Synthesis of cinnamide dimers as potential antibacterial and antifungal agents

Article abstract of DOI:10.2174/157018011797655205

A series of new cinnamide dimers was synthesized (5a-6a) and evaluated for th e i r antimicrobial and antifungal activity. All the compounds investigated have shown significant antimicrobial a c t iv i ty against gram-positive and gram-negative bacterial

Full text of DOI:10.2174/157018011797655205

Letters in Drug Design & Discovery, 2011, 8, 957-965
957
Synthesis of Cinnamide Dimers as Potential Antibacterial and Antifungal
Agents
Ahmed Kamal*,a, G. Ramakrishnaa, P. Rajua, A.V. Subba Raoa, Joveeta Josepha, B. Siddhardhab and
U.S.N. Murtyb
aDivision of Organic Chemistry, bBiology Division, Indian Institute of Chemical Technology, Hyderabad -500 607, India
Received July 12, 2011: Revised August 29, 2011: Accepted September 19, 2011
Abstract: A series of new cinnamide dimers was synthesized (5a-6a) and evaluated for their antimicrobial and
antifungal activity. All the compounds investigated have shown significant antimicrobial activity against gram-positive
and gram-negative bacterial strains, as well as few fungal strains. The compounds having withdrawing group exhibited
significant biological activity than their precursors. Moreover all the compounds containing electron withdrawing
substituent showed good antimicrobial activity in comparison with the standards.
Keywords: Antibacterial, Antifungal, Cinnamide dimers, Piperazine.
INTRODUCTION
In continuation of our search for prominent antibacterial
and antifungal agents with therapeutic efficacy, in the
present invention we have prepared cinnamide dimers with
piperzine scaffold and evaluated their antibacterial and
antifungal activity. The main objective behind the synthesis
of cinnamide dimers with piperzine is to enhance the
biological activity and the solubility of these compounds.
Some of the cinnamide derivatives reported as antibacterial
agents have been shown in Fig. (1).
Microorganisms are the major threat to the public health
worldwide due to their drug resistance [1]. The multidrug
resistant Gram positive bacteria including methicillin
resistant Staphylococcus aureus (MRSA), Staphylococcus
epidermidis (MRSE) and vancomycin resistant enterococci
(VRE) are the major drug resistant bacteria and despite the
tremendous progress in medicinal chemistry, they are still
challenging to the public health [2]. The bacterial resistance
to antibiotics is a major health problem and pointed the need
to discover novel hybrid compounds with potent antimicro-
bial activity. The need for the synthesis of antifungal drugs is
much required because of limited progress in this field.
Recently, cinnamic acid derivates play an important role in
medicinal chemistry. Moreover, cinnamic acid derivatives
exhibit a wide range of pharmacological activities, such as
inhibitors of hepatic glucose-6-phosphate translocase [3],
antiatherogenic [4], vanilloid receptor-1 antagonists [5],
antagonists of leukocyte function [6], anticonvulsant activity
[7], antioxidative [8], antitumor [9], antimicrobial [10-12]
and antituberculosis [13,14].
CHEMISTRY
The synthetic pathway (Scheme 1) involves the use of
commercially available substituted cinnamic acid as the
starting material, which was treated with thionyl chloride
and then coupled to N-Boc piperazine in the presence of a
base to give the corresponding compounds 2a-c. This upon
deprotection of Boc by employing TFA in CH2Cl2 gives the
compounds 3a-c, which was coupled with substituted
cinnamic acid chloride which provides the required
cinnamide dimers, 5a-z and 6a.
Moreover, previous studies in this laboratory on the
synthesis of pyrrolobenzodiazepine (PBD) dimers incor-
porating a piperazine moiety enhanced the bioavailability as
well as bioefficacy [15]. Piperazine is a pharmacologically
attractive scaffold that is present in many important drugs
such as the Merck HIV protease inhibitor, Crixivan and
drugs under development [16]. It is well known that this
heterocyclic backbone could act on various pharmacological
targets and is known to display anticancer [17-24], calcium
channel blocking [25-28], antibacterial [29] and histamine
antagonist properties [30,31]. Recently, piperazine deriva-
tives containing tetrazole nucleus have been reported as
antifungal Agents [32].
RESULTS AND DISCUSSION
Antimicrobial Activity
Antimicrobial efficacy of the Compounds 5a-z and 6a
was tested for their minimum inhibitory concentration (MIC)
by tube dilution method against various test bacterial strains
and antifungal activity against Aspergillus and Candida sps
was tested by well diffusion method [33-35]. The in vitro
antibacterial activity of the newly synthesized compounds
5a-6a was studied against the following bacterial strains of
gram-positive organisms viz. Staphylococcus aureus (MTCC
96), Staphylococcus epidermidis (MTCC 435), Bacillus
subtilis (MTCC 441) and gram-negative organisms viz.,
Escherichia coli (MTCC 443), Pseudomonas aeruginosa
(MTCC 741) by MIC method. Aspergillus niger (MTCC
1344), Aspergillus parasiticus (MTCC 2797), Candida
albicans (MTCC 227) and Saccharomyces cereviseae
(MTCC 36) which were taken as test fungi to find out the
antifungal activity of the synthesized compounds.
*Address correspondence to this author at the Division of Organic
Chemistry, Indian Institute of Chemical Technology, Hyderabad -500 607,
India; Tel: +91-40-27193157; Fax: +91-40-27193189;
E-mail: ahmedkamal@iict.res.in
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers

958 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Kamal et al.
O
O
O
N
HO
OH
R
N
R3
R4
OH
R1
R2
O
O
R5
5a-6a
Licochalcone A
B
Fig. (1).
O
O
R
R
a
Cl
N
HN
NBoc
b
NBoc
R1
R1
R2
R2
2a-c
1a-c
O
O
O
R
O
R
R3
N
N
A
Cl
N
c
NH
R1
R1
R4
R3
B
R2
R2
R5
R4
3a-c
4
R5
5a-z, 6a
5a: R, R1, R2 = OMe, R3, R4, R5 = H
5b: R, R1, R2 = OMe, R3, R4, R5 = OMe
5d: R, R1, R2 = OMe, R3 = OCF3, R4, R5 = H
5f : R, R1, R2 = OMe, R3, R5 = H, R4 = Cl
5h: R, R1, R2 = OMe, R3 = H, R4, R5 = F
5j : R, R1, R2 = OMe, R3 = H, R4 = OH, R5 = OMe
5l : R, R1, R2 = H, R3 = OCF3, R4, R5 = H
5n: R, R1, R2 = H, R3, R5 = H, R4 = Cl
5c: R, R1, R2 = OMe, R3, R5 = H, R4 = CF3
5e: R, R1, R2 = OMe, R3, R5 = H, R4 = F
5g: R, R1, R2 = OMe, R3, R5 = H, R4 = Br
5i : R, R1, R2 = OMe, R3 = H, R4, R5 = Cl
5k: R, R1, R2 = H, R3, R5 = H, R4 = CF3
5m: R, R1, R2 = H, R3, R5 = H, R4 = F
5o: R, R1, R2 = H, R3, R5 = H, R4 = Br
5q: R, R1, R2 = H, R3 = H, R4, R5 = F
5p : R, R1, R2 = H, R3, R4, R5 = H
5r: R, R1, R2 = H, R3 = H, R4, R5 = Cl
5s : R, R1, R2 = H, R3 = H, R4 = OH, R5 = OMe
5u : R, R2 = H, R1 = CF3, R3 = OCF3, R4, R5 = H
5w: R, R2 = H, R1 = CF3, R3, R5 = H, R4 = Cl
5y: R, R2 = H, R1 = CF3, R3 = H, R4, R5 = F
5t : R, R2 = H, R1 = CF3, R3, R5 = H, R4 = CF3
5v : R, R2 = H, R1 = CF3, R3, R5 = H, R4 = F
5x: R, R2 = H, R1 = CF3, R3, R5 = H, R4 = Br
5z : R, R2 = H, R1 = CF3, R3 = H, R4, R5 = Cl
6a: R, R2 = H, R1 = CF3, R3 = H, R4 = OH, R5 = OMe
Scheme 1.Reagents and conditions: a) TEA, N-Boc piperazine, dry THF, 0 oC to RT, 2h; b) CF3COOH, CHCl3, RT, 8h; c) TEA, dry THF, 0
oC to RT, 2h.
Licochalcone and trans-cinnamic acid were used as
reference standards.
electron releasing group. These compounds showed
moderate or no activity against all organisms tested. The
type II compounds 5k-5s possessing without substitution on
ring A showed moderate activity. Similarly, the type III
compounds 5t-6a comprising of electron withdrawing
substituent on ring A exhibited better antibacterial activity
than type I and type II compounds. From these results the
withdrawing group is necessary to get better antibacterial
activity on the ring A. It should also be noted that all these
compounds showed better antibacterial activity than standard
cinnamic acid, as shown in Table 1.
