Novel chalcones and 1,3,5-triphenyl-2-pyrazoline derivatives as antibacterial agents

Article abstract of DOI:10.1111/j.1747-0285.2010.01020.x

Novel sixteen chalcones and thirteen 1,3,5-triphenyl-2-pyrazolines were synthesized and characterized using FT-IR, HR-Mass, NMR (¹H-NMR, ¹³C-NMR, 135 DEPT, ¹H-¹H CoSY and ¹H and ¹³C CoSY) a

Full text of DOI:10.1111/j.1747-0285.2010.01020.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01020.x
Chem Biol Drug Des 2010; 76: 407–411
Research Article
Novel chalcones and 1,3,5-triphenyl-2-pyrazoline
derivatives as antibacterial agents
Received 21 June 2010, revised 21 June 2010 and accepted for publica-
tion 3 July 2010
Ponnurengam Malliappan Sivakumar*,
Suresh Ganesan, Prabhawathi Veluchamy
and Mukesh Doble*
Bacterial infection and their emergence to resistance toward anti-
biotics is a serious threat to present and future populations. These
resistant bacteria are involved in diseases including diarrhea,
respiratory tract infections, meningitis, sexually transmitted infec-
tions, and hospital-acquired infections (nosocomial infections).a The
use of more antibiotics or less antibiotics leads to the develop-
ment of drug resistance in bacterial strains. These resistant strains
cause fatal morbidity and also death in patients who are already
infected with the disease and hence are immunocompromised (1).
Clinical isolates of Escherichia coli O157 from human, cattle,
swine, and food sources were found to be resistant against the
frontline antibiotics, tetracycline, sulfa drugs, cephalosporins, and
penicillins (2). b-lactamases produced by E. coli has developed
resistance to b-lactam antibiotics (3). It is found that the muta-
tions that affect the expression of chromosomal class I, b-lactam-
ase expression in Pseudomonas aeruginosa and Proteus vulgaris
can lead to resistance against many newer b-lactam antibiotics
(4). Seventy to eighty percentage of Staphylococcus aureus strains
are resistant against penicillins, whereas methicillin was effective
until 1980. Methicillin-resistant S. aureus produces a penicillin-
binding protein PBP2a, which binds less with methicillin and other
b-lactams that are present in the bacterial cell wall (3). Vancomy-
cin was effective against methicillin-resistant S. aureus, but resis-
tance against glycopeptide class of vancomycin had delineated the
therapy (5). Salmonella typhi responds to ciprofloxacin by inducing
double mutation in gyrA and single mutation in parC genes (6).
Streptomycin-resistant Bacillus subtilis has two mutations namely
fun and strR (7).
Department of Biotechnology, Indian Institute of Technology
Madras, Adyar, Chennai 600 036, India
*Corresponding author: Mukesh Doble, mukeshd@iitm.ac.in
The authors Ponnurengam Malliappan Sivakumar, Suresh Ganesan and
Prabhawathi Veluchamy wishes to dedicate this work to their guide Prof
MD on the occassion of his birthday
Novel sixteen chalcones and thirteen 1,3,5-triphe-
nyl-2-pyrazolines were synthesized and character-
ized using FT-IR, HR-Mass, NMR (1H-NMR, 13C-NMR,
135 DEPT, 1H–1H CoSY and 1H and 13C CoSY) and
XRD. These compounds were evaluated for their
antibacterial activity against six micro-organisms,
namely Bacillus subtilis NCIM 2718, Staphylococ-
cus aureus NCIM 5021, Salmonella typhi NCIM
2501, Enterobacter aerogenes NCIM 5139, Pseudo-
monas aeruginosa NCIM 5029, and Proteus vulgaris
NCIM 2813 by twofold dilution method using res-
azurin as the indicator dye. In the case of chal-
cones, compounds with hydroxyl and bromo
substitutions in the B-ring favor activity and benzyl-
oxy substitution irrespective of its position in the
A-ring. In the case of 1,3,5-triphenyl-2-pyrazolines,
chloro substitution in the A-ring favors activity.
