SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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� General introduction.
� Introduction:
Chalcones are the compounds where aromatic substituent are introduced into
the terminal position of the system -C=C-C=O. So, chalcones are characterized by
their possession of a structure in which two aromatic rings A and B are linked by an
aliphatic three-carbon chain [(A) Ar-CO-CH=CH-Ar (B)].
C
O
CH CHBA
Thus chalcones are phenyl styryl ketones containing reactive keto-ethylenic
group -CO-CH=CH-. Chalcones possess conjugated double bonds and a completely
delocalized Π-electron system on both benzene rings. Molecules possessing such
system have relatively low redox potentials and have a greater probability of
undergoing electron transfer reactions.
These are coloured compounds because of the presence of the chromophor and
auxochromes. Chalcones are also known as benzalacetophenones or bezylidene
acetophenones, beta-phenyl-alphabenzoyl-ethylene*. Kostanecki and Tambor [1, 2]
gave the name “Chalcones”.
The chemistry of chalcone has been recognized as a significant field of study.
An interesting feature of chalcone is that it serves as starting materials for the
synthesis of various heterocyclic compounds such as pyrimidines, pyrazolines,
pyrazoles, flavones, flavonols, flavanones, aurones and benzoyl coumarones as well
as certain compounds like deoxybenzoins and hydantoins, which are of some
therapeutic value. Natural chalcones occur mainly as petal pigments and have also
been found in the heartwood, bark, leaf, fruit and root of a variety of trees and plants.
Chalcone-containing plants such as Glycyrrhiza species have long been used as folk
remedies.
Naturally occurring and synthetic chalcone compounds have shown interesting
biological activity as antioxidant, antiinflammatory, anticancer and antiinfective
agents. They play an ecological role in relation to plant colour, since they contribute
significantly to the corrole pigmentation of the flawers in a number of families.
The chalcones have been found to be useful in providing structure of natural
products, like cynamaclurin [3], munchiwarin [4] (I), ploretin [5], medicagenin [6]
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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(II), homoeriodictyol [7], sakuranetin [8], licochalcone-A [9, 10, 11] (III),
hemlocktanin [12], 3-methoxy-4-hydroxylonchocarpin [13] (IV), xanthohumol [14]
(V) etc.
* Chalcone is also known as 1, 3- disubstituted-2-propene-1-ones.
O
OH
OH
OH
O
OH
O
OH
(I) M unchiwarin (II) Medicagenin
O
OH
OCH3
OH
O
O
OH
O
CH3
OH (III) Licochalcone A (IV) 3-Methoxy-4-hydroxylonchocarpin
O
OH
OH
OH OCH3
(V) Xanthohumol
� Nomenclature:
Chalcone is trivial name in old literature; the chalcones have been given
different nomenclature time to time. In the numbering system used by chemical
abstract, the prime numbers are given to phenyl ring, which is nearer to carbonyl
group.
1'
2'3'
4'
5'
6'1
2
3
4
56
C
O
CH CH
(VI)
The following system has been followed by the British Chemical Abstracts
and Journal of Chemical Society.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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1'
2'3'
4'
5'6'
1
23
4
56
C
O
CH CH
(VII)
In recent literature in chemical abstracts chalcones are reported the IUPAC
name 1, 3-diphenyl-2-propene-1-one. Till 1971 they were reported as chalcones.
� Reactivity of Chalcones:
Chalcones contain reactive keto-ethylenic group -CO-CH=CH- and therefore,
chalcones are reactive towards a number of regents. The reactivity was investigated
by several chemists. Some of the important reactions are described below.
1. Reactivity of chalcones
Chalcones bear an active keto-ethylenic linkage -CO-CH=CH- and therefore
reactive towards a number of reagents yielding various heterocyclic compounds. The
reactivity of chalcones was investigated by several scientists. Some of the important
reactions are described as below:
[1] Dibromide of chalcones was obtained by action of bromine on the chalcones
has been reported by Vanderwalla H. P. et al. [15] and Naik V. R. et al. [16].
O O
Br
Br
Br2
CH3COOH
[2] Flavones can be easily prepared form 2’-hydroxy chalcones by the action of I2
crystal in DMSO [17, 18].
O
OH
O
OI2
DMSO
[3] Chalcones and Cu (II) Cl2 to give chloro flavones [19].
O
OH
O
O
Cl
Cu2Cl2
DMSO
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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[4] Chalcones, 30% H2O2 and NaOH were reacted in presence of methanol and
further reacts with dimethyl sulphate in presence of K2CO3 in acetone to give
flavanols [20], methoxy flavones. [21] In basic media reaction of chalcone and
H2O2 produce oxirane. [22].
O
OH
O
O
OH
H2O2 /NaOH
Methanol
[5] Chalcone react with ethyl acetoacetate in presence of dry K2CO3 to give 6-
carboxy cyclohexenones, further it reacts with hydrazine hydrate to afford 3-
oxo-1-indazole [23].
O
O CH3
O
O
EAA/ K2CO3
Acetone
[6] Isoxazoline [24] and oxazoles [25] can be prepared by the treatment of
chalcone with hydroxylamine hydrochloride and sodium acetate in different
conditions. O
N O
NH2OH HCl
[7] 1H-2-pyrazolines were prepared by refluxing chalcones with hydrazine
hydrate in ethanol [26, 27] or pyridine. O
N NH
NH2NH2 H2O
Ethanol
[8] Pyrazoline and its derivatives can be prepared by the condensation of
chalcones with hydrazine hydrate and acetic acid [28, 29]. O
N NO
CH3
NH2NH2 H2O
Acetic acid/ Ethanol
[9] Chalcone on reaction with thio semicarcazide hydrochloride in ethanol affords
1-thiocarbamoyl-2- pyrazolines [30, 31].
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O
N NS
NH2
NH2NHCSNH2 .HCl
Ethanol
[10] 2-Aminothiophenol reacts with 2’-hydroxy chalcones in methanol/ acetic acid
to give propiophenones which immediately undergo cyclization to give 1, 5 –
benzothiazepines [32].
O
SN2-Aminothiophenol
CH3OH/AcOH
[11] Pyrazole can be prepared by the condensation of chalcone and hydrazine in
piperidine and methanol [33].
O
N N
R
R-NHNH2
Piperidine/Mthanol
[12] Aurones can be easily prepared form chalcones by the action of mercuric
acetate in DMSO [34].
O
OH O
O
Mercuric acetate
DMSO
[13] Chalcones were reacted with guanidine nitrate in the presence of aqueous
sodium hydroxide (40%) in ethanol to give 2-aminopyrimidines [35, 36].
Chalcones react with sodium nitrile in presence of glacial acetic acid in
ethanol produces 2-1H-pyrimidines [37].
O
NN
NH2
NH2CNHNH2.HNO3
Ethanol / KOH
[14] Chalcones on treatment with urea in presence of alkali affords 2-
oxopyrimidines [38].
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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O
NHN
O
NH2CONH2
Ethanol KOH
[15] Chalcones on reaction with thiourea in presence of alkali yields 2-
thionepyrimidines [39].
O
NHN
S
NH2CSNH2
Ethanol KOH
[16] 2-amino-3-cyano pyridines has been prepared by the condensation of chalcone
and malononitrile in presence of ammonium acetate [40].
O
N
NH2
CN
CH(CN)2
CH3COONH4
Chalcone on condensation with malononitrile and pyridine yields 2-amino-3-
cyano –pyrans [41].
O
O
NH2
CN
CH(CN)2
Pyridine
[17] Chalcone with monoethanolamine in ethanol gives 1, 4-oxazipines [42].