From the results in Table 1, it was observed that almost
all the compounds in our series exhibited high antibacterial
activity against the test bacterial strains viz., Gram-positive
organisms viz., B. subtilis, S. aureus and S. epidermidis and
Gram-negative organisms viz., E. coli and P. aeruginosa.
Compounds 5i-5q and 5w exhibited better or similar activity
against B. subtilis. The compounds 5r, 5s, 5v, 5w, 5x, 5y, 5z
and 6a showed equipotent activity against S. aureus and
compounds 5t, 5u, 5v, 5x, 5y, 5z and 6a had equipotent
activity against S. epidermidis in comparison to the standard
licochalcone. Only compound 5u had good activity against
P. aeroginosa, whereas other compounds 5w, 5y, and 6a
were highly active against E. coli, though not comparable to
the standard. The type I compounds 5a-5j were designed in
such a way that the aromatic ring A would have a strong
Antifungal Activity
From the results in Table 2, it has been observed that
most of the compounds exhibited significant in vitro
inhibitory activity against the fungal strains viz., A. niger, A.

Synthesis of Cinnamide Dimers as Potential Antibacterial
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 959
Table 1. Antibacterial Activity of Compounds 5a-6a
MIC (ꢀg/ml)
Compound
Gram-positive
Gram-negative
P. aeroginosa
B. subtilis
S. epidermidis
S. aureus
E. coli
5a
50
50
100
100
100
100
50
100
>100
100
>100
>100
>100
100
25
100
100
50
5b
5c
50
12.5
25
12.5
25
5d
100
>100
>100
100
100
25
50
5e
12.5
50
>100
50
50
5f
50
5g
50
>100
50
50
5h
50
50
5i
50
50
50
5j
12.5
25
>100
>100
>100
>100
50
>100
>100
>100
>100
50
100
25
50
5k
50
5l
25
50
50
5m
25
50
>100
50
5n
25
50
5o
25
>100
>100
>100
12.5
12.5
6.25
6.25
6.25
12.5
6.25
6.25
6.25
6.25
6.25
>100
>100
>100
>100
6.25
6.25
12.5
12.5
6.25
6.25
6.25
6.25
6.25
6.25
6.25
>100
50
50
5p
25
50
50
5q
25
50
50
5r
>100
50
25
50
5s
25
>100
>100
50
5t
>100
>100
>100
12.5
>100
>100
>100
>100
25
25
5u
12.5
25
5v
>100
12.5
>100
12.5
>100
12.5
12.5
>100
5w
>100
>100
>100
>100
>100
12.5
>100
5x
5y
5z
6a
licochalcone
cinnamic acid
>100
parasiticus, C. albicans and S. cerevisiae. Compounds 5n,
5v, 5x, 5y and 6a showed similar or higher growth inhibition
for A. niger than the standards used. Compounds 5m-5q, 5s,
5t, 5v, 5y and 6a have also shown similar or higher growth
inhibition for A. parasiticus compared to the standards.
Compounds 5h, 5y and 6a were active against S. cerevisiae
whereas 5w, 5x, 5y and 6a were active against C. albicans.
Interestingly all these compounds showed higher inhibition
than one of the precursor cinnamic acid. The newly designed
cinnamide dimers may act as cell wall inhibitors and more
specifically act on FAS-II, which uses ꢀ,ꢁ-enoyl systems as
substrates, as shown in previous reports [36]. However, these
dimer molecules are exhibiting better activity probably based
on the synergistic aspects on combination of licochalcone
and trans-cinnamic acid moieties.
CONCLUSION
In summary, we have synthesized a library of cinnamide
dimers with piperazine scaffold and evaluated their
antimicrobial activity against various bacterial and fungal
strains. Interestingly, compounds 5s-z and 6a have shown
significant antibacterial as well as antifungal activity when
compared to standards. Among the synthesized molecules,
compound 6a shows promising results as an antimicrobial
agent that could have potential for commercial application.

960 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Kamal et al.
Table 2. Antifungal Activity of Compounds 5a-6a
Zone of inhibition (mm)
Filamantous Fungi
Yeast
Compd
A. niger
A. parasiticus
C. albicans
S. cervisiae
5a
12
10
8
12
13
14
18
13
12
15
14
13
16
13
14
22
23
25
21
20
19
20
21
16
23
18
11
23
19
21
20
<8
-
-
-
-
5b
5c
-
-
5d
12
14
11
12
14
10
10
11
12
20
24
18
19
18
18
21
19
20
22
20
28
22
20
24
22
<8
-
-
5e
8
-
5f
10
8
-
5g
-
5h
14
-
-
5i
-
5j
8
-
5k
8
-
5l
10
12
11
10
11
-
-
5m
15
13
15
14
17
16
18
18
14
16
20
24
22
18
20
20
<10
5n
5o
5p
5q
5r
12
10
13
11
13
11
11
14
12
16
14
<10
5s
5t
5u
5v
5w
5x
5y
5z
6a
licochalcone
cinnamic acid
Thus this strategy could prove useful in desiging useful lead
compounds for further development as antimicrobial agents.
Using a separate pipette 1 ml from 2nd tube was transferred
to the third tube. The serial dilutions were continued in this
manner to the tube number 8. One ml from the 8th tube was
discarded and the ninth tube serves as a control. 1 ml of the
10-7CFU/ml culture was taken from the Muller-Hinton broth,
which was prepared by incubating overnight. This was done
for all the four test bacteria and separate set of dilutions was
prepared for all the compounds. The tubes were thoroughly
EXPERIMENTAL SECTION
Antibacterial Assay
The minimum inhibitory concentration (MIC) was tested
as per the CLSI/NCCLS standards [37-39]. Sterile capped
test tubes were taken and numbered from 1 to 9. 150ꢀg of
the compound was weighed and dissolved in 150ꢀl of
DMSO. It was added to the first tube and 1 ml of the sterile
broth (Muller-Hinton Broth) to all other tubes.1ml of the
solution was transferred from first tube to the second tube.
o
mixed and incubated at 37 C for 24 h. The tube which does
not contain the visible growth / turbidity after overnight
incubation was taken as Minimal Inhibitory Concentration
90 (MIC90). The MIC values obtained from the following
experiments were compared with the standards.

Synthesis of Cinnamide Dimers as Potential Antibacterial
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 961
Antifungal Assay
Tert-butyl 4-[(E)-3-phenyl-2-propenoyl]-1-piperazinecarbo-
xylate (3b)
Agar cup bioassay was employed for testing antifungal
activity. The Potato Dextrose Agar (PDA) medium
(Himedia) was poured into sterile Petri dishes under aseptic
conditions in a laminar flow chamber. When the medium in
the plates solidified, 0.5 mL of (week old) culture of test
organism was inoculated and uniformly spread over the agar
surface with a sterile L-shaped rod. Solutions were prepared
by dissolving the compound in DMSO and 100 μg/mL
concentrations solutions were prepared. After inoculation,
cups were scooped out with 6 mm sterile cork borer and the
lids of the dishes were replaced. To each cup different
compound solutions of concentrations (100 μg/mL) were
added. Controls were prepared dissolving clotrimazole in
DMSO and maintaining the concentration of solution (100
o
1
Yield 70%; White solid; mp >300 C; H NMR (300
MHz, CDCl3): ꢀ: 7.65 (d, 1H, J = 15.29 Hz), 7.51-7.47 (m,
2H), 7.38-7.31 (m, 3H), 6.81 (d, 1H, J = 15.29 Hz), 3.65
(brs, 4H), 3.48-3.44 (m, 4H), 1.47 (s, 9H). ESI-MS: m/z 317
[M+1]+.
Tert-butyl 4-(E)-3-[4-(trifluoromethyl)phenyl]-2-propenoyl-
1-piperazinecarboxylate (3c)
o
1
Yield 85%; White solid; mp >300 C; H NMR (300
MHz, CDCl3): ꢀ: 7.64 (d, 1H, J = 15.10 Hz), 7.61 (s, 4H),
6.87 (d, 1H, J = 15.10 Hz), 3.66 (brs, 4H), 3.49-3.47 (m,
4H), 1.47 (s, 9H). ESI-MS: m/z 385 [M+1]+.
General Procedure for Preparation of (E)-1-piperazino-3-
(substitute phenyl)-2-propen-1-one) (3a-c)
o
μg /mL). The treated and the controls were kept at 27 C for
48 h. Inhibition zones were measured and the diameter was
calculated in millimeter. Triplicates were maintained for
each treatment [33, 34].