Hydrophilic ⁄ lipophilic balance of the compounds
plays a major role in their antibacterial activity.
Key words: 1,3,5-triphenyl-2-pyrazolines, antibacterial, resazurin
Antibacterial evaluation by two fold dilution method using resazurin dye
MIC
Chalcones
Color change denotes bacterial growth
1,3,5-Triphenyl-2-
pyrazolines
407

Sivakumar et al.
Although methicillin, vancomycin and linezolid are designed to com-
bat the problem of antibiotic resistance, the micro-organisms have
developed resistance to these drugs as well. So there is a need for
newer drugs to treat the bacterial infections and combat the bacte-
rial resistance. Hence, medicinal chemists have to discover new
chemical moieties that may exhibit anti-infective properties. Chal-
cones are such small molecules that have been known to exhibit a
wide range of activities including antibacterial, antifungal, antituber-
cular, and antioxidant. Pyrazolines are another class of small mole-
cules that can be prepared using chalcones as the starting
material.
acetophenone derivatives were added together with methanol
(10 mL) and stirred at room temperature. Two molar NaOH solutions
was added to the above mixture and maintained under rapid stir-
ring at room temperature. In majority of the cases, an almost pale
yellowish solid precipitate was obtained, which was washed with
50% ethanol followed by water, recrystallized and then dried. The
yield in most of the cases was more than 80%.
Synthesis of 1,3,5-triphenyl-2-pyrazolines
Appropriate chalcone (4 mmol) was mixed with 8 mmol of phen-
ylhydrazine and 10 mL of acetic acid (17). It was boiled under reflux
for 2–7 h. The synthesized 1,3,5-triphenyl-2-pyrazoline usually pre-
cipitated out on cooling, but in some cases, it was precipitated out
by adding 50% of aqueous ethanol. In majority of the cases, the
yield was more than 70%.
Alcaraz et al. (8) tested eleven natural and synthesized chalcones
for antistaphylococcal activity against methicillin-resistant S. aureus
and showed the importance of the carbonylic region for its perfor-
mance. Asebogenin, which was isolated from licorice, was active
against methicillin-resistant S. aureus (MRSA) with an IC50 of
4.5 lg ⁄ mL (9). Earlier, our research has proved that chalcones are
very active against Gram-positive and Gram-negative bacteria (10),
fungi (11), and resistant antimycobacterial strain, Mycobacterium
tuberculosis H37Rv (12).
Antibacterial activity evaluation
In vitro antibacterial inhibitory activities (MIC) of the chalcones
and 1,3,5-triphenyl-2-pyrazolines were determined by microdilution
broth assay method (18) using resazurin as an indicator (19).
Muller-Hinton broth was used to culture the bacterial strains to a
final inoculum size of 5 · 105 CFU ⁄ mL. The chalcones and 1,3,5-tri-
phenyl-2-pyrazolines were dissolved in absolute ethanol to a
concentration of 10 mg ⁄ mL (20). Serially diluted chalcone and 1,3,5-
triphenyl-2-pyrazoline solutions were added to successive wells in a
96-well microtitre plate and incubated with respective micro-organ-
ism for 18 h at 37 ꢀC. After the incubation period, 10 lL of 0.01%
resazurin solution was added and incubated for 2 h. The color
change was assessed visually. Growth of organism changed the
color from blue to pink. Growth and sterility controls were also
maintained during the experiment. Test compounds serially diluted
with ethanol were also kept in the 96-well microtitre plates (unin-
oculated dilution) to determine whether they precipitated out during
the course of the experiments. One entire column had antibiotics as
a positive control (norfloxacin ⁄ erythromycin). A blank assay with
ethanol alone was taken into account to discount any possible
effect of the solvent.
1-Aryloxy-3-aryl-5-hydroxy-5-aryl-pyrazolines (13), sulfone-linked bis
heterocycle pyrazolines in combination with thiadiazoles, oxadiaz-
oles, and triazoles (14), N1-substituted 3,5-diphenyl pyrazolines
(15) have been evaluated as antibacterial agents by other
researchers.