NH2
OH
O
N O
[18] Cyanopyridone derivatives can be prepared by the condensation of chalcone
with ethyl cynoacetate [43].
O
NH
ON
Ethylcyno acetate
Ammonium acetate
[19] Chalcone reacted with H2O2 in acetone and gave corresponding epoxides [44].
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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O O
O
H2O2 / acetone
� Alkali as condensing agent
Ellison [45] and later on by Mahal, Rai and Venkataraman [46] et. al.
condensation of resacetophenone and galloacetophenone with benzaldehyde in
presence of alkali. Instead of the expected chalcones the corresponding flavanones
were obtained.
The condensation of aldehydes other than benzaldehyde did not succeed, but
resacetophenone 4-benzylether readily gave chalcones with benzaldehyde,
anisaldehyde etc. [47].
Deodhar Mandar et al. [48] have prepared 2- hydroxy chalcones by the
condensation of 2- hydroxy acetophenone with benzaldehyde in presence of aqueous
KOH solution and ethanol in good yield. U. S. Patent 2004242907 [49] has also
reported the synthesis of chalcone by the above mentioned method.
OOH
OCH3H3CO
H3CO
O CH3
OHH3CO
OCH3
OCH3
O
+KOH, H2O
EtOH
Singh R. J. et al. [50] have synthesized 2, 5- dihydroxy chalcones by the
reaction of 2, 5-dihydroxy acetophenone and 4-(dimethylamino) benzaldehyde using
KOH as condensing agent in ethanol.
OOH
OH
NCH3
CH3
O CH3
OH
OH
O
NCH3 CH3
+KOH, H2O
EtOH, RT over night
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Claisen condensation of substituted 2'-hydroxyacetophenones with aromatic
aldehydes in methanol using aq. KOH as condensing agent has been reported by
Singh Om V. and Muthukrishnan M. et al. [51].
OOH
H3CO
H3CO
OCH3
OCH3
OCH3
OCH3
OH
OCH3
H3CO
O
OCH3
H3CO OCH3
+KOH, H2O
CH3OH
2. Hydrochloric acid gas
The simple chalcone, benzylidene acetone was prepared by Claisen and
Claparede [52] by condensing acetone with benzaldehyde in presence of acetic
anhydride and zinc chloride at 160-170oC. Further the benzylidene acetophenone have
also been demonstrated by condensing acetophenone with benzaldehyde using
hydrochloric acid as a condensing agent.
OO CH3O
+
CH3
O
CH3
O
CH3
O
+
HCl gas
acetic anhydride
ZnCl2 160-170 °C
Jonathan, R. and co-workers [53] have synthesized chalcones by the
condensation of 3, 5-bis (dimethylaminomethyl)-4-hydroxy acetophenone
dihydrochloride and 4-hydroxybenzaldehyde with saturated hydrogen chloride in
ethanol at room temperature.
OH
CHO
+OH
N(CH3)2
N(CH3)2
COCH3
OHOH
N(CH3)2
N(CH3)2 O
Hydrogen Chloride
Et-OH
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3. Presence of Aluminum chloride Friedel-Craft reaction:
Szell and Sipos [54] have condensed 2-hydroxyl-5-nitro-aceto-phenone with
benzaldehyde using AlCl3.
O
Cl
OCH3
+
O
OCH3
AlCl3
CS2
Tri-methoxy chalcone have been prepared by the condensation of 1, 3, 5 tri methoxy
benzene and hydroxyl cinnamoyl chloride chloroform in presence of AlCl3 at -5 oC by
Bhatt Douglas G. et al. [55].
OCH3
OCH3
H3COO
Cl
+
H3CO
OCH3H3CO
O
AlCl3
CH2Cl2-50C
4. Presence of Lithium methoxide and Lithium hydroxide
Jung, Jae-Chul co-workers [56] have synthesized and reported treatment of
various vanillins with several acetophenones in the presence of lithium hydroxide (Li
OH) as the most effective coupling base in methanol produced high yields of 1, 3-
diphenyl-2-propen-1-ones.
HO
OH
H3CO
CH3O
OCH 3
FMe-OH
O
OCH 3
F
OH
OCH 3
+LiOH
5. Presence of Silica-sulfuric acid reagent
Ganesamoorthy Thirunarayanan and Ganesan Vanangamudi [57, 58] have
synthesized a series of α, β unsaturated ketones derived from 4-bromo-1-napthyl
ketones with various substituted benzaldehydes under solvent free condition using
silica-sulfuric acid as a reagent in an oven. In this method the catalyst silica is
reusable and the yields of chalcone are more than 90%.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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Br
CH3CO
+
CHO
R
SiO2-H2SO4
Solvent free 800C
Br
O
R
6. Heck reaction using Palledium catalyst
Christina Reichwald et al. [59] have prepared chalcone by Heck reaction,
condensation of 9-substituted 2-iodo-7, 12-dihydroindolo [3, 2-d] [1] benzazepin-
6(5H)-one and a ketone Mannich base hydrochloride in presence of
palladium(II)acetate, triphenylphosphine, triethylamine using DMF as solvent at
1500C.
N
NH O
I
HR
1
+
O
NCH3
CH3 N
NO
O
H
HR
1Pb(AcO) 2,triethylamine
P(Ph)3, DMFHCl
1500C ,
7. Phosphonate Carbanion and Benzaldehyde
Chalcone has been obtained by the reaction of benzaldehyde with phosphonate
carbanion [60-61] derived from diethylphenylacyl phosphonate with sodium hydride
in witting reaction. Carbonyl stabilized phosphonium yields [62] also resulted in
several substituted chalcones similar to phosphonium yields.
O
P(OC2H5)2
CHO OO
+
10. Activated Ba (OH)2
Narender T. et al. [63] have used activated Ba (OH)2 in methanol under
refluxing condition to synthesize chalcone. Mastsukoa and Fujise [64] have used this
method to prepare several chalkones from 2-hydroxy acetophenone having methoxy
or methyl groups as substituents and meta- or para-nitrobenzaldehyde. It is reported
that in some instances the yield of the chalkone is more than 60%.
Barium hydroxide as condensing agent for the condensation of 2-hydroxy
acetophenone and arylaldehyde in dry DMSO medium.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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OOH
OCH3
O
CH3CH3
CH3
CH3
CH3
OOH
OH
CH3 CH3
CH3
CH3
HO
OCH3
+ Ba(OH)2
EtOH, Reflux
12. Concentrate sulfuric acid as condensing agent
Kalluraya Balakrishna et al. [65] have described the synthesis of heterocyclic
chalcone using concentrate sulfuric acid as condensing agent in ethanol from various
acetophenone and (5-nitro-2-yl) methanediyl diacetate.
O NO2HC
(CH3COO)2
O
CH3R
+O
NO2
O
Con. H2SO4
EtOH
13. Presence of sodium acetate and cupric chloride
An entirely different method for the preparation of chalcones has been
discovered by Mehra and Mathur. [66] First aryl diazonium chloride has been treated
with β benzoyl acrylic acid, in the presence of sodium acetate and cupric chloride and
desired chalcone is obtained.
COOHO
+
ONNCl
CH3COONa
Cupric Cloride
15. Sodium Methoxide
Claisen [67] condensed benzaldehyde with actophenone by the action of
sodium methoxide in methyl alcoholic solution and got the simple chalcone.
Later on this method was used by several workers [68].
