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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME CHALCONE DERIVATIVES

AND THEIR COPPERCOMPLEXES

Article  in  International Journal of Pharmaceutical Sciences and Research · March 2012

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 Rachmale, IJPSR, 2012; Vol. 3(3): 901-908 ISSN: 0975-8232

IJPSR (2012), Vol. 3, Issue 03 (Research Article)

Received on 19 November, 2011; received in revised form 09 January, 2012; accepted 23 February, 2012

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME CHALCONE DERIVATIVES AND THEIR COPPERCOMPLEXES

P. M. Rachmale

Dr. D.Y. Patil College of Pharmacy, Akurdi, Pune, Tal- Ahmedpur, Dist- Latur, Maharashtra, India
Keywords:
chalcone, ABSTRACT
chalcone semicarbazone,
chalcone Isonicotyl hydrazone, In the present investigation, 4-chloro acetophenone on condensation with 2-
copper complexes, nitro benzaldehydes in methanolic NaOH solution yielded the corresponding
antibacterial activity, chalcone. These chalcone were further reacted with Isonicotyl hydrazide and
antifungal activity
semicarbazide in ethanol which led to the formation of chalcone Isonicotyl
Correspondence to Author:
hydrazone and chalcone semicarbazone derivatives respectively. The newly
P. M. Rachmale synthesized derivatives and there copper complexes were characterized on
the basis of their chemical properties and spectroscopic data such as IR, NMR
Dr. D.Y. Patil College of Pharmacy, Akurdi, and UV. All newly synthesized compounds were evaluated for their
Pune, Tal- Ahmedpur, Dist- Latur,
Maharashtra, India antibacterial activities against E. coli and S. aureus also for antifungal
activities against P. notatum.

INTRODUCTION: Benzelideneacetophenones belong to of flavones.Chemically they are open- chain flavonoids

the class of naturally occurring pigments which are in which the two aromatic rings are joined by a three-
often referred to as "chalcones". The term was first carbon alpha-beta- unsaturated carbonyl system (1,3-
coined by Kostanecki, who pioneered work in the diphenyl-2-propen-1-one) 2.
synthesis of natural coloring compounds. An
interesting feature of chalcones is that they serve as Chalcones exhibit many pharmacological activities,
starting materials for another class of naturally including antileishmanial 3, antiinflammatory 4, 6,
occurring and widely distributed pigments called antimitotic 7, antiinvasive 8, 9, as well as
flavones 1. Chalcones (fig. 1) have shown promising antituberculosis 10, antifungal 11, cysteinyl leukotriene
therapeutic efficacy for the management of human receptor-1 [CyLT1](LTD4) antagonist 12, antimalarial 13,
14
cancers. , antiplasmodial, immunosupressive, cytotoxic,
antitumor, and antioxidant properties 15, anti
fibrogenic activities and modulation of P-glycoprotein-
mediated multi-drug resistance 16.

Recent studies have shown that chalcones inhibit

cancer cell proliferation and are effective agents in
vivo against skin carcinogenesis 17, 18. They induce
apoptosis in various cell types, including breast cancers
FIG. 1: CHALCONE 19, 20
. Several oxygenated chalcones, bischalcones, and
They are considered to be precursors of flavonoids and some quinolinyl chalcone analogs reportedly show
isoflavonoids which are abundant in edible plants. antimalarial activity 21, 22. Some chalcones demonstrate
Chalcones are intermediates in the aurones synthesis the ability to block voltage-dependent potassium
channels 23.
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 Rachmale, IJPSR, 2012; Vol. 3(3): 901-908 ISSN: 0975-8232

