Synthesis, characterization, and in vitro antibacterial activities of macromolecules derived from bis-chalcone

Article abstract of DOI:10.1002/jhet.942

We investigated the antibacterial activity of some new macromolecules such as bis-pyrazoline, bis-pyrazole, bis-pyrimidines prepared from the reaction of bis-chalcone with thiosemicarbazide/phenyl hydrazine/guanidine hydrochloride/thiourea. All the macrom

Full text of DOI:10.1002/jhet.942

1434
Synthesis, Characterization, and In Vitro Antibacterial Activities
Vol 49
of Macromolecules Derived from Bis-Chalcone
a
Abdullah M. Asiria,b and Salman A. Khan
*
aChemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
bThe Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia
*
E-mail: sahmad_phd@yahoo.co.in
Received January 4, 2011
DOI 10.1002/jhet.942
View this article online at wileyonlinelibrary.com.
We investigated the antibacterial activity of some new macromolecules such as bis-pyrazoline, bis-pyra-
zole, bis-pyrimidines prepared from the reaction of bis-chalcone with thiosemicarbazide/phenyl hydrazine/
1
guanidine hydrochloride/thiourea. All the macromolecules have been characterized by IR, H NMR, 13C
NMR, mass and elemental analyses. The antibacterial activity of these compounds was first tested in vitro
by the disc diffusion assay against two Gram-positive and two Gram-negative bacteria, and then the
minimum inhibitory concentration was determined with the reference to standard drug chloramphenicol.
The results showed that pyrazoline derivative showed better antibacterial activity on S. typhimurium and
E. coli than the reference drug chloramphenicol.
J. Heterocyclic Chem., 49, 1434 (2012).
INTRODUCTION
in the design of biologically active molecules [13]. A prac-
tical method for the synthesis of such compounds is of
great interest in synthetic organic chemistry. Among the
heterocycles, pyrazoline and pyrazole are a class of com-
pounds with biological activities, such as antimicrobial
[14], antitumor [15], antioxidant [16], calcium channel mod-
ulators [17], and antipyretic [18]. On the other hand, the
classes of pyrimidines possess a broad spectrum of biologi-
cal effectiveness such as antitubercular [19], calcium chan-
nel blockers [20], and many classes of chemotherapeutic
agents containing pyrimidine nucleus are in clinical use.
Apart from these, we derived the pyrazoline, pyrazole, and
pyrimidines from the chalcone as a antibacterial agents.
Chalcones (trans-1,3-diphenyl-2-propen-1-ones) are
carbonyl system; chemically, they consist of open-chain
flavonoids in which the two aromatic rings are joined by
a three-carbon a,b-unsaturated carbonyl system [1]. The
naturally occurring compounds of chalcones belong to a
flavonoid family and are present in variety of plant
species such as fruits, vegetables, spices, tea, and soy-
based foodstuff. Chalcones have been recently focused as
a pharmacologically significant group for their interesting
biological activities. Chalcones isolated from natural pro-
ducts are known to possess several important activities in-
cluding antifungal [2], leishmanicidal [3], and antimalarial
[4]. Recent reports indicate the importance of chalcones as
anti-inflammatory agents involved in inhibition of cell
migration and inhibition of TNF synthesis in mouse [5].
Plethora of literature is available describing the role of
chalcones and related derivatives such as anticancer [6],
anti-inflammatory [7], antimitotic [8], antitubercular [9],
cardiovascular [10], and hyperglycemic agents [11].
Chalcones are also used as intermediates for the forma-
tion of heterocyclic compounds. Five- and six-member
heterocycles are abundant in nature and are of great signif-
icance to life because their structural subunits exist in many
natural products such as vitamins, hormones, and antibio-
tics [12]. Hence, they have attracted considerable attention
RESULTS AND DISCUSSION
Chemistry.
In this work, bis-chalcones such as bis-
pyrazoline, bis-pyrazole, and bis-pyrimidines were prepared
by the reaction of chalcone with In the present work,
the cyclization of a bis-chalcone into the corresponding
bis-pyrazoline, bis-pyrazole and bis-pyrimidine derivatives
was accomplished by the reaction of the chalcone with
thiosemicarbazide /phenyl hydrazine/guanidine hydrochlo-
ride/thiourea [21–23]. The synthetic route of compounds is
outlined in Scheme 1. The chemical structures of the
© 2012 HeteroCorporation

November 2012
Synthesis, Characterization, and In Vitro Antibacterial Activities of Macromolecules
Derived from Bis-Chalcone
1435
Scheme 1. The synthesis of the chalcone and their cyclized products.
synthesized compounds were established by spectroscopic
(FTIR, 1H NMR, 13C NMR, mass) and elemental analyses.
