Novel aryloxy azolyl chalcones with potent activity against Mycobacterium tuberculosis H37Rv

Article abstract of DOI:10.1016/j.ejmech.2011.06.037

A series of twenty seven novel aryloxy azolyl chalcones were synthesized and evaluated in vitro for the growth inhibition of Mycobacterium tuberculosis H37Rv. Ten compounds from this series exhibited good activity with MIC in the range of 3.12-0.78 μg/mL

Full text of DOI:10.1016/j.ejmech.2011.06.037

European Journal of Medicinal Chemistry 46 (2011) 4302e4310
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel aryloxy azolyl chalcones with potent activity against Mycobacterium
tuberculosis H37Rv
Vijay K. Marrapu a, Vinita Chaturvedi b, Shubhra Singh b, Shyam Singh b, Sudhir Sinha b,
,
Kalpana Bhandari a
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226001, India
b Drug Target Discovery and Development Division, Central Drug Research Institute, CSIR, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of twenty seven novel aryloxy azolyl chalcones were synthesized and evaluated in vitro for the
growth inhibition of Mycobacterium tuberculosis H37Rv. Ten compounds from this series exhibited good
activity with MIC in the range of 3.12e0.78 mg/mL and six of them were found non-toxic against VERO
cells and MBMDMøs (mouse bone-marrow derived macrophages), were further evaluated ex-vivo for
their potential to kill intracellular bacilli. Two compounds 4 and 19 showed 99% and 71% killing
respectively, of intracellular bacilli in MBMDMøs infection model. Further, compound 19, an imidazolyl
chalcone with a 2,4-difluorobenzyloxy moiety also exhibited moderate in vivo activity in mice against
virulent M. tuberculosis, thus providing a new structural lead towards TB drug development.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Received 25 March 2011
Received in revised form
14 June 2011
Accepted 27 June 2011
Available online 3 July 2011
Keywords:
Chalcones
Aryloxy azoles
Anti-tubercular
Isoniazid
1. Introduction
and is a major cause of death among HIV/AIDS patients. The
emergence of multidrug-resistant (MDR) strains and the increasing
Tuberculosis is largely a disease of poverty with the highest
cases of the disease occurring in Africa and Asia. The drugs for
treatment of tuberculosis have been available for nearly 50 years,
still TB remains a global health crisis, killing nearly two million
people each year (one person dies every 10 s) [1]. Tuberculosis (TB),
caused by Mycobacterium tuberculosis (M.tb), a facultative intra-
cellular bacillus, is the world’s number one killer among infectious
diseases and the leading cause of death among women of repro-
ductive age. The World Health Organization (WHO) has estimated
that one-third of the world’s population is infected with Myco-
bacterium tuberculosis [2]. Current TB treatment regimen DOTS
(directly observed therapy short-course) requires patients to take
a combination of three or four drugs, namely, isoniazid (INH),
rifampin (RMP), pyrazinamide (PZA), and ethambutol (EMB) (or
alternatively streptomycin (SM)), throughout a 6e12 month period.
The long treatment regimen, which is necessary due to the pres-
ence of a nonreplicating persistent M.tb phenotype (NRP-TB) [3],
results in poor patient compliance, causes undesired side effects,
and makes a significant contribution to the emergence of drug
resistant M.tb strains [2,4]. TB is aggravated by the spread of HIV
prevalence of global human immunodeficiency virus (HIV), as
a frequent coinfection, have amplified the incidence of TB [5e7].
Though a number of lead molecules are known today and some of
them are at various stages of development [8], however no new
drug has been introduced in the past 40 years [9,10]. Hence, there is
an urgent need for affordable and effective alternative anti-TB
drugs with improved properties such as enhanced activity against
MDR strains, reduced toxicity and shortened duration of therapy.
Use of small molecules in the current treatment regimen
encouraged us to work on chalcone derivatives [11]. Further, the
appeal of working with chalcones (1,3-diarylprop-2-en-1-one) stems
from their synthetic accessibility, the various ways the core structure
can be diversified. Several reports have documented the wide range
of biological properties of natural and synthetic chalcones. They are
also cited as being antibacterial, with chemotherapeutic potential
against M. tuberculosis H37Rv [12]. Licochalcone A (Fig.1), a chalcone
from the roots of Glycyrrhizae inflata, showed low MICs against three
of the species such as M. tuberculosis, Mycobacterium avium, and
Mycobacterium bovis [13]. On the other hand azoles are important as
heterocyclic components of many natural products, drugs, and bio-
logically active molecules [14]. They are also reported as potent
inhibitor of cell growth of M. bovis and Mycobacterium smegmatis,
two mycobacterial species which closely resemble M.tb [15]. Azole
* Corresponding author. Tel.: þ91 522 2262411x4379; fax: þ91 522 2623405.
E-mail address: bhandarikalpana@rediffmail.com (K. Bhandari).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.06.037

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
4303
antifungal drugs such as econazole and clotrimazole (Fig. 1) are also
proved to have anti-tubercular activities in mice [16].
Cl
Cl
O
In this context, we would like to mention our ongoing efforts
devoted to the synthesis of novel heterocyclics as anti-infective
agents. We have recently identified the antileishmanial effective-
ness of variously substituted aryloxy cycloalkyl, aryloxy arylalkyl
and aryloxy heteroaryl azoles [17]. We presumed that the azolyl
and aryloxyl portion of the molecule is crucial for the high activity.
Based on above reports and our interest on azole moiety has
induced us to extended our studies to the synthesis of some novel
chalcone analogues bearing these aryloxyl and the azolyl func-
tionalities (Fig. 1.; 3e13 and 16e27) as potential anti-mycobacterial
agents. In this communication we described the synthesis of hybrid
molecules consisting of chalcones and azoles (imidazoles or tri-
azoles) along with aryloxy moiety and highlighted their anti-
tubercular activity against M. tuberculosis H37Rv. For structure
activity relationship (SAR) studies, variously substituted aryloxy/
benzyloxy moieties were chosen and bis azolyl (28, 29), bis ben-
zyloxy (30) and monobenzyloxy (31) chalcones were also explored.
HO
OH
N
N
Econazole
O
OCH3
Licochalcone A
Cl
N
R1
R2
Cl
O
N
X
B
A
N
O
Clotrimazole
N
R1
R2
N
X
R1
R2
B
A
O
N
A
B
O
28-31
R1, R2= Benzyloxy, azole, H
16-27
O
2. Chemistry
Fig. 1. Representative anti-mycobacterials and target compounds.
A one-step ClaiseneSchmidt condensation was used to prepare
the chalcones linked with aryloxyl/benzyloxy and azolyl residues
(3e13 and 16e27). As shown in Scheme 1, the new chalcones 3e13,
OH
F
N
n
R1
X
+
X
+
N
H
OHC
R2
COCH3
ii
i
X=Cl, Br
n=0, 1
N
X
OHC
N
O
n
R1
1a-b
a; X=CH
2a-f
R2
b
; X=N
O
1
2
a
b
c
; n=1, R =3-Cl, R =H
; n=1, R =2-Cl, R =4-Cl
; n=1, R =2-Cl, R =5-Cl
d; n=1, R1=2-F, R2=4-F
e; n=1, R1=2-F, R2=5-F
1
2
1
2
iii
1
2
f
; n=0, R =2-NO2, R =4-CF3
R1
N
R2
N
O
X
n
O
3-14
1
2
3
1
2
; X= CH, n=1, R =3-Cl, R =H
9
; X= N, n=1, R =2-Cl, R =4-Cl
4; X= CH, n=1, R1=2-Cl, R2=4-Cl
2
10
; X= N, n=1, R1=2-Cl, R =5-Cl
5; X= CH, n=1, R1=2-Cl, R2=5-Cl
11; X= N, n=1, R1=2-F, R2=4-F
12; X= N, n=1, R1=2-F, R2=5-F
13; X= CH, n=0, R1=2-NO2, R2=4-CF3
1
2
6
7
8
; X= CH, n=1, R =2-F, R =5-F
1
2
; X= CH, n=1, R =2-F, R =4-F
1
2
; X= N, n=1, R =3-Cl, R =H
Scheme 1. Reagents and conditions: (i) dry K2CO3, DMF, 12e14 h, 110 ꢀC; (ii) t-BuOK, DMSO, 5e6 h, 5 ꢀCert; (iii) 10% NaOH-EtOH, 9e10 h, rt.

4304
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
bearing azole moiety and aryloxy/benzyloxy groups, were prepared
by the sodium hydroxide catalyzed condensation of appropriate 4-
azolylacetophenones (1aeb), with the required aryloxy aromatic
aldehydes (2aef) in moderate to high yield (59e86%). In this case,
the 4-azolylacetophenone precursor (1aeb) were obtained by
substitution of 4-fluoro acetophenone with imidazole/triazole. The
aryloxy/benzyloxy benzaldehydes (2aef) were prepared by alkyl-
ation of 4-hydroxy benzaldehydes with variously substituted aryl/
benzyl halides in the presence of t-BuOK in DMSO. Similarly the
chalcones 16e27 (Scheme 2) were obtained by condensation of the
appropriate aryloxy/benzyloxy acetophenones (14aef) with azo-
lylbenzaldehydes (15aeb). Condensation gave predominantly
single isomer. 1H NMR spectrometry indicated that the chalcone
products (3e13 and 16e27) to be as the E-stereoisomer
(JCH¼CH ¼ 15.4e16.8 Hz range). For SAR studies bis imidazolyl (28),
bis triazolyl (29), bis benzyloxy (30), monobenzyloxy (31) chal-
cones were also prepared from the respective acetophenones and
benzaldehydes (Fig. 2).
