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CHAPTER _ 2

STUDIES ON

CHALCONES

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME HETEROCYCLIC DERIVATIVES

Page No. 4

� 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]


Page No. 5

(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.


Page No. 6

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


Page No. 7

[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].


Page No. 8

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].


Page No. 9

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].


Page No. 10

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


Page No. 11

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


Page No. 12

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%.


Page No. 13

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.


Page No. 14

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%

°°°°


Page No. 15

� 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


Page No. 16

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).


Page No. 17

� 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.


Page No. 18

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

+


Page No. 19

� 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].


Page No. 20

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)


Page No. 21

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-


Page No. 22

[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.


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.


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]


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)


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)


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


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


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


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


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


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


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


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].


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


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%.


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


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


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.


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.


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.).


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


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


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


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.


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.


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


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=moderate,

100=poor active, 100< inactive.

100=excellent, 125=good, 200=poor

active 200< inactive.


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.


Page No. 50

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