Chalcone and their Derivatives: The Yakuchinones and Ronot, Xavier et al., reported that Chalcones (1, 3-
their analogues are interesting due to their inhibitory diphenylpropen- 1- ones) are naturally occurring
effects on active oxygen, nematocidal activity, compounds belonging to the flavonoid family and are
inhibition of lipid peroxidation and inhibition of acyl- largely investigated in various therapeutic area and
CoX. especially as antitumor drugs. In the latter field, the
literature survey indicates that effect on the cell cycle
Iwata and co-workers have reported isomerisation of is one of the most important targets domains of
E-chalcone to the Z form by exposing the methanolic chalcones.
solution of the chalcone to normal visible light 31.
Interestingly, the Z isomer showed more potent Metal Complexes of Chalcone: Anjaneyulu et al., 33
antitumor activity than the original E have suggested mechanism for the toxic action shown
form.Photoisomerisation of the predominant E isomer by metal chelates on the growth of the microorganism.
to the Z isomer may cause change in biological activity The high toxic nature of the metal complexes towards
and the ease with which the reaction occurs suggest viruses can be explained on the basis of the Chelation
that it is prudent to protect solution of chalcones from therapy. Structural studies on several metal chelates of
light. beta-diketones and 2-hydroxycarbonyl compounds
have been reviewed by Holm and O'Connor 34.
Ducki et al., noted that the two bonds were positioned
cis with respect to each other in several X-ray crystal Lense et al., 35 as well as Palaniandavar and coworkers
structures of chalcones 7. The s-cis conformer was 36
have reported that o-hydroxychalcones are much
more stable than the s-trans conformer by at least 3.9 more reactive with metal ions than the ketones and
kJ/mol. On the other hand, when a methyl group was aldehyders from which these are synthesized. The o-
introduced at the C(α) position, the disposition of the hydroxycarbonyl compounds form a distinct category
carbonyl and C(α)-C(β) double bonds altered to the among chalcones which can form chelates with metal
trans orientation. ions with low spin square-planar configuration, which
do not easily form adducts and this has been
For these alpha-methyl chalcones, molecular attributed to the presence of extensive
mechanics calculations showed that the minimum conjugation.Extensive conjugation was found to be
energy contemners were s-trans and no s-cis responsible for the strong field nature of the ligands.
conformation was evident within a 10 kJ/mol range of
the global energy minimum. The alpha -methyl group Rao and co-workers 37 reported the synthesis and
also caused significant loss of planarity between ring A structural studies of complexes of Co (II), Ni (II), Cu (II),
and the enone ( 56-88°). The α-methylchalcones are Zn (II) and Cd (II) with substituted chalcones.The
found to have greater cytotoxic activity against a electronic spectral data suggest that all the Co(ll)
human leukemia cell line than the unsubstantiated complexes and Ni(ll) complex of 3-(2-pyridyl)-1-(2-
analogues. Their unique geometrical features were hydroxy phenyl)-2-propen-1-one (PHPO) complex are
cited as a possible factor contributing to the enhanced octahedral and all the Cu(ll) and Ni(ll) of 3-(1-
biological activity. naphthyl)-1-(2- hydroxy phenyl)-2-propen-1-one
(NHPO) and 3-(3, 4-dimethoxy phenyl)-1-(2- hydroxy
Hadjeri M. et al., conveniently substituted flavones, phenyl)-2-propen-1-one (DMPHPO) complex are
chalcones and quinolones are highly attractive square-planar. The complex of Zn (II) and Cd (II) are
derivatives due to their therapeutic potential. The tetrahedral. Devi and co-workers 38 have studied the
substitution pattern of these compounds is crucial for thermal properties of metal (II) complexes of
their biological activity. Structure-activity relationship chalcones. The thermal diffusivity of chalcone metal
of flavone, indicates that: azaflavones are highly active complexes is enhanced when compared to the parent
molecules; the 5 and 7 positions are the most ligands. So among metal complexes, thermal diffusivity
important; hydroxyls, methoxy and amino groups are increases with the increase in the free electron density
the most beneficial. of the metal ion coordination.