To a solution of boc-protected compounds 2a-c (1 mmol)
in dry dichloromethane was added trifluoroacetic acid (11
mmol) at 0 oC and stirred under nitrogen for 12 h, the
reaction mixture was concentrated under vacuum to afford
compounds 3a-c and then it was used directly in the next
step.
Characterization
All chemicals and reagents were obtained from Aldrich
(Sigma-Aldrich, St. Louis, MO, USA), Lancaster (Alfa
Aesar, Johnson Matthew Company, Ward Hill, MA, USA)
and were used without purification. Reactions were
monitored by TLC, performed on silica gel glass plates
containing 60 F-254, and visualization on TLC was achieved
by UV light or iodine indicator. Column chromatography
General Procedure for Preparation of Compounds 5a-6a
To a stirred solution of (E)-1-piperazino-3-(substitute
phenyl)-2-propen-1-one) 3a-c (1.0 mmol) in dry THF was
added triethylamine (1.5 mL) followed by (E)-3-(substituted
phenyl)-2-propenoyl chlorides (4) in dry THF (1.0 mmol) at
o
1
0 C. The reaction mixture was stirred for 2 hours and the
was performed with Merck 60-120 mesh silicagel. H NMR
reaction was monitored by TLC. After completion of the
reaction, THF was evaporated under vacuum to get the crude
product. This was further purified by column chromato-
graphy (CHCl3-MeOH) to afford the pure compounds 5a-6a.
spectra were recorded on Gemini Varian VXR-unity (400
and 500 MHz) or Bruker UXNMR/XWIN-NMR (300 MHz)
instruments. Chemical shifts (ꢀ) were reported in ppm
downfield from internal TMS standard. ESI spectra were
recorded on Micro mass, Quattro LC using ESI+ software
with capillary voltage 3.98 KV and ESI mode positive ion
trap detector. High-resolution mass spectra (HRMS) were
recorded on QSTAR XL Hybrid MS/MS mass spectrometer.
Melting points were determined with an Electrothermal
melting point apparatus, and were uncorrected.
(E)-3-Phenyl-1-4-[(E)-3-(3,4,5-trimethoxyphenyl)-2-pro-
penoyl]piperazino-2-propen-1-one (5a)
o
1
Yield 85%; White solid; mp 168-173 C; H NMR (300
MHz, CDCl3): ꢀ: 7.68 (d, 1H, J = 15.29 Hz), 7.59 (d, 1H, J =
15.29 Hz), 7.52-7.47 (m, 2H), 7.40-7.34 (m, 3H), 6.83 (d,
1H, J = 15.29 Hz), 6.70 (s, 2H), 6.68 (d, 1H, J = 15.10 Hz),
3.89 (s, 6H), 3.84 (m, 3H), 3.75 (brs, 8H); 13C NMR (CDCl3,
150 MHz): ꢀ 165.5, 153.3, 143.6, 143.5, 139.6, 134.8, 130.4,
129.7, 128.7, 127.7, 116.2, 115.4, 104.9, 60.8, 56.1, 45.4,
42.0; IR (KBr) (Umax/cm-1): ꢁ 3473 (br), 2929, 1642, 1583,
1505, 1419, 1384, 1340, 1274, 1253, 1218, 1154, 1038,
1000, 988, 974, 817; ESI-MS: m/z 437 [M+1]+, HRMS
calcd for C25H28N2O5Na [M+Na]+ 459.1895, found
459.1909.
General procedure for preparation of Tert-butyl 4-[(E)-3-
(substituted phenyl)-2-propenoyl]-1-piperazinecarboxylate
(2a-c)
To a stirred solution of N-boc piperazine (1.0 mmol) in
dry THF was added triethylamine (4.0 mmol) followed by
(E)-3-(substituted phenyl)-2-propenoyl chloride (1.0 mmol)
o
at 0 C. The reaction mixture was stirred for 2 hours and the
reaction was monitored by TLC. After completion of the
reaction, THF was evaporated under vacuum to get the crude
product. This was further purified by column
chromatography (30% EtOAc-Hexane) to afford the pure
compounds 2a-c.
(E)-3-(3,4,5-Trimethoxyphenyl)-1-4-[(E)-3-(3,4,5-trimetho-
xyphenyl)-2-propenoyl]piperazino-2-propen-1-one (5b)
o
1
Yield 72%; White solid; mp 139-143 C; H NMR (300
MHz, CDCl3): ꢀ: 7.63 (d, 2H, J = 15.29 Hz), 6.74 (s, 4H),
6.74 (d, 2H, J = 15.10 Hz), 3.90 (s, 12H), 3.88 (s, 6H), 3.83-
3.70 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ 165.6, 153.3,
143.7, 139.8, 130.4, 115.4, 105.1, 60.9, 56.1, 45.6, 42.1; IR
(KBr) (Umax/cm-1): ꢁ 3434 (br), 2926, 1648, 1608, 1582,
1504, 1459, 1419, 998, 816; ESI-MS: m/z 550 [M+Na]+,
HRMS calcd for C28H34N2O8Na [M+Na]+ 550.2332, found
550.2322.
Tert-butyl 4-[(E)-3-(3,4,5-trimethoxyphenyl)-2-propenoyl]-
1-piperazinecarboxylate (3a)
o
1
Yield 80%; White solid; mp >300 C; H NMR (300
MHz, CDCl3): ꢀ: 7.64 (d, 1H, J = 15.13 Hz), 6.75 (s, 2H),
6.73 (d, 1H, J = 15.13 Hz), 3.95 (s, 6H), 3.90 (s, 3H), 3.65
(brs, 4H), 3.49-3.45 (m, 4H), 1.49 (s, 9H); ESI-MS: m/z 407
[M+1]+.

962 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Kamal et al.
(E)-3-[4-(trifluoromethyl)phenyl]-1-4-[(E)-3-(3,4,5-trimeth-
oxyphenyl)-2propenoyl]piperazino-2-propen-1-one (5c)
Hz),6.73 (d, 1H, J = 15.10 Hz ), 6.70 (s, 2H), 3.87 (s, 6H),
3.85 (s, 3H), 3.75 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ
165.5, 165.2, 152.3, 143.8, 142.1, 138.8, 134.6, 133.5, 130.2,
129.2, 128.7, 115.8, 115.2, 105.2, 60.7, 56.3, 45.2, 42.1; IR
(KBr) (Umax/cm-1): ꢁ 3483 (br), 2931, 1644, 1603, 1584,
1505, 1488, 1420, 1273, 1217, 1156, 1127, 1072, 1038, 989,
816; ESI-MS: m/z 515 [M]+, HRMS calcd for
C25H27N2O5BrNa [M+Na]+ 537.1001, found 537.0987.
o
1
Yield 83%; White solid; mp 138-142 C; H NMR (300
MHz, CDCl3): ꢀ: 7.70 (d, 1H, J = 15.32 Hz), 7.50 (d, 1H, J =
14.87 ), 7.32 (d, 2H, J = 8.00 Hz), 6.97 (d, 1H, J = 15.32),
6.82 (d, 1H, J = 14.87), 6.73 (s, 2H), 3.92 (s, 6H), 3.87 (s,
3H), 3.78 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ 165.5,
164.9, 153.3, 143.7, 141.7, 139.7, 138.2, 131.0, 130.3, 127.8,
125.7, 118.8, 115.3, 105.0, 60.8, 56.1, 45.5, 42.1; IR (KBr)
(Umax/cm-1): ꢁ 3433 (br), 2922, 1606, 1584, 1505, 1447,
1418, 1183, 1123, 1067, 1037, 991, 829; ESI-MS: m/z 505
[M+1]+, HRMS calcd for C26H27N2O5F3Na [M+Na]+
527.1769, found 527.1749.
(E)-3-(3,4-Difluorophenyl)-1-4-[(E)-3-(3,4,5-trimethoxy-
phenyl)-2-propenoyl]piperazino-2-propen-1-one (5h)
o
1
Yield 75%; White solid; mp 143-150 C; H NMR (500
MHz, CDCl3): ꢀ: 7.57 (d, 2H, J = 15.60 Hz), 7.37-7.33 (m,
2H), 7.18-7.13 (m, 1H), 6.74 (d, 1H, J = 15.60 Hz),6.70 (s,
2H ), 6.66 (d, 2H, J = 15.60 Hz), 3.89 (s, 6H), 3.84 (s, 3H),
3.74 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ 165.5, 165.0,
153.3, 143.7, 141.2, 130.3, 124.6, 124.5, 117.8, 117.5, 117.4,
115.9, 115.7, 115.4, 105.0, 60.8, 56.1, 45.5, 42.0; IR (KBr)
(Umax/cm-1): ꢁ 3421 (br), 2937, 1647, 1605, 1586, 1507,
1434, 1419, 1337, 1296, 1277, 1248, 1220, 1126, 1049, 992,
814; ESI-MS: m/z 495 [M+Na]+, HRMS calcd for
C25H26N2O5F2Na [M+Na]+ 495.1707, found 495.1709.