MeO
CHO
+
OMe
MeO
Ac
OH 1.2 R:HCl, S:H2O
1.1 R:Ba(OH)2, S:DMSO, 30 min, 100 C
OMe
OMe
MeO
CCH
O
CH
HO
70%
°°°°
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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� Other condensing agents:
Besides the above mentioned condensing agents pyridine [69], have also been
used as condensing agents in chalkone synthesis. Chalkones have also been prepared
by using acetic anhydride and potassium acetate [70] as condensing agents.
The other condensing agents used in the synthesis of chalcones apart from the
above are as follows.
Amino acid [71]
Piperidine [72]
Organocadmium Compound [73]
� Properties and tests of chalcones
The chalkones are highly coloured substances usually yellow, orange, red or
brown in colour. They are comparatively more soluble in ethanol and ethyl acetate
than flavanones 2’-hydroxy chalkones dissolve in dilute alkali with orange to deep red
colour.
� Colour reaction :
The chalkones give the following colour test:
(i) Chalkones give characteristic deep red colour with concentrated sulphuric
acid, which is used as a diagnostic test for their class of compounds. This test
is often used to distinguish them from the isomerio flavanones.
(ii) Ethanolic Ferric chloride Test:
O-Hydroxy chalkones (2’-Hydroxy chalkones) give a reddish brown or wine
red colouration with ethanolic ferric chloride.
(iii) Wilson’s Boric acid Test :
This test has been described by Wilson [74] who used it successfully to
distinguish the chalkones from flavanones. A solution of the substance in
acetone is tested separately with dqual volumes of citric acid-boric acid-
acetone reagent and citric acid-acetone solution. Any definitely strong colour
with the boric acid reagent is considered positive. This test is claimed to be
specific for 5-hydroxy- and 5-methoxy flavones and flavonols and o-hydroxy.
and methoxy chalcones. It is not given by flavanones and simple aromatic
ketones. Even a drop of water discharges the colour. Rangaswami and
Seshadri [75] have also successfully used this test.
(iv) King and White [76] observed that on treatment with a 200:1 (vol/vol) mixture
of acetic anhydride and sulphuric acid chalkones gave orange to purple colour
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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and flavones gave yellow colour and flavonols no colour. The nature of the
colour or its intensity depended on the number of hydroxy and methoxy
substituents.
� Chalcones as analytical reagent:
Chalcones react with a number of metal ions and are reported to be more
reactive than the aldehyde or ketone from which they have been prepared [77]. This
reaction has been exhibited for the detection of Fe (III) by 2’, 4’-dihydroxy chalcones,
provided the concentration of interfering ions kept at a minimum 2’, 3’, 4’ trihydroxy
chalcones was used as an analytical reagent for amperometric estimation of copper
[78] and for spectrophotometric study of the germanium[79]. Bharadwaj and Singh
[80] introduced 2’-hydroxy-2, 5’ di chloro-4’-methyl benzalaceto-phenone oxime as
an analytical reagent for Cu (II), Ni (II) and Pd (II).
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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� Mechanism of Chalcone Formation:
Kinetic study was reported for the base catalyzed formation of chalcone [81-
83] and its derivatives [84].
Two alternative mechanisms have been advanced for the reaction of
benzaldehyde with acetophenone in the presence of a basic catalyst:
(I)
CH2CO Ph + Ph CHO
-Ph - C - CH
2 CO Ph
O
H
-
Ph -C-CH2-COPh + H2O
O
-
H
Ph -C-CH2-COPh + OH
OH
H
-
Ph -C-CH2-COPh
OH
H
Ph-CH = CH - CO -Ph + H2O
(II)
Ph CHO + C2H5O Ph- CH -OC
2H5
O -
H
CH3 CO Ph + Ph- C -OC
2H
5
O -
H
Ph- C -CH2COPh + C
2H
5OH
H
O -
Ph- C -CH2COPh
H
OH
Ph - CH = CH - CO Ph + H2O
In chalcone formation by the acid-catalysed condensation of benzaldehyde and
acetophenone was studied [85-86]. It was reported that the rate of reaction depends on
the first power of the concentration of benzaldehyde the Hammett activity function.
Also the condensation (see below) has been shown as the rate-determining step in this
reaction.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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The following mechanism seems to be comparable
C
O
CH3R C
OH
CH2R
C
O
HR'+ SH
+
OH
R' - C - H+ S (S = Solvent)
+
C
OH
CH2R+
OH
R' - C - H
+
Transition
complex C
OH
CH2R CH -R'
OH
+
C
OH
R CH -R'
OH+
+ S CH2
C
O
R CH -R'
OH
CH2
+ SH
C
O
R CH -R'
OH2
CH2
+ SH
+
+
C
O
R CH -R'
OH2
CH2
+
C
O
R CH = CH - R' + H2O + H
+
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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� Biological activity shown by chalcone:
Nielsen Simon F. et al. [87] have synthesized cationic chalcone which exhibit
high bacterial activity against both gram positive and gram negative pathogens. They
have reported that most potent compound (VIII) has an MIC value of 2 µM against
methicillin resistant Staphylococcus aureus.
O
NHN
H
H
N
NH
CH3CH3
(VIII)
Chikhalia Kishor H. et al. [88] have synthesized novel quninoyl chalcones
(IX) and evaluated for antibacterial activity against gram positive and gram negative
bacterial. Among them compounds having –OCH3 group exhibited excellent
antibacterial activity against bacterial strain Bacillus subtillis.
N
N
N
O
NCH3
ONH
NH
O
R
Cl
Cl
F
Where, R = 3, 4, 5-(OCH)3; 4-Cl; 2-OCH3; 4-CH3; 4-OCH3; 4-F; 2-OH. (IX)
Quaternary amino-fuction chalcone derivatives and analogues are patented for
bacterial infections such as gram-negative and gram-positive bacteria, including
antibiotic-sensitive or resistant strains. Compound (X) exhibits high activity against E.
coli. [89].
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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ONH2
CH3 CH3
O
N+
CH3
CH3
CH3
I
(X)
Dal. P. A. et al. [90] have synthesized a series of substituted (E)-3-(4-phenyl
benzoyl) chalcones (XI, XII) as potential anti bacterial agents.
O
NH2
CH3
CH3
O
N+
CH3
CH3CH3
I
O
O
R (XI) (XII)
Sato. [91] studied the growth inhibitory properties of derivatives of 2’hydroxyl
chalcone and 2, 5 –dihydroxy chalcone (XIII) against oral candida species, like C.
albicans, C. tropicalis and C. glabrata. The structure-activity relationship indicated
that the presence of a hydroxyl group at the 2-position potentially improved the
antifungal property. O
OH
OH (XIII)
Malik H. et al. [92] have synthesized chalcone derivatives and reported for
their antifungal activity. Some chalcones incorporated with indole (XIV) moiety were
synthesized and tested for their antifungal activity [93].
NH Ar
O R1
R2
Where, Ar = C6H5, F-C6H5 (XIV)
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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Mrs. Singh Suman Rajvir et al. [94] have discovered some 1, 3 Bis (4-
methylphenyl)2- propen -1-one (XV) and screened their anti fungal activity.
O
CH3 CH3
(XV)
V. Kozmik et al. [95] have prepared azabischalcones (XVI(a), (b)) and screened
against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium
as usual as INH-resistant strains as tuberculostatic agent.
(a) (b)
NR R
R1 O
Ar-
Ar-
O
NCH3 CH3
R1 O
PhCH3
O
(XVI)
Lin, Yuh-Meei et al. [96] has discovered the chalcone derivatives and
antitubercular activity was screened. Compounds (XVII a, b) have inhibited 98%,
97%, 96% and 96% growth of Mycobacterium tuberculosis H37Rv.
