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Synthesis and pharmacological properties of chalcones: a review
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DOI: 10.1007/s11164-017-2977-5
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Synthesis and pharmacological properties of
chalcones: a review
Santosh L. Gaonkar & U. N. Vignesh
Research on Chemical Intermediates
ISSN 0922-6168
Volume 43
Number 11
Res Chem Intermed (2017)

43:6043-6077
DOI 10.1007/s11164-017-2977-5
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Res Chem Intermed (2017) 43:6043–6077
DOI 10.1007/s11164-017-2977-5
Synthesis and pharmacological properties of chalcones:

a review
Santosh L. Gaonkar1 • U. N. Vignesh1
Received: 2 February 2017 / Accepted: 3 May 2017 / Published online: 28 June 2017
Springer Science+Business Media Dordrecht 2017
Abstract Chalcones and their analogs have been an area of great interest in recent
years. Numerous research papers have been published, and chalcones continue to
show promise for new drug investigations. Researchers have explored new
approaches for the synthesis of chalcone derivatives, which have revealed an array
of pharmacological and biological effects. These chalcone derivatives have shown
important antimicrobial, antifungal, anti-mycobacterial, antimalarial, antiviral, anti-
inflammatory, antioxidant, antileishmanial anti-tumor, and anticancer properties.
This review highlights the synthesis and pharmacological properties of chalcone
derivatives.
Keywords Chalcone Synthesis Pharmacological properties
Introduction
The framework 1,3-diphenylprop-2-en-1-one (Fig. 1) is well known by the generic

term ‘‘chalcone,’’ a name coined by Kostanecki and Tambor [1]. It is also known as
benzalacetophenone and benzylidene acetophenone. Chalcones belong to the
flavonoid family [2–4]. These open-chain flavonoids have two aromatic rings that
are linked by an aliphatic three-carbon chain. The versatile molecule chalcone is an
a,b-unsaturated ketone that contains the reactive keto-ethylenic group –CO–
CH=CH–, a chromophore responsible for the color in chalcone compounds,
depending on the presence of other auxochromes.
& Santosh L. Gaonkar

gaonkarslg@rediffmail.com
1
Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal,
Karnataka 576104, India
123
6044 S. L. Gaonkar, U. N. Vignesh
Fig. 1 Structure of chalcone or O

(2E)-1,3-diphenylprop-2-en-1-
β
one
Chalcone has conjugated double bonds with absolute delocalization and two
aromatic rings that possess an p-electron system, which gives them relatively low
redox potential and a greater chance of undergoing electron transfer reactions.
Chalcones are naturally abundant in edible plants [5], including vegetables, fruits,
spices, tea and natural foodstuffs. Chalcones can be designed as precursors for
flavonoids and isoflavonoids [6]. They act as synthons by which a range of analogs
and novel heterocycles with pharmaceutical structures can be targeted [7–9].
Various chalcone derivatives show antimicrobial, antifungal, antimalarial, antiviral,
anti-inflammatory, antileishmanial anti-tumor and anticancer properties [10–19].
The a,b-unsaturated carbonyl system in chalcones makes them biologically active
[20], and exclusion of the carbonyl system makes them biologically inactive,
ensuring stability in both cis and trans forms. Chalcones can be used to obtain
several heterocyclic rings through ring closure reactions (Scheme 1).
Ar'
Ar
N
N
H
Pyrazole
Hydrazine
Ar'
O
Ar Ar' CN
Guanidine Malononitrile
Ar Ar'
N N
Ar N
Chalcone
NH2
Pyrimidine Cyanopyridine
Hydroxylamine
Ar'
Ar
N
O
Isoxazole
Scheme 1 Ring closure reactions of chalcones
123
Synthesis and pharmacological properties of chalcones: a… 6045
Cyanopyridines, pyrazolines, isoxazoles and pyrimidines having different hetero-