Hydrophobic substitutions in the A-ring of chalcone are considered
to be more active (16). Hence, we attempted to synthesize
chalcones A-ring with benzyloxy and chloro substitutions at R1 and
R2 positions (in the A-ring) and their corresponding 1,3,5-triphenyl-
2-pyrazolines (substitutions at R1) to test their antibacterial activity.
These compounds are novel and their synthesis has not been
reported elsewhere.
Materials and Methods
All the chemicals used for the synthesis and antibacterial evalua-
tions were purchased from Sigma-Aldrich (St. Louis, MO, USA),
Hi-media (Mumbai, India) and SRL (Mumbai, India) and the bacte-
rial strains (B. subtilis NCIM 2718, S. aureus NCIM 5021, S. typhi
NCIM 2501, Enterobacter aerogenes NCIM 5139, P. aeruginosa
NCIM 5029, and Proteus vulgaris NCIM 2813) were purchased
from National Chemical Laboratory, Pune, India. The following
scheme shows the synthesis of chalcones and 1,3,5-triphenyl-2-
pyrazolines:
Results and Discussions
The chalcones and 1,3,5-triphenyl-2-pyrazolines were synthesized
(Tables 1 and 2) and characterized by NMR (1H, 13C, DEPT, H–1H
1
CoSY, 1H–13C CoSY), mass (HR-MS) spectroscopy. Reference (21)
gives the NMR, HR-MS data for a representative chalcone and
1,3,5-triphenyl-2-pyrazoline. The synthesized compounds were tested
for antibacterial activity against six bacterial strains including Gram-
positive and Gram-negative, namely S. aureus NCIM 5021, B. subtil-
is NCIM 2718, P. vulgaris NCIM 2813, E. coli NCIM 2931, S. typhi
NCIM 2501, and P. aeruginosa NCIM 5029 by twofold dilution assay
using reaszurin as an indicator. Tables 1 and 2 lists the antibacterial
Synthesis of chalcones
The various substituted chalcones were synthesized based on the
method described by Lin et al. (17). Ten millimoles of the corre-
sponding substituted benzaldehydes and 1 mmol of the
O
N
CHO
R
1
COCH
N
3
C H NHNH
2
6
5
EtOH
NaOH
R
1
CH COOH
R
3
1
R
R
R
408
Chem Biol Drug Des 2010; 76: 407–411

Antibacterial chalcones and pyrazolines
Table 1: Structure and antibacterial activities (in lM) of chalcones
R1
O
R3
B
R4
R5
A
R2
Antibacterial activity
(against Gram-positive
organisms)
Antibacterial activity (against Gram-negative
organisms)
Substitutions at A-ring
Substitutions at B-ring
Bacillus Staphylococcus Pseudomonas Escherichia Salmonella Proteus
Compound No R1
R2
R3
R4
Br
R5
subtilis
aureus
aeruginosa
coli
typhi
vulgaris
PMS-1
PMS-2
C6H5CH2O
C6H5CH2O
C6H5CH2O
C6H5CH2O
C6H5CH2O OH
C6H5CH2O Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OCH2CH3 0.349
F
0.697
0.376
0.636
0.378
0.378
0.717
0.872
0.826
0.479
0.902
0.777
0.872
0.826
0.917
0.902
0.318
0.376
0.084
0.002
0.349
0.376
0.318
0.378
0.189
0.358
0.436
0.413
0.479
0.451
0.389
0.436
0.413
0.458
0.451
0.318
0.376
0.084
0.002
0.174
0.188
0.020
0.012
0.024
0.179
0.218
0.206
0.240
0.226
0.194
0.218
0.206
0.229
0.226
0.159
0.188
0.005
0.001
0.174
0.188
0.159
0.189
0.189
0.179
0.218
0.206
0.240
0.113
0.194
0.218
0.206
0.115
0.226
0.318
0.376
0.084
0.004
0.174
0.188
0.159
0.095
0.095
0.179
0.218
0.103
0.240
0.226
0.194
0.218
0.206
0.229
0.226
0.159
0.188
0.168
0.001
0.376
0.636
0.378
0.378
0.358
PMS-3
PMS-4
OH
PMS-5
PMS-6
PMS-7
PMS-8
PMS-9
OCH2CH3 0.436
OCH3
F
OCH3
0.413
0.479
0.451
0.777
0.872
0.826
0.458