(E)-3-[3-(Trifluoromethoxy)phenyl]-1-4-[(E)-3-(3,4,5-trim-
ethoxyphenyl)-2-propenoyl] piperazin-2-propen-1-one(5d)
o
1
Yield 87%;White solid; mp 260-265 C; H NMR (300
MHz, CDCl3): ꢀ: 7.65 (d, 1H, J = 15.10 Hz), 7.60 (d, 1H, J =
14.32 Hz), 7.43 (s, 2H), 7.37 (s, 1H), 7.27-7.23 (m, 1H), 6.86
(d, 1H, J = 15.10 Hz), 6.74 (s, 3H), 3.90 (s, 6H), 3.87 (s,
3H), 3.78 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ 165.5,
165.0, 153.3, 149.4, 143.7, 141.7, 139.7, 136.9, 130.3, 130.1,
126.3, 121.8, 119.6, 118.1, 115.4, 104.9, 60.8, 56.0, 45.5,
42.1; IR (KBr) (Umax/cm-1): ꢁ 3448 (br), 2927, 1646, 1607,
1581, 1506, 1456, 1426, 1267, 1211, 1128, 1032, 989, 823;
ESI-MS: m/z 521 [M]+, HRMS calcd for C26H27N2O6F3Na
[M+Na]+ 543.1718, found 543.1732.
(E)-3-(3,4-Dichlorophenyl)-1-4-[(E)-3-(3,4,5-trimethoxy-
phenyl)-2-propenoyl]piperazino-2-propen-1-one (5i )
o
1
Yield 83%; White solid; mp 168-173 C; H NMR (300
MHz, CDCl3): ꢀ: 7.62 (d, 2H, J = 14.87 Hz), 7.42-7.38 (m,
2H), 7.20-7.17 (m, 1H), 6.82 (d, 1H, J = 14.87 Hz),6.68 (s,
2H ), 6.52 (d, 1H, J = 14.87 Hz), 3.89 (s, 6H), 3.82 (s, 3H),
3.71 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢀ 165.6, 165.1,
153.2, 143.8, 141.4, 130.2, 124.8, 124.5, 117.8, 117.6, 117.4,
115.9, 115.6, 115.3, 105.2, 60.8, 56.1, 45.5, 42.2; IR (KBr)
(Umax/cm-1): ꢁ 3453 (br), 2936, 1646, 1602, 1581, 1552,
1504, 1455, 1384, 1337, 1272, 1255, 1124, 1028, 990, 922,
819; ESI-MS: m/z 505 [M]+, HRMS calcd for
C25H26N2O5Cl2Na [M+Na]+ 527.1116, found 527.1129.
(E)-3-(4-Fluorophenyl)-1-4-[(E)-3-(3,4,5-trimethoxyphenyl)-
2-propenoyl]piperazino-2-propen-1-one (5e)
o
1
Yield 67%; White solid; mp 172-178 C; H NMR (300
MHz, CDCl3): ꢀ: 7.62 (d, 1H, J = 15.10 Hz), 7.56 (d, 1H, J =
15.10 Hz), 7.50 (dd, 2H, J = 5.28 Hz), 7.06 (2H, t),6.73 (d,
1H, J = 15.10 Hz ), 6.70 (s, 2H), 6.66 (d, 1H, J = 14.80),
3.89 (s, 6H), 3.84 (s, 3H), 3.75 (brs, 8H); 13C NMR (CDCl3,
150 MHz): ꢀ 165.5, 165.4, 153.3, 143.7, 142.3, 139.8, 131.1,
130.4, 129.6, 116.0, 115.4, 105.0, 60.8, 56.1, 45.2, 42.1; IR
(KBr) (Umax/cm-1): ꢁ 3448 (br), 2924, 1608, 1583, 1508,
1446, 1274, 1247, 1126, 1033, 1001, 986, 829; ESI-MS: m/z
455 [M+1]+, HRMS calcd for C25H27N2O5FNa [M+Na]+
477.1801, found 477.1807.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-4-[(E)-3-(3,4,5-trim-
ethoxyphenyl)-2-propenoyl] piperazino-2-propen-1-one (5j)
o
1
Yield 87%; White solid; mp 180-185 C; H NMR (300
MHz, CDCl3): ꢀ: 7.65 (d, 1H, J = 15.10 Hz), 7.62 (d, 1H, J =
15.10 Hz), 7.09 (d, 1H, J = 8.30 Hz), 7.00 (s, 1H),6.90 (d,
1H, J = 8.30 Hz ), 6.74 (d, 1H, J = 14.35 Hz), 6.72 (s, 2H),
6.68 (d, 1H, J = 14.35 Hz), 6.19 (brs, 1H), 3.93 (s, 3H), 3.90
(s, 6H), 3.87 (s, 3H), 3.76 (brs, 8H); 13C NMR (CDCl3, 150
MHz): ꢀ 165.9, 165.5, 153.3, 147.7, 146.8, 143.8, 143.7,
130.4, 127.3, 122.0, 115.5, 114.8, 113.5, 109.9, 105.0, 60.8,
56.1, 55.9, 45.5, 42.1; IR (KBr) (Umax/cm-1): ꢁ 3448 (br),
2928, 1639, 1607, 1572, 1506, 1431, 1384, 1337, 1247,
1125, 1032, 989, 822; ESI-MS: m/z 460 [M+1]+, HRMS
calcd for C26H30N2O7Na [M+Na]+ 505.1950, found
505.1975.
(E)-3-(4-Chlorophenyl)-1-4-[(E)-3-(3,4,5-trimethoxyphenyl)-
2-propenoyl]piperazino-2-propen-1-one (5f)
o
1
Yield 84%; White solid; mp 153-158 C; H NMR (300
MHz, CDCl3): ꢀ: 7.60 (d, 1H, J = 15.10 Hz), 7.56 (d, 1H, J =
14.35 Hz), 7.43 (d, 2H, J = 9.06 Hz), 7.32 (d, 2H, J = 8.30
Hz),6.78 (d, 1H, J = 15.10 Hz ), 6.70 (s, 2H), 6.66 (d, 1H, J
= 13.80), 3.89 (s, 6H), 3.84 (s, 3H), 3.74 (brs, 8H); 13C NMR
(CDCl3, 150 MHz): ꢀ 165.6, 165.3, 153.3, 143.7, 142.2,
139.8, 135.6, 133.3, 130.4, 129.0, 128.9, 116.8, 115.4, 105.0,
60.9, 56.1, 45.3, 42.0; IR (KBr) (Umax/cm-1): ꢁ 3429 (br),
2924, 1644, 1604, 1584, 1491, 1446, 1432, 1340, 1275,
1248, 1156, 1124, 1090, 1038, 1010, 991, 980, 820; ESI-
MS: m/z 471 [M]+, HRMS calcd for C25H27N2O5ClNa
[M+Na]+ 493.1506, found 493.1514.
(E)-3-Phenyl-1-(4-(E)-3-[4-(trifluoromethyl)phenyl]-2-pro-
penoylpiperazino)-2-propen-1-one (5k)
o
1
Yield 76%; White solid; mp 182-187 C; H NMR (500
MHz, CDCl3): ꢀ: 7.82 (s, 3H), 7.72 (d, 2H, J = 14.32 Hz),
7.67 (d, 2H, J = 8.23 Hz), 7.62-7.54 (m, 1H),7.42 (d, 1H, J =
14.32 Hz ), 7.39 (s, 3H), 7.32 (d, 1H, , J = 14.28 Hz ), 3.76
(brs, 4H), 3.72 (brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢀ
165.4, 153.2, 143.8, 143.4, 139.7, 134.8, 130.6, 129.8, 128.4,
127.6, 116.4, 115.2, 105.3, 45.4, 42.1; IR (KBr) (Umax/cm-
(E)-3-(4-Bromophenyl)-1-4-[(E)-3-(3,4,5-trimethoxyphenyl)-
2-propenoyl]piperazino-2-propen-1-one (5g)
o
1
Yield 79%; White solid; mp 155-160 C; H NMR (300
MHz, CDCl3): ꢀ: 7.59 (d, 2H, J = 15.10 Hz), 7.47 (d, 2H, J =
8.30 Hz), 7.36 (d, 2H, J = 7.55 Hz), 6.82 (d, 1H, J = 15.10

Synthesis of Cinnamide Dimers as Potential Antibacterial
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 963
1): ꢀ 3438 (br), 2919, 1644, 1600, 1496, 1435, 1411, 1364,
1328, 1280, 1224, 1167, 1127, 1110, 1068, 1039, 1016, 995,
967, 827, 761; ESI-MS: m/z 415 [M+1]+, HRMS calcd for
C23H21N2O2F3Na [M+Na]+ 437.1452, found 437.1464.