N
O
F
O
OH
(a) (b)
(XVII)
The oxygenated chalcone, 2, 4-dimethoxy-4’-butoxychalcone (XVIII, XIX),
exhibited potent activity against human malaria parasite Plasmodium yoelii in vitro
and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo [97].
O
O CH3H3CO
OCH3
N
O
H3CO
H3CO
OCH3
(XVIII) (XIX)
Domnguez Jos N. and coworkers [98] have demonstrated a new phenylurenyl
chalcone derivative as antimalarial agent. They have found most active derivative 1-
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
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[3’-N-(N-phenylurenyl) phenyl] -3(3, 4, 5-trismethoxyphenyl)-2-propen-1-one (XX)
with an IC50 of 1. 76 µM against cultured P. falciparum.
OCH3
OCH3
OCH3NH
O
NH
O (XX)
Some interesting finding have reported by Srinivas K. Kumar et al. [99] for a
series of synthesized boronic-chalcone derivatives (XXI) and tested for antitumor
activity against human breast cancer cell lines. The results show that boronic-
chalcones are more toxic to breast cancer cells as compared to other known chalcones.
O
BOH
OH
R1
R
Where R = I, Cl, F R1= H, Cl, Br (XXI)
Recently, Paula Lorenzo. et al. [100] have synthesized novel chalcones
containing adamantyl arotonoids (XXII) and evaluated their IKBα kinase β (IKKβ)
activity which inhibits cell growth and induces apoptosis in cancer cells.
O
COOHORMEMO
Where R = ,
(XXII)
Nakamura Chika, Kawasaki Nobuhide et al. [101] have synthesized
fluorinated chalcones and evaluated antitumor activity against human cancer cells.
Compound (XXIII) was reported as the most effective compound.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 23
O
O OHOCH3
CH3
OH
F
(XXIII)
Meng, Charles Q. et al. [102] have synthesized the series of carboxylated
hetroaryl-substituted chalcones as inhibitors of Vascular Cell Adhesion Molecule-1
expression for use in chronic inflammatory diseases. They have studied structure
activity relationship (SAR) and found novel chalcone (XXIV) which showed
significant anti-inflammatory effect in a mouse model of allergic inflammation.
Compound (XXV) 4- [3E-(2-morpholinoethoxy-4-methoxy-5-thien-2-yl)acryoloyl]
benzoic acid potently inhibited the expression of VCAM-1.
HOOC
O
OCH3
S
O
N
OH3CO
O
OCH3
S
OCH3
OCH3
H3CO
(XXIV) (XXV)
Some interesting finding have reported that chalcone (XXVI) showed
inhibited TNF-α induced VCAM-1(vascular cell adhesion molecule-1) expression at
IC50 values in the micromolar range. The authors also noted that the presence of at
least two methoxy groups on ring A led to compounds with good anti-inflammatory
agents. Nowakowska, Z. [103] reported that chalcone as anti-inflammatory agents.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 24
H3CO
O
OCH3
S
H3CO
H3CO
H3CO
(XXVI)
Ducki, S. et al. [104] have demonstrated potent antimitotic and cell growth
inhibitory properties of substituted chalcones and reported methoxy functionalized
chalcones [XXVII and XXVIII ] are highly active in K562 leukemia cells.
O
H3CO
H3CO
OCH3
OHOCH3
H
O
H3CO
H3CO
OCH3
OHOCH3
CH3
XXVII XXVIII
Kim, D. Y. and Kim, K. H. [105] have designed new chalcone derivatives and
evaluated their cytotoxic activities. Among these, compounds (XIXa, b, c)
consistently exhibited potent activities and merits for the further evaluation as novel
antimitotic agents.
O
N
NH O
O
O
N
NH O
CH3
O
N
NH O
N
CH3
CH3
(a) (b) (XXIX) (C)
A series of 2’ hydroxy chalcone derivatives containing thiazolodinone (TZD)
(XXX) has been synthesized and evaluated their peroxisome proliferator-activated
receptor-γ (PPAR-γ) ligand-binding activities. Among chalconylidene-TZDs
derivatives compound 2’-hydroxy-5’-methoxychalconylidene-TZD showed potent
peroxisome proliferator-activated receptor- γ (PPAR- γ) ligand-binding active. [106]
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 25
OOH
R1
S
NH
O
O
Where, R1 = 5’-OCH3 (XXX)
Anti diabetic activities of chalcone derivatives have been reported by Lim S.
S. et al. Jung S. H. et al. [107-108]. Kamei R. and co workers [109] have reported 3-
nitro-2’-benzyloxychalcone (XXXI) showed potent anti diabetic activity.
O O
O2N
(XXXI)
Tatsuji Enoki et al. [110] have found that the ethanol extract from a Japanese
herb “Ashitaba”, Angelica keiskei, contained two major chalcones of 4-
hydroxyderricin (XXXII) and xanthoangelol (XXXIII) that showed strong insulin-like
activities.
O
OH
OH
OH
CH3
CH3
CH3
O
OH
OCH3
OH
CH3
CH3
(XXXII) (XXXIII)
Parmar V. S. et al. [111] have synthesized some chalcones (XXXIV) and
(XXXV) reported as potent anti invasive agents.
O
O
CH3
OHO
O
CH3
CH3
O CH3
(XXXIV) (XXXV)
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 26
Nam Nguyen-Hai et al. [112] have synthesized a series of 2', 5'-
dihydroxychalcones and evaluated for cytotoxicity towards HUVEC. Among the all
compounds (XXXVI) showed the highest activity on HCT116 cells.
O
OH
OH
Cl
(XXXVI)
Komazawa Yukio, Takeda Shigefumi et al. [113] have patented the chalcone
molecule as anti-ulcer agent. Novel chalcone derivatives (XXXVII) having such an anti-
ulcer action were used for treatment of gastric ulcer and a duodenal ulcer.
O
R7
R3
R2
R6
X
R4
R1
Y
R5
(XXXVII)
Wang Q, Ding Z H et al. [114] have reported the anti HIV-1 inhibitory activity
of natural compound Xanthohumol (XXXIII).
O
OH
O
OH
CH3
OH
CH3CH3 (XXXVIII)
Cheenpracha Sarot, Karalai Chatchanok et al. [115] have founded new
chalcone derivatives (XXXIX and XL) from Boesenbergia pandurata and evaluated
anti-HIV-1 protea.
O
OH
O
OH
CH3O
O OHOH
OH
CH3 (XXXIX) (XL)
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 27
Giuseppina Cioffi et al. [116] have isolated some important chalcone from
Maclura tinctoria and screened their anti oxidant activity. 3‘-(3-methyl-2-butenyl)-4‘-
O-β-D-glucopyranosyl-4, 2‘-dihydroxychalcone(XLI)was the most active compound
among all. Lambert Didier M. et al. [117] have synthesized 2(3H)-benzoxazolone
heterocycle containing chalcones and evaluated their antioxidant activity.
OOH
OHR
CH3
CH3
Where, R = O-β–Dglucopyranosyl (XLI)
Hui Zhanga, Jia-Jia Liu et. Al [118] have been designed and synthesized, and
their biological activities were also evaluated as potential inhibitors of tubulin. These
compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell
lines in vitro. Compound [XLII] showed the most potent antiproliferative activity
against MCF-7 and A549 cell lines with IC50 values of 0. 03 and 0. 95 µg/mL and
exhibited the most potent tubulin inhibitory activity with IC50 of 1. 42 µg/mL.
Docking simulation was performed to insert compound into the crystal structure of
tubulin at colchicines binding site to determine the probable binding model. Based on
the preliminary results, compound with potent inhibitory activity in tumor growth
may be a potential anticancer agent.