(DMSO) to make stocks and their working dilutions were also made
in DMSO. To 1.9 mL MB 7H10 agar medium (containing OADC
supplement), 0.1 mL of compound or DMSO (negative control) or
isoniazid (positive control) was added, mixed and allowed to
solidify as slants. Culture of M. tuberculosis H37Rv was harvested
from LowensteineJensen (LeJ) medium and its suspension was
made in normal saline containing 0.05% Tween-80. 10 ml of this
suspension (w105 bacilli) was inoculated into each tube and
incubated at 37 ꢀC for 4 weeks. The lowest concentration of
a compound which produced no visible bacterial growth was
considered as its minimal inhibitory concentration (MIC).
Compounds having MIC of ꢁ3.12
mg/mL were selected for further
development.
3.2. Assays for in vitro cytotoxicity against VERO cells and mouse
bone-marrow derived macrophages (MBMDMQs)
In vitro cytotoxicity of active compounds (having MIC ꢁ 3.12
mg/
mL) was measured using Vero cells and mouse bone-marrow
derived macrophages [19]. The cell suspensions were plated in
96-well tissue culture plates (20,000 cells/well) and incubated
overnight (37 ꢀC, 5% CO2) to allow their adherence. Test compounds
at different concentrations were added to the wells. A known toxic
compound was used as a positive control and DMSO was used as
3. Biological activity
3.1. In vitro screening of compounds using virulent strain of
M. tuberculosis
The ‘proportion method’ described by McClachy (1978) was
negative control. After 24 h incubation, 20 ml of MTS solution
adopted [18]. Test compounds were dissolved in dimethyl sulfoxide
(tetrazolium compound) was added to each well and incubated for
R1
N
F
HO
X
+
R2
X
N
+
n
OHC
H
O
x=Cl, Br
ii
i
n=0, 1
R1
N
N
O
n
X
R2
OHC
O
14a-f
15a-b
a; n=1, R1=3-Cl, R2=H
a
; X=CH
b; n=1, R1=2-Cl, R2=4-Cl
b
; X=N
1
2
c
d
e
; n=1, R =2-Cl, R =5-Cl
1
2
; n=1, R =2-F, R =4-F
iii
1
2
; n=1, R =2-F, R =5-F
f; n=0, R1=2-NO2, R2=4-CF3
N
R1
N
X
R2
O
16-27
O
16; X= CH, n=1, R1=3-Cl, R2=H
22; X= N, n=1, R1=2-Cl, R2=4-Cl
1
2
1
2
17
; X= CH, n=1, R =2-Cl, R =4-Cl
23
24
25
; X= N, n=1, R =2-Cl, R =5-Cl
1
2
1
2
18
; X= CH, n=1, R =2-Cl, R =5-Cl
; X= N, n=1, R =2-F, R =4-F
19; X= CH, n=1, R1=2-F, R2=4-F
20; X= CH, n=1, R1=2-F, R2=5-F
21; X= N, n=1, R1=3-Cl, R2=H
1
2
; X= N, n=1, R =2-F, R =5-F
26; X= CH, n=0, R1=2-NO2, R2=4-CF3
27; X= N, n=0, R1=2-NO2, R2=4-CF3
Scheme 2. Reagents and conditions: (i) t-BuOK, DMSO, 5e6 h, 5ꢀC-rt; (ii) dry K2CO3, DMF, 12e14 h, 110 ꢀC; (iii) 10% NaOH-EtOH, 9e10 h, rt.

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
Table 1
4305
O
O
N
N
X
In vitro and ex-vivo anti-mycobacterial activities of targeted compounds against
M. tuberculosis H37Rv.
Cl
Cl
N
N
X
O
S. no.
Comp.no.
aMIC(
against M.tb
m
g/mL)
bCytotoxicity
Vs. VERO
cIntracellular
killing
30
Cl
28
Cl
O
; X= CH
Vs. MBMDM
29; X= N
H37Rv
within
MBMDM
(ex-vivo)
R1
R2
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
3.12
3.12
12.50
3.12
0.78
12.50
25.00
>25.00
12.50
>25.00
12.50
6.25
T
ND
NT
ND
ND
NT
ND
ND
ND
ND
ND
ND
ND
NT
ND
NT
NT
NT
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
NT
ND
99%
ND
ND
<50%
ND
ND
ND
ND
ND
O
NT
ND
T
1
; R =2,4-dichlorobenzyloxy, R2 = H
31
Fig. 2. Bis azolyl and bis benzyloxy chalcones.
NT
ND
ND
ND
ND
ND
ND
ND
NT
T
NT
NT
NT
ND
ND
ND
T
ND
ND
ND
ND
ND
ND
NT
further 2 h (37 ꢀC, 5% CO2). O. D. was read at 490 nm using a plate
reader. A compound was considered as potentially toxic if its IC50
(concentration causing 50% loss in cell viability) was ꢁ10 times
its MIC.
10
11
12
13
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
INH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
ND
ND
1.56
3.12
1.56
3.12
<50%
ND
71%
<50%
<50%
ND
ND
ND
ND
ND
3.3. Use of ex-vivo (macrophage) model of TB
The macrophage model mimics growth environment of natural
0.78
infection. Effect of selected test compounds (non-toxic, MIC ꢁ 3.12
mg/
>25.00
>25.00
12.50
3.12
12.50
12.50
>25.00
>25.00
>25.00
12.50
0.025
mL) on the survival and multiplication of M. tuberculosis H37Rv
within mouse bone-marrow derived macrophages was evaluated as
per described protocol [20] (Tuberculosis Drug Screening Program,
2001). 5-day old cultures of adherent macrophages (106 cells/well)
were infected (3 h) with 5 ꢂ 106 bacilli in 1 mL of antibiotic-free
medium. Later, the wells were washed to remove extra-cellular
bacteria and replenished with fresh antibiotic-free medium contain-
ing 4ꢂ MIC of standard drugs or test compounds. In order to deter-
mine the number of bacilli phagocytosed during the 3 h infection
period, cells in one well were lysed with 0.1% saponin and the lysate
plated on MB7H11 agar. Cells in other wells, after further 4 days of
incubation, were washed, lysed and plated on MB7H11 agar. All CFUs
were counted after 4 weeks of incubation at 37 ꢀC. Results were
expressed as percent reduction in intracellular CFU (100% ¼ CFU of
untreated, infected wells). An inhibition of ꢃ50% was considered as
positive.
ND
ND
ND
ND
ND
a
MIC ¼ Minimum inhibitory concentration, the lowest concentration of the
compound which inhibits the growth of mycobacterium >90%; MIC of the drugs
used as control (INH).
b
Non-toxic (at a dose of 10ꢂ MIC) against VERO and MBMDMø; ND ¼ not done.
c
Intracellular (ex-vivo) activity of non-toxic compounds against M. tuberculosis in
mouse bone-marrow derived macrophages at
a
concentration of 5ꢂ MIC;
INH ¼ Isoniazid, NT: non-toxic; T: Toxic (A compound is considered toxic if it causes
50% inhibition at concentration 10 fold higher than its MIC).
3.4. In vivo screening of compounds in mouse model of tuberculosis
compounds, showing anti-tubercular potential (MIC ꢁ 3.12
mg/mL),
was done against a mammalian cell line (VERO 1008) as well as
mouse bone-marrow derived macrophages. Six compounds were
considered non-toxic based on their selectivity index (SI ꢃ 10, ratio
of IC50 against mammalian cells and the MIC) and were evaluated
ex-vivo to determine their potential to kill intracellular bacilli. On
the basis of ex-vivo results (Table 1), two compounds were evalu-
ated for their protective efficacy against tuberculosis infection in
mouse model. Results revealed a marginal protective efficacy of
compound 19 as it reduced 40% infection load in the lungs of
infected mice with reference to untreated control (Table 2). The
poor in-vivo activity of compounds 4 and 19 is perhaps attributable
to one or more of the following reasons, (a) instability of the
compound in gastrointestinal tract, (b) poor absorption from the
intestine, (c) rapid biodegradation after absorption and (d) poor
bioavailability.
When infected with a high number of M. tuberculosis by i.v.
route, the mouse harbours a bacillary population that is similar in
number and metabolic state to that present in the lung cavity of
human TB [21,22]. Outbred Swiss mice were infected with
M. tuberculosis H37Rv (107 CFU/mouse, i.v.) and divided into groups
of 6e8 animals. Each experimental group received daily oral dose of
test compound (100 mg/kg body weight, for 28 days) dissolved in
a suitable vehicle (peanut oil). The drug-treated control groups
received isoniazid (25 mg/kg) for 28 days. The untreated control
group received only the vehicle. At least 3 mice from each group
were sacrificed on day 30 for determination of viable bacilli in the
lungs. Serial dilutions of lung homogenates were placed on
MB7H11 agar medium and colonies (CFU) were counted after 3e4
weeks of incubation at 37 ꢀC.
The in vitro biological activities of azole-appended chalcones
(3e13, 16e31) have shown encouraging results. Table 1 displays
the in vitro,cytotoxicity and ex-vivo activities of the synthesized
compounds against M. tuberculosis H37Rv. Some of the
compounds showed quite good in vitro anti-TB activity as indi-
4. Results and discussion
All the synthesized compounds were tested for their ability to
inhibit the growth of M. tuberculosis H37Rv by Agar-based
proportion Assay (Table 1). Out of twenty seven compounds
screened for their in vitro anti-tubercular activity against M.
tuberculosis H37Rv, nineteen compounds were found active with
cated by their low MICs, i.e., 0.78
m
g/mL (compound 7 and 21),
g/mL (compounds
1.56 g/mL (compounds 17 and 19), and 3.12
m
m
3, 4, 6, 18, 20 and 25). Further, the chalcones 3e13, with azolyl
MIC in the range of 12.5e0.78
m
g/mL (Table 1) and the rest were
moiety in ring A and aryloxyl moiety in ring B showed the MIC
with MIC >12.5 g/mL. Subsequently, cytotoxicity evaluation of 10
m
of 0.78e12.5 mg/mL. Surprisingly, on interchanging the positions

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V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
Table 2
Detailed in vivo efficacy of compounds 4, 19 and isoniazid against M. tuberculosis H37Rv in mice.