cyclic ring systems and multiple derivatives can be synthesized using chalcones
[21–25].
There are several methods for the preparation of chalcones, the most convenient
of which is the Claisen-Schmidt condensation [26–29] of equimolar quantities of
aryl methyl ketone and aryl aldehyde in the presence of alcoholic alkali. Typically,
high-alkaline media such as KOH, NaOH, LiHMDS and Ba(OH)2, as well as natural
phosphates, are chosen as suitable media for preparation [30–35]. Even the use of
Lewis acid (B2O3, RuCl3, BF3, AlCl3, p-toluene sulfonic acid and dry HCl) has been
reported [36–41].
Nomenclature
Various nomenclature methods have been put forward for chalcones at various
times. The naming pattern (Fig. 2) has been accepted by Chemical Abstracts,
published by the American Chemical Society.
The British Chemical Abstracts and Journal of the Chemical Society have used
the following scheme (Fig. 3).
Methods of preparation
Condensing agents for synthesis
Alkali as condensing agent
Alkali, the most commonly used condensing agent for the synthesis of chalcones, is
used as an aqueous solution of an appropriate concentration of 30, 40, 50 or 70%.
Hydrochloric acid as condensing agent
Dry hydrochloric gas in a proper solvent such as ethylacetate at 0 C has been used
as a condensing agent in a few preparations of chalcones from aromatic ketones. A
methanolic solution of dry hydrochloric acid gas at 0 C has also been used [42, 43].
Fig. 2 Numbering as per

Chemical abstarct
123
Fig. 3 Numbering as per

British Chemical abstract
Other condensing agents
Raval and Shah [44] used phosphorus oxychloride as a condensing agent to prepare
chalcones. Szell and Sipos [45] condensed 2-hydroxy-5-nitroacetophenone with
benzaldehyde, employing anhydrous AlCl3. Kuroda and Matsukuma [46] produced
chalcone by condensing acetophenone derived from anisole and other polymethoxy
benzenes with certain methoxy-aldehydes in the presence of anhydrous aluminium
chloride.
In addition to the above, condensing agents such as amino acid, aqueous solution
of borax, perchloric acid, piperidine, boron trifluoride, alkali metal alkoxide,
magnesium tert-butoxide, and organocadmium compounds have been used in the
synthesis of chalcones [47–54].
Claisen-Schmidt reaction
Several approaches for the synthesis of chalcones have been presented in research
papers, the most convenient of which is one involving the Claisen-Schmidt
condensation (Scheme 2) of equimolar quantities of a substituted acetophenone and
substituted aldehydes in the presence of aqueous alcoholic alkali [55–62].
In the Claisen-Schmidt reaction, the concentration of alkali frequently ranges
between 10 and 60% [63, 64]. The reaction is carried out at around 50 C for
12–15 h or at room temperature for 1 week. Under these conditions, a Cannizzaro
reaction [65] also takes place and thus reduces the yield of the desired product. As a
Scheme 2 Chalcones by Claisen-Schmidt condensation
123
O O
O
H3C
base
H
+
Benzaldehyde Acetophenone Chalcone
Scheme 3 Chalcones by Aldol condensation
means to avoid the disproportionation of aldehyde, the use of benzylidene-diacetate

in place of aldehyde has been reported [66].
Aldol condensation reaction
The preparatory material for this reaction is acetophenone and benzaldehyde

(Scheme 3) as a Claisen-Schmidt reaction. In the very first step, acetophenone is
treated with a base similar to KOH, which converts it into a more active form, its
enolate form. Later it is reacted with benzaldehyde to form an intermediate which,
upon heating, loses a molecule of water to form chalcone [67–70].
Suzuki reaction
Chalcones can be obtained by Suzuki reaction [71] (Scheme 4). In general, the
scheme consists of a reaction between phenyl boronic acid (I) and cinnamyl chloride
(II) or among benzoyl chloride (III) and phenyl vinyl boronic acid (IV).
Heck reaction
Chalcones and other flavonoids can be prepared by coupling an aryl vinyl ketone
with an aryl iodide under Heck reaction conditions (Scheme 5) [72].
Preparation of bis-chalcone
Venkatraman and Nagrajan [73] prepared bis-chalcone using dihydroxy-diacetyl-

benzene and anisaldehyde with an alkali medium (Figs. 4, 5).
HO OH
O Cl
OH Ph Ph B
O
Ph B + +
OH O Ph Cl
Ph
Ph
(I) (II) Chalcone (III) (IV)
Scheme 4 Chalcones by Suzuki coupling
123
OMe O
OAc MeO OMe OAc
+
I
MeO
O
Scheme 5 Chalcones by Heck coupling
Fig. 4 Preparation of bis-halcones
Fig. 5 Preparation of bis-halcones
Preparation of hydroxy-nitrochalcone
Several hydroxy-nitrochalcones have been prepared using dry hydrogen chloride

gas [38, 74, 75]. Onoda and Sasaki [76, 77] reported the use of hydrochloric acid to
synthesize hydroxy-nitrochalcone (Fig. 6) from 2-hydroxy-5-nitroacetophenone and
p-anisaldehyde.
Alkali metal alkoxide, magnesium tert-butoxide, borax, piperidine, aluminium
chloride, boron trifluoride, amino acids and perchloric acid are other condensing
agents which have been employed in several reported studies [53, 78, 79].
Fig. 6 Preparation of hydroxy-nitrochalcones
123
Reaction of benzaldehyde with phosphonate carbanion
A typical reaction (Scheme 6) of benzaldehyde (I) with phosphonate carbanion (II)

