Synthesis and antimicrobial evaluation of new chalcones containing piperazine or 2,5-dichlorothiophene moiety

Article abstract of DOI:10.1016/j.bmcl.2007.08.021

Two new series of chalcones have been synthesized by reacting 1-(4-piperazin-1-yl-phenyl)ethanone and 1-(2,5-dichloro-3-thienyl)-1-ethanone with different substituted benzaldehydes in turn by Claisen-Schmidt condensation. The compounds have been character

Full text of DOI:10.1016/j.bmcl.2007.08.021

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5321–5324
Synthesis and antimicrobial evaluation of new chalcones
containing piperazine or 2,5-dichlorothiophene moiety
V. Tomar,a G. Bhattacharjee,a,* Kamaluddina and Ashok Kumarb
aDepartment of Chemistry, Indian Institute of Technology Roorkee (IIT R), Roorkee 247667, UA, India
bDepartment of Pharmacology, LLRM Medical College, Meerut, UP, India
Received 15 March 2007; revised 22 July 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract—Two new series of chalcones have been synthesized by reacting 1-(4-piperazin-1-yl-phenyl)ethanone and 1-(2,5-dichloro-
3-thienyl)-1-ethanone with different substituted benzaldehydes in turn by Claisen–Schmidt condensation. The compounds have been
characterized by IR, 1H NMR spectral and microanalysis data. All the synthesized compounds have been evaluated for antimicro-
bial activity. Some of these derivatives are potentially active against Gram-positive bacteria, Staphylococcus aureus and Escherichia
coli while the most potent compound (1) in this study showed MIC50 value of 2.22 lg/mL against Candida albicans.
Ó 2007 Elsevier Ltd. All rights reserved.
Infectious diseases caused by bacteria, fungi, viruses and
parasites are still a major threat to public health, despite
tremendous progress in medicinal chemistry. The impact
is more acute in developing countries due to nonavail-
ability of desired medicines and emergence of wide-
spread drug resistance.1 Antimicrobial resistance
settings have failed to address this essential aspect of
drug usage.2 Specifically, multi-drug-resistant Gram-po-
sitive bacteria including methicillin-resistant Staphylo-
coccus aureus (MRSA), Staphylococcus epidermidis
(MRSE) and vancomycin resistant enterococci (VRE)
are of major concern.3 There are a number of clinically
efficacious antibiotics becoming less effective due to
development of resistance. The bacterial resistance to
antibiotics is a major health problem and resulted in
emergence of an endless area for study and debate.
Chalcones, considered as the precursor of flavonoids
and isoflavonoids, are abundant in edible plants. Chem-
ically they consist of open-chain flavonoids in which the
two aromatic rings are joined by a three-carbon a,b-
unsaturated carbonyl system. Studies revealed that com-
pounds with chalcone-based structure have shown an
array of pharmacological activities, such as antiproto-
zoal,4–6 antifungal,7 anti-inflammatory,8–10 antileishma-
nial,11–14 nitric oxide inhibition,15 inhibition of the
production of interleukin-116 and anticancer17 activities.
Licochalcone A (Fig. 1), an oxygenated chalcone iso-
lated from the root of Chinese liquorice,18 was shown
to possess activity against Gram-positive strains of
bacteria.19,20
Piperazinyl linked Ciprofloxacin dimers are reported to
be potent antibacterial agents against resistant strains, a
novel class of mixed D2/D4 receptor antagonists, dual
calcium antagonist, antimalarial agents and potential
antipsychotic agents.21 Recently, piperazine derivatives
containing tetrazole nucleus have been reported as anti-
fungal agents.22
The requirement is to synthesize novel molecules having
good potential with high therapeutic index. Keeping in
view the diverse therapeutic activities of chalcones for
the preparation of bioactive heterocycles, it was contem-
plated to synthesize a novel series of chalcones. Atten-
HO
OH
Keywords: Chalcones; Claisen–Schmidt reaction; Antibacterial;
Antifungal.
O
O
*
Corresponding author. Tel.: +91 1332 285793; fax: +91 1332
273560; e-mail: wordgfcy@iitr.ernet.in
Figure 1. Licochalcone A.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.08.021