The IR spectra of compound 1.1 show the characteristic
band at 1655 cmꢀ1, which indicates the presence of —
C═O group. The IR spectra of compound 1.2 show the
characteristic band at 1539 and 1353 cmꢀ1, which indicate
the presence of —C═N and C═S group. The IR spectra of
compound 1.3 also show the characteristic bands at 1593
and 1495 cmꢀ1, which indicate the presence of —C═C
and C═N group. The IR spectra of compound 1.4 shows
the characteristic band at 3356 and 1572 cmꢀ1, which indi-
cate the presence of NH2 and C═N group. The IR spectra
of compound 1.5 show the characteristic band at 1180 and
715 cmꢀ1, which indicate the presence of C—N and C—S
group. The structure of the chalcone and their cyclized pro-
prove diagnostic tool for the positional elucidation of the
proton. Assignments of the signals are based on chemical
shift and intensity pattern.
1H NMR spectra of compound 1.1 show two doublets at
7.22 ppm (J = 15.6 Hz) and 7.72 ppm (J = 15.6 Hz), indi-
cating that the ethylene moiety in the enone linkage is in
1
the trans-conformation in the chalcone. H NMR spectra
of compound 1.2 shows multiplet of —CH2 at 3.11–5.94
ppm, which confirmed the cyclization of chalcone into in
1
pyrazoline 1.2. H NMR spectra of compound 1.3 show a
singlet at 7.75 ppm due to CH═C protons and no peak in
the range 3.11–5.94 ppm is observed, indicating that the
oxidation of pyrazoline occurred and pyrazoline converted
1
into pyrazole. H NMR spectra of compound 1.4 show a
sharp singlet at d 8.17 due to NH2 protons; they also show
a sharp singlet at d 6.47 due to HC═C, which confirmed
1
ducts was further confirmed by H NMR spectra, which
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. M. Asiri and S. A. Khan
Vol 49
Table 1
Antibacterial activity of chalcone and their cyclized products, positive control chloramphenicol (Chlora.) and negative control (DMSO) measured by the
halo zone test (unit, mm).
Corresponding effect on microorganisms
Compounds
S. aureus
S. pyogenes
S. typhimurium
E. coli
1.1
1.2
1.3
1.4
1.5
Chlora.
DMSO
10.8 ꢂ 0.3
16.8 ꢂ 0.4
11.8 ꢂ 0.5
13.8 ꢂ 0.5
15.8 ꢂ 0.2
17.0 ꢂ 0.5
–
10.2 ꢂ 0.4
17.6 ꢂ 0.5
12.3 ꢂ 0.4
13.5ꢂ 0.4
16.2 ꢂ 0.5
18.2 ꢂ 0.4
–
10.6 ꢂ 0.3
18.5 ꢂ 0.5
12.4 ꢂ 0.5
13.1 ꢂ 0.2
17.5 ꢂ 0.4
17.2 ꢂ 0.8
–
11.2 ꢂ 0.4
18.6 ꢂ 0.5
13.2 ꢂ 0.4
14.2 ꢂ 0.4
15.5ꢂ 0.3
20.0 ꢂ 0.2
–
1
apparatus and are uncorrected. IR absorption spectra were
recorded on Shimadzu FTIR-8400s using KBr pellets in the range
the cyclization of chalcone into pyrimidine ring. H NMR
spectra of compound 1.5 show a sharp singlet at d 3.31
due to S—H protons; they also show a sharp singlet at d
7.28 due to HC═C, which confirmed the cyclization of
chalcone into pyrimidine ring.
of 4000–400 cmꢀ1 1H NMR and 13C NMR spectra were
.
recorded on Brucker-Avance-III 600 MHz spectrophotometer us-
ing tetramethylsilane (TMS) as an internal standard. The 1H NMR
and 13C NMR chemical shifts were reported as parts per million
(ppm) downfield from TMS (Me4Si). The splitting patterns are
designated as follows: s, singlet; d, doublet; m, multiplet. Mass
spectra were recorded on EI-MS spectrometer. IR, 1H NMR,
13C NMR, and mass spectra were consistent with the assigned
structures. Elemental analyses (C, H, N) were done on a CHN
rapid analyzer. All the new compounds gave C, H, and N analysis
within 0.03% of the theoretical values. Purity of the compounds
was checked by thin layer chromatography (TLC) on Merck silica
gel 60 F254 precoated sheets in chloroform/methanol mixture and
spots were developed using iodine vapors/ultraviolet light as visu-
alizing agent.