derived from diethyl phenacyl phosphonate yielded chalcones (III) [80–83].
Reaction of ketones and aromatic aldehyde
Researchers have prepared chalcones (III, V) by reacting ketones (II, IV) and
aromatic aldehyde (I) in ethanol as an energy transfer medium (Schemes 7, 8)
[84, 85].
Preparation of a chalcone derivative using 2-hydroxy-3-bromo-5-ethyl

acetophenone
A chalcone derivative (Fig. 7) was synthesized by Naik and Naik from 2-hydroxy-
3-bromo-5-ethyl acetophenone [86].
Preparation of chalcones using cinnamic acid
Chalcones have been obtained using cinnamic acid and its derivatives.
Cinnamic acid and phenol, cinnamic derivatives such as cinnamic anhydride,
cinnamoyl chloride and benzene, cinnamoyl chloride and phenol have been used to
prepare chalcones and their analogs [87–90].
Preparation of chalcone using O-iodophenyl acetate and palladium
Palladium-catalyzed synthesis of O-hydroxychalcones and flavanones has been

described where common precursor is O-iodophenyl acetate [91].
Preparation of chalcones using Schiff bases
Aryl-aminoketones derived from Schiff bases in the presence of acid will undergo
hydramine cleavage and yield primary aromatic amine and chalcones as products
[92].
Preparation of chalcones from organometallic compounds
Studies have reported the synthesis of chalcones using organometallic compounds

such as acetylenic Grignard reagents, cadmium derivatives and cinnamyl chloride in
123
Scheme 6 Chalcones by benzaldehyde and phosphonate anions
Scheme 7 Chalcones from aromatic aldehydes and ketones
Scheme 8 Chalcones from aromatic aldehydes and ketones
Br
Br
OH
OH
R-CHO
Aq. KOH (40%) R

C 2H 5
C 2H 5
O
O
Fig. 7 Chalcones from 2-hydroxy-3-bromo-5-ethyl acetophenone
123
ether, phenyl magnesium bromide and cinnamonitrile in the presence of ammonium

chloride and methylmagnesium iodide with benzaldehyde [93].
Microwave-assisted synthesis of chalcones
Mistry and Desai [94] used a microwave technique to synthesize chalcones (Fig. 8).
Heterogeneous catalysts including potassium carbonate, barium hydroxide,
p-Toluenesulfonic acid, KF-Al2O3, zirconium tetrachloride, piperidine and aqueous
alkali have been used for the synthesis of chalcones and their analogs using
microwave irradiation [95–97].
Chalcone synthesis using ultrasound irradiation
Heterogeneous catalysts such as potassium carbonate, basic Al2O3, amino-grafted

zeolite, Ba (OH)2, pulverized KOH and KF-Al2O3 have been used effectively for
the synthesis of chalcones and their analogs under ultrasound irradiation [98–100].
Solvent-free synthesis of chalcones
Rothenberg and co-workers [101] showed that reactions between solids occurred
because of the formation of a liquid melt. This indicated that the existence of a
liquid phase—which could be a eutectic mixture formed upon mixing the reactants
or one of the reactants itself—is a prerequisite for reaction to occur. The high
concentration of reactants in these solvent-free but liquid environments would be
responsible for the observed acceleration of reaction rates. Upon mixing the
benzaldehyde and the acetophenone (Scheme 9), the mixture melted even before
adding the NaOH. With grinding of the solid NaOH, the liquid mixtures became
pasty as the solid product of chalcone was formed and separated from the solution.
Siddiqui et al. [102] reported a convenient green approach for the HClO4–SiO2-
catalyzed synthesis of coumarinyl chalcones (Scheme 10) under solvent-free
conditions.
One-pot synthesis of chalcones
One-pot synthesis of chalcones [103] was recently performed using CuI/carbon

sphere (CSP) nanocomposites with anomalous selectivity under green conditions.
Fig. 8 Microwave assisted synthesis of chalcones
123
O O O
H H3C NaOH
+ + H2O
R1 R2 R2
R1
Scheme 9 Solvent-free synthesis of chalcones
Scheme 10 Synthesis of coumarinyl chalcones
CuI/CSP nanocomposites were synthesized by refluxing the mixture of CuI and CSP
in ethanol. The CSP were prepared by hydrothermal carbonization of glucose at
180 C. The CuI was then stabilized on the polysaccharide surface of CSP by
mixing CuI and CSP in an equal ratio in ethanol under conventional reflux
conditions. E-selective heterocyclic chalcones with 75–93% yield were obtained as
major products in the presence of 3-methylpiperidine, piperidine, pyrrolidine and
piperazine.
Mechanism of chalcone formation
Base-catalyzed formation of chalcone and its derivatives has been reported in

kinetic studies (Scheme 11). Alternate mechanisms (I and II) have been advanced
for the reaction of benzaldehyde with acetophenone in the presence of a basic
catalyst [104–107].
The formation of chalcone through the acid-catalyzed condensation of
acetophenone and benzaldehyde has been investigated (Scheme 12) [108].
Importance of chalcones
Chalcones have a close relationship with flavones, aurones, tetralones and

aziridines. Chalcone derivatives find application as artificial sweeteners, scintilla-
tors, polymerization catalysts, fluorescent whitening agents and organic brightening
agents. Chalcone is a stabilizer against heat, visible light, ultraviolet light and aging
[109–138]. 3,20 ,40 ,60 -Tetrahydroxy-4-propoxy-dihydrochalcone-4-b0 -neohesper-
doside has been used as a synthetic sweetener which is 2200 times sweeter than
glucose [139, 140]. The keto-ethylenic group found in chalcone is reactive towards
123
Scheme 11 Mechanism of base catalyzed chalcone synthesis
several reagents including phenyl hydrazine and 2-amino thiophenol. Chalcones are
useful in elucidating the structure of natural products such as hemlock tannin,
cyanomaclurin, phloretin, eriodictyol and homoeriodictyol, and naringenin.
[141–145].
Chalcones show diverse biological activity including insecticidal, anticancer,
anti-inflammatory, bactericidal, fungicidal, antiviral, anti-tumor, antimalarial and
antiulcer effects [13, 146–153]. Studies in the literature show that licochalcone and
oxygenated chalcone have potent antileishmanial properties [154, 155]. Chalcones
exhibiting powerful activity against human malaria parasites have also been
reported [156]. Many researchers have noted the various pharmaceutical properties
of chalcones and their analogs [157–160]. Modi et al. [161] studied the antibacterial
activity of various substituted chalcones, and Vincenzo et al. [162] reported the anti-
inflammatory activity of certain chalcone derivatives. Aldose reductase inhibitor
activity of chalcone derivatives has also been reported [163]. Toru et al. [164] noted
anticancer activity of chalcones, and Seo et al. [165] reported chalcones as a-
glucosidase inhibitors. Antiplasmodial activity of ferrocenyl chalcones was studied
by Xiang et al. [166]. Bhatt and co-workers [167] investigated the cytotoxic
properties of chalcones and their pyrazole derivatives.
123
Pharmacological properties of chalcones
Heterocyclic compounds play an important role in the field of medicinal chemistry,

ensuring a major share in synthetic drugs. These compounds serve as key templates
Scheme 12 Mechanism of acid catalyzed chalcone synthesis
123
in the development of several vital therapeutic agents. The presence of a wide range
of physicochemical and pharmacological activity, as well as an outstanding
contribution in life sustenance processes, have fascinated biologists and chemists.
Numerous groups of heterocycles with valuable synthetic analogs derived from
chalcones offer enhanced therapeutic properties, and structural modifications have
proven to be potential chemotherapeutic and pharmacotherapeutic agents.
Anti-inflammatory activity
Won and co-workers [168] prepared (E)-1-(2-hydroxyphenyl)-3-(thiophen-2-

yl)prop-2-en-1-one (Fig. 9), which is a chalcone derivative, and confirmed
bioactivity in vitro for its inhibitory effect on chemical mediators released from
mast cells, macrophages, neutrophils and microglial cells, with good results.
20 -hydroxy-3,4-dichlorochalcone (Fig. 10), which possesses anti-inflammatory
and cancer chemopreventive activity, was synthesized by Shen et al. [168].
Dihydro xanthohumol (Fig. 11), which was isolated from the fruit of Mallotus
philippensis by Zhao and co-workers [169], exhibited anti-inflammatory activity.
A reduced chalcone (Fig. 12) having cyclooxygenase-2 inhibitory activity was
isolated by Ito et al. [170].
Antimicrobial activity
The antimicrobial activity of chalcones has been reported in many research papers.
The existence of a reactive a,b-unsaturated keto function in chalcones will undergo
conjugate addition with a nucleophilic group in an essential protein, thus
contributing to antimicrobial activity. Alterations can be made depending on the
type and position of the substituents present on the aromatic rings.
Baviskar et al. [171] reported the synthesis of novel benzimidazolyl chalcones
(Fig. 13) to produce antimicrobial agents through condensation of N-(4-(1H-
benzo[d]imidazol-2-yl) phenyl) acetamide with aromatic aldehydes in the presence
of aqueous KOH at room temperature.
A number of nitrofuryl chalcones were prepared and tested for their antibacterial
activity by Devaux et al. [172, 173]. Staphylococcus aureus at a concentration of
1 lg/ml was inhibited by the compound (Fig. 14), which was the most efficient
among all derivatives synthesized.
Dandia and co-workers [174] synthesized chalcones containing an indole moiety
(Fig. 15) and tested them for antibacterial and antifungal activity.
Fig. 9 (E)-1(2- O
hydroxyphenyl)-3(thiophen-2-
yl)prop-2-en-1-one
OH
123
Fig. 10 20 -hydroxy-3,4-
dichlorochalcone
Fig. 11 Dihydroxanthohumol
Fig. 12 Reduced chalcone
Fig. 13 Benzimidazolyl
chalcone
Compounds in which electron-releasing groups such as methoxy and hydroxyl

are present exhibit higher antibacterial activity than other groups. Compounds with
pharmacophores such as chloro, dichloro, bromo and fluoro groups display
increased antifungal activity. The same holds true for chalcone derivatives with
such substituents. This was revealed in studies by Prasad and co-workers [175]. The
authors synthesized 3-[1-oxo-3-(2,4,5-trimethoxyphenyl)-2-propenyl]-2H-1-ben-
zopyran-2-ones (Fig. 16), which exhibited significant antimicrobial activity against
123
Fig. 14 Nitrofuryl chalcone
Fig. 15 Indole derived X X

chalcones
O Where
Ar Ar-substituted phenyl
N
H
Bacillus subtilis, B. pumilus and Escherichia coli, tested at a concentration of

1000 lg/ml.
Karthikeyan et al. [176] reported that the compound 3-aryl-1-(2,4-dichloro-5-
fluorophenyl)-2-propen-1-ones (Fig. 17) showed antimicrobial activity, and con-
cluded that the halogens possess favorable lipophilic properties required for
antimicrobial activity.
Nielsen and co-workers [177] studied the bioisosteric replacement of the
essential 40 -hydroxy group in hydroxychalcones with bioisosters of varying degrees
of acidity, which resulted in both more potent and more soluble compounds.
Replacing the hydroxyl group with a carboxyl group (Fig. 18) yielded an effective
compound with high aqueous solubility. Optimization and structure–activity
relationship (SAR) analysis resulted in soluble and potent carboxy-chalcones
having di-bromo or tri-fluoromethyl substitution on the B-ring. When these
compounds were tested against the Gram-positive bacterium Staphylococcus
aureus, the minimum inhibitory concentration (MIC) values were found to be
2 lM and 40 lM, respectively. On the B-ring, di-bromo or tri-fluoromethyl
Fig. 16 3-[1-oxo-3-(2,4,5-
trimethoxyphenyl)-2-propenyl]-
2H-1-benzopyran-2-ones
123
Fig. 17 3-aryl-1-(2, 4-dichloro-

5-fluorophenyl)-2-propen-1-one
Fig. 18 Chalcones with

carboxylic group
substitution was found to increase lipophilicity, while on the A-ring, the carboxy
group provided required aqueous solubility.
Tsukiyama et al. [178], isolated a retrochalcone, licochalcone C (Fig. 19), from
Glycyrrhiza inflata, which displayed effective antibacterial activity.
Prasad et al. [179] prepared chalcone with a naphthalene moiety on one side and
an aryl moiety having substituents on the other side (Fig. 20). This compound
demonstrated antifungal activity against Aspergillus niger and Rhizopus oryzae. It is
considered to provide optimal hydrophilic and hydrophobic properties, as shown by
the hydroxyl groups and halogens.
Stevaz et al. [180] isolated 20 ,40 -dihydroxy-30 -methoxychalcone (Fig. 21) from
the methanolic extract of Zuccagnia punctata, which exhibited antifungal activity.
Novel xanthoxylin-derived chalcones (Fig. 22) synthesized by Boeck et al. [181]
demonstrated antifungal activity.
Rao et al. [182] reported the synthesis of chalcones having chlorine and fluorine
substitution (Fig. 23), which exhibited antimicrobial activity.
Antifungal activity was shown by phenylated chalcones (Fig. 24) isolated from
the leaves of Maclura tinctoria by Sohly and co-workers [183].
OH
HO
OC H 3
Fig. 19 Licochalcone-C isolated from Glycyrrhiza infant
123
Fig. 20 Naphthol derived

chalcone
Fig. 21 20 , 40 -dihydroxy-30 -
methoxychalcone
Fig. 22 Xanthoxylin-derived
chalcone
Fig. 23 Fluoro and chloro

substituted chalcone
Fig. 24 Naturally occurring HO OH

chalocne isolated form leaves of
Malclura tinctoria
Machodo and co-workers [184] isolated isoliquiritigenin (Fig. 25), which showed
antibacterial activity.
A series of substituted chalcones (Fig. 26) were synthesized by Nowakowska and
co-workers [185] and were tested for their antibacterial and antifungal properties.
Burmaoglu et al. [186] developed new fluorine-substituted chalcone analogs
(Fig. 27) and tested them for antimicrobial activity against five common pathogenic
bacterial and three common fungal strains. Most of the compounds exhibited
moderate to potent activity against the bacteria and fungi.
123
Fig. 25 Naturally occurring OH

chalcone isoliquiritigenine
HO
OH O
Fig. 26 Substituted chalcone Y

N X
n
Fig. 27 Fluorine-substituted
chalcones
Antioxidant activity
The many free radicals and oxygen species produced during biological processes
can damage DNA, proteins and lipids via their oxidation, and have been implicated
in the initiation of several degenerative processes related to aging, cancer and
atherosclerosis. Hence the removal of free radicals from biological systems is vital
to cell sustainability. Antioxidants are well known as free radical scavengers and
tend to trap free radical species, specifically inhibiting or delaying the oxidation of
oxidizable substrates in the chain reactions.
Miranda and co-workers [187] synthesized a phenylated chalcone (Fig. 28) that
exhibited antioxidant activity.
20 -Hydroxychalcones (Fig. 29) prepared by Kostova et al. [188] demonstrated
antioxidant activity.
Various analogs of chalcones and their copper and zinc complexes (Fig. 30) were
prepared by Aly et al. [189] and were subjected to antioxidant screening. Evaluation
of anti-obesity and cytotoxicity effects was also reported.
Novel chalcones (Fig. 31) (I) and their allylated analogs (II) were synthesized by
Doan and co-workers [190], and were evaluated for their antioxidant activity. All
allylated chalcones were found to exhibit excellent antioxidant activity, whereas
123
Fig. 28 Prenylated chalcone
Fig. 29 Substituted 20 -
hydroxychalcone
Fig. 30 Analogs of chalcones and metal complexes
Fig. 31 Novel chalcones and their allylated analogs
non-allylated chalcones were found to be inactive. The compound with –OH and –
CH3 groups at positions 2 and 5 of ring A stood out as a superior antioxidant among
the compounds investigated.
Sivakumar et al. [191] synthesized several chalcone derivatives (I) and screened
for antioxidant activity by means of four assays: hydrogen peroxide scavenging,
123
reducing power, DPPH radical scavenging and superoxide radical scavenging

(Fig. 32).
The compounds (II) with an –OH moiety group in ring A, and –SCH3 and –OCH3
groups in the para-position of ring B showed powerful antioxidant activity. The
compound possessing hydroxyl and methoxy groups at the meta-position of rings A
and B was also found to be a potent antioxidant.
Qian et al. [192] reported the synthesis of hydroxyl-chalcones (Fig. 33) and
evaluation of their antioxidant effects against the stable galvinoxyl (GO*) radical in
ethanol and ethyl acetate, and free radical-mediated lipid peroxidation of human red
blood cells and DNA strand breakage.
Padhye et al. [193] synthesized fluorinated chalcones (Fig. 34) (I and II) in order
to overcome their limitations of poor bioavailability and rapid elimination from the
biological system. In addition to evaluation of their anticancer activity, the
compounds were subjected to antioxidant screening using superoxide dismutase
(SOD) scavenging assay. All synthesized compounds exhibited good antioxidant
activity, with the highest level shown by the compound (II) with two fluorine atoms
(ring B) and one hydroxyl group (ring A).
Antileishmanial activity
Santos et al. [194] prepared 20 ,60 -dihydroxy-40 -methoxychalcone (Fig. 35) that
exhibited significant antileishmanial activity.
Hermoso and co-workers [195] synthesized a di-hydrochalcone (Fig. 36) having
antileishmanial activity.
The synthesis, molecular modeling and SAR studies of tri-methoxy chalcones
(Fig. 37) and their antileishmanial effects were reported by Bello et al. [196].
Among active compounds, analogs (I), (II) and (III) exhibited good antileishmanial
activity.
Nazarian et al. [197] synthesized a series of chalconoids having a 6-chloro-2H-
chromen-3-yl group (Fig. 38) and they in vitro screened against the promastigote
form of Leishmania major using the MTT assay These compounds were found to
possess antileishmanial activity.
Fig. 32 Substituted chalcones derivatives
123
Fig. 33 Hydroxy chalcones derivatives
Fig. 34 Fluorinated chalcones
Fig. 35 20 , 60 -dihydroxy-40 -
methoxychalcone
Fig. 36 Substituted di-

hydrochalcone
Fig. 37 Tri-methoxy chalcones
123
Fig. 38 6-chloro-2H-chromenyl chalcones
Foroumadi and co-workers [198] reported synthesis of chromene-based chal-

cones (Fig. 39) and their biological evaluation.
Antimalarial activity
Advanced and more efficient antimalarial drugs are greatly needed, as malaria
parasites are increasingly resistant to the available drugs. In 1994, Chen et al. [199]
first reported the potential for chalcones as antimalarial agents. Dominguez et al.
[200] reported the synthesis of phenylurenyl chalcones (Fig. 40) that exhibited
antimalarial activity.
Dominguez and co-workers [201] synthesized chalcones with a sulfonamide
moiety (Fig. 41) exhibiting antimalarial activity.
Yadav and co-workers [202] prepared several chalcone derivatives (Fig. 42)
(I) and evaluated their antimalarial properties. Compounds with –OCH3 groups at
positions 2 and 4 on ring B showed good activity, while similar groups on positions
3, 4 and 5 induced less activity. The most active compound, 1-(4-benzimidazol-1-
yl-phenyl)-3-(2,4-dimethoxyphenyl-propen-1-one) (II), exhibited better antimalarial
activity.
Sharma and co-workers [203] reported the synthesis and antimalarial evaluation
of a series of allylated chalcones (Fig. 43).
New chalcone–quinoline hybrids (Fig. 44) were recently reported by Guantai
et al. [204] and were tested for their antimalarial properties.
Wanare et al. [205] reported the synthesis and antimalarial activity of pyran ring-
substituted chalcones (Fig. 45) (I). The compound (II) bearing 2, 3, 4-OCH3 groups
at ring B showed good activity.
Tomar et al. [206] synthesized chalcone derivatives with an acridine moiety
(Fig. 46) and tested their antimalarial potency.
Wu et al. [207] isolated a chalcone (Fig. 47) that showed anti-HIV activity with a
good therapeutic index.
Antitubercular activity
Sivakumar et al. [208] synthesized chalcones (Fig. 48) possessing anti-mycobac-

terial activity.
A chalcone that exhibited antitubercular activity was synthesized (Fig. 49) by
Sivakumar and co-workers [209].
123
Fig. 39 Chromene-based chalcones
Fig. 40 Phenylurenyl chalcone
Fig. 41 Sulfonamide substituted chalcone
Fig. 42 Substituted chalcones derivatives
Burmaoglu et al. [204] synthesized new fluorine-substituted chalcone analogs

(Fig. 50) and evaluated their antitubercular efficacy against the Mycobacterium
tuberculosis H37Rv strain.
123
Fig. 43 Allylated chalcones
Fig. 44 Chalcone-quinoline hybrids
Fig. 45 Pyran substituted chalcones
Anticancer activity
Cunha and co-workers [210] isolated the chalcone lonchocarpin (Fig. 51) from the
roots of Lonchocarpus sericeus, which displayed cytotoxic activity.
123
Fig. 46 Acridine substituted

chalcones
Fig. 47 Naturally occurring

chalcone
Fig. 48 Substituted chalcone
Fig. 49 Substituted hydroxy

chalcone
OMe O
MeO OMe
Fig. 50 Fluorine-substituted chalcone
A fluorinated chalcone (Fig. 52) exhibiting anticancer activity was prepared by

Sato et al. [211].
Methylenedioxychalcone (Fig. 53) isolated from the stem bark of Millettia
leucantha showed moderate cytotoxicity [212].
123
Fig. 51 Natural chalcone

lonchocarpin isolated from the
roots of Lonchocarpus sericeus
Fig. 52 Fluorinated hydroxy

chalcone
Fig. 53 Methylenedioxychalcone isolated from the stem bark of Millettia leucantha
Fig. 54 Methoxylated chalcone
Lawrence and co-workers [213] synthesized a methoxylated chalcone having