0.902
0.636
0.376
0.168
0.001
PMS-10
PMS-11
PMS-12
PMS-13
PMS-14
PMS-15
PMS-16
PMS-17
Ampicillin
Tetracycline
Cl
Br
OCH2O
OCH3 OCH3
OCH3
Cl
C6H5CH2O
C6H5CH2O
Br
F
Table 2: Structure and antibacterial activities (in lM) of 1,3,5-triphenyl-2-pyrazoline derivatives
R2 R3
N
N
B
R4
A
R1
Antibacterial activity
(against Gram-positive
organisms)
Antibacterial activity (against Gram-negative
organisms)
Substitutions at A-ring
R1
Substitutions at B-ring
Bacillus Staphylococcus
Pseudomonas
aeruginosa
Escherichia Salmonella
Proteus
vulgaris
Compound No
R2
R3
Br
R4
subtilis
aureus
coli
typhi
PMSPY-1
PMSPY-2
PMSPY-3
PMSPY-4
PMSPY-5
PMSPY-6
PMSPY-7
PMSPY-8
PMSPY-9
PMSPY-10
PMSPY-11
PMSPY-12
PMSPY-13
Ampicillin
C6H5CH2O
C6H5CH2O
C6H5CH2O
C6H5CH2O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OCH2CH3
F
1.115
2.367
1.034
0.595
0.663
0.636
0.713
0.681
0.304
0.663
0.636
0.689
0.681
0.168
0.001
0.557
2.367
1.034
0.297
0.332
0.318
0.356
0.340
0.304
0.332
0.318
0.689
0.681
0.084
0.002
0.557
1.183
0.517
0.297
0.332
0.159
0.356
0.170
0.152
0.332
0.159
0.172
0.170
0.084
0.002
1.115
0.592
1.034
1.189
2.653
0.636
0.713
0.681
0.607
0.663
0.636
0.344
0.681
0.005
0.001
0.139
0.148
0.259
0.297
0.332
0.159
0.178
0.170
0.152
0.166
0.159
0.172
0.170
0.084
0.004
0.139
0.148
0.129
0.149
0.166
0.159
0.178
0.170
0.076
0.166
0.159
0.172
0.170
0.168
0.001
OH
OCH2CH3
OCH3
F
OCH3
Cl
Br
–OCH2O–
OCH3
OCH3
OCH3
Cl
Tetracycline
Chem Biol Drug Des 2010; 76: 407–411
409

Sivakumar et al.
activity of chalcones and 1,3,5-triphenyl-2-pyrazolines, respectively,
in terms of micromolar (lM) concentration.
compounds PMS-9, PMS-10, PMS-14, and PMS-15 were
least active. The more active compounds have essential features
like hydroxyl substitution in B-ring, substitution at R4, and hydropho-
bic substitution like benzyloxy in the A-ring. Chloro substitution in
A-ring leads to medium to lower active compounds. In the case of
1,3,5-triphenyl-2-pyrazolines, compounds PMSPY-6, PMSPY-9,
PMSPY-10, and PMSPY-11 were the most active ones and
compounds PMSPY-1, PMSPY-2, and PMSPY-3 were the
least active. All the most active 1,3,5-triphenyl-2-pyrazolines have
chloro substitution in their A-ring at R1 position. The least active
compounds PMSPY-1, PMSPY-2, and PMSPY-3 have benzyl-
oxy substitution in their A-ring at R1 position. In conclusion,
lipophilic ⁄ hydrophilic balance is required for antibacterial activities
of chalcones and 1,3,5-triphenyl-2-pyrazolines. Our studies revealed
that, in the case of chalcone, A-ring requires slightly hydrophobic
substitution including benzyloxy substitution and B-ring requires
hydrophilic substitution including hydroxyl and bromo groups. It is
opposite in the case of 1,3,5-triphenyl-2-pyrazolines. Chloro substi-
tution is required in A-ring for the activity and slightly hydrophilic
substitution like dimethoxy and methylene dioxy compared to hydro-
xyl substitution that is required for good antibacterial activity. A
detailed group-based QSAR (GQSAR) could give more information
on structure–activity relationship, which will be performed and
published later. This research gives additional knowledge to
researchers to design newer chalcones and 1,3,5-triphenyl-2-pyrazo-
lines exhibiting antibacterial activity.