O
R
O
O2N
NO2
CF3
(XLII)
A series of deoxybenzoin oximes were recently reported as potent
immunosuppressive agents by Yin [119] Luo, Ran Song et. al. In order to continue the
original research for potential immunosuppressive agents with high efficacy and low
toxicity, they synthesized a series of new chalcone oximes [XLIII] and evaluated
them for their cytotoxicities and immunosuppressive activities. Among the
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 28
synthesized compounds, chalcone oximes exhibited lower cytotoxicities and higher
inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other
compounds. Specially, compound displayed 200-fold lower cytotoxicity
(CC50 = 2174. 39 µM) than cyclosporin A (CC50 = 10. 10 µM) and showed SI value
(SI = 176. 69) close to cyclosporin A (SI = 154. 13).
NOH
(XLIII)
Younghwa Na [120], et. al have designed and synthesized oxiranylmethoxy-
and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological
activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds
prepared compound [XLlV] showed comparable or better cytotoxic activity against
cancer cell lines tested. Compound inhibited MCF7 (IC50: 0. 49 ± 0. 21 µM) and
HCT15 (IC50: 0. 23 ± 0. 02 µM) carcinoma cell growth more efficiently than
references. In the topoisomerases inhibition test, all the compounds were inactive to
topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially,
compound inhibited topoisomerase II activity with comparable extent to etoposide at
100 µM concentrations. Correlation between cytotoxicity and topoisomerase II
inhibitory activity implies that compound can be a possible lead compound for
anticancer drug impeding the topoisomerase II function.
(XLIV)
With the aim to further improve the vasorelaxant activities of chalcones, nine
hybrid chalcone derivatives conjugated with nitric oxide (NO) donor or 1, 4-
dihydropyridyl (1, 4-DHP) moiety were designed and synthesized based on molecular
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 29
hybridization strategy by Xiaowu Dong et. al. [121] Their vasorelaxant activities were
evaluated in aortic rings with endothelium pre-contracted with phenylephrine (PE).
All of these compounds [XLVa, b, c]showed preferable vasorelaxant activities which
were more potent than their parent compounds.
O
O
O
OHOH
OHO
O
O
O
OH OH
O2NO
O
O
O
OO
O
ONO2
O2NO
O2NO
(a) (XLV) (b) (c)
Suthar Sharad Kumar, Aggarwal Vaibhav, Chauhan Monika, Sharma Ankesh, Bansal
Sumit, Sharma, Manu et.al. have reported molecular docking and biological
evaluation of hydroxy-substituted (Z)-3-benzylideneindolin-2-one chalcones(XLVI)
for the lead identification as tyrosinase inhibitors[122].
(XLVI)
Manjusri, C. H.; Sivasubramanyan, P.; Sushma, P.; Krishnachaithanya, M.;
Gessaiero, Lamack et.al. have reported synthesis and antimicrobial activity of some
chalcone derivatives(XLVII) [123].
(XLVII)
Pingaew, Ratchanok; Saekee, Amporn; Mandi, Prasit; Nantasenamat, Chanin;
Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong et al. have
reported synthesis, biological evaluation and molecular docking of novel chalcone-
coumarin hybrids (XLVIII, XLIX) as anticancer and antimalarial agents[124].
HN
OR
R1
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 30
(XLVIII) (XLIX)
Zhu, Cuige; Zuo, Yinglin; Wang, Ruimin; Liang, Baoxia; Yue, Xin; Wen,
Gesi; Shang, Nana; Huang, Lei; Chen, Yu; Du, Jun; et al have reported discovery of
potent cytotoxic ortho-aryl chalcones (L)as new scaffold targeting tubulin and mitosis
with affinity- based fluorescence[125].
(L)
Sadula, Anitha; Peddaboina, Usha Rani; J, Prameela Subhashini N. are
reported Synthesis and characterization of novel chalcone linked imidazolones (LI)as
potential antimicrobial and antioxidant agents[126].
(LI)
Wang, Yanyan; Zhang, Shuxiang; Niu, Wenying; Yu, Shuang have reported
novel chalcone compound(LII) with anti-ageing activity, its pharmaceutical
composition and application [127].
(LII)
O
F
R
N
N N
O
Ph
O
R
N
O
OH
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 31
Aisa, Ajiaikebaier; Niu, Chao et.al. have reported preparation of 1, 2, 3-
triazole containing chalcone derivative (LIII)and reported as cosmetics and useful in
treatment of vitiligo. [128, 129].
(LIII)
Wan, Maosheng; Hua, Li; Li, Ailing; Zhang, Limin; Li, Shuqing et.al have
reported isoxazol aryl chalcone derivatives(LIV) as anticancer drugs and use for
inhibiting proliferation of human lung cancer cells [130].
(LIV)
Ahn, Yongchel; Oh, Sangtae; Lee, Seong Jun; Park, Byong-Gon; Park, Yoon-
Sun; Shin, Woon-Seob; Jang, Hyuk Jai; Park, Jin Hoon; Kwon, Daeho; Lee, Seokjoon
et.al. have reported the synthesis of diethylamino-curcumin mimics with substituted
triazolyl groups (LV)and their sensitization effect of TRAIL against brain cancer cells
[131].
(LV)
Yu, Peng; Chen, Zhemin; Wang, Haomeng; Yang, Yao; Song, Binbin; Lu, Kui
have reported 4, 2', 4'-trimethoxy-5'-substituted chalcone derivatives(LVI) [132].
(LVI)
O
ON
NN
ON
CH3
O
R
O2N
O
N
N
NN
OH
O
N
N
NN
Br
O
R
O O
O
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 32
Sashidhara, Koneni V.; Dodda, Ranga Prasad; Sonkar, Ravi; Palnati, Gopala
Reddy; Bhatia, Gitika have reported novel indole-chalcone(XLII) fibrates as lipid
lowering agents [133].
(LVII)
Gupta, Shweta; Shivahare, Rahul; Korthikunta, Venkateswarlu; Singh, Rohit;
Gupta, Suman; Tadigoppula, Narender have reported chalcones (LVIII)as potential
antileishmanial agents [134].
(LVIII)
Sashidhara, Koneni V.; Rao, K. Bhaskara; Kushwaha, Vikas; Modukuri, Ram
K.; Verma, Richa; Murthy, P. K. have reported antifilarial activity of chalcone-
thiazole derivatives (LIX)against a human lymphatic filarial parasite, Brugiamalayi
[135].
(LIX)
Wu, Ruibo; Zhou, Jingwei; Gu, Qiong have reported b-Substituted chalcone
analogues (LX) as histone deacetylase inhibitor [136].
HN
O
O
O
O
O
R2O
R1
OH
R
R1O
N N
S
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 33
(LX)
Lim, Yung Ho; Lee, Yeong Han; Ko, Dong Su; Shin, Sun Yeong have
reported methoxychromenyl-chalcone derivative(LXI) as anticancer agent [137].
(LXI)
Sharma, Nandini; Mohanakrishnan, Dinesh; Sharma, Upendra Kumar; Kumar,
Rajesh; Richa; Sinha, Arun Kumar; Sahal, Dinkar have reported antiplasmodial
evaluation of vanillin derived allylated chalcones (LXII)and their marked synergism
with artemisinin against chloroquine resistant strains of Plasmodium falciparum
[138].
(LXII)
R2
R1
O
R3
O
H2C
O
O
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 34
� Importance of chalcones :
[1]. Chalcones, considered as the precursor of flavonoids and isoflavonoids are
abundant in edible plants. They have close relationship to flavones flavanones
and dihydro flavonols.