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Angadi et al., reported the Antimicrobial activity of Cu of some chalcone analogues and their copper
(II), Co (II) and Ni (II) complexes of chalcones. The conjugation and evaluation of their antimicrobial
antibacterial activity of chalcones and its complexes Cu activity.
(II), Co (II) and Ni (II) shows weak activity against E.coli
and S.aureus when compared with standard MATERIALS AND METHODS: 2-Nitro benzaldehyde
streptomycin. The antifungal activity results revealed (Sisco,India), 4-Chloro actophenone (Sisco, India).
that the chalcones and its Cu (II), Co (II) and Ni (II), Semicarbazide (Sisco, India), Thiosemicarbazide (Sisco,
complexes have exhibited weak to good activity India), isonicotinyl hydrazides (Aldrich, USA)copper
against A.niger and A.flavous. The chalcone and its Cu chloride dihydrate (Qualigens, India) and Zinc nitrate
(II) and Co (II) complexes show weak activity when hexahydrate (Qualigens, India) were used as received.
compared to the standard drug chlotrimazole. Solvents used in the synthesis of compounds were
purified prior to their use according to literature
Sharma and co-workers 38 reported the Ruthenium (III) protocols. Figure 2 provides the scheme of synthesis.
and Rhodium (III) Complexes with Chalcone
Semicarbazones (2-hydroxychalcone) 40. Mishra et al., A. Synthesis of Chalcone: An ethanolic solution of 2-
have studied the Anti-HIV and Cytotoxic Activities of Ru Nitro benzaldehyde (0.0035mol) was added to 4-
(ll)/Ru (III) mixed ligand complexes containing 2,6-(2'- Chloro acetophenone (0.0035mol) with 0.5 ml of
Benzimidazolyl)-pyridine and chalcone Ligands. Their methanolic NaOH (15mole). The reaction mixture
interaction with aqueous buffered calf thymus DNA was stirred for 30 min and monitored by TLC using
was measured and these results prompted additional Chloroform: methanol (9:1) as developing solvent.
screening for anti-HIV (human immunodeficiency virus) A yellow colored precipitate separated out at the
activity against DNA replication in H9 lymphocytes and end of the reaction which was filtered out and was
cytotoxic activity against eight tumor cell lines. The washed with ether and dried under in vacuum over
most active compound was in the former assay have anhydrous CaCl2.
EC50 <0.1 μg/Ml. B. Synthesis of Schiff Base Ligands: The Schiff base
Nature of investigation: Chalcones continue to attract ligands of above chalcone were prepared by
considerable scientific attention because of their reacting the respective chalcone and the respective
association with a variety of biological activities. Only semicarbazide (CLS),isonicotinyl hydrazide (CLI) in
the cytotoxic and chemoprotective activities have been 1:1 stichiometric amounts in minimum amount of
reviewed and even with this restriction, it is apparent methanol with a few drops of glacial acetic acid.
that meaningful structure-activity correlations are The reaction mixture was refluxed on the water
difficult to establish for a specific activity. More bath for 6-8 hours. Completion of the reaction was
importantly, the structural features of chalcones monitored by TLC using chloroform: methanol (9:1)
presence of a reactive enone moiety and its relative as the developing solvent. A dark green colored
flexibility compared to other related natural products Product separated out when the mixture was
like flavonoids may predispose the template to allowed to cool. It was filtered out, washed with
interactions with diverse receptors and enzymes. The ether and dried in vacuum over anhydrous CaCl2.
C6-C3-C6 motif is recognized as a "privileged structure" C. Synthesis of Copper Complexes of Ligands: The
in drug design. general procedure involved interaction of the
Goals of investigation: In the present study employed methanolic solutions of copper Sulphate and
chalcone (CL) moiety as the primary motif to achieve respective chalcone ligands in 1:1 metal: ligand
the inhibitory function which is appended with stoichiometry and maintaining the reaction mixture
Semicarbazone and hydrazone pharmacophores as at neutral pH at room temperature with constant
depicted in order to target intermediate kinases of the stirring for 4 hrs. The precipitating metal
cell cycle. Conjugation of such ligands with copper is conjugates were collected by filtration, washed
expected to endow antimicrobial property. The with cold water and methanol. Finally, all
present study describes synthesis and characterisation compounds were dried under vacuum.