Chalcones PMS-1, PMS-3, PMS-4, PMS-5, and PMS-16
were more active (at least against four of the six strains) and
compounds PMS-9, PMS-10, PMS-14, and PMS-15 were
least active (at least against four of the six strains) in general
when compared to others against all six bacterial strains.
The most active compounds have benzyloxy substitution either in
the R1 or in the R2 position in A-ring which is the hydrophobic ring
(10) in chalcone, and compounds PMS-3 and PMS-16 have bro-
mine in their R4 position of the B-ring. It is also observed that com-
pounds which have substitution at R4 when compared to R5 and R3
positions were more active, which was observed by other research-
ers too (16,22). It is found that the substitution in the B-ring is
important for antibacterial activity (22). Compounds PMS-4 and
PMS-5 have hydroxyl substitution in their B-ring at R5 and R3
position. Our earlier research and other researchers too have found
the importance of hydroxyl and bromo substitutions in B-ring for
enhanced antibacterial activity (10,16,23,24). Compound PMS-1
has ethoxy substitution in R5 position of the B-ring. Alkoxy substitu-
tion in R5 position of the B-ring was also found to be important for
the antibacterial activity (16). The least active compounds have
chloro substitution in their A-ring. The chloro-substituted chalcones
(in A-ring) also exhibit activity when they have polar substitutions
such as hydroxyl in their R4 position of the B-ring (25). Compounds
PMS-9, PMS-10, and PMS-15 have halogen substitution in
their B-ring. Lipophilic ⁄ hydrophilic balance appears to determine the
antibacterial activity of chalcones. Even though increase in the
hydrophobic surface increases the antibacterial activity, it appears
that the dipole and quadropole moments related to polarizability of
the molecules are also important (26).
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PMS-5, and PMS-16 were found to be more active and
410
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PMS – 13: FTIR (KBr) 1665 cm)1(C=O). 1H NMR
(500 MHz): d 3.97 (6H, s), 6.93 (1H, d, J = 8 Hz), d 7.37 (2H, dd,
J = 8.5 Hz), d 7.56–7.58 (2H, m), d 7.61 (1H, d, J = 2 Hz), d
7.67 (1H, dd, J = 2 Hz, J¢ = 8.5 Hz), d 7.75 (1H, d, J = 15.5 Hz).
13C NMR (500 MHz): d 56.05, 56.10, 109.98, 110.76, 122.08,
123.05, 129.16,129.19, 129.22, 129.50, 131.14, 133.57, 136.18,
142.43, 149.31, 153.41, 188.23. HR-MS (m ⁄ z) for molecular for-
mula C17H15ClO3: calculated = 303.0784, found = 303.0788.