5322
V. Tomar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5321–5324
R'
R'
tion has been focused on the modification of the aceto-
phenone moiety of chalcones to achieve a new antimi-
crobial profile. The present study describes synthesis of
the title compounds and screening them for their
in vitro microbial activity.
H
NaOH
MeOH
R
R
O
O
=
O
Cl
and
N
H
R
A series of substituted chalcones has been prepared by
introducing new functionality 40-piperazinoacetophe-
none or 3-acetyl-2,5-dichlorothiophene in place of ace-
tophenone. All the chalcone derivatives have been
prepared by the Claisen–Schmidt condensation using
catalytic amount of sodium hydroxide in ethanol.23
The residues were treated with 10% HCl in methanol
to obtain the corresponding chalcones in good yield
(Table 1). All spectral data (IR, 1H NMR and MS)
obtained were consistent with the structures assigned.
S
Cl
X
and
=
CH
CH
R'
X
=
H, 3-CH3, 4-CH3, 4-OCH3, 3,4,5-trimethoxy, 4-Cl, 3-NO2,
Scheme 1. Synthesis of chalcones.
The spectral data confirm the presence of AC@O and
AC@CA and benzene ring (IR at 1670–1643, 1583–
1510, 815 and 840 cmꢀ1). Similarly NMR multiplets in
the range of (6.7–8) ppm also confirm the presence of
aromatic rings. Coupling constant values in NMR show
that trans isomer has formed. The synthesis of A (1–8)
and B (9–16) is depicted in Scheme 1.
methanol) was also run to note the activity of the blank
(solvent). The above-mentioned standard drug was also
screened under similar conditions for comparison. All
the compounds were also screened for their in vitro anti-
fungal activity against Candida albicans, C. albicans
ATCC 10231 and Candida glabrata. The antifungal
activities of test compounds were compared to that of
standard fluconazole. The results of these experiments
are summarized in Tables 2 and 3. Biological screening
results were mentioned in mm, showing diameter of inhi-
bition zone (i.e.) and these are categorised, as 0–6 mm
for mild, 7–13 mm for moderate and 14–26 mm for effi-
cacy, respectively.
The synthesized compounds were tested for their anti-
bacterial activity by adopting (Cup-plate method)24 agar
well diffusion technique. The following bacterial cultures
were used for anti-bacterial activity studies.
(i) S. aureus 209 p, (ii) E. coli ESS 2231, (iii) Proteus vul-
garis, (iv) Klebsiella pneumoniae and (v) Aspergillus
fumigatus.
From Table 2 it is evident that compounds 7, 9, 10, 12
and 15 indicated good activity against S. aureus (24–
26), 9 and 15 for E. coli while the remaining compounds
are statistically equivalent in antibacterial activity
against their microorganisms with moderate activity
(14–24). Most of the tested compounds possess potent
in vitro activity against P. vulgaris, K. pneumoniae and
A. fumigatus but were less active than the reference
drugs.
Ciprofloxacin was used as the standard drug. Nutrient
agar was poured onto the sterilized petri dishes (20–
25 mL: each petri dish). The poured material was al-
lowed to set (1–1.5 h) and thereafter the ‘CUPS’
(10 mm diameter) was made by punching into the agar
surface with a sterile cork borer and scooping out the
punched part of the agar. Into these cups the test com-
pound solution was added with the help of a sterile syr-
inge. The plates were incubated at 37 °C for 48 h and the
results were noted. A solvent control (10% DMSO in
MIC50s were recorded as the minimum concentration
of a compound that inhibits the 50% growth of the
tested microorganisms. All of the compounds tested
Table 1. Physical data of the synthesized compounds
Compound
R
R0 (benzaldehyde)
Yield (%)
Mp (°C)
1
2
H
3-CH3
4-CH3
83
76
81
86
72
86
84
88
83
78
73
77
69
79
63
74
53–54
45–46
188–9
58
Cl
3
4
4-OCH3
3,4,5-Trimethoxy
4-Cl
S
5
189–92
98–99
148–52
152–3
48–9
6
7
3-NO2
Cl
8
Cinnamaldehyde
H
3-CH3
9
10
11
12
13
14
15
16
94–96
146–7
135–6
161–3
167–8
158–9
108–110
4-CH3
4-OCH3
3,4,5-Trimethoxy
4-Cl
N
NH
3-NO2
Cinnamaldehyde