Finally, 13C NMR (600 MHz, CDCl3) spectra of chal-
cone and their cyclized product were recorded in CDCl3
and spectral signals are in good agreement with the proba-
ble structure details of 13C NMR spectra of all compounds
and those data are given in Experimental section.
Characteristic peaks were observed in the mass spectra
of chalcone and their cyclized products by the molecular
ion peak. The ms spectrum of compound 1.5 shows a mo-
lecular ion peak (M+) m/z 488.
Antimicrobial activity: Disc-diffusion and microdilution
assay.
The compounds (1.1–1.5) were tested for their
2E,20E-3,30-(1,4-Phenylene)bis(1-(2,5-dimethylfuran-3-yl)
prop-2-en-1-one.
A solution of 3-acetyl-2,5-dimethylfuran
antibacterial activities by disc diffusion method using
nutrient broth medium [contained (g/L): beef extract 3 g;
peptone 5 g; pH 7.0] [24]. The Gram-positive bacteria
and Gram-negative bacteria used in this study consisted
of Staphylococcus aureus, Streptococcus pyogenes,
Salmonella typhimurium, and Escherichia coli. In the disc-
diffusion method, sterile paper discs (0.5 mm) impregnated
with compound dissolved in dimethylsulfoxide (DMSO) at
concentration 100 mg/mL were used. Then, the paper discs
impregnated with the solution of the compound tested
were placed on the surface of the media inoculated with
the microorganism. The plates were incubated at 35ꢁC for
24 h. After incubation, the growth inhibition zones are
shown in Table 1. The chalcone and their cyclized
products were further checked by minimum inhibitory
concentration (MIC) method. The results are presented in
Table 2.
(2.34 mL, 0.028 mol) and terephthalaldehyde (2 g, 0.014 mol)
in ethanolic solution of NaOH (6 g in 10 mL of ethanol) was
stirred for 20 h at room temperature. The solution was poured
into ice cold water of pH ~2 (pH adjusted by HCl). The solid
was separated and dissolved in CH2Cl2, washed with saturated
solution of NaHCO3, and evaporated to dryness. The residual
was recrystallized from methanol/chloroform.
1
Yield: 78%; mp 182ꢁC; H NMR (DMSO-d6) (d/ppm): 7.72
(d, 2H, J = 15.6 Hz, C═CH), 7.22 (d, 2H, J = 15.6 Hz, CO═CH),
7.63 (s, 4H, Ar—H), 6.34 (s, 2H, thiophene-H), 2.62 (s, CH3),
2.30 (s, CH3), 2.09 (s, CH3), 1.93 (s, CH3); 13C NMR (600
MHz, CDCl3) d: 185.65, 158.20, 150.17, 141.60, 136.70,
Table 2
Minimum inhibition concentration (MIC) of chalcone and their cyclized
products, positive control: chloramphenicol.
MIC (mg mLꢀ1) compound
Positive
Bacterial strain
1.1 1.2 1.3
1.4
1.5
control
EXPERIMENTAL
S. aureus
256 64 128 128
64
64
32
64
32
32
32
32
All the chemicals and solvents used for this work were
obtained from Merck (Germany) and Aldrich chemical company
Melting points of the synthesized compounds were determined
in open-glass capillaries on Stuart-SMP10 melting point
S. pyogenes
S. typhimurium
E. coli
512 32 256
256 32 128
64
64
512 64 256 128
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012
Synthesis, Characterization, and In Vitro Antibacterial Activities of Macromolecules
Derived from Bis-Chalcone
1437
128.99, 125.00, 122.41, 105.54, 14.53, 13.05; EI-MS m/z
(rel. int.%): 376 (76) [M+1]+. IR (KBr) vmax (cmꢀ1): 2956
(C—H), 1655 (C═O), 1567 (C═C); Anal. calc. for C24H22O4:
C, 76.99, H, 5.92, O, 17.09; Found: C, 76.95, H, 5.88, O, 19.98.
(NH2), 2923 (C—H), 1572 (C═N); Anal. calc. for C26H24N6O2:
C, 69.01, H, 5.35, N, 18.57, Found: C, 68.97, H, 5.31,
N, 18.53.
Synthesis of pyrimidine (1.5) from thiourea. A mixture of
chalcone (0.004 mol), thiourea (0.009 mol) in 15 mL DMF was
refluxed at 80ꢁC for 12 h in the presence of few drops of HCl.