(E)-3-Phenyl-1-4-[(E)-3-phenyl-2-propenoyl]piperazino-2-
propen-1-one (5p)
o
1
Yield 87%; White solid; mp 234-239 C; H NMR (500
MHz, CDCl3): ꢀ: 7.71 (d, 2H, J = 15.12 Hz), 7.51 (d, 4H, J =
5.50 Hz), 7.37-7.36 (m, 6H), 6.85 (d, 2H, J = 15.12 Hz), 3.79
(brs, 4H), 3.72 (brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢁ
165.2, 153.4, 143.4, 142.5, 139.1, 133.8, 130.6, 129.8, 128.4,
127.5, 116.2, 115.7, 105.0, 45.6, 42.3; IR (KBr) (Umax/cm-
1): ꢀ 3430 (br), 2975, 2936, 1645, 1600, 1498, 1453, 1435,
1397, 1330, 1275, 1220, 1038, 986, 976, 761; ESI-MS: m/z
347 [M+1]+, HRMS calcd for C22H23N2O2 [M+H]+
347.1759, found 347.1775.
(E)-3-Phenyl-1-(4-(E)-3-[3-(trifluoromethoxy)phenyl]-2-
propenoylpiperazino)-2-propen-1-one (5l)
o
1
Yield 69%; White solid; mp 162-165 C; H NMR (300
MHz, CDCl3): ꢀ: 7.76 (s, 3H), 7.72 (d, 2H, J = 13.78 Hz),
7.62 (d, 1H, J = 7.90 Hz), 7.48 (s, 2H), 7.41 (d, 1H, J = 7.89
Hz ), 6.92 (d, 2H, J = 13.78 Hz), 6.81 (s, 1H ), 3.78 (brs,
4H), 3.68 (brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢁ
165.7, 165.2, 153.1, 149.4, 143.7, 141.8, 139.6, 136.9, 130.2,
130.3, 126.5, 121.8, 119.6, 118.2, 115.5, 105.2, 45.6, 42.0;
IR (KBr) (Umax/cm-1): ꢀ 3447 (br), 2923, 1645, 1601, 1496,
1452, 1435, 1364, 1279, 1219, 1167, 1041, 988, 973, 849,
802, 762, 700, 681; ESI-MS: m/z 431 [M+1]+, HRMS calcd
for C23H21N3O3F3Na [M+Na]+ 453.1401, found 453.1424.
(E)-3-(3,4-Difluorophenyl)-1-4-[(E)-3-phenyl-2-propenoyl]
piperazino-2-propen-1-one (5q)
o
1
Yield 90%; White solid; mp 249-254 C; H NMR (300
MHz, CDCl3): ꢀ: 7.57 (d, 2H, J = 15.62 Hz), 7.53 (m, 2H),
7.38-7.31 (m, 5H), 7.20-7.19 (m, 1H), 6.74 (d, 2H, J = 15.62
Hz), 3.87 (brs, 4H), 3.64 (brs, 4H); 13C NMR (DMSO-d6,
150 MHz): ꢁ 165.6, 165.2, 153.4, 143.6, 141.3, 130.4, 124.5,
124.3, 117.8, 117.7, 117.3, 115.8, 115.7, 115.4, 105.2, 45.5,
42.2; IR (KBr) (Umax/cm-1): ꢀ 3435 (br), 3032, 2858, 1647,
1601, 1515, 1498, 1434, 1299, 1276, 1220, 1115, 1039, 976,
817, 763; ESI-MS: m/z 383 [M+1]+, HRMS calcd for
C22H21N2O2F2 [M+H]+ 383.1571, found 383.1569.
(E)-3-(4-Fluorophenyl)-1-4-[(E)-3-phenyl-2-propenoyl]pip-
erazino-2-propen-1-one (5m)
o
1
Yield 74%; White solid; mp 151-155 C; H NMR (300
MHz, CDCl3): ꢀ: 7.67 (d, 1H, J = 15.17 Hz), 7.58 (d, 1H, J =
15.17 Hz), 7.52-7.42 (m, 2H), 7.38-7.32 (m, 3H), 7.27 (d,
2H, J = 7.82 Hz ), 7.18 (d, 2H, J = 8.02 Hz), 6.84 (d, 1H, J =
15.16 Hz ), 6.68 (d, 1H, J = 15.17 Hz), 3.65 (brs, 4H), 3.42
(brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢁ 165.6, 165.3,
153.2, 142.8, 141.2, 139.8, 134.6, 133.2, 130.2, 129.3, 128.7,
116.5, 115.0, 105.8, 45.3, 42.1; IR (KBr) (Umax/cm-1): ꢀ
3428, (br), 2930, 1636, 1614, 1490, 1433, 1410, 1360, 1325,
1270, 1210, 1152, 1120, 1090, 1012, 990, 960, 820, 786;
ESI-MS: m/z 365 [M+1]+, HRMS calcd for C22H21N2O2FNa
[M+Na]+ 387.1484, found 387.1474.
(E)-3-(3,4-Dichlorophenyl)-1-4-[(E)-3-phenyl-2-propenoyl]
piperazino-2-propen-1-one (5r)
o
1
Yield 69%; White solid; mp 230-235 C; H NMR (300
MHz, CDCl3): ꢀ: 7.62 (d, 2H, J = 15.42 Hz), 7.58 (m, 2H),
7.42-7.37 (m, 5H), 7.32-7.20 (m, 1H), 6.89 (d, 2H, J = 15.42
Hz), 3.82 (brs, 4H), 3.54 (brs, 4H); 13C NMR (DMSO-d6,
150 MHz): ꢁ 165.4, 165.0, 153.4, 143.7, 141.6, 130.4, 124.6,
124.7, 117.8, 117.4, 117.2, 115.9, 115.6, 115.2, 105.0, 45.2,
42.0; IR (KBr) (Umax/cm-1): ꢀ 3430 (br), 2976, 1643, 1602,
1475, 1439, 1397, 1383, 1218, 1171, 1075, 1036, 983, 850,
808, 762; ESI-MS: m/z 415 [M]+, HRMS calcd for
C22H20Cl2N2O2Na [M+H]+ 438.0752, found 438.0764.
(E)-3-(4-Chlorophenyl)-1-4-[(E)-3-phenyl-2-propenoyl]pip-
erazino-2-propen-1-one (5n)
o
1
Yield 84%; White solid; mp 250-255 C; H NMR (500
MHz, CDCl3): ꢀ: 7.83 (s, 1H), 7.78 (d, 2H, J = 16.79 Hz),
7.77 (s, 1H), 7.58-7.51 (m, 4H), 7.47-7.41 (m, 3H ), 7.36 (d,
1H, J = 16.79 Hz), 7.32 (d, 1H, J = 16.79 Hz ), 3.80 (brs,
4H), 3.68 (brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢁ
165.5, 165.2, 152.3, 144.7, 142.6, 139.9, 135.4, 132.3, 130.4,
129.3, 128.6, 117.8, 115.2, 105.3, 45.1, 42.0; IR (KBr)
(Umax/cm-1): ꢀ 3434 (br), 3031, 2861, 1646, 1599, 1491,
1435, 1405, 1294, 1274, 1217, 1035, 1012, 988, 818, 789,
763; ESI-MS: m/z 381 [M]+, HRMS calcd for C22H23ClN2O2
[M+H]+ 381.1380, found 381.1391.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-4-[(E)-3-phenyl-2-
propenoyl]piperazino-2-propen-1-one (5s)
o
1
Yield 83%; White solid; mp 248-253 C; H NMR (300
MHz, CDCl3): ꢀ: 7.64 (d, 1H, J = 15.12 Hz), 7.62 (d, 1H, J =
15.12 Hz), 7.53 (m, 2H), 7.36-7.32 (m, 3H), 7.09 (d, 1H, J =
8.23 Hz ), 7.00 (s, 1H), 6.89 (d, 1H, J = 8.23 Hz), 6.74 (d,
1H, J = 15.12 Hz), 6.68 (d, 1H, J = 15.12 Hz), 3.87 (s, 3H),
3.64 (brs, 8H); 13C NMR (DMSO-d6, 150 MHz): ꢁ 165.7,
165.3, 153.1, 147.5, 146.8, 143.7, 143.4, 130.4, 127.3, 122.2,
115.3, 114.8, 113.2, 109.9, 105.3, 56.7, 45.4, 42.3; IR (KBr)
(Umax/cm-1): ꢀ 3428 (br), 2977, 1647, 1600, 1490, 1432,
1368, 1280, 1212, 1170, 1032, 986, 852, 800, 760, 680; ESI-
MS: m/z 393 [M+1]+, HRMS calcd for C23H24Cl2N2O4Na
[M+H]+ 415.3720, found 415.3732.