[2]. The chalcones are intermediate compounds useful for the synthesis of various
heterocyclic compounds like pyrmidines, flavanones, flavones, flavonols,
benzal coumaranones, and anthocyanins as well as certain compounds like
deoxybenzoin and hydantions which are found to have some therapeutic
importance as antispasmodic and mydrinatics.
[3]. The chalcone have been found to be useful in elucidating the structures of
natural products like hemlocktannin [12], cyanomaclurin [3], ploretin [5],
eriodictyol and homo eriodictyol [7].
[4]. They contain a keto-ethlenic group and are therefore reactive towards several
regents e. g. (a) hydrazine hydrate (b) guanidine nitrate (c) ethyl aceto acetate
producing pyrazoline derivatives, 2-amino pyrimidine and oxo cyclohaxenone
respectively.
[5]. 4-chloro chalcone and methyl chalcone [139] are patented as light stabilizing
agent for polyvinylidene chloride or polyvinylidene polymers. Berger and
Hogue [140] have patented a preparation of light fast, water dispersible wood
stain obtained from chalcones and flavanoid derivatives like hesperidin and
narignain by the action of aluminum chloride in carbon disulphide.
[6]. Boronic chalcone analogues have been used as fluorescent probes that may be
useful for detection of fluorides and saccharides such as glucose that may be
applicable to the design of biosensors for diabetes. [141].
[7]. Tejima et al. [142] reported chalcone derivative is effective in protecting the
skin when made into ultraviolet absorber agents including anti-sunburn oil.
[8]. Many of the chalcones are used as agrochemicals and drugs [143].
[9]. Chalcone reacts with a number of metal ions [144].
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 35
� Reaction Scheme:
Synthesis of 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(substituted-phenyl) prop-2-
en-1-one (1 a-f):
Step-1:Preparationof1-(2, 5-dimethoxyphenyl)ethanone: OCH3
OCH3
1,4-dimethoxybenzene
OCH3
H3CO
OCH3
1-(2,5-dimethoxyphenyl)ethanone
0-5 0C
EDC
Anhy.AlCl3,
CH3COCl,
Step-2: Preparation of 2-methyl-1, 4-dimethoxybenzene:
OCH3
H3CO
OCH3
1-(2,5-dimethoxyphenyl)ethanone
CH3
OCH3
H3CO
205-210 0C
NHNH2 H2O
KOH,
2-methyl-1,4-dimethoxybenzene
Step-3: Preparation of 1-(4-methyl-2, 5-dimethoxyphenyl)ethanone: O
OCH3
H3CO
CH3
CH3
0-5 0C
EDC
Anhy.AlCl3,
CH3COCl,
1-(4-methyl-2,5-
dimethoxyphenyl)ethanone
2-methyl-1,4-dimethoxybenzene
OCH3
H3CO
CH3
Step-4: Preparation of 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(substituted-phenyl)
prop-2-en-1-one (1a-f) : HO
R
Substituted
Benzaldehyde
+
O
CH3
OCH3
OCH3
R
35-400C.40% KOH,
Et-OH
O
OCH3
H3CO
CH3
CH3
1-(4-methyl-2,5-
dimethoxyphenyl)ethanone
1-(4-methyl-2,5-dimethoxyphenyl)-
3-(substituted-phenyl) prop-2-en-1-
one
Compd.No. R
1a 2-Cl, 3-OC2H5, 4-OCH3
1b 2, 4 di Cl
1c 3-Cl, 4-OH, 5-OC2H5
1d 2- Cl
1e 3-Cl, 4-OH, 5-OCH3
1f 3-Br, 4-OH, 5-OCH3
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 36
� Experimental:
Step-1:
Synthesis of 1-(2, 5-dimethoxyphenyl) ethanone :
A mixture of 1, 4 Di methoxy benzene (13.8 gm, 0.1 mol) and aluminum
chloride (26.6 gm, 0.2 mol) in 1, 2 di chloro ethane (150 ml) was stirred at 0°C. acetyl
chloride (9.3 gm, 0.12mol) was added slowly at 0°C, the resulting mixture was stirred
6 hours at room temperature. The solution was then poured into the mixture of
crushed ice and water. The chilled mixture was stirred for 15 minute and separated
organic layer, again the mixture was extracted with dichloroethane (3X 50 ml). The
organic layer was washed with water, dried over sodium sulphate and evaporated to
give yellowish crude. The crude product, then on distillation to gave 2, 5-
dimethoxyacetophenone (16.2 gm) as almost white oil. Yield: 90 %.
Analysis:
C10H12O3 Found : C : 66.60%, H : 6.68%,
O : 26.59%,
Calculated: C: 66.65%, H: 6.71%,
O: 26.64%.
Step-2:
Synthesis of 2-methyl-1, 4-dimethoxybenzene :
The mixture of 1-(2, 5-dimethoxyphenyl)ethanone (18 gm, 0.1 mol), KOH
pellets (12.7 gm, 0.22 mol), 65% hydrazine(22.5 gm, 0.45 mol) and tri ethylene glycol
(100 ml) was brought up to a boil by heating mantle and the distillate was removed,
allowing the temperature of the pot contents to continuously increase. When the pot
temperature had reached 210 0C, reflux was established and maintained for an
additional 3 hours. After cooling, the reaction mixture poured into water and extracted
with 3x100 ml 1, 2 di chloromethane. The solvent was removed yielding 13.2 gm (80
%) of a pale straw-colored liquid of 2-methyl 1, 4-di methoxy benzene. Yield: 80 %,
bp.: 66 0C, (Reported; 650 C).
Analysis:
C9H12O2, Found: C: 71.03%, H: 7.95%,
O: 21.03%,
Calculated: C: 71.06%, H: 8.00%,
O: 21.05%.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 37
Step-3:
Synthesis of 1-(4-methyl-2, 5-dimethoxyphenyl)ethanone :
A mixture of 4-methyl 1, 4 di methoxy benzene (15.2 gm, 0.1 mol) and
aluminum chloride (26.6 gm, 0.2 mol) in 1, 2 di chloro ethane (150 ml) was stirred at
0°C. Acetyl chloride (9.3 gm, 0.12mol) was added slowly at 0°C to a stirred mixture.
The resulting mixture was further stirred for 6 hours at room temperature. The
solution was then poured into the mixture of crushed ice and water. The chilled
mixture was stirred for 15 minute to separate organic layer, again the mixture was
extracted with dichloromethane (3 x 50 ml). The organic layer was washed with
water, dried over sodium sulphate and evaporated to give yellowish crude (18.7gm,
90%). The crude product that, recrystalization from methanol to give 1-(4-methyl-2,
5-dimethoxyphenyl)ethanone as colorless solid mp.;70 0C, Yield : 90 %.
Analysis:
C11H14O3, Found : C: 68.12%, H: 7.27%,
O: 24.71%,
Calculated: C: 68.14%, H: 7.24%,
O: 24.75%.
Step-4:
Synthesis of 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(2-chloro-3-ethoxy-4-methoxy
phenyl) prop-2-en-1-one (1a):
To a mixture of 1-(4-methyl-2, 5-dimethoxyphenyl)ethanone (0.01 mole) and
2-chlor-, 3-ethoxy, 4-methoxy benzaldehyde (0.01 mole) in ethanol (30 ml) was
added a solution of potassium hydroxide (40 ml, 40%) with constant shaking of the
reaction flask. The reaction mixture was stirred for a 24 hours on a magnetic stirrer
and poured in to crushed ice and acidified with diluted HCl (2N). The solid mass
which separated out was filtered, washed with water, dried and crystallized from
methanol to give light yellow needles. m.p.:182 0C; Yield: 82%, Rf value: 0.78.