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FIG. 2: SCHEME OF SYNTHESIS

Year of experimentation: 2010-11 RESULTS AND DISCUSSION:

Site: Dr. D.Y. Patil College of Pharmacy, Akurdi , Pune. 1. Physicochemical Characteristics:

TABLE 1: MELTING POINT AND R.F. VALUE OF CHALCONE SCHIFF BASE LIGANDS AND THEIR COPPER COMPLEXES.
Sr. No Name of Compound Structure MoL. Wt. Colour M.P. R.F. Value

Cl
DARK
1 CHALCONE 119˚ C 0.6
GREENISH
NO 2 287.69

Cl

CHALCONE SEMICA- NO 2
2 344.76 PURPLE 130- 0.4
RBAZIDE
N
135˚ C
NH

O NH2

Cl

CHALCONE SEMICA- NO 2 DARK

3 RBAZIDE 602.44 Degradation -
GREENISH
COPPER COMPLEX O 4S N
O 4S Cu NH
O
NH2

Cl

NO 2
CHALCONE ISONIC-
4 406.82 VIOLET 140-145˚ C 0.3
OTYL HYDRAZIDE N
NH

O
N

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Cl

CHALCONE ISONI-OTYL NO 2
5 HYDRAZI-DE COPPER 664.50 DARK PURPLE Degradation -
COMPLEX O 4S N
O 4S Cu NH
O
NH2

2. Infrared Spectroscopy: The significant peaks in hydrazinic N-N stretch occurs in the range 1235-
the IR spectra of the synthesized chalcone, ligands 1251 cm-1. The appearance of metal-donor atom
and their copper complexes with possible stretching vibrations such as v M-N (440 cm-1) v M-
assignment are summarized in Table 2. The IR O (520cm-1) and confirm the presence of N and O
spectrum of the parent chalcone (CL) exhibits a donor atom sets for these compounds. All
sharp intense band at 1720 /cm due to carbonyl complexes exhibits a sharp band at 1330 cm-1
group. Upon Schiff base formation the free originating from v(Cu-SO4) vibration indicating the
carbonyl stretch disappears accompanied by the presence of sulphate ion in the metal coordination
appearance of C=N stretching near 157O -1660 cm- supporting the square planar geometry for the
1 which undergoes shift to low energy side upon present complexes. Also, Nitro group exhibit sharp
metal coordination. The aromatic C=C stretch can peak at cm-1 region.
be observed in the region 1521-1591 cm-1 while the

TABLE 2: SIGNIFICANT PEAK IN IR SPECTRA OF CHALCONE SCHIFF BASE LIGANDS AND THEIR COPPER COMPLEXES
Probable Assignment (cmˉ¹)
Compound
v (NH2,NH) v (C=O) v (C=N) v (C=C) v (N-N) v (M-Cl)
CL - 1720 _ 1591 _ _
CLS 3308, 3248 _ 1656 1591 1240 _
CLSC 3371, 3268 _ 1573 1535 1247 1270
CLI 3380 _ 1654 1518 1251 _
CLIC 3416 _ 1660 1523 1238 1159

3. Electronic spectroscopy: The electronic spectra for

all ligands and their copper complexes were
recorded in DMSO solvent (table 3). The chalcone
ligands are found to exhibit signals in the region
400-260 nm arising from n→π and π →π intra-
ligand transition respectively.The metal based d-d
transitions for the copper conjugates are observed
in the region 600-700 nm in fig. 3 characteristics of
square-planar geometry with dx2-y2 ground state.
TABLE 3: ELECTRONIC SPECTRAL ASSIGNMENTS FOR THE
CHALCONE LIGANDS AND THEIR COPPER COMPLEXES.
Electronic spectral data (nm)
compounds
Intraligand MLCT d-d
CL 352 _ _
CLSC 325 400 670
CLIC 308 359 673

FIG 3. UV SPECTRAS OF SCHIFF BASE OF CHALCONE AND THEIR

COPPER COMPLEX

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4. ¹H-NMR Spectroscopy: NMR spectroscopy enables

us to record differences in magnetic nuclei present
and to deduce in the large measure about the
position of these nuclei within molecule . the
proton NMR spectrum enables us to know different
chemical and magnetic enviorments corresponding
to protons in a molecules. The synthesized
compound were subjected to ¹H-NMRstudies on
varian FT-NMR spectrophotometer (300 mhz).