(E)-3-(4-Bromophenyl)-1-4-[(E)-3-phenyl-2-propenoyl]pip-
erazino-2-propen-1-one (5o)
o
1
Yield 78%; White solid; mp 248-252 C; H NMR (300
MHz, CDCl3): ꢀ: 7.72 (s, 3H), 7.70 (d, 2H, J = 13.62 Hz),
7.60 (d, 2H, J = 8.30 Hz ), 7.55-7.42 (m, 1H), 7.40 (d, 1H, J
= 13.59 Hz ), 7.39 (s, 3H), 7.27 (d, 1H, J = 13.59 Hz ), 3.76
(brs, 4H), 3.62 (brs, 4H); 13C NMR (DMSO-d6, 150 MHz): ꢁ
165.5, 165.2, 151.3, 142.8, 142.0, 138.6, 135.6, 133.3, 130.6,
129.3, 127.7, 115.4, 115.0, 105.4, 45.2, 42.1; IR (KBr)
(Umax/cm-1): ꢀ 3436 (br), 3030, 2860, 1647, 1600, 1486,
1455, 1434, 1401, 1273, 1216, 1035, 1008, 986, 814, 786;
ESI-MS: m/z 425 [M]+, HRMS calcd for C22H21BrN2O2Na
[M+H]+ 448.0639, found 448.0653.
(E)-3-[3-(Trifluoromethoxy)phenyl]-1-(4-(E)-3-[4-(trifluo-
romethyl)phenyl]-2-propenoylpiper-azino)-2-propen-1-one
(5t)
o
1
Yield 76%; White solid; mp 145-150 C; H NMR (300
MHz, CDCl3): ꢀ: 7.71 (d, 2H, J = 15.29 Hz), 7.63 (s, 4H),
7.43-7.37 (m, 3H), 7.21 (s, 1H), 6.88 (d, 1H, J = 16.80 Hz ),
6.85 (d, 1H, J = 16.05 Hz), 3.75 (s, 8H); 13C NMR (CDCl3,
150 MHz): ꢁ 165.4, 165.1, 153.4, 149.5, 143.5, 141.5, 140.4,

964 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Kamal et al.
136.9, 130.4, 130.3, 126.3, 121.8, 119.9, 118.1, 115.4, 105.4,
45.6, 42.0; IR (KBr) (Umax/cm-1): ꢀ 3446 (br), 2921, 1646,
1604, 1491, 1448, 1437, 1330, 1278, 1218, 1168, 1068,
1039, 1017, 987, 848, 829, 803, 748; ESI-MS: m/z 499
[M+1]+, HRMS calcd for C24H20N2O3F6Na [M+H]+
521.1275, found 521.1266.
HRMS calcd for C23H20BrN2O2F3Na [M+H]+ 516.3120,
found 516.3108.
(E)-3-(3,4-Difluorophenyl)-1-(4-(E)-3-[4-(trifluoromethyl)
phenyl]-2-propenoylpiperazino)-2-propen-1-one (5y)
o
1
Yield 65%; White solid; mp 215-220 C; H NMR (300
MHz, CDCl3): ꢀ: 7.70 (d, 1H, J = 15.86 Hz), 7.64 (s, 4H),
7.59 (d, 1H, J = 15.10 Hz), 7.43-7.34 (m, 2H), 7.18 (s, 1H),
6.94 (d, 1H, J = 15.86 Hz ), 6.80 (d, 1H, J = 15.10 Hz ), 3.77
(brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢁ 165.7, 165.1,
153.2, 143.7, 141.3, 130.1, 124.6, 124.3, 117.9, 117.6, 117.2,
115.9, 115.6, 115.3, 105.0, 45.3, 42.1; IR (KBr) (Umax/cm-
1): ꢀ 3435 (br), 2976, 1649, 1612, 1475, 1435, 1413, 1397,
1383, 1365, 1325, 1270, 1219, 1171, 1113, 1067, 1037, 990,
850, 820; ESI-MS: m/z 451 [M+1]+, HRMS calcd for
C23H19N2O2F5Na [M+Na]+ 473.1264, found 473.1257.
(E)-3-[4-(Trifluoromethyl)phenyl]-1-(4-(E)-3-[4-(trifluoro-
methyl)phenyl]-2-propenoylpiperaz-ino)-2-propen-1-one
(5u)
o
1
Yield 80%; White solid; mp 279-284 C; H NMR (300
MHz, CDCl3): ꢀ: 7.72 (d, 2H, J = 15.12 Hz), 7.51 (d, 4H, J =
5.50 Hz), 7.37-7.36 (m, 6H), 6.85 (d, 2H, J = 15.12 Hz ),
3.79 (brs, 4H), 3.72 (brs, 4H); 13C NMR (CDCl3, 150 MHz):
ꢁ 165.8, 153.2, 143.4, 139.6, 130.2, 115.6, 105.2, 45.6, 42.0;
IR (KBr) (Umax/cm-1): ꢀ 3432 (br), 2929, 1650, 1617, 1577,
1435, 1413, 1364, 1323, 1277, 1126, 1157, 1111, 1066,
1035, 1016, 987, 831, 749; ESI-MS: m/z 483 [M+1]+,
HRMS calcd for C24H20N2O2F6Na [M+H]+ 505.1326, found
505.1336.
(E)-3-(3,4-Dichlorophenyl)-1-(4-(E)-3-[4-(trifluoromethyl)
phenyl]-2-propenoylpiperazino)-2-propen-1-one (5z)
o
1
Yield 72%; White solid; mp 230-235 C; H NMR (300
MHz, CDCl3): ꢀ: 7.69 (d, 1H, J = 15.10 Hz), 7.64 (s, 4H),
7.59 (d, 1H, J = 15.86 Hz), 7.44 (s, 1H), 7.36 (dd, 2H, J =
8.30, 6.04 Hz), 6.93 (d, 1H, J = 15.86 Hz ), 6.85 (d, 1H, J =
15.10 Hz), 3.76 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢁ
165.7, 165.2, 153.2, 143.6, 141.4, 130.2, 124.7, 124.3, 117.8,
117.5, 117.2, 115.9, 115.5, 115.3, 105.0, 45.6, 42.1; IR
(KBr) (Umax/cm-1): ꢀ 3435 (br), 2977, 2938, 1648, 1612,
1475, 1434, 1412, 1397, 1384, 1364, 1325, 1281, 1215,
1171, 1125, 1066, 1037, 990, 850, 826; ESI-MS: m/z 483
[M]+, HRMS calcd for C23H19N2O2F3Cl2Na [M+Na]+
505.0673, found 505.0671.
(E)-3-(4-Fluorophenyl)-1-(4-(E)-3-[4-(trifluoromethyl)
phenyl]-2-propenoylpiperazino)-2-propen-1-one (5v)
o
1
Yield 73%; White solid; mp 225-230 C; H NMR (300
MHz, CDCl3): ꢀ: 7.70 (d, 1H, J = 15.10 Hz), 7.64 (d, 1H, J =
15.10 Hz), 7.60 (s, 4H), 7.54-7.47 (m, 2H), 7.06 (t, 2H, J =
8.30 Hz ), 6.93 (d, 1H, J = 15.10 Hz ), 6.76 (d, 1H, J = 15.86
Hz ), 3.75 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢁ 165.3,
165.2, 153.1, 142.6, 141.0, 139.6, 134.7, 133.1, 130.4, 129.5,
128.4, 116.7, 115.2, 105.9, 45.2, 42.0; IR (KBr) (Umax/cm-
1): ꢀ 3422 (br), 2977, 1649, 1613, 1475, 1433, 1412, 1384,
1364, 1326, 1277, 1215, 1171, 1158, 1114, 1067, 1037, 990,
850, 807; ESI-MS: m/z 433 [M+1]+, HRMS calcd for
C23H20N2O2F4Na [M+H]+ 455.3067, found 455.3055.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(4-(E)-3-[4-(trifluo-
romethyl)phenyl]-2-propenoylpipera zino)-2-propen-1-one
(6a)
(E)-3-(4-Chlorophenyl)-1-(4-(E)-3-[4-(trifluoromethyl)
phenyl]-2-propenoylpiperazino)-2-propen-1-one (5w)
o
1
Yield 59%; White solid; mp 260-265 C; H NMR (300
MHz, CDCl3): ꢀ: 7.72 (d, 1H, J = 15.32 Hz), 7.65 (s, 4H),
7.62 (d, 1H, J = 15.32 Hz), 7.06 (d, 1H, J = 8.30 Hz), 6.92
(s, 1H), 6.87 (d, 1H, J = 8.30 Hz ), 6.76 (d, 1H, J = 15.32 Hz
), 6.65 (d, 1H, J = 15.32 Hz ), 6.06 (brs, 1H), 3.98 (s, 3H),
3.78 (brs, 8H); 13C NMR (CDCl3, 150 MHz): ꢁ 165.6, 165.1,
153.1, 147.7, 146.4, 143.8, 143.3, 130.4, 127.1, 122.4, 115.5,
114.6, 113.4, 110.6, 105.0, 55.8, 45.5, 42.0; IR (KBr)
(Umax/cm-1): ꢀ 3436 (br), 2978, 1640, 1605, 1496, 1432,
1360, 1280, 1210, 1172, 1036, 982, 850, 807, 760, 684; ESI-
MS: m/z 461 [M+1]+, HRMS calcd for C24H23N2O4F3Na
[M+Na]+ 483.4422, found 483.4412.
o
1
Yield 84%; White solid; mp 280-285 C; H NMR (500
MHz, CDCl3): ꢀ: 7.72 (d, 1H, J = 14.67 Hz), 7.65 (d, 1H, J =
14.67 Hz), 7.64 (s, 4H), 7.46 (d, 2H, J = 7.82 Hz), 7.35 (d,
2H, J = 8.80 Hz ), 6.92 (d, 1H, J = 15.65 Hz ), 6.82 (d, 1H, J
= 15.65 Hz ), 3.81 (brs, 4H), 3.73 (brs, 4H); 13C NMR
(CDCl3, 150 MHz): ꢁ 165.4, 165.2, 152.4, 144.6, 142.5,
140.2, 135.6, 132.4, 130.5, 129.6, 128.6, 117.6, 115.2, 105.1,
45.3, 42.1; IR (KBr) (Umax/cm-1): ꢀ 3421 (br), 2925, 1649,
1615, 1492, 1433, 1412, 1364, 1325, 1277, 1216, 1157,
1123, 1089, 1066, 1011, 991, 960, 821, 788; ESI-MS: m/z
471 [M+Na]+, HRMS calcd for C23H20N2O2F4Na [M+H]+
471.8612, found 471.8604.
ACKNOWLEDGEMENT
(E)-3-(4-Bromophenyl)-1-(4-(E)-3-[4-(trifluoromethyl)
phenyl]-2-propenoylpiperazino)-2-prop- -en-1-one (5x)
The authors (G. R. K, P. R, A. V. S and B. S) thank to
CSIR and UGC, New Delhi for financial assistance.
o
1
Yield 78%; White solid; mp 290-295 C; H NMR (300
MHz, CDCl3): ꢀ: 7.71 (d, 1H, J = 15.10 Hz), 7.63 (s, 4H),
7.61 (d, 1H, J = 16.61 Hz), 7.50 (d, 2H, J = 7.55 Hz), 7.37
(d, 2H, J = 8.30 Hz ), 6.91 (d, 1H, J = 16.61 Hz ), 6.82 (d,
1H, J = 16.61 Hz ), 3.75 (brs, 8H); 13C NMR (CDCl3, 150
MHz): ꢁ 165.3, 165.1, 151.5, 142.6, 142.2, 138.7, 135.3,
133.6, 130.6, 129.5, 127.4, 115.2, 115.2, 105.2, 45.1, 42.2;
IR (KBr) (Umax/cm-1): ꢀ 3436 (br), 2926, 1649, 1615, 1488,
1432, 1412, 1399, 1363, 1324, 1277, 1216, 1122, 1067,
1041, 1006, 991, 832, 817, 749; ESI-MS: m/z 493 [M]+,
REFERENCES
[1]
Walsh, C.T. Where will new antibiotics come from?. Nat. Rev.
Microbiol, 2003, 1, 65-70.
[2]
Grundmann, H.; Aires-de-Sousa, M.; Boyce, J.; Tiemersma, E.
Emergence and resurgence of meticillin-resistant Staphylococcus
aureus as a public-health threat. Lancet 2006, 368, 874-885.
Hemmerle, H.; Burger, H.; Below, P.; Schubert, G.; Rippel, R.;
Schindler, P.W.; Paulus, E.; Herling. A.W. Chlorogenic acid and
synthetic chlorogenic acid derivatives: Novel inhibitors of hepatic
[3]

Synthesis of Cinnamide Dimers as Potential Antibacterial
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 965
glucose-6-phosphate translocase. J. Med. Chem., 1997, 40, 137-
145.
piperazine hydroxamates and their histone deacetylase (HDAC)
inhibitory activity. Bioorg. Med. Chem. Lett. 2010, 20, 3906-3910.
Galisteo, J.; Navarro, P.; Campayo, L.; Yunta, M.J.R.; Gomez-
Contreras, F.; Villa-Pulgarin, J.A.; Sierra, B.G.; Mollinedo, F.;
Gonzalez, J.; Garcia-Espana, E. Synthesis and cytotoxic activity of
[4]
[5]
Lapeyre, C.; Delomenede, M.; Bedos-Belval, F.; Duran, H.; Negre-
Salvayre, A.; Baltas, M. Design, synthesis and evaluation of
pharmacological properties of cinnamic derivatives as
antiatherogenic agent. J. Med. Chem., 2005, 48, 8115-8124.
Doherty, E.M.; Fotsch, C.; Bo, Y.; Chakrabarti, P.P.; Chen, N.;
Gavva, N.; Han, N.; Kelly, M.G.; Kincaid, J.; Klionsky, L.; Liu, Q.;
Ognyanov, V.I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M.H.;
Treanor, J.J.S. Discovery of potent, orally available vanilloid
receptor-1 antagonists. Structure-activity relationship of N-aryl
cinnamides. J. Med. Chem., 2005, 48, 71-90.
Winn, M.; Reilly, E.B.; Liu, G.; Huth, J.R.; Jae, H.; Freeman, J.;
Pei, Z.; Xin, Z.; Lynch, J.; Kester, J.; von Geldern, T.W.; Leitza,
S.; DeVries, P.; Dickinson, R.; Mussatto, D.; Okasinski, G.F.
Discovery of novel p-arylthio cinnamides as antagonists of
leukocyte function-associated antigen-1/intercellular adhesion
molecule-1 interaction. 4. Structure-activity relationship of
substituents on the benzene ring of the cinnamide. J. Med. Chem.,
2001, 44, 4393-4403.
[21]
a
new potential DNA bisintercalator: 1,4-Bis{3-[N-(4-
chlorobenzo[g]phthalazin-1-yl)aminopropyl]}piperazine. Bioorg.
Med. Chem. 2010, 18, 5301-5309.
[22]
[23]
[24]
Yang, J.S.; Song, D.; Lee, B.; Ko, W.J.; Park, S.; Won, M.; Lee,
K.; Kim, H.M.; Han, G. Synthesis and biological evaluation of
novel aliphatic amido-quaternary ammonium salts for anticancer
chemotherapy: part I. Eur. J. Med. Chem. 2011, 46, 2861-2866.
Lee, Y.B.; Gong, Y.; Yoon, H.; Ahn, C.; Jeon, M.; Kong, J.
Synthesis and anticancer activity of new 1-[(5 or 6-substituted 2-
alkoxyquinoxalin-3-yl)aminocarbonyl]-4-(hetero)arylpiperazine
derivatives. Bioorg. Med. Chem. 2010, 18, 7966-7974.
Zou, H.; Wu, H.; Zhang, X.; Zhao, Y.; Stockigt, J.; Lou, Y.; Yu, Y.
Synthesis, biological evaluation, and structure-activity relationship
study of novel cytotoxic aza-caffeic acid derivatives. Bioorg. Med.
Chem. 2010, 18, 6351-6359.
[6]
[7]
Balsamo, A.; Crotti, P.; Lapucci, A.; Macchia, B.; Macchia, F.;
Cuttica, A.; Passerini, N. Structure--activity relationship in
cinnamamides. 3. Synthesis and anticonvulsant activity evaluation
[25]
[26]
Guo, C.C.; Tong, R.B.; Li, K.L. Chloroalkyl piperazine and
nitrogen mustard porphyrins: synthesis and anticancer activity.
Bioorg. Med. Chem. 2004, 12, 2469-2475.
Choi, Y.; Baek, D.J.; Seo, S.H.; Lee, J.K.; Pae, A.N.; Cho, Y.S.;
Min, S-J. Facile synthesis and biological evaluation of 3,3-
diphenylpropanoyl piperazines as T-type calcium channel blockers.