The progress of reaction was monitored by TLC. After the
completion of reaction, the reaction mixture was poured into
ice water; the obtained precipitated solid was filtered and
recrystallized in methanol and the residue obtained was purified
by column chromatography (40:50, diethyl ether:petroleum
ether) and the obtained solid was crystallized from ethanol.
Yield: 72.8%; mp 176ꢁC; 1H NMR (DMSO-d6) (d/ppm): 7.75
(dd, 2H, Ar—H), 7.34 (dd, 2H, Ar—H), 7.71 (s, 2H, thiophene-
H), 7.28 (s, 2H, Ar—Pym) 3.31 (s, 2H, SH), 2.54 (s, CH3),
2.38 (s, CH3); 13C NMR (DMSO-d6) (d/ppm): 185.02
(SH—C═N), 157.49, 149.84, 141.18, 136.41, 128.89, 125.01,
122.29, 105.71, 40.38, 29.33, 14.13, 13.05; EI-MS m/z (rel.
int.%): 488 (62) [M+1]+; IR (KBr) vmax cmꢀ1: 2919 (Ar—H),
1655 (C═C), 1567 (C═N), 1180 (C—N), 715 (C—S); Anal.
calc. for C26H22N4O2S2: C, 64.18, H, 4.56, N, 11.51, Found:
C, 64.13, H, 4.52, N, 11.48.
Synthesis of pyrazoline (1.2) from thiosemicarbazide.
A
mixture of bis-chalcone (1.1) (0.004 mol), thiosemicarbazide
(0.009 mol), and NaOH (0.002 mol) in dry ethanol (30 mL)
was refluxed at 80ꢁC for 12 h. The progress of reaction was
monitored by TLC. After the completion of reaction, the
reaction mixture was poured into acidic ice water to ~pH 2
(adjusted by HCl); the obtained precipitated solid was filtered
and recrystallized in methanol and the residue obtained was
purified by column chromatography (20:80, diethyl ether:
petroleum ether) and the obtained solid was crystallized from
EtOH to yield pyrazoline.
Yield: 76.5%; mp 250ꢁC; 1H NMR (DMSO-d6) (d/ppm): 7.26
(s, 4H, NH2), 7.17 (s, 4H, Ar—H), 7.14 (s, 2H, thiophene-H),
5.94 (dd, 2H, Hx, JXA= 3.0 Hz, JXB = 3.6 Hz), 3.68 (dd, 2H,
HA, JAB = 3.0 Hz, JAX = 11.4 Hz), 3.11 (dd, 2H, HB, JBA = 2.4
Hz, JBX = 12.6 Hz), 2.43 (s, CH3), 2.36 (s, CH3);13C NMR
(DMSO-d6) (d/ppm): 175.46 (C═S), 152.39 (C═N), 151.05,
140.96, 126.01 (Ar—C), 62.45 (CH), 44.48 (CH2), 14.21, 13.19
(CH3); EI-MS m/z (rel. int.%): 522(45) [M+1]+; IR (KBr) vmax
(cmꢀ1): 3304 (NH), 2953 (C—H), 1539 (HC═N), 1353 (C═S),
1090 (C—N); Anal. calc. for C26H28N6O2S2: C, 59.98, H, 5.42,
N, 16.14, Found: 59.95, H, 5.38, N. 16.11.
Organism culture and in vitro screening.
Antibacterial
activity was done by the disc diffusion method with minor
modifications. S. aureus, S. pyogenes, S. typhimurium, and E.
coli were subcultured in BHI medium and incubated for 18 h at
37ꢁC, and then the bacterial cells were suspended, according to
Synthesis of pyrazole (1.3) from phenyl-hydrazine.
A
mixture of bis-chalcone (0.004 mol) (1.1) was refluxed with
phenyl hydrazine (0.009 mol) in dry EtOH (20 mL) and
catalytic amount of glacial acetic acid at 80ꢁC for 8 h. The
progress of reaction was monitored by TLC. After completion
of the reaction, the solvent was removed under reduced pressure
and the residue obtained was purified by column chromatography
(20:80, diethyl ether:petroleum ether) and obtained solid was
crystallized from EtOH to yield pyrazole 1.3.
the McFarland protocol in saline solution to produce
a
suspension of about 10ꢀ5 CFU mLꢀ1: 10 mL of this suspension
was mixed with 10 mL of sterile antibiotic agar at 40ꢁC and
poured onto an agar plate in a laminar flow cabinet. Five paper
discs (6.0 mm diameter) were fixed onto nutrient agar plate.