V. Tomar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5321–5324
Table 2. Antibacterial and antifungal data of chalcones
5323
Compound
A
B
C
D
E
F
G
H
1
18
11
12
14
12
14
24
09
22
24
16
24
06
18
24
10
22
20
20
16
18
14
16
22
16
24
22
14
22
08
22
26
16
24
22
06
09
14
12
14
18
11
20
20
14
14
06
16
18
08
24
18
10
08
16
06
08
20
07
18
16
14
16
09
14
14
05
24
24
20
06
22
14
18
16
20
22
20
18
18
12
12
20
14
24
26
10
26
22
26
14
12
18
20
14
14
16
24
22
24
18
09
14
18
06
2
3
16
20
10
18
4
5
06
24
22
22
6
7
18
08
12
16
8
9
10
24
16
24
24
11
12
22
22
22
14
13
14
09
18
12
20
15
16
16
09
18
14
Ciprofloxacin
Fluconazole 29
Fluconazole 29
Fluconazole 29
Zone of inhibition is expressed in mm at concentration level of 250 lg/mL of chalcones.
A, Staphylococcus aureus 209 p; B, Escherichia coli ESS 2231; C, Proteus vulgaris; D, Klebsiella pneumoniae; E, Aspergillus fumigatus; F, Candida
albicans; G, Candida krusei GO3; H, Candida glabrata HO3.
Table 3. MIC50 values (lg/mL) of chalcones
Compound
A
B
C
D
E
F
G
H
1
80
90
20
12.70
100
40
14.15
28.02
30
4.13
32.13
70
2.22
51.13
70
3.17
42.34
70
4.65
65
2
22.76
25.65
9.13
60
3
75
60
80
4
40
50
65
50
9.26
55
5
78
18.16
40.13
70
16.37
45.13
40
5
60
50
6
60
40
65
30
40
16.75
60
4.65
5.97
75
7
3.25
100
100
3.13
70
6.27
40
7.17
60
50
50
60
8
60
55.65
5.38
5.69
7.02
50
9
10
3.58
5.62
50
3.95
3.85
45
12.75
18.64
40
6.85
5.56
18.35
35
4.56
6.89
8.75
9.12
65
7.57
9.94
7.66
16.25
60
11
12
5.25
70
10.28
80
75
45
45
55
65
13
14
75
50
75
60
75
70
60
50
50
55
60
15
16
4.75
100
100
200
100
2.75
35
7.17
50
6.75
90
18.56
60
16.8
75
200
100
200
100
70
Ciprofloxacin
Carbencillin
Amoxycillin
100
200
100
100
200
100
100
200
100
Fluconazole 50
Fluconazole 50
Fluconazole 50
A, Staphylococcus aureus 209 p; B, Escherichia coli ESS 2231; C, Proteus vulgaris; D, Klebsiella pneumoniae; E, Aspergillus fumigatus; F, Candida
albicans; G, Candida krusei GO3; H, Candida glabrata HO3.
illustrated significant antibacterial and antifungal
activity compared to reference drugs. The MIC50 values
are generally within the range of 2.22–100 lg/mL
against all evaluated strains. While comparing MIC50
values with that of Ciprofloxacin, all compounds were
found to be effective against S. aureus. Compounds 7,
10, 12 and 15 especially showed very high activity. All
the compounds were effective against E. coli. Com-
pounds 9, 10 and 15 showed very high activity. Com-
pounds 4, 7 and 12 especially showed strong activity
while compounds 2 and 3 showed moderate activity.
activity. On the other hand the compounds exhibited
comparable activities against K. pneumoniae. Compound
7 showed high activity and compounds 1, 2, 9 and 10
showed moderate activity. From the results obtained with
A. fumigatus, out of all the 16 compounds, 1, 4, 9, 10 and
15 showed moderate activity, whereas compounds 2, 7
and 11 showed less activity compared to Ciprofloxacin.
The antifungal activity of the compounds was studied
with three pathogenic fungi. The results are summarized
in Tables 2 and 3. Fluconazole has been used as refer-
ence for inhibitory activity against fungi. All the com-
pounds showed good antifungal activity. Compounds
1, 9, 10 and 11 showed activity against all the three fun-
gi. In addition compounds 4, 6, 7 and 12 also exhibited
good activity against C. albicans while 4 and 15 showed
In comparing their MIC values with that of Ciprofloxa-
cin, it is apparent that all compounds were effective
against P. vulgaris. Compounds 9 and 10 especially
showed high activity and compound 1 showed good

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V. Tomar et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5321–5324
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