Comp.
In vitro
In vivo
MIC
(mg/mL)
On day 30
On day 40
%Survivors
Viable bacilli (CFUs) in
lungs (on day 30)
%Survivors
bMST
MST
[Per gm tissue]
% Inhibition
Control (no drug)
a4 (100 mg/kg)
a19 (100 mg/kg)
INH (25 mg/kg)
83
100
100
100
29.66
30.00
30.00
30.00
83
83
100
100
38.00
38.50
40.00
40.00
6.0 ꢂ 107
5.2 ꢂ 107
3.6 ꢂ 107
1.0 ꢂ 104
3.12
1.56
0.025
13
40
99.98
a
Non-toxic against mammalian cell line, VERO and mouse bone-marrow derived macrophages.
MST, mean survival time.
b
of these two functionalities (16e27), a similar MIC pattern was
available reagents. The compounds were evaluated against
M. tuberculosis H37Rv in vitro with impressive MIC values. Most of
the compounds with potent in vitro activities were found non-toxic
against VERO cell line and mouse derived macrophages. Two
compounds 4 and 19 showed good ex-vivo activity with 99% and
71% inhibition of growth of intracellular bacilli. Thus the newly
designed aryloxy azolyl chalcone derivatives represent a highly
potent and versatile series of anti-TB compounds and as such
present attractive lead compounds for further TB drug develop-
ment. Further studies on these compounds and optimization of its
structure leading to novel analogues with superior biological
properties are ongoing in our laboratory.
observed. However, chalcones with 4-imidazolyl moiety (3e7
and 16e20) were found to be more active than their triazolyl
counterparts (8e12 and 21e25) except compound 21 with 1,2,4-
triazolyl group in ring B and a 3-chloro benzyloxy group in ring
A showed a MIC value of 0.78 mg/mL. Replacement of the ben-
zyloxy group with aryloxy group (2-NO2, 4-CF3-aryloxy) in
compounds 13, 26 and 27 resulted in loss of activity with MIC
values of 12.5 mg/mL indicating that the presence of benzyloxy
group is essential for anti-tubercular activity. For SAR studies we
also prepared and evaluated the bis azolyl chalcones (Fig. 2, 28
and 29), however, the bis imidazolyl (28) and bis triazolyl (29)
derivatives were found inactive with MIC values >25 mg/mL. We
also explored the bis benzyloxy chalcone 30 and monobenzyloxy
chalcone 31. The activity in these compounds was also signifi-
6. Experimental
cantly dropped as both of them showed MIC ꢃ 12.5
mg/mL only.
These findings indicate that the occurrence of both the moieties,
the benzyloxy group and the imidazolyl group together is
necessary for the anti-tubercular activity.
All reagents were commercial and were used without further
purification. Chromatography was carried on silica gel
(60e120 mesh) or basic alumina (pH ¼ 9.5 ꢄ 5, 100 mesh). All
reactions were monitored by TLC (silica gel plates with fluorescence
F254 were used). Melting points were recorded on an electrically
heated melting point apparatus and are uncorrected. The 1H NMR
and 13C NMR spectra were determined on Bruker Advance DRX-
300 MHz spectrometer using TMS as an internal reference. All shifts
are given in ppm and multiplicity (s ¼ singlet, d ¼ doublet,
m ¼ multiplet). The electrospray mass spectra were recorded on
a Thermo Finnigan LCQ Advantage max ion trap mass spectrometer.
IR spectra were recorded on Perkin Elmer AC-1 spectrophotometer
Interestingly, irrespective of substitution in the benzyloxy
moiety, compounds (7 and 21), (17 and 19) and (3, 4, 6, 18, 20 and
25) have shown equal potency with 0.78
3.12 g/mL MICs respectively. Out of these ten compounds, four
compounds viz. (3-chlorobenzyloxy), and 25 (2,5-
mg/mL, 1.56 mg/mL and
m
3
6
difluorobenzyloxy), 18 (2,5-dichlorobenzyloxy) were found to
be toxic in cytotoxicity assay against VERO cells and MBMDMQs.
The six non-toxic compounds 4, 7, 17, 19, 20 and 21 showing
potent in vitro activity were evaluated further for their intracel-
lular (ex-vivo) effect on CFU in mouse bone-marrow derived
macrophages. Among these, four of the chalcones 7, 17, 20 and 21
were found inactive as they reduced <50% of CFU count (Table 1).
Compound 4, with an imidazolyl moiety in ring A and a 2,4-
in the range of 400e4000 cmꢅ1
.
6.1. General procedure for the synthesis of compounds (1aeb and
15aeb)
dichlorobenzyloxy moiety in ring
B was the most active
compound as it led to an inhibition of 99% growth of intracellular
bacilli, while compound 19 (imidazolyl moiety in ring B and a 2,4-
difluorobenzyloxy moiety in ring A) displayed 71% inhibition. The
two promising compounds 4 and 19 were further evaluated for
their in vivo oral efficacy against M. tuberculosis H37Rv in mice and
the results are shown in Table 2. Among these, compound 19
exhibited moderate activity with a marginal protection of 40%
against virulent M. tuberculosis. It is apparent from the activity
results (Table 1) that the presence of both the substructures
benzyloxy as well as azolyl in A and B rings of chalcone molecule
is crucial for the anti-tubercular activity. Further, the benzyloxy
moiety with a 2,4-difluoro- and 2,4-dichloro- substituent should
be investigated for the development of highly selective anti-
tubercular compounds.
A
mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde
(10 mmol) and imidazole/triazole (10 mmol) were dissolved in
dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion
within a period of 15 min to the above stirred solution. Mixture was
stirred for 10e12 h at 110 ꢀC. Heating discontinued, K2CO3 was
filtered off, filtrate extracted with ethyl acetate (3 ꢂ 15 mL). Organic
layer was washed with water (3 ꢂ 15 mL), dried over anhydrous
sodium sulphate and concentrated to given an oil which was
purified on silica gel column (60e120 mesh) taking methanol:
chloroform (1:99) as an eluent.
6.1.1. 1-(4-(1H-imiazol-1-yl)phenyl)ethanone (1a)
With 4-fluoro acetophenone aþnd 1H-imidazole; Yield: 78%; M.P:
112e114 ꢀC; MS(ESI): 187 [M þ 1] ; IR (KBr): 3117, 2366, 2213,1668,
1604, 1523, 1266, 1058, 953, 738 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
5. Conclusion
d
2.64 (s, 3H), 7.25 (s,1H), 7.35 (s,1H), 7.53 (d, 2H, J ¼ 8.6 Hz), 7.96 (s,
In conclusion, we have identified a new cheap chalcone
molecular scaffold that can be easily prepared from commercially
1H), 8.09 (d, 2H, J ¼ 8.6 Hz); 13C NMR (CDCl3, 75 MHz,):
d 26.6, 117.7,
120.6, 130.3, 131.1, 135.3, 135.7, 140.7, 196.5.

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
4307
6.1.2. 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (1b)
J ¼ 8.7 Hz), 9.90 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d
66.7, 115.1,
With 4-fluoro acetophenone and 1H-1,2,4-triazole; Yield: 74%;
128.5, 129.3, 130.5, 130.6, 131.1, 132.0, 133.2, 135.5, 163.0, 190.7.
M.P: 142e143 ꢀC; MS(ESI): 188 [M þ 1]þ; IR (KBr): 3117, 2356, 1677,
1607, 1215, 759 cmꢅ1
;
1H NMR (CDCl3, 300 MHz):
d
2.62 (s, 3H),
6.2.4. 4-(2,4-Difluorobenzyloxy)benzaldehyde (2d)
7.81e7.84 (d, 2H, J ¼ 8.5 Hz), 8.09e8.12 (d, 2H, J ¼ 8.5 Hz), 8.13 (s,
With 4-hydroxy benzaldehyde and 2,4-difluorobenzyl bromide;
1H, triazole H), 8.70 (s, 1H, triazole H); 13C NMR (CDCl3, 75 MHz):
Yield: 73%; M.P: 76e77 ꢀC; MS(ESI): 249 [M þ 1]þ; IR (KBr): 3036,
d
26.4, 118.7, 121.8, 131.6, 133.3, 142.4, 152.9, 196.3.
2832, 2371, 1674, 1602, 1496, 1215, 1012, 852, 776 cmꢅ1 1H NMR
;
(CDCl3, 300 MHz):
J ¼ 8.7 Hz), 7.43e7.50 (m, 1H), 7.85 (d, 2H, J ¼ 8.7 Hz), 9.89 (s, 1H);
13C NMR (CDCl3, 75 MHz):
63.7, 115.3, 115.4, 116.1, 116.3, 117.3,
d 5.15 (s, 2H), 6.83e6.95 (m, 2H), 7.08 (d, 2H,
6.1.3. 4-(1H-imidazol-1-yl)benzaldehyde (15a)
With 4-fluoro benzaldehyde and 1H-imidazole; Yield: 76%; M.P:
d
147e148 ꢀC; MS(ESI): 173 [M þ 1]þ; IR (KBr): 3125, 2360, 1697,
130.7, 132.3, 156.9, 161.2, 163.2, 190.1.
1603, 1480, 1260, 1219, 771 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d 7.25
(s,1H, imidazole H), 7.39 (s,1H, imidazole H), 7.59 (d, 2H, J ¼ 12.2 Hz),
6.2.5. 4-(2,5-Difluorobenzyloxy)benzaldehyde (2e)
8.00e8.05 (m, 3H, ArH þ imidazole H), 10.04 (s, 1H); 13C NMR
With 4-hydroxy benzaldehyde and 2,5-difluorobenzyl bromide;
(CDCl3, 75 MHz): d 118.2, 121.7, 131.6, 140.1,135.6, 135.9, 142.3, 191.2.