Spectral data for compound PMSPY – 7: FTIR (KBr)
1587 cm)1(C=N). 1H NMR (500 MHz): d 3.06 (1H, dd,
J = 7.5 Hz, J¢ = 17 Hz), d 3.80 (1H, dd, J = 12.5 Hz, J¢ = 17 Hz),
d 5.23 (1H, dd, J = 7.5 Hz, J¢ = 12.5 Hz), d 6.78–6.81 (1H, m), d
7.01–7.03 (2H, m), d 7.05–7.08 (2H, m), d 7.16–7.19 (2H, m), d
7.23–7.25 (2H, m), d 7.29–7.31 (2H, m), d 7.68–7.69 (2H, m). 13C
NMR (500 MHz): d 43.55, 64.00, 113.38, 115.57, 115.75, 119.44,
127.31, 127.51, 127.48, 127.54, 128.82, 128.84,128.99, 129.02,
129.37, 133.39, 140.94, 144.63, 145.80, 162.08, 164.06. HR-MS
(m ⁄ z) for molecular formula C21H16ClFN2: calculated = 351.1064,
found = 351.1064. Spectral data for compound PMSPY – 11:
FTIR (KBr) 1587 cm)1(C=N). 1H NMR (500 MHz): d 3.05
(1H, dd, J = 7.5 Hz, J¢ = 17 Hz), d 3.78 (1H, dd, J = 12.5 Hz,
J¢ = 17 Hz), d 3.89 (3H, s), d 3.97 (3H, s), d 5.18 (1H, dd,
J = 7.5 Hz, J¢ = 12.5 Hz), d 6.77–6.83 (2H, m), d 7.00–7.03 (3H,
m), d 7.16–7.19 (2H, m), d 7.23–7.30 (4H, m), d 7.48 (1H, d,
J = 1.5 Hz). 13C NMR (500 MHz): d 43.65, 55.95, 63.92, 108.14,
110.67, 113.33, 119.12, 119.19, 125.41, 125.28, 127.36, 128.79,
128.96, 129.09, 129.32, 129.43, 129.96, 133.28, 141.20, 144.89,
146.91, 149.18, 150.03. HR-MS (m ⁄ z) for molecular formula
C23H21ClN2O2: calculated = 393.1373, found = 393.1370.
22. Nielsen S.F., Boesen T., Larsen M., Schønning K., Kromann D.
(2004) Antibacterial chalcones – bioisosteric replacement of the
4¢-hydroxy group. Bioorg Med Chem;12:3047–3054.
23. Liu X.L., Xu Y.J., Go M.L. (2008) Functionalized chalcones
with basic functionalities have antibacterial activity against drug
sensitive Staphylococcus aureus. Eur J Med Chem;43:1681–
1687.
24. Nowakowska Z. (2007) A review of anti-infective and anti-
inflammatory chalcones. Eur J Med Chem;42:125–137.
25. Ansari F.L., Baseer M., Iftikhar M., Kulsoom A., Ullah S., Nazir
A., Shaukat I-ul-H, Mirza B. (2009) Microwave assisted synthe-
sis, antibacterial activity against Bordetella bronchiseptica of a
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descriptors-based SAR. ARKIVOC;X:318–332.
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A., Akpulat A. (2003) Antioxidant and antimicrobial activity of
the essential oil and methanol extracts of Achillea millefolium
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220.
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of 2,5disubstituted benzimidazoles as potential antihookworm
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sis of 1,3-diaryl-2-propen-1-ones and their indole analogs
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21. Spectral data for compound PMS -10: FTIR (KBr)
27. Munawar M.A., Azad M., Athar M., Groundwater P.W. (2008)
Synthesis and antimicrobial activity of quinoline-based 2-pyrazo-
lines. Chem Pap;62:288–293.
1665 cm)1(C=O). 1H NMR (500 MHz):
d 7.12 (1H, d,
J = 16 Hz), d 7.34–7.37 (3H, m), d 7.40 (1H, s), d 7.42 (1H, d,
J = 1.5 Hz), d 7.43–7.44 (2H, m), d 7.46–7.49 (3H, m). 13C NMR
(500 MHz): d193.41, 144.48, 138.95, 136.80, 132.94, 131.57,
131.31, 130.33, 129.71, 129.68, 129.40, 129.37, 129.29, 126.92,
126.63. HR-MS (m ⁄ z) for molecular formula C15H10Cl2O: calcu-
lated = 277.0631, found = 277.0631. Spectral data for compound
Note
ahttp://www.who.int/mediacentre/factsheets/fs194/en/ [accessed on
September 01 2010].
Chem Biol Drug Des 2010; 76: 407–411
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