Each test compound (1 mg) was dissolved in 100 mL of DMSO
to prepare stock solution; from stock solution, different
concentrations 10, 20, 25, 50, and 100 mg/mL of each test
compound were prepared. These compounds of different
concentration were poured over disc plate. Chloramphenicol
(30 mg/disc) was used as standard drug (positive control).
DMSO-poured disc was used as negative control. The
susceptibility of the bacteria to the test compounds was
determined by the formation of an inhibitory zone after 18 h of
incubation at 36ꢁC. Table 1 reports the inhibition zones (mm)
of each compound and the controls. The MIC was evaluated by
the macrodilution test using standard inoculums of 10ꢀ5 CFU
mLꢀ1. Serial dilutions of the test compounds, previously
dissolved in DMSO were prepared to final concentrations of
512, 256, 128, 64, 32, 16, 8, 4, 2, and 1 mg/mL. 100 mL of a 24
h old inoculum was added to each tube. The MIC, defined as
the lowest concentration of the test compound, which inhibits
the visible growth after 18 h, was determined visually after
incubation for 18 h, at 37ꢁC, and the results are presented in
Table 2. Tests were done using DMSO and chloramphenicol as
negative and positive controls.
1
Dark yellow solid (chloroform); Yield: 83.8%; mp 198ꢁC; H
NMR (DMSO-d6) (d/ppm): 7. 28 (m, 10H, Ar—H), 6.42 (s, 2H,
thiophene-H), 7.75 (s, 2H, C═CH), 5.93 (s, 4H, Ar—H), 2.49
(s, CH3), 2.37 (s, CH3);13C NMR (DMSO-d6) (d/ppm): 151.88,
148.88, 144.04, 140.53, 136.53, 130.87, 129.27, 128.93,
126.82, 120.14, 113.03, 112.88, 110.54, 106.83, 105.43, 13.84,
13.69; EI-MS m/z (rel. int.%): 552(76) [M+1]+; IR (KBr) vmax
(cmꢀ1): 3216 (Ar—H), 2918 (C—H), 1593 (C═C), 1495
(HC═N), 1063 (C—N); Anal. calc. for C36H30N4O2: C, 78.52,
H, 5.49, N, 10.17, Found: C, 78.49, H, 5.45, N, 10.14.
Synthesis of pyrimidine (1.4) from guanidine hydrochloride.
A mixture of chalcone (1.1) (0.004 mol), guanidine hydrochloride
(0.009 mol), and sodium methoxide (0.004 mol) in 15 mL DMF
was refluxed at 80ꢁC for 30 h. The progress of reaction was
monitored by TLC. After the completion of reaction, the reaction
mixture was poured into ice water; the obtained precipitated solid
was filtered and recrystallized in methanol and the residue
obtained was purified by column chromatography (40:50, diethyl
ether:petroleum ether) and the obtained solid was crystallized
from ethanol.
Yield: 74.68%; mp 284ꢁC; 1H NMR (DMSO-d6) (d/ppm):
8.17 (s, 4H, NH2), 7.17 (s, 4H, Ar—H), 6.47 (s, 2H, Ar—Pym),
7.89 (s, 2H, thiophene-H), 2.57 (s, CH3), 2.13 (s, CH3);13C
NMR (DMSO-d6) (d/ppm): 163.76 (C—NH2), 162 (C═N), 149
(C—O), 139.49 (C═N), 139.20, 126.95, 119.50, 105.63,
102.98, 40.32, 36.16, 31.55, 29.29, 22.34, 14.34, 13.23; EI-MS
m/z (rel. int.%): 454(62) [M+1]+; IR (KBr) vmax (cmꢀ1): 3356
CONCLUSION
A chalcone was prepared by the reaction of terephthalalde-
hyde with 3-acetyl-2,5-dimethylfuran. Treatment of this
chalcone with thiosemicarbazide/phenyl hydrazine/guanidine
hydrochloride/thiourea afforded the corresponding pyrazoline,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. M. Asiri and S. A. Khan
Vol 49
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pyrazole, and pyrimidine in good yields. The antibacterial
activity of these compounds was examined using culture of
bacteria and the results showed that the pyrazoline and
pyrimidine increased the antibacterial activity. Among the
entire five compounds, pyrazoline derivative showed better
antibacterial activity on S. typhimurium and E. coli than the ref-
erence drug chloramphenicol.
Acknowledgments. The authors would like to thank the deanship
of scientific research at King Abdulaziz University for the
financial support of this work via Grant No. 3-045/430.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet