.,
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