Analysis:
C21H23ClO5
Calculated: C: 64.53%, H : 5.93%,
O: 20.47%. X : 9.07%,
Found: C: 64.52%, H : 5.97%,
O: 20.43%. X : 9.09%,
Similarly, other 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(substituted phenyl)
prop-2-en-1-one were prepared. The physical data are recorded in Table No: 1
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 38
Table-1: Physical data of 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(substituted-
phenyl) prop-2-en-1-one (1a-f):
R
O
CH3
O
O
CH3
CH3
No. -R
Molecular
Formula
(M.W)
Mp
0c Rf
% of
Yield
% of
C
% of
H
% of
O
% of
X
(Cal)
Found
(Cal)
Found
(Cal)
Found
(Cal)
Found
1a OCH 3
OCH 2CH3
Cl
C21H23ClO5
(390)
182-
185
0.78 82
64.53 5.93 20.47
9.07
64.52 5.97 20.43
9.09
1b
Cl
Cl
C18H16Cl2O3
(351)
143-
145
0.65 84
61.55 4.59 13.67 20.19
61.58 4.58 13.69 20.21
1c Cl
OH
OCH 2CH3
C20H21ClO5
(376)
119-
122
0.49 76
63.75 5.62 21.23 9.41
63.76 5.61 21.24 9.43
1d
Cl
C18H17ClO3
(316)
130-
136 0.56 69
68.25 5.41 15.15
11.19
68.24 5.42 15.17
11.16
1e Cl
OH
OCH 3
C19H19ClO5
(362)
103-
107 0.48 80
62.90 5.28 22.05
9.77
62.93 5.29 22.07
9.75
1f Br
OH
OCH 3
C19H19BrO5
(407)
97-
100 0.64 76
56.03 4.70 19.64
19.62
56.04 4.76 19.61
19.63
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 39
� Spectroscopic evaluation :
Spectroscopic analysis 1-(4-methyl-2, 5-dimethoxyphenyl)-3-(2-chlorophenyl)
prop-2-en-1-one (1a-f):
The IR spectra of of 1-(4, 5-dimethoxy-2-methylphenyl) -3-(2-chlorophenyl) –
prop – 2 – en – 1 - one (1d) showed a carbonyl absorption at 1653 cm-1 which is
characteristic band of the α, β- unsaturated carbonyl group. The absorption band due
to C-O stretching appeared at 1263 cm-1. Due to the ether linkage two stretching
bands are observed at 1275-1200 cm-1 (symmetric) and 1089-1020 cm-1
(asymmetric). Ethylinic double bond stretching of chalcone showed at 1661 cm-1 .C-
Cl stretching displayed at 665 cm-1
A medium to strong absorption band seen at 865 cm-1 is due to trans CH=CH
out of plane deformation (wagging) and Trans CH=CH (vinyl) stretching shown in the
range of 3090-3000 cm-1. The aromatic in plane bending was observed at 1159 cm-1
and out of plane bending was observed at 833 cm-1 [].
In addition to above mentioned peaks, IR spectrum consists other stretching
and bending vibration common to compound under study. The IR spectrum of the
compound (1d) is given on page no.41.
���� 1HNMR Spectra
The 1H NMR spectrum of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2-bromo-4-
hydroxy-5-imethoxyphenyl)-prop-2-en-1-one (1f) showed a pair of doublets at
7.62δppm(J=16.2Hz). and 7.45 δppm (which is merged with aromatic proton)
consistent with trans olefinic-protons attached to aromatic ring (-CH=CH-Ar) and
attached to carbonyl carbon (-COCH=CH) of a chalcone moiety. The signal appeared
at 2.28 δppm suggest presence of methyl group. Nine protons of methoxy group
displayed in the range of 3.83-3.93 δppm. confirmed the presence of methoxygroup.
OH group showed as singlet 6.81 δppm.
In the aromatic region, Singlet of one proton showed at 6.81δppm.Multiplate
of the two protons showed in the range of 7.19-7.54δppm, Doublet of proton
displayed at 6.94δppm (J=1.8 Hz) and meta coupled proton showed as doublet at 7.58
δppm(J=1.6Hz).respectively. The 1H NMR spectra of the compound (1f) is given on
page no.42.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 40
���� 13C NMR Spectra
In the 13C NMR Spectra of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2-chlorophenyl)-
prop-2-en-1-one showed two carbons of keto-ethylenic group -CO-CH=CH-
were resonated at 123.25 δppm (C-8), 142.64 δppm (C-9) and carbonyl carbon
showed signal at 191.60 δppm (C-7).
The aromatic carbon showed signals at 151.83(C-1), 130.61(C-2),
131.97(C-3), 152.56(C-4), 115.69(C-5), 121.63(C-6), 129.28(C-10), 136.81(C-11),
128.47(C-12), 128.59(C-13), 127.95(C-14), 137.03(C-15), 56.03(C-16), 55.87(C-17),
16.64(C-18) δppm. The 13C NMR spectrum of the compound (1d) is given on
page no.43.
���� LC Mass Spectra
The mass spectra of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2, 4di
chlorophenyl)-prop-2-en-1-one (1b) showed strong molecular ion peak at 351m/e..
The LC mass spectra of compound (1b) is given on page no.44.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 41
IR spectrum of 1-(4, 5-dimethoxy-2-methylphenyl) -3-(2-chlorophenyl) – prop – 2
– en – 1 - one (1d)
IR (cm-1) : 2943 (C-H str. (asym) alkyl), 2834 (C-H str. (sym) alkyl), 1402(C-H def
(asym) alkyl), 1356 (C-H def (sym) alkyl), 1503 (C=C str. arom.), 1159 (C-H i.p.def
arom.), 803 (C-H o.o.p.def.arom.), 1263 (C-O-C (sym) ether), 1040 (C-O-C (asym)
ether), 1653 (C=O str., chalcone), 865 (CH=CH def.chalcone), 3081 (CH=CH str.
chalcone), 1661 (C=C str. chalcone), 665(C-Clstr.).
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 42
1H NMR spectrum of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2-bromo-4-
hydroxy-5-imethoxyphenyl)-prop-2-en-1-one (1f)
1H NMR (CDCl 3) δδδδppm: 2.28 (s, 3H), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.93
(s, 3H, OCH3), 6.81(s, 1H), 6.94(d, 1H, J=1.8Hz), 7.19(S, 1H), 7.45(m, 1H+1H
chalcone), 7.58(d, 1H, J=1.6Hz), 7.62(d, 1H, J=15.8Hz, chalcone).
CH3
H3CO
O
OCH3
Br
OH
OCH3
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 43
13C NMR Spectra of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2-chlorophenyl)-
prop-2-en-1-one (1d)
13C NMR (CDCl 3) δδδδppm: 151.83(C-1), 130.61(C-2), 131.97(C-3), 152.56(C-4),
115.69(C-5), 121.63(C-6), 191.60(C-7), 123.25(C-8), 142.64(C-9), 129.28(C-10),
136.81(C-11), 128.47(C-12), 128.59(C-13), 127.95(C-14), 137.03(C-15), 56.03(C-
16), 55.87(C-17), 16.64(C-18).