Yield: 71%; M.P: 79e80 ꢀC; MS(ESI): 249 [M þ 1]þ; IR (KBr): 3084,
2856, 2366, 1690, 1602, 1493, 1258, 1038, 816, 721 cmꢅ1 1H NMR
;
6.1.4. 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (15b)
(CDCl3, 300 MHz):
J ¼ 8.7 Hz), 7.19e7.25 (m, 1H), 7.86 (d, 2H, J ¼ 8.7 Hz), 9.90 (s, 1H);
13C NMR (CDCl3, 75 MHz):
63.4, 115.0, 115.6, 115.9, 116.3, 116.7,
d 5.19 (s, 2H), 7.00e7.08 (m, 2H), 7.09 (d, 2H,
With 4-fluoro benzaldehyde and 1þH-1,2,4-triazole; Yield: 72%;
M.P: 146e147 ꢀC; MS(ESI): 174 [M þ 1] ; IR (KBr): 3123, 2363, 1704,
d
1600, 1517, 1438, 1204, 830 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d
7.92
130.5, 132.0, 157.6, 160.4, 163.0, 190.6.
(d, 2H, J ¼ 8.5 Hz), 8.05 (d, 2H, J ¼ 8.5 Hz), 8.16 (s, 1H, triazole H),
8.71 (s, 1H, triazole H), 10.08 (s, 1H, CHO); 13C NMR (CDCl3 þ CD3OD,
6.2.6. 4-(2-Nitro-4-(trifluoromethyl)phenoxy)benzaldehyde (2f)
With 4-hydroxy benzaldehyde and 1-chloro-2-nitro-4-(tri-
fluoromethyl)benzene; Yield: 77%; M.P: 82e83 ꢀC; MS(ESI): 312
[M þ 1]þ; IR (KBr): 3051, 2856, 2365, 1697, 1626, 1590, 1531, 1353,
75 MHz):
d 119.8, 131.3, 135.4, 140.8, 141.4, 152.5, 191.0.
6.2. General procedure for the synthesis of compounds 2aef and
14aef
1252, 1136, 1049, 902, 850 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d 7.12
(d, 1H, J ¼ 9.1 Hz), 7.27 (d, 2H, J ¼ 8.6 Hz), 8.00 (d, 2H, J ¼ 8.6 Hz),
To a stirred suspension of 4-hydroxy benzaldehyde/4-hydroxy
acetophenone (1 mmol) in dimethyl sulfoxide (DMSO) (5 mL) at
5e10 ꢀC was added potassium t-butoxide (1.2 mmol) was added in
small portions in the period of 10 min. After stirring of 30 min,
substituted benzyl/aryl halide (1 mmol) was added and then stir-
ring was continued at room temperature for 4e5 h. The reaction
mixture was quenched with ice cold water (5 mL) and extracted
with ethyl acetate (3 ꢂ 5 mL), the combined organic layers were
washed with water (3 ꢂ 5 mL) dried over Na2SO4 and concentrated
under reduced pressure to obtain the crude product which was
purified by column chromatography by using silica gel
(60e120 mesh) and ethyl acetate: Hexane (4:94) as eluent to give
the compounds (2a-f and 14a-f).
8.37e8.41 (m, 1H), 8.61 (d, 1H, J ¼ 2.6 Hz), 10.02 (s, 1H); 13C NMR
(CDCl3, 75 MHz):
d 119.4, 120.2, 121.7, 122.2, 123.9, 128.9, 132.2,
133.7, 142.7, 159.2, 159.3, 190.4.
6.2.7. 1-(4-(3-Chlorobenzyloxy)phenyl)ethanone (14a)
With 4-hydroxy acetophenone and 3-chlorobenzyl chloride; Yield:
73%; M.P: 91e93 ꢀC; MS(ESI): 261 [M þ 1]þ; IR (KBr): 3315, 3050, 2365,
1662, 1601, 1505, 1275, 1109, 1004, 785 cmꢅ1 1H NMR (CDCl3,
;
300 MHz):
d
2.54 (s, 3H), 5.08 (s, 2H), 6.98 (d, 2H, J ¼ 8.8 Hz), 7.30e7.42
(m, 4H), 7.92 (d, 2H, J ¼ 8.8 Hz); 13C NMR (CDCl3, 75 MHz):
d 26.3, 69.1,
114.5, 125.3, 127.3, 128.3, 129.9, 130.6, 130.7, 134.5, 138.3, 162.2, 196.6.
6.2.8. 1-(4-(2,4-Dichlorobenzyloxy)phenyl)ethanone (14b)
With 4-hydroxy acetophenone and 2,4-dichlorþobenzyl chloride;
Yield: 82%; M.P: 95e97 ꢀC; MS(ESI): 295 [M þ 1] ; IR (KBr): 3330,
6.2.1. 4-(3-Chlorobenzyloxy)benzaldehyde (2a)
With 4-hydroxy benzaldehyde and 3-chloroþbenzyl chloride;
Yield: 79%; M.P: 89e91 ꢀC; MS(ESI): 247 [M þ 1] ; IR (KBr): 3052,
2821, 2365, 1690, 1599, 1509, 1265, 1090, 827 cmꢅ1; 1H NMR (CDCl3,
3095, 2918, 1671, 1597, 1258, 1032, 834 cmꢅ1 1H NMR (CDCl3,
;
300 MHz):
d
2.56 (s, 3H), 5.18 (s, 2H), 7.00 (d, 2H, J ¼ 8.9 Hz),
7.26e7.30 (m, 1H), 7.43e7.48 (m, 2H), 7.95 (d, 2H, J ¼ 8.9 Hz); 13C
300 MHz):
7.43 (s, 1H), 7.82e7.86 (m, 2H), 9.88 (s, 1H); 13C NMR (CDCl3,
75 MHz): 69.3, 115.1, 125.3, 127.4, 128.4, 130.0, 130.3, 132.0, 134.6,
d
5.11 (s, 2H), 7.06 (d, 2H, J ¼ 8.7 Hz), 7.31e7.34 (m, 3H),
NMR (CDCl3, 75 MHz): d 26.4, 66.3, 114.4, 127.4, 129.3, 129.6, 130.6,
130.7, 132.6, 133.2, 134.4, 162.0, 196.8.
d
138.0, 163.3, 190.6.
6.2.9. 1-(4-(2,5-Dichlorobenzyloxy)phenyl)ethanone (14c)
With 4-hydroxy acetophenone and 2,4-dichlorobenzyl
bromide; Yield: 86%; M.P: 91e93 ꢀC; MS(ESI): 295 [M þ 1]þ; IR
(KBr): 3097, 2917, 2362, 1669, 1600, 1564, 1257, 1032, 833 cmꢅ1; 1H
6.2.2. 4-(2,4-Dichlorobenzyloxy)benzaldehyde (2b)
With 4-hydroxy benzaldehyde and 2,4-dichlorþobenzyl chloride;
Yield: 82%; M.P: 93e95 ꢀC; MS(ESI): 281 [M þ 1] ; IR (KBr): 3072,
NMR (CDCl3, 300 MHz):
J ¼ 12.4 Hz), 7.22e7.35 (m, 2H), 7.54 (s, 1H), 7.95 (d, 2H, J ¼ 12.4 Hz);
13C NMR (CDCl3, 75 MHz):
26.7, 67.0, 115.2, 127.8, 128.8, 129.5,
d 2.55 (s, 3H), 5.16 (s, 2H), 7.01 (d, 2H,
2824, 2357, 1669, 1595, 1254, 1031, 772 cmꢅ1 1H NMR (CDCl3,
;
300 MHz):
d
5.19 (s, 2H), 7.07 (d, 2H, J ¼ 8.6 Hz), 7.26e7.30 (m, 1H),
d
7.42e7.48 (m, 2H), 7.85 (d, 2H, J ¼ 8.6 Hz), 9.89 (s, 1H); 13C NMR
130.9, 131.1, 131.4, 133.5, 136.1, 162.3, 197.0.
(CDCl3, 75 MHz):
d 67.1, 115.5, 128.1, 129.6, 130.5, 130.7, 131.5, 131.9,
132.9, 136.2, 163.8, 190.1.
6.2.10. 1-(4-(2,4-Difluorobenzyloxy)phenyl)ethanone (14d)
With 4-hydroxy acetophenone and 2,4-difluorobenzyl bromide;
Yield: 68%; M.P: 85e87 ꢀC; MS(ESI): 263 [M þ 1]þ; IR (KBr): 3078,
2923, 2366, 1677, 1603, 1508, 1261, 960, 837 cmꢅ1; 1H NMR (CDCl3,
6.2.3. 4-(2,5-Dichlorobenzyloxy)benzaldehyde (2c)
With 4-hydroxy benzaldehyde and 2,5-dichlorobenzyl bromide;
Yield: 84%; M.P: 91e93 ꢀC; MS(ESI): 281 [M þ 1]þ; IR (KBr): 3074,
300 MHz):
d 2.58 (s, 3H), 5.16 (s, 2H), 6.85e6.90 (m, 1H), 6.91e6.97
2826, 2367, 1689, 1604, 1508, 1255, 1035, 863, 817 cmꢅ1
;
1H NMR
(m, 1H), 7.02 (d, 2H, J ¼ 8.9 Hz), 7.44e7.52 (m, 1H) 7.97 (d, 2H,
(CDCl3, 300 MHz):
(m, 1H), 7.35 (d, 1H, J ¼ 8.5 Hz), 7.54e7.55 (m, 1H), 7.87 (d, 2H,
d
5.20 (s, 2H), 7.10 (d, 2H, J ¼ 8.7 Hz), 7.24e7.28
J ¼ 8.9 Hz); 13C NMR (CDCl3, 75 MHz):
d 26.3, 67.2, 115.2, 126.9,
129.3, 129.8, 130.1, 131.3, 133.1, 159.2, 159.6, 162.3, 198.2.

4308
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
6.2.11. 1-(4-(2,5-Difluorobenzyloxy)phenyl)ethanone (14e)
(m, 3H), 7.46e7.50 (m, 1H), 7.57 (d, 1H, J ¼ 8.5 Hz), 7.69 (d, 1H,
J ¼ 2.5 Hz), 7.75 (d, 1H, J ¼ 15.4 Hz), 7.86e7.92 (m, 6H), 8.27e8.33
(m, 2H), 8.45 (s, 1H); Anal. Calcd. for C25H18Cl2N2O2 : C, 66.83; H,
4.04; N, 6.23; Found C, 66.91; H, 3.92; N, 6.29.
With 4-hydroxy acetophenone and 2,5-difluorobenzyl bromide;
Yield: 71%; M.P: 83e85 ꢀC; MS(ESI): 263 [M þ 1]þ; IR (KBr): 3010,
2928, 1684, 1506, 1210, 896, 787 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d
2.56 (s, 3H), 5.16 (s, 2H), 7.01 (d, 2H, J ¼ 8.9 Hz), 7.05e7.10 (m, 2H),
7.18e7.26 (m, 1H), 7.95 (d, 2H, J ¼ 8.9 Hz); 13C NMR (CDCl3,
6.3.4. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(2,4-difluorobenzy-
loxy)phenyl)prop-2-en-1-one (6)
75 MHz):
d 26.6, 67.5, 115.3, 125.7, 128.8, 129.4, 130.2, 131.6, 132.9,
158.8, 159.7, 162.4, 198.5.
With 1a and 2d; Yield: 68%; M.P: 168e169 ꢀC; MS(ESI): 417
[M þ 1]þ; IR (KBr): 3428, 3128, 2364, 1659, 1604, 1518, 1252, 1030,
6.2.12. 1-(20-nitro-40-(trifluoromethyl)biphenyl-4-yl)ethanone
(14f)
815 cmꢅ1 1H NMR (DMSO-d6, 300 MHz):
; d 5.19 (s, 2H), 7.11e7.16
(m, 4H), 7.27e7.35 (m, 1H), 7.61e7.69 (m, 1H), 7.75 (d, 1H,
J ¼ 15.4 Hz), 7.86e7.92 (m, 6H), 8.29 (d, 2H, J ¼ 8.7 Hz), 8.46 (s, 1H);
Anal. Calcd. for C25H18F2N2O2 : C, 72.11; H, 4.36; N, 6.73; Found C,
72.17; H, 4.43; N, 6.68.
With 4-hydroxy acetophenone and 1-chloro-2-nitro-4-(tri-
fluoromethyl)benzene; Yield: 73%; M.P: 72e73 ꢀC; MS(ESI): 326
[M þ 1]þ; IR (KBr): 3123, 3064, 2928, 2364, 1687, 1590, 1525, 1484,
1340, 1251, 1047, 858, 739 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d 2.62 (s,
3H), 7.02 (d, 1H, J ¼ 9.1 Hz), 7.17 (d, 2H, J ¼ 8.5 Hz), 8.06 (d, 2H,
6.3.5. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(2,5-difluorobenzy-
loxy)phenyl)prop-2-en-1-one (7)
J ¼ 8.5 Hz), 8.33e8.37 (m, 1H), 8.62 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d
26.5, 118.5, 119.4, 121.6, 122.0, 123.9, 128.8, 131.0, 134.6, 142.6, 158.2,
With 1a and 2e; Yield: 66%; M.P: 187e188 ꢀC; MS(ESI): 417
[M þ 1]þ; IR (KBr): 3468, 3129, 2359, 1653, 1596, 1513, 1223, 1032,
159.6, 196.4.
817 cmꢅ1 1H NMR (DMSO-d6, 300 MHz):
; d 5.17 (s, 2H), 7.02e7.11
6.3. General procedure for the synthesis of chalcones (3e13 and
16e31)
(m, 4H), 7.22e7.24 (m, 2H), 7.43 (d, 1H, J ¼ 15.5 Hz), 7.56e7.58 (m,
1H), 7.65 (d, 2H, J ¼ 8.6 Hz), 7.82 (d, 1H, J ¼ 15.5 Hz), 7.84e7.91 (m,
2H), 8.15e8.17 (m, 2H), 8.39 (s, 1H); Anal. Calcd. for C25H18F2N2O2 :
C, 72.11; H, 4.36; N, 6.73; Found C, 72.14; H, 4.31; N, 6.76.
A mixture of azolyl ketone (1a/1b) (1 mmol) and aryloxy
benzaldehyde (2aef) (1 mmol) were dissolved in 10% NaOH-EtOH
(5 mL), it was stirred at room temperature for 9e10 h. After
completion, 5 mL water was added to the reaction mixture. The
separated solid compound was filtered and washed with water. It
was purified by crystallization with methanol/chloroform or basic
alumina column chromatography to give the desired compounds
(3e13).
6.3.6. E)-1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(3-chlorobenzy-
loxy)phenyl)prop-2-en-1-one (8)
With 1b and 2a; Yield: 74%; M.P: 197e198 ꢀC; MS(ESI): 416
[M þ 1]þ; IR (KBr): 3431, 3125, 2924, 2364, 1658, 1600, 1512, 1252,
1026, 812 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.21 (s, 2H), 7.11
(d, 2H, J ¼ 8.5 Hz), 7.39e7.44 (m, 3H), 7.53 (s, 1H), 7.74 (d, 1H,
J ¼ 15.5 Hz), 7.84e7.89 (m, 3H), 8.07 (d, 2H, J ¼ 8.8 Hz), 8.31e8.34
(m, 3H), 9.49 (s, 1H); Anal. Calcd. for C24H18ClN3O2: C, 69.31; H,
4.36; N, 10.10; Found C, 69.38; H, 4.41; N, 10.06.
The compounds (16e31) were prepared by the reaction of their
corresponding aldehyde and ketone partners.
6.3.1. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(3-chlorobenzyloxy)
phenyl)prop-2-en-1-one (3)
6.3.7. (E)-1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(2,4-dichlorobenz-
yloxy)phenyl)prop-2-en-1-one (9)
With 1a and 2a; Yield: 63%; M.P: 178e179 ꢀC; MS (ESI): 415
(100) [M þ 1]þ; IR (KBr): 3393, 2362, 1669, 1597, 1487, 1231, 1021,
With 1b and 2b; Yield: 67%; M.P: 183e185 ꢀC; MS(ESI): 450
[M þ 1]þ; IR (KBr): 3429, 2964, 2329, 1657, 1608, 1512, 1222, 1026,
786; 1H NMR (CDCl3, 300 MHz):
d 5.09 (s, 2H), 7.00 (d, 2H,
J ¼ 8.6 Hz), 7.25e7.31 (m, 4H), 7.36e7.44 (m, 3H), 7.52 (d, 2H,
J ¼ 8.5 Hz), 7.62 (d, 2H, J ¼ 8.6 Hz), 7.82 (d, 1H, J ¼ 15.7 Hz), 7.96 (s,
1H), 8.14 (d, 2H, J ¼ 8.5 Hz); 13C NMR (CDCl3, 75 MHz): 61.9, 115.2,
117.8, 119.1, 120.7, 125.2, 127.2, 127.6, 128.1, 129.8, 130.22, 130.29,
130.3, 134.4, 135.2, 137.1, 138.2, 140.0, 145.3, 160.6, 189.1; Anal.
Calcd. for C25H19ClN2O2: C, 72.37; H, 4.62; N, 6.75. Found C, 72.28;
H, 4.58; N, 6.69.
814 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.23 (s, 2H), 7.13 (d, 2H,
J ¼ 8.7 Hz), 7.47e7.51 (m, 1H), 7.64 (d, 1H, J ¼ 8.2 Hz), 7.70 (d, 1H,
J ¼ 2.0 Hz), 7.76 (d, 1H, J ¼ 15.5 Hz), 7.88 (d, 1H, J ¼ 15.5 Hz), 7.90 (d,
2H, J ¼ 8.8 Hz), 8.07 (d, 2H, J ¼ 8.8 Hz), 8.31 (s, 1H), 8.34 (d, 2H,
J ¼ 8.8 Hz), 9.47 (s, 1H); Anal. Calcd. for C24H17Cl2N3O2: C, 64.01; H,
3.81; N, 9.33; Found C, 64.11; H, 3.86; N, 9.35.
6.3.8. (E)-1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(2,5-dichlorobenz-
yloxy)phenyl)prop-2-en-1-one (10)
6.3.2. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(2,4-dichlorobenzy-
loxy)phenyl)prop-2-en-1-one (4)
With 1b and 2c; Yield: 71%; M.P: 201e203 ꢀC; MS(ESI): 450
[M þ 1]þ; IR (KBr): 3451, 3297, 2925, 2367, 1657, 1600, 1513, 1258,
With 1a and 2b; Yield: 73%; M.P: 168e170 ꢀC; MS(ESI): 449
[M þ 1]þ; IR (KBr): 3462, 3095, 2368, 1665, 1600, 1518, 1236, 1030,
1021, 816 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.24 (s, 2H), 7.15
820 cmꢅ1
;
1H NMR (CDCl3, 300 MHz):
d
5.18 (s, 2H), 7.02 (d, 2H,
(d, 2H, J ¼ 8.6 Hz), 7.47e7.50 (m, 1H), 7.57 (d, 1H, J ¼ 8.5 Hz), 7.70 (d,
1H, J ¼ 2.2 Hz), 7.76 (d, 1H, J ¼ 15.5 Hz), 7.86e7.92 (m, 3H), 8.07 (d,
2H, J ¼ 8.6 Hz), 8.31 (s, 1H), 8.34 (d, 2H, J ¼ 8.6 Hz), 9.48 (s, 1H);
Anal. Calcd. for C24H17Cl2N3O2 : C, 64.01; H, 3.81; N, 9.33; Found C,
64.07; H, 3.78; N, 9.29.
J ¼ 8.6 Hz), 7.26e7.30 (m, 3H), 7.38 (d, 1H, J ¼ 7.4 Hz), 7.46 (d, 2H,
J ¼ 7.7 Hz), 7.50e7.54 (m, 2H), 7.63 (d, 2H, J ¼ 8.6 Hz), 7.83 (d, 1H,
J ¼ 15.5 Hz), 7.96 (s, 1H), 8.14 (d, 2H, J ¼ 8.5 Hz); 13C NMR (CDCl3,
75 MHz): 66.7, 115.3, 117.7, 119.3, 120.7, 127.4, 128.0, 129.3, 129.6,
130.41, 130.45, 130.9, 132.7, 133.2, 134.4, 135.4, 137.1, 140.3, 145.1,
160.4, 188.7; Anal. Calcd. for C25H18Cl2N2O2: C, 66.83; H, 4.04; N,
6.23; Found C, 66.92; H, 4.11; N, 6.18.
6.3.9. (E)-1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(2,4-difluorobenz-
yloxy)phenyl)prop-2-en-1-one (11)
With 1b and 2d; Yield: 86%; M.P: 199e200 ꢀC; MS(ESI): 418
[M þ 1]þ; IR (KBr): 3466, 3126, 2923, 2367, 1658, 1601, 1512, 1257,
6.3.3. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(2,5-dichlorobenzy-
loxy)phenyl)prop-2-en-1-one (5)
1215, 1034, 970, 815, 670 cmꢅ1 1H NMR (DMSO-d6, 300 MHz):
;
With 1a and 2c; Yield: 76%; M.P: 171e172 ꢀC; MS(ESI): 449
[M þ 1]þ; IR (KBr): 3119, 2361, 1651, 1604, 1512, 1153, 1012,
d
5.20 (s, 2H), 7.13 (d, 2H, J ¼ 8.7 Hz), 7.17 (d, 1H, J ¼ 2.4 Hz),
7.28e7.35 (m, 1H), 7.65 (d, 1H, J ¼ 6.7 Hz), 7.76 (d, 1H, J ¼ 15.5 Hz),
798 cmꢅ1 1H NMR (DMSO-d6, 300 MHz):
; d 5.24 (s, 2H), 7.11e7.16
7.86e7.91 (m, 3H), 8.07 (d, 2H, J ¼ 8.7 Hz), 8.31 (s, 1H), 8.34 (d, 2H,

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
4309
J ¼ 8.7 Hz), 9.48 (s, 1H); Anal. Calcd. for C24H17F2N3O2: C, 69.06; H,
(m, 2H), 7.20 (d, 2H, J ¼ 8.9 Hz), 7.29e7.36 (m, 1H), 7.62e7.67 (m,
1H), 7.72e7.78 (m, 3H), 7.85e7.86 (m, 1H), 8.00 (d, 1H, J ¼ 15.7 Hz),
8.04 (d, 2H, J ¼ 8.8 Hz), 8.20 (d, 2H, J ¼ 8.9 Hz), 8.39 (s, 1H); Anal.
Calcd. for C25H18F2N2O2. C, 72.11; H, 4.36; N, 6.73; Found C, 72.15; H,
4.39; N, 6.77.
4.11; N, 10.07; Found C, 68.97; H, 4.06; N, 9.98.
6.3.10. (E)-1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(2,5-difluoroben-
zyloxy)phenyl)prop-2-en-1-one (12)
With 1b and 2e; Yield: 61%; M.P: 207e208 ꢀC; MS(ESI): 418
[M þ 1]þ; IR (KBr): 3467, 3129, 2366, 1654, 1600, 1257, 1034,
6.3.16. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2,5-difluorobenz-
yloxy)phenyl)prop-2-en-1-one (20)
815 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.22 (s, 2H), 7.15 (d, 2H,
J ¼ 8.6 Hz), 7.27e7.37 (m, 2H), 7.45 (s, 1H), 7.76 (d, 1H, J ¼ 16.0 Hz),
7.87 (d, 2H, J ¼ 8.3 Hz), 7.97 (d, 1H, J ¼ 16.0 Hz), 8.07 (d, 2H,
J ¼ 8.5 Hz), 8.31 (s, 1H), 8.34 (d, 2H, J ¼ 8.6 Hz), 9.47 (s, 1H); Anal.
Calcd. for C24H17F2N3O2: C, 69.06; H, 4.11; N, 10.07; Found C, 69.13;
H, 4.17; N, 10.02.
With 14e and 15a; Yield: 74%; M.P: 149e151 ꢀC; MS(ESI): 417
[M þ 1]þ; IR (KBr): 3470, 3072, 2363, 1665, 1256, 1035, 879 cmꢅ1
;
1H NMR (DMSO-d6, 300 MHz):
d
5.29 (s, 2H), 7.21 (d, 2H, J ¼ 8.8 Hz),
7.49e7.52 (m, 1H), 7.66 (d, 2H, J ¼ 8.4 Hz), 7.71 (d, 2H, J ¼ 2.0 Hz),
7.78 (d, 1H, J ¼ 15.5 Hz), 7.87e7.93 (m, 2H), 8.08 (d, 1H, J ¼ 15.5 Hz),
8.16 (d, 2H, J ¼ 8.6 Hz), 8.22 (d, 2H, J ¼ 8.8 Hz), 8.34 (s, 1H); Anal.
Calcd. for C25H18F2N2O2 : C, 72.11; H, 4.36; N, 6.73; Found C, 72.03;
H, 4.24; N, 6.81.
6.3.11. (E)-1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(2-nitro-4-(trifluoro-
methyl)phenoxy)phenyl)prop-2-en-1-one (13)
With 1a and 2f; Yield: 59%; M.P: 158e160 ꢀC; MS(ESI): 480
[M þ 1]þ; IR (KBr): 3433, 3155, 2326, 1657, 1607, 1266, 1031,
6.3.17. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(3-chlorobenz-
yloxy)phenyl)prop-2-en-1-one (21)
842 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d
7.03 (d, 2H, J ¼ 9.1 Hz), 7.18
(d, 2H, J ¼ 8.6 Hz), 7.38 (s, 1H), 7.50e7.57 (m, 3H), 7.76 (d, 2H,
J ¼ 8.6 Hz), 7.86 (d, 1H, J ¼ 15.6 Hz), 7.98 (s, 1H), 8.17 (d, 2H,
J ¼ 8.6 Hz), 8.32e8.36 (m, 1H), 8.61e8.62 (m, 1H); 13C NMR (CDCl3,
75 MHz): 114.0, 117.9, 120.2, 120.8, 121.2, 121.8, 123.8, 123.92,
123.99, 128.8, 130.5, 130.7, 131.1, 132.5, 136.6, 140.6, 142.3, 143.6,
156.1, 160.0, 188.4; Anal. Calcd. for C25H16F3N3O4: C, 62.63; H, 3.36;
N, 8.77; Found C, 62.82; H, 3.42; N, 8.71.
With 14a and 15b; Yield: 75%; M.P: 164e166 ꢀC; MS(ESI): 416
[M þ 1]þ; IR (KBr): 3459, 3124, 2368, 1657, 1600, 1521, 1226, 1030,
817 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.29 (s, 2H), 7.21 (d, 2H,
J ¼ 8.9 Hz), 7.43e7.48 (m, 3H), 7.58 (s, 1H), 7.77 (d, 1H, J ¼ 15.5 Hz),
7.98 (d, 2H, J ¼ 8.7 Hz), 8.04 (d, 1H, J ¼ 15.5 Hz), 8.11 (d, 2H,
J ¼ 8.7 Hz), 8.22 (d, 2H, J ¼ 8.8 Hz), 8.30 (s, 1H), 9.42 (s, 1H); Anal.
Calcd. for C24H18ClN3O2; C, 69.31; H, 4.36; N, 10.10; Found C, 69.34;
H, 4.33; N, 10.17.
6.3.12. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(3-chlorobenzyloxy)
phenyl)prop-2-en-1-one (16)
6.3.18. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(2,4-dichloroben-
zyloxy)phenyl)prop-2-en-1-one (22)
With 14a and 15a; Yield: 62%; M.P: 136e137 ꢀC; MS(ESI): 415
[M þ 1]þ; IR (KBr): 3457, 3128, 2363, 1655, 1601, 1523, 1228, 1015,
With 14b and 15b; Yield: 77%; M.P: 168e170 ꢀC; MS(ESI): 450
[M þ 1]þ; IR (KBr): 3468, 3125, 2364, 1655, 1600, 1518, 1236, 1165,
821 cmꢅ1 1H NMR (CDCl3, 300 MHz):
; d 5.13 (s, 2H), 7.06 (d, 2H,
J¼ 8.8 Hz), 7.24 (s,1H), 7.29e7.33(m,4H),7.43e7.46(m,3H),7.57(d,1H,
J ¼ 15.6 Hz), 7.75 (d, 2H, J ¼ 8.5 Hz), 7.81 (d,1H, J ¼ 15.6 Hz), 7.92 (s,1H),
8.05 (d, 2H, J ¼ 8.8 Hz); 13C NMR (CDCl3, 75 MHz): 69.3, 114.7, 117.8,
119.7, 121.4, 122.5, 125.3, 127.4, 128.3, 129.8, 129.9, 130.8, 131.3, 134.2,
134.6, 135.3, 138.2, 138.4, 142.2, 162.3, 188.2; Anal. Calcd. for
C25H19ClN2O2:C, 72.37;H, 4.62; N, 6.75;FoundC, 72.42; H, 4.59; N, 6.73.
1030, 820 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.28 (s, 2H), 7.20
(d, 2H, J ¼ 8.8 Hz), 7.48e7.52 (m, 1H), 7.66 (d, 1H, J ¼ 8.3 Hz), 7.72 (d,
1H, J ¼ 2.0 Hz), 7.76 (d, 1H, J ¼ 15.6 Hz), 7.96 (d, 2H, J ¼ 8.6 Hz), 8.03
(d, 1H, J ¼ 15.6 Hz), 8.10 (d, 2H, J ¼ 8.6 Hz), 8.21 (d, 2H, J ¼ 8.9 Hz),
8.28 (s, 1H), 9.41 (s, 1H). Anal. Calcd. for C24H17Cl2N3O2; C, 64.01; H,
3.81; N, 9.33; Found C, 64.06; H, 3.84; N, 9.42.
6.3.13. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2,4-dichlorobenz-
yloxy)phenyl)prop-2-en-1-one (17)
6.3.19. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(2,5-dichloroben-
zyloxy)phenyl)prop-2-en-1-one (23)
With 14b and 15a; Yield: 78%; M.P: 171e173 ꢀC; MS(ESI): 449
[M þ 1]þ; IR (KBr): 3468, 3136, 2369, 1653, 1600, 1521, 1238, 1031,
With 14c and 15b; Yield: 69%; M.P: 204e205 ꢀC; MS(ESI): 450
[M þ 1]þ; IR (KBr): 3446, 3111, 2910, 2364, 1657, 1603, 1519, 1250,
820 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d
5.28 (s, 2H), 7.13 (s, IH),
1035, 813, cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d 5.29 (s, 2H), 7.23
7.20 (d, 2H, J ¼ 8.9 Hz), 7.48e7.52 (m, 1H), 7.66 (d, 1H, J ¼ 8.3 Hz),
7.72 (d, 1H, J ¼ 2.1 Hz), 7.76 (d, 2H, J ¼ 6.1 Hz), 7.78 (s, 1H), 7.85e7.86
(m,1H), 8.00 (d,1H, J ¼ 16.8 Hz,), 8.04 (d, 2H, J ¼ 8.8 Hz), 8.20 (d, 2H,
J ¼ 8.9 Hz), 8.39 (s, 1H); Anal. Calcd. for C25H18Cl2N2O2: C, 66.83; H,
4.04; N, 6.23; Found C, 66.85; H, 4.09; N, 6.16.
(d, 2H, J ¼ 8.8 Hz), 7.48e7.52 (m, 1H), 7.58 (d, 1H, J ¼ 8.6 Hz), 7.73 (d,
1H, J ¼ 2.7 Hz), 7.76 (d, 1H, J ¼ 15.6 Hz), 7.97 (d, 2H, J ¼ 8.6 Hz), 8.03
(d, 1H, J ¼ 15.6 Hz), 8.10 (d, 2H, J ¼ 8.7 Hz), 8.22 (d, 2H, J ¼ 8.8 Hz),
8.28 (s, 1H), 9.40 (s, 1H). Anal. Calcd. for C24H17Cl2N3O2. C, 64.01; H,
3.81; N, 9.33; Found C, 63.92; H, 3.79; N, 9.37.
6.3.14. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2,5-dichlorobenz-
yloxy)phenyl)prop-2-en-1-one (18)
6.3.20. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(2,4-difluoroben-
zyloxy)phenyl)prop-2-en-1-one (24)
With 14c and 15a; Yield: 76%; M.P: 188e189 ꢀC; MS(ESI): 449
[M þ 1]þ; IR (KBr): 3468, 3136, 2369, 1653, 1600, 1521, 1238, 1031,
With 14d and 15b; Yield: 76%; M.P: 197e198 ꢀC; MS(ESI): 418
[M þ 1]þ; 3447, 2928, 2369, 1663, 1600, 1520, 1247, 1032, 818, 1H
820 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d
5.28 (s, 2H), 7.14 (s, IH),
NMR (DMSO-d6, 300 MHz): d 5.24 (s, 2H), 7.11e7.14 (m, 1H),7.20 (d,
7.22 (d, 2H, J ¼ 8.5 Hz), 7.51e7.56 (m, 3H), 7.72e7.79 (m, 3H), 7.83 (d,
1H, J ¼ 15.4 Hz), 7.98e8.06 (m, 3H), 8.22 (d, 2H, J ¼ 7.9 Hz), 8.40 (s,
1H); Anal. Calcd. for C25H18Cl2N2O2 : C, 66.83; H, 4.04; N, 6.23.
Found C, 66.91; H, 4.07; N, 6.25.
2H, J ¼ 8.8 Hz), 7.28e7.36 (m, 1H), 7.63e7.73 (m, 1H), 7.76 (d, 1H,
J ¼ 15.6 Hz), 7.96 (d, 2H, J ¼ 8.6 Hz), 8.02 (d, 1H, J ¼ 15.6 Hz), 8.09 (d,
2H, J ¼ 8.6 Hz), 8.20 (d, 2H, J ¼ 8.9 Hz), 8.28 (s, 1H), 9.40 (s, 1H);
Anal. Calcd. for C24H17F2N3O2. C, 69.06; H, 4.11; N, 10.07; Found C,
69.12; H, 4.14; N, 10.04.
6.3.15. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2,4-difluorobenz-
yloxy)phenyl)prop-2-en-1-one (19)
6.3.21. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(2,5-difluoroben-
zyloxy)phenyl)prop-2-en-1-one (25)
With 14d and 15a; Yield: 63%; M.P: 143e145 ꢀC; MS(ESI): 417
[M þ 1]þ; IR (KBr): 3451, 3095, 2366, 1657, 1600, 1258, 1019,
With 14e and 15b; Yield: 74%; M.P: 168e170 ꢀC; MS(ESI): 418
[M þ 1]þ; IR (KBr): 3427, 3117, 2364, 1658, 1586, 1518, 1256, 1027,
819 cmꢅ1 1H NMR (DMSO-d6, 300 MHz):
; d 5.25 (s, 2H), 7.13e7.14

4310
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 4302e4310
820 cmꢅ1; 1H NMR (DMSO-d6, 300 MHz):
d
5.29 (s, 2H), 7.23 (d, 2H,
162.6, 188.2; Anal. Calcd. for C29H20Cl4O3. C, 62.39; H, 3.61; Found C,
62.28; H, 3.53.
J ¼ 8.8 Hz), 7.48e7.52 (m, 1H), 7.58 (d, 1H, J ¼ 8.4 Hz), 7.72 (d, 1H,
J ¼ 2.4 Hz), 7.78 (d, 1H, J ¼ 15.7 Hz), 7.91 (d, 2H, J ¼ 8.5 Hz), 8.03 (d,
1H, J ¼ 15.7 Hz), 8.15 (d, 2H, J ¼ 8.6 Hz), 8.23 (d, 2H, J ¼ 8.7 Hz), 8.30
(s, 1H), 9.59 (s, 1H). Anal. Calcd. for C24H17F2N3O2. C, 69.06; H, 4.11;
N, 10.07; Found C, 69.11; H, 4.08; N, 10.16.
6.3.27. (E)-1-(4-(2,4-dichlorobenzyloxy)phenyl)-3-phenylprop-2-
en-1-one (31)
With 14c and benzaldehye; Yield: 76%; M.P: 137e138 ꢀC;
MS(ESI): 383 [M þ 1]þ; IR (KBr): 3411, 3223, 3129, 2371, 1657, 1251,
6.3.22. (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2-nitro-4-(trifluor-
omethyl)phenoxy)phenyl)prop-2-en-1-one (26)
1039, 812 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d 5.25 (s, 2H), 7.21 (d,
2H, J ¼ 8.6 Hz), 7.24e7.28 (m, 2H), 7.31e7.33 (m, 2H), 7.39e7.43 (m,
1H), 7.69 (d, 1H, J ¼ 15.6 Hz), 7.72e7.78 (m, 2H), 7.98 (d, 1H,
J ¼ 15.6 Hz), 8.09e8.13 (m, 1H), 8.16e8.22 (m, 2H); 13C NMR (CDCl3,
75 MHz): 66.4, 114.4, 126.4, 126.7, 127.2, 127.4, 129.2, 129.3, 130.7,
130.9, 131.1, 132.4, 134.1, 134.3, 134.7, 144.7, 162.3, 187.8; Anal. Calcd.
for C22H16Cl2O2. C, 68.94; H, 4.21; Found C, 68.79; H, 4.16.
With 14f and 15a; Yield: 71%; M.P: 159e161 ꢀC; MS(ESI): 480
[M þ 1]þ; IR (KBr): 3427, 3126, 2358,1658,1263,1052, 819 cmꢅ1; 1H
NMR (CDCl3, 300 MHz):
d
7.09 (d, 1H, J ¼ 9.0 Hz), 7.24e7.28 (m, 3H),
7.37 (s, 1H), 7.50 (d, 2H, J ¼ 7.4 Hz), 7.57 (d, 1H, J ¼ 15.7 Hz), 7.80 (d,
2H, J ¼ 8.3 Hz), 7.89 (d, 1H, J ¼ 15.6 Hz), 7.96 (s, 1H), 8.18 (d, 2H,
J ¼ 7.4 Hz), 8.40 (d, 1H, J ¼ 9.0 Hz), 8.66 (s, 1H); 13C NMR (CDCl3,
75 MHz): 114.0, 117.8, 118.5, 120.0, 121.4, 122.0, 124.0, 128.4, 128.8,
130.0, 130.8, 131.2, 133.8, 135.3, 135.4, 138.7, 142.6, 143.5, 158.1,
159.6, 188.3; Anal. Calcd. for C25H16F3N3O4. C, 62.63; H, 3.36; N,
8.77; Found C, 62.69; H, 3.31; N, 8.83.
Acknowledgements
V.K.M. thanks the Council of Scientific and Industrial Research
(India) for the award of Senior Research Fellowship. Authors are
thankful to S.A.I.F. Division, CDRI, Lucknow, for providing spectro-
scopic data. Thanks are also due to Anoop K Srivastava, Ajay S. Verma
and Hori Lal for technical assistance. CDRI communication No: 8093.
6.3.23. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-(2-nitro-4-(trifl-
uoromethyl)phenoxy)phenyl)prop-2-en-1-one (27)
With 14f and 15b; Yield: 77%; M.P: 162e163 ꢀC; MS(ESI): 481
[M þ 1]þ; IR (KBr): 3423, 3130, 2364,1655,1268,1047, 830 cmꢅ1; 1H
References
NMR (CDCl3, 300 MHz):
d
7.06 (d, 1H, J ¼ 9.3 Hz), 7.24e7.27 (m, 3H),
7.54 (s, 1H), 7.56 (d, 1H, J ¼ 15.6 Hz), 7.77e7.80 (m, 2H), 7.87 (d, 1H,
J ¼ 15.6 Hz), 8.14e8.17 (m, 3H), 8.35e8.39 (m, 1H), 8.61e8.64 (m,
2H); 13C NMR (CDCl3, 75 MHz): 118.5, 120.0, 120.1, 121.6, 122.3,
123.9, 124.0, 128.8, 129.9, 131.2, 134.5, 135.4, 138.2, 140.8, 142.6,
143.4, 152.8, 158.2, 159.6, 188.3; Anal. Calcd. for C24H15F3N4O4. C,
60.00; H, 3.15; N, 11.66; Found C, 60.08; H, 3.18; N, 11.61.
[1] (a) S. Khasnobis, V.E. Escuyer, D. Chatterjee, Expert Opin. Ther. Targets 6
(2002) 21e40;
(b) S.H.E. Kaufmann, Nat. Rev. Immun. 1 (2001) 20e30.
[2] World Health Organization, Global Tuberculosis Control: Surveillance, Plan-
ning, and Financing WHO Report 2008. WHO Press, Geneva, Switzerland,
2008.
[3] L.G. Wayne, C.D. Sohaskey, Annu. Rev. Microbiol. 55 (2001) 139e163.
[4] (a) E. Manoharam, K.R. John, A. Joseph, K.S. Jacob, Ind. J. Tub 48 (2001) 77e80;
(b) D.B. Young, Nature 393 (1998) 515e516.
[5] Y. Zhang, Annu. Rev. Pharmacol. Toxicol. 45 (2005) 529e564.
[6] J.S. Freundlich, F. Wang, C. Vilchèze, G. Gulten, R. Langley, G.A. Schiehser,
D.P. Jacobus, W.R. Jacobs Jr., J.C. Sacchettini, Chem. Med. Chem. 4 (2009)
241e248.
[7] A. Nayyar, R. Jain, Curr. Med. Chem. 12 (2005) 1873e1886.
[8] E.C. Rivers, R.L. Mancera, Drug Discov. Today 13 (2008) 1090e1098.
[9] A. Hudson, T. Imamura, W. Gutteridge, T. Kanyok, P. Nunn, W.H.O. TDR/PRD/
03.1W, Geneva, 2003.
[10] R.P. Tripathi, N. Tewari, N. Dwivedi, V.K. Tiwari, Med. Res. Rev. 25 (2005)
93e131.
[11] L. Ballell, R.A. Field, K. Duncan, R.J. Young, Antimicrob. Agents Chemother. 49
(2005) 2153e2163.
[12] Y.M. Lin, Y. Zhou, M.T. Flavin, L.M. Zhou, W. Nie, F.C. Chen, Bioorg. Med. Chem.
10 (2002) 2795.
[13] A. Friis-Møller, M. Chen, K. Fuursted, S.B. Christensen, A. Kharazmi, Planta
Med. 68 (2002) 416e419.
[14] (a) M.R. Grimmett, M.R. Imidazoles, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven
(Eds.), Comprehensive Heterocyclic Chemistry II, vol. 3, Pergamon, Oxford,
1996, pp. 77e220;
(b) F.W. Hartner, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.), Compre-
hensive Heterocyclic Chemistry II, vol. 3, Pergamon, Oxford, 1996, pp. 261e318;
(c) A. Craig, D. Zificsak, J. Hlasta, Tetrahedron 60 (2004) 8991e9016.
[15] K.J. McLean, K.R. Marshall, A. Richmond, I.S. Hunter, K. Fowler, T. Kieser,
S.S. Gurcha, G.S. Besra, A.W. Munro, Microbiology 148 (2002) 2937e2949.
[16] Y.L. Janin, Bioorg. Med. Chem. 15 (2007) 2479e2513.
[17] (a) N. Srinivas, S. Palne, Nishi, S. Gupta, K. Bhandari, Bioorg. Med. Chem. Lett.
19 (2009) 324e327;
6.3.24. (E)-1,3-bis(4-(1H-imidazol-1-yl)phenyl)prop-2-en-1-one (28)
With 1a and 15a; Yield: 74%; M.P: 188e190 ꢀC; MS(ESI): 341
[M þ 1]þ; IR (KBr): 3462, 3125, 2364, 1655, 1600, 1165, 1037,
845 cmꢅ1 1H NMR (CDCl3, 300 MHz):
; d 7.29 (s, 1H), 7.38 (s, 1H),
7.52e7.64 (m, 2H), 7.81 (d, 1H, J ¼ 15.5 Hz), 7.92 (d, 2H, J ¼ 8.5 Hz),
8.03e8.09 (m, 3H), 8.17 (d, 2H, J ¼ 8.6 Hz), 8.21e8.26 (m, 2H), 8.31
(s, 1H), 8.38 (s, 1H); 13C NMR (CDCl3, 75 MHz): 118.2, 118.9, 120.8,
125.3, 126.7, 126.9, 129.7, 130.8, 131.1, 133.4, 136.4, 136.9, 137.5,
138.8, 141.4, 144.8, 188.4; Anal. Calcd. for C21H16N6O. C, 74.10; H,
4.74; N, 16.46; Found C, 74.79; H, 4.21; N, 16.34.
6.3.25. (E)-1,3-bis(4-(1H-1,2,4-triazol-1-yl)phenyl)prop-2-en-1-
one (29)
With 1b and 15b; Yield: 68%; M.P: 195e197 ꢀC; MS(ESI): 343
[M þ 1]þ; IR (KBr): 3462, 3125, 2364, 1655, 1600, 1165, 1037,
845 cmꢅ1; 1H NMR (CDCl3, 300 MHz):
d
7.84 (d, 1H, J ¼ 15.6 Hz), 7.98
(d, 2H, J ¼ 8.6 Hz), 8.06 (d, 2H, J ¼ 8.7 Hz), 8.11e8.17 (m, 3H), 8.28 (s,
1H), 8.38 (s, 1H), 8.38 (d, 2H, J ¼ 8.7 Hz), 9.41 (s, 1H), 9.49 (s, 1H); 13C
NMR (CDCl3, 75 MHz): 121.4, 121.9, 127.3, 129.1, 133.5, 136.7, 136.8,
137.2,141.3,143.7,144.1,157.1,158.6,188.6; Anal. Calcd. for C19H14N6O.
C, 66.66; H, 4.12; N, 24.55; Found C, 66.79; H, 4.21; N, 23.96.
(b) K. Bhandari, N. Srinivas, V.K. Marrapu, A. Verma, S. Srivastava, S. Gupta,
Bioorg. Med. Chem. Lett. 20 (2010) 291e293;
(c) V.K. Marrapu, N. Srinivas, M. Mittal, N. Shakya, S. Gupta, K. Bhandari,
Bioorg. Med. Chem. Lett. 21 (2011) 1407e1410;
(d) V.K. Marrapu, M. Mittal, R. Shivahare, S. Gupta, K. Bhandari, Eur. J. Med.
Chem. 46 (2011) 1694e1700.
6.3.26. (E)-1,3-bis(4-(2,4-dichlorobenzyloxy)phenyl)prop-2-en-1-
one (30)
With 2c and 14c; Yield: 67%; M.P: 151e153 ꢀC; MS(ESI): 557
[M þ 1]þ; IR (KBr): 3223, 3129, 2371, 1657, 1251, 1039, 812 cmꢅ1; 1H
[18] J.K. McClachy, Lab. Med. 9 (1978) 47e52.
NMR (CDCl3, 300 MHz):
d 5.23 (s, 2H), 5.28 (s, 2H), 7.24 (d, 2H,
[19] T. Mosmann, J. Immunnol Methods 65 (1983) 55e63.
[20] Tuberculosis Drug Screening Program, Search of new drugs for treat-
ment of tuberculosis, Antimicrob. Agents Chemother. 45 (2001)
1943e1946.
J ¼ 8.5 Hz), 7.31e7.34 (m, 2H), 7.38 (d, 2H, J ¼ 8.7 Hz), 7.43e7.49 (m,
3H), 7.73 (d, 1H, J ¼ 15.4 Hz), 7.77e7.80 (m, 3H), 8.07 (d, 1H,
J ¼ 15.4 Hz), 8.28e8.31 (m, 2H); 13C NMR (CDCl3, 75 MHz): 67.1,
68.2, 114.5, 115.6, 120.8, 126.3, 126.7, 126.9, 128.7, 129.0, 129.7, 131.3,
131.6, 131.7, 131.8, 132.3, 132.4, 134.3, 134.6, 134.9, 135.1, 145.1, 159.4,
[21] G. Canetti, F. Grumbach, J. Grosset, Am. Rev. Respir. Dis. 82 (1960)
295e313.
[22] F. Fenner, Am. Rev. Tuberc. Dis. 64 (1951) 252e383.