In the CL (fig. 4), parent chalcone aromatic CH-group of

ring A exhibits signal at δ 7.45 -7.48 ppm and δ 7.45-
7.77 ppmrespectively. In case of Schiff base ligand’s FIG. 6: NMR OF CHALCONE ISONICOTYL HYDRAZONE
CLS (fig. 5) , CLI (fig. 6) this signal is shifted to δ 7.29-
7.30 ppm and δ 7.58-7.60 ppm The signal corespond’s 5. Antimicrobial activity: The antimicrobial activity of
to NH group appear’s at δ 6.7 ppm while NH2 group chalcone and its ligands studied by cup-plate
appear’s at δ 6.0 ppm in CLS but in CLI pyridyl proton method (table 5). In this method, agar is melted
appear’s at δ 7.96 ppm and δ 9.08 ppm in singlet form. and cooled at 45°c , inoculated with the test micro-
Ethylene proton appear’s in all ligand’s at δ 5.62 pm organisms and poured into a sterile petriplate. In
and δ 7.0 ppm in doublet form and in CL at δ 5.78 ppm the cup-plate method, inoculated agar has
and δ 7.9 ppmin the doublet form. solidified, holes about 5mm in diameter are cut in
the medium with a sterile cork borer. The
antimicrobial agent is directly placed in the holes
and plates are incubated at 37°c for 48 hrs. and
measure the zone of inhibition.

Procedure:

a) Preparation the Stock Solution of 1000μM/ml:

(chalcone- 2.88mg in 10 ml DMSO.) (chalcone
semicarbazide- 3.45mg in 10 ml DMSO.) (chalcone
semicarbazide Cu-complex- 6.02mg in 10ml DMSO)
(chalcone Isonicotyl Hydrazide- 4.06mg in 10 ml
DMSO.) (chalcone Isonicotyl Hydrazide Cu-complex
- 4.06mg in 10 ml DMSO.)
FIG. 4: NMR OF CHALCONE
b) Preperation of Standard Solution: By dissolving
18.33mg penicillin in 10 ml DMSO to prepare 1000
μM/ml. Further dilution done using DMSO. prepare
Nutrient Agar Media (28gm Nutrient Agar powder
in 1000ml distilled water)and sterilized it. Prepare
bacterial suspension in distilled water and spread
on petriplate using spreader. Add 0.5 ml test
solution in each bore. Incubate all petriplates at
37°c for 48 hrs .Measure the zone of inhibition.

S. aureus – Staphylococcus aureus

E. coli - Escherichia coli
P. notatum – Penicillium notatum
FIG.5: NMR OF CHALCONE SEMICARBAZONE

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TABLE 5: ANTIMICROBIAL ACTIVITY OF TEST COMPOUND AND STANDARD COMPOUND

Dilution (μM/ml)
Compound Micro-organism 100 150 200 250 300
ZOI in mm
S.aureus 7 8 8.6 9 10
Standard E. coli 7.1 7.2 7.4 8.6 9.2
P. notatum 9.4 10.8 11.2 12.4 13.6
S. aureus 9.4 15.6 17.2 17.4 17.7
CL E. coli 7.2 7.4 8.4 9.6 10
P. notatum 11.4 13.8 15.2 17.4 21.6
S. aureus 9.2 15.6 11.6 12.4 10.6
CLS E. coli 5.6 5.8 6.2 6.8 7.2
P. notatum 11.6 13.4 18.4 20.6 13.8
S. aureus 7 7.4 8 8.6 8
CLSC E. coli 7 9 10 11 11.4
P. notatum 6.6 8 8.4 14 15
S. aureus 9 10 13 13.4 14
CLI E. coli 13 17 15 16.4 16.8
P. notatum 7 8 9 11 17
S. aureus 7 8 9.4 15 23
CLIC E. coli 11 12 13.2 11 7
P. notatum 15 16 17.2 17.7 18

TEST COMPOUND STANDARD designing such agents. Metal chelation seems to be

helpful in enhancing the antimicrobial activity .In
antimicrobial activity concentration increases the zone
of inhibition also increases.chalcone (CL=21.6mm at
300µM/ml) and chalcone semicarbazone derivative
(CLS=20.6mm at 250 µM/ml) exhibiting potent
antifungal activity towards P. notatum as compared to
standard ( standard = 12.4mm at 250 µM/ml) . As well
as copper complex of cxhalcone isonicotyl hydrazone
derivative ( CLIC = 23mm at 300µM/ml) exhibit
promising antibacterial activity towords S. aureus.This
strategy can be refined further for optimization.

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