12
3
4
5
67 8
9
10
1112
13
1415
CH3
H3CO
O
OCH3 Cl
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 44
LC MASS Spectra of 1-(2, 5-dimethoxy-4-methylphenyl)- 3-(2, 4di
chlorophenyl)-prop-2-en-1-one (1b)
CH3
H3CO
O
OCH 3 Cl Cl
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 45
Biological Evaluation
Antibacterial and antifungal activities of the synthesized compounds
Determination of Minimal inhibition Concentrations (MIC)
by Broth Dilution Method
� Materials and Method
1. All the synthesized drugs were used for antibacterial tests.
2. All necessary controls, viz. drug, vehicle, broth of organism were used.
� The drug Gentamycin was used as control.
� Muller Hinton Broth was used as nutrient medium to grow the strains
and dilute the drug suspensions for test.
� All MTCC cultures were tested against above-mentioned known and
unknown drugs.
3. Serial dilution technique was followed by micro method as per NCCLS-
1992 manual [148].
4. Inoculum size: Inoculum size for test strain was adjusted to 108 cfu (colony
forming unit) per ml.
5. The strains used for screening of antibacterial and antifungal activities were,
the strains procured from Institute of Microbial Technology (IMTECH),
Chandigarh.
The following stains procured from IMTECH-Chandigarh were used for
screening antibacterial and antifungal activities.
� Staphylococcus aureus (Gram positive) MTCC-96
� Escherichia coli (Gram negative) MTCC-443
� Streptococcus pyogenes (Gram positive) MTCC-442
� Pseudomonas aeruginosa (Gram negative) MTCC-1688
� Candida albicans MTCC-227
� Aspergillus niger MTCC-282
6. DMSO was used as diluent/vehicle to get desired concentration of drugs to
test upon standard bacterial strains.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 46
� Minimal inhibition Concentrations (MIC) of Bacteria l and Fungal
strains:
The main advantage of the ‘Broth Dilution Method’ for MIC determination
lies in the fact that it can readily be converted to determine the MIC as well.
1. Serial dilutions were prepared in primary and secondary screening.
2. The control tube containing no antibiotic is immediately subcultured
(before incubation) by spreading a loopful evenly over a quarter of plate of
medium suitable for the growth of the test organism and incubated at 370C
for 24 hrs.
3. The MIC of the control organism is read to check the accuracy of drug
concentrations.
4. The lowest concentration that inhibits growth of the organism is recorded as
the MIC.
5. The amount of growth from the control tube before incubation (which
represents the original inoculum) was compared.
���� Methods used for Primary & Secondary Screening
Each synthesized drug was diluted obtaining 2000 µg/ml concentration, as a
stock solution.
� Primary screening: In primary screening 1000, 500, 250 and 125 µg/ml
concentrations of the synthesized drugs were taken. The active synthesized
drugs found in this primary screening were further tested in a second set of
dilution against all microorganisms.
� Secondary screening: The drugs found active in primary screening were
similarly diluted to obtain 100, 50, 25, 12.5, 6.250 µg/ml concentrations.
� Interpretation of Results: The highest dilution showing at least 99%
inhibition is taken as MIC. The result of this test is affected by the size of the
inoculum. The test mixture should contain 108 organism /ml.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 47
In the present work the results are interpreted in comparision with
standard drug as follows: Bacterial Strains: 12.5, 6.25 = excellent active,
25=good active, 50=moderate active, 100=poor active, 100< inactive. Fungal
Strains: 100= excellent, 125=good, 200=poor, 200< inactive.
� The Standard Drug: The standard drugs “ Gentamycin” used in the present
study for evaluating antibacterial activity which showed 0.25, 0.5, 0.05, 1.0,
µg/ml MIC against bacterial strains S.aureus, S.pyogenes, E.coli and
P.aeruginosa, respectively. “K.Nystatin” is used as the standard drug for
antifungal activity, which showed 100 µg/ml MIC against all the species, used
for the antifungal activity.
���� Minimal Inhibitiry Concentrations (MIC)
Each synthesized drug was diluted obtaining 2000 µg /ml concentration, as a
stock solution.
� Primary screen: In primary screening 500 µg /ml, 250 µg /ml, and 125 µg /ml
concentrations of the synthesized drugs were taken. The active synthesized
drugs found in this primary screening were further tested in a second set of
dilution against all microorganisms.
� Secondary screen: The drugs found active in primary screening were
similarly diluted to obtain 100 µg/ml, 50 µg /ml, 25 µg /ml, 12.5 µg /ml and
6.250 µg/ml, concentrations.
� Interpretation of Results: The highest dilution showing at least 99 %
inhibition zone is taken as MIC. The result of this is much affected by the size
of the inoculum. The test mixture should contain 108 organism/ml.
In the present work the results are interpreted in comparision with
standard drug as follows : 25=excellent, 50=moderate, 100 =inactive
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 48
Table: 1 Antibacterial and Antifungal activities of 1-(4-methyl-2, 5-
dimethoxyphenyl)-3-(substituted-phenyl) prop-2-en-1-one
Six novel compounds, contain keto-ethylenic -CO-CH=CH- linkage were
synthesized from and tested for their in vitro growth inhibitory activity against
pathogenic microorganism i.e., S.aureus, S.pyogenes, E.coli, P.aeruginosa, and
antifungal strain C. albicans. The results of antimicrobial activities are depicted in
following Table-1.
Sr.
No. -R
Bacterial activity
Minimal Inhibition Concentrations
(MIC) in µg/ml
Fungal activity
Minimal Inhibition
Concentration
(MIC) in µg/ml
S.
aureus
MTCC
96
S.
pyogenes
MTCC
442
E.
coli
MTCC
443
P.
aeruginosa
MTCC
1688
C. albicans
MTCC
227
1a OCH 3
OCH 2CH3
Cl
50 50 50 50 1000
1b
Cl
Cl
12.5 6.25 250 250 500
1c Cl
OH
OCH 2CH3
25 50 50 50 500
1d
Cl
100 500 250 250 125
1e Cl
OH
OCH 3
100 100 500 500 1000
1f Br
OH
OCH 3
50 25 25 25 100
Interpretation of results
Antibacterial activity Antifungal activity
6.25, 12.5=excellent, 25=good, 50=mode- rate,
100=poor active, 100< inactive.
100=excellent, 125=good, 200=poor
active 200< inactive.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 49
� Result and discussion:
The results of the primary and secondary antimicrobial screening of the 06
new compounds (1 a-f) and the antibacterial antibiotics Gentamicin and the antifungal
drug K.Nystatin are showed in Table-1. The results revealed that they showed varying
degrees of inhibition against the tested micro organisms. The antimicrobial activity
was considerably affected by substitution pattern on the phenyl ring.
Preliminary microbiological screening results showed that the test compound
group is 1b bearing di chloro proved to be beneficial and exhibited excellent
antibacterial activity against both gram-positive bacterial strains S.aureus and
S.pyogenes comparable to reference agent Gentamycin, respectively. The antibacterial
activities of compounds were enhanced due to the introduction of halogen group in
ortho position of the heterocyclic frame work. Compound 1f showed good activity
against both the gram negative bacterial strains. In addition, It is our observation that
introduction of ethoxy group in compound 1a enhanced the activity and it exhibited
moderate activity against gram-positive and gram-negative bacterial strains
respectively, comparable to reference agent Gentamycin. The MIC value of the test
compound 1f showed excellent activity against fungal strain C.albicans comparable to
reference agent K Nystatin. When we inserted substituent 2-bromo group in phenyl
nucleus increment in activity was observed enormously and it exhibited excellent
activity. In addition, compound 1d exhibited good activity against fungal strain
C.albicans. Thus we have discussed and compared antibacterial and antifungal
activities based on standard drugs Ampicillin and Griseofulvin respectively.
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES
Page No. 50
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