Bioorg. Med. Chem. Lett. 2011, 21, 215-219.
Kam, Y.L.; Rhee, H-K.; Rhim, H.; Back, S.K.; Na, H.S.; Choo, H-
Y.P. Synthesis and T-type calcium channel blocking activity of
novel diphenylpiperazine compounds, and evaluation of in vivo
analgesic activity. Bioorg. Med. Chem. 2010, 18, 5938-5944.
Park, J.H.; Choi, J.K.; Lee, E.; Lee, J.K.; Rhim, H.; Seo, S.H.; Kim,
Y.; Reddy, M.D.; Pae, A.N.; Kang, J.; Roh, E.J. Lead discovery
and optimization of T-type calcium channel blockers. Bioorg. Med.
Chem. 2007, 15, 1409-1419.
Khalaj, A.; Nakhjiri, M.; Negahbani, A.S.; Samadizadeh, M.;
Firoozpour, L.; Rajabalian, S.; Samadi, N.; Faramarzi, M.A.;
Adibpour, N.; Shafiee, A.; Foroumadi, A. Discovery of a novel
nitroimidazolyl–oxazolidinone hybrid with potent anti Gram-
positive activity: Synthesis and antibacterial evaluation. Eur. J.
Med. Chem. 2011, 46, 65-70.
Liu, X.L.; Xu, Y.J.; Go, M.L. Functionalized chalcones with basic
functionalities have antibacterial activity against drug sensitive
Staphylococcus aureus. Eur. J. Med. Chem. 2008, 43, 1681-1687.
Ting, P.C.; Lee, J.F.; Albanese, M.M.; Wu, J.; Aslanian, R.;
Favreau, L.; Nardo, C.; Korfmacher, W.A.; West, R.E.; Williams,
S.M.; Anthes, J.C.; Rivelli, M.A.; Corboz, M.R.; Hey, J.A. The
synthesis and structure–activity relationship of 4-benzimidazolyl-
piperidinylcarbonyl-piperidine analogs as histamine H3 antagonists.
Bioorg. Med. Chem. Lett. 2010, 20, 5004-5008.
Xu, J.; Cao, Y.; Zhang, J.; Yu, S.; Zou, Y.; Chai, X.; Wu, Q.;
Zhang, D.; Jiang, Y.; Sun, Q. Design, synthesis and antifungal
activities of novel 1,2,4-triazole derivatives. Eur. J. Med. Chem.
2011, 46, 3142-3148.
Chaudhary, P.; Kumar, R.; Verma, A.K.; Singh, D.; Yadav, V.;
Chhillar, A.K.; Sharma, G.L.; Chandra, R. Synthesis and
antimicrobial activity of N-alkyl and N-aryl piperazine derivatives.
Bioorg.Med. Chem. 2006, 14, 1819-1826.
Linday, E.M. Practical Introduction to Microbiology, E & F.N.
Spon: UK 1962; 177.
of
some
derivatives
of
(E)-
and
(Z)-m-
(trifluoromethyl)cinnamamide. J. Med. Chem., 1981, 24, 525-532.
Chung, H.S.; Shin, J.C. Characterization of antioxidant alkaloids
and phenolic acids from anthocyanin-pigmented rice (Oryza sativa
cv. Heugjinjubyeo). Food. Chem., 2007, 104, 1670-1677.
Bezerra, D.P.; Castro, F.O.; Alves, A.P.N.N.; Pessoa, C.; Moraes,
M.O.; Silveira, E.R.; Lima, M.A.S.; Elmiro, F.J.M.; Costa-Lotufo,
L.V. In vivo growth-inhibition of Sarcoma 180 by piplartine and
piperine, two alkaloid amides from Piper. Braz. J. Med. Biol. Res.,
2006, 39, 801-807.
Naz, S.; Ahmed, S.; Rasool, S.A.; Sayeed, S.A.; Siddiqi, R.
Antibacterial activity directed isolation of compounds from
Onosma hispidum. Microb. Res., 2006, 161, 43-48.
Carvalho, S.A.; da Silva, E.F.; de Souza, M.V.N.; Lorenco, M.C.S.;
Vicente, F.R. Synthesis and antimycobacterial evaluation of new
trans-cinnamic acid hydrazide derivatives. Bioorg. Med. Chem.
Lett. 2008, 18, 538-541.
Narasimhan, B.; Belsare, D.; Pharande, D.; Mourya, V.; Dhake, A.
Esters, amides and substituted derivatives of cinnamic acid:
synthesis, antimicrobial activity and QSAR investigations. Eur. J.
Med. Chem. 2004, 39, 827-834.
Rastogi, N.; Goh, K.S.; Horgen, L.; Barrow, W.W. Synergistic
activities of antituberculous drugs with cerulenin and trans-
cinnamic acid against Mycobacterium tuberculosis. FEMS
Immunol. Med. Microbiol. 1998, 21, 149-157.
De, P.; Yoya, G.B.; Constant, P.; Bedos-Belval, F.; Duran, H.;
Saffon, N.; Daffe, M.; Baltas, M. Design, synthesis, and biological
evaluation of new cinnamic derivatives as antituberculosis agents.
J. Med. Chem. 2011, 54, 1449-1461.
Nowakowska, Z. A review of anti-infective and anti-inflammatory
chalcones. Eur. J. Med. Chem. 2007, 52, 125-137.
[8]
[9]
[27]
[28]
[29]
[10]
[11]
[12]
[13]
[14]
[30]
[31]
[32]
[33]
[15]
[16]
Kamal, A.; Reddy, P.S.; Reddy, D.R.; Laxman, E. DNA binding
potential
and
cytotoxicity
of
newly
designed
pyrrolobenzodiazepine dimers linked through a piperazine side-
armed-alkane spacer. Bioorg. Med. Chem. 2006, 14, 385-394.
Tomar, V.; Bhattacharjee, G.; Kamaluddin.; Kumar, A. Synthesis
and antimicrobial evaluation of new chalcones containing
piperazine or 2,5-dichlorothiophene moiety. Bioorg. Med. Chem.
Lett. 2007, 17, 5321-5324.
Kamal, A.; Reddy, M.K.; Ramaiah, M.J.Rajender, Reddy, J.S.;
Srikanth, Y.V.V.; Dastagiri, D.; Bharathi, E.V.; Pushpavalli,
S.N.C.V.L.; Sarma, P.; Pal-Bhadra, M. Synthesis and biological
evaluation of estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine
(PBD) conjugates as potential anticancer agents. Bioorg. Med.
Chem. 2011, 19, 2565-2581.
[17]
[18]
[34]
[35]
[36]
Perez, V.; Paul, M.; Bazerque, P. An Antibiotic assay by the agar
well diffusion method Acta. Bio. Med. Exz. 1990, 15, 113-115.
Yoya, G.K.; Belval, B.F.; Constant, P.; Duran, H.; Daffe M.;
Baltas, M. Synthesis and evaluation of a novel series of pseudo-
cinnamic derivatives as antituberculosis agents. Bioorg. Med.
Chem. Lett. 2009, 19, 341-343.
Kalemba, D.; Kunicka, A. Antibacterial and antifungal properties
of essential oils. Curr. Med. Chem. 2003, 10, 813-829.
National committee for clinical laboratory standards. Performance
standards for antimicrobial disks susceptibility tests, approved
standard, 8th ed, M2-A8 v. 23, n. 1 replaces M2-A7, v. 20, n.1.
NCCLS: Wayne, PA, USA, 2003.
[37]
[38]
[19]
[20]
Kamal, A.; Shetti, R.V.C.R.N.C.; Ramaiah, M.J.; Swapna, P.;
Reddy, K.S.; Reddy, A.M.; Rao, M.P.N.; Chourasia, M.; Sastry,
G.N.; Juvekar, A.; Zingde, S.; Sarma, P.; Pushpavalli, S.N.C.V.L.;
Pal-Bhadra,
M. Carbazole-pyrrolo[2,1-c][1,4]benzodiazepine
conjugates: Design, synthesis, and biological evaluation. Med.
Chem. Commun. 2011, 2, 780-788.
Chetan, B.; Bunha, M.; Jagrat, M.; Sinha, B.N.; Saiko, P.; Graser,
G.; Szekeres, T.; Raman, G.; Rajendran, P.; Moorthy, D.; Basu, A.;
Jayaprakash, V. Design, synthesis and anticancer activity of
[39]
Kamal, A.; Adil, S.F.; Tamboli, J.R.; Siddardha, B.; Murthy,
U.S.N. Synthesis of coumarin linked naphthalimide conjugates as
potential anticancer and antimicrobial agents. Letters in Drug
Design & Discovery, 2009, 6, 201-209.