(Fig. 54) good cytotoxic activity.
Furanochalcones (Fig. 55) with anticancer activity have been reported [214].
A new fluorinated 3,4-dihydroxychalcone was synthesized and evaluated for its
biological activity [215]. 6-Fluoro-3,4-dihydroxy-20 ,40 -dimethoxychalcone (Fig. 56)
showed good anticancer activity.
An a-substituted chalcone was reported by Salvie, Richard and John [216]. The
compound (Fig. 57) was found to be the most active and was tested for use in the
treatment of leukemia.
123
Fig. 55 Furan-fused chalcone
Fig. 56 6-Fluoro-3,4-
dihydroxy-20 ,40 -
dimethoxychalcone
Fig. 57 a-substituted chalcone O
H3CO
H3CO OCH3
OCH3 OH
O O Where, Ar= Heteroaryl

R= -OH, O-alkyl
Ar R' R'= -H, alkyl
Fig. 58 Heterocyclic substituted chalcones
Bombardeli and Valenti [217] prepared heterocyclic-substituted chalcones

(Fig. 58) and reported that some of these were introduced for the treatment of
breast cancer, menopausal disorders and osteoporosis.
123
Anti-HIV activity
Uenaka et al. [218] synthesized b-hydroxy chalcones (Fig. 59). The compound
bearing the fluoro substitution exhibited significant activity against the human
immunodeficiency virus (HIV).
Xu and co-workers [219] isolated butein (Fig. 60), which showed anti-HIV
activity.
A unique chalcone from the genus Desmos (Fig. 61) was isolated by Nakagawa
et al. [220], and showed anti-HIV activity.
Carbonic anhydrase inhibitory activity
Arslan et al. [221] synthesized and evaluated the carbonic anhydrase (CA)
inhibitory properties of novel chalcone-substituted benzenesulfonamides (Fig. 62).
All of the newly synthesized sulfonamides demonstrated important inhibitory
profiles against these CA isoforms, with inhibitor constant (Ki) values in the range
of 9.88–55.43 nM, making these compounds interesting leads, with potential
application in medicinal chemistry.
R1 R4
R2 R3
HN
N
N
Fig. 59 Triazole substituted chalcones
Fig. 60 Natural chalconoid OH O

Butein
OH
HO OH
Fig. 61 Chalcone isolated from

genus Desmos
123
Fig. 62 Chalcone substituted

benzenesulfonamides
Fig. 63 Bischalcone
Fig. 64 Bischalcone
Arslan et al. [222] synthesized for the first time a new type of bischalcone
(Figs. 63, 64) as an alternative to natural and synthetic bischalcones. These
compounds were screened for carbonic anhydrase inhibition activity. Almost all
bischalcones exhibited moderate to good inhibitory effects.
Inhibitors of tubulin polymerization
The biological importance of microtubules in mitosis makes them an interesting

target for the development of anticancer agents. Qiu et al. [223] synthesized a series
of novel chalcone-containing shikonin derivatives (Fig. 65) and evaluated them for
tubulin polymerization-inhibitory activity. Further investigation showed that these
123
Fig. 65 Chalcone-containing
shikonin derivatives
derivatives could induce MCF-7 cell apoptosis, reduce the mitochondrial trans-
membrane potential, and arrest the cell cycle at the G2/M phase. These studies may
provide a new molecular scaffold for the further development of anti-tumor agents
targeting tubulin.
Conclusion
Chalcones are versatile scaffolds for synthetic modification and exhibit diverse
pharmacological properties. Due to their better bioavailability and high tolerance in
the body, research on chalcones and derived compounds is gaining interest
worldwide for the development of pharmacological compounds. A number of
molecules containing a chalcone moiety are currently available in the market or in
clinical trials. This review updates recent developments regarding synthetic and
pharmacological properties of chalcones.
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Synthesis and pharmacological properties of chalcones: a review

Article in Research on Chemical Intermediates · November 2017

Santosh L Gaonkar Vignesh Udyavara Nagaraj

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Santosh L. Gaonkar & U. N. Vignesh

Research on Chemical Intermediates

Res Chem Intermed (2017)

Synthesis and pharmacological properties of chalcones:

Santosh L. Gaonkar1 • U. N. Vignesh1

Keywords Chalcone Synthesis Pharmacological properties

The framework 1,3-diphenylprop-2-en-1-one (Fig. 1) is well known by the generic

& Santosh L. Gaonkar

Fig. 1 Structure of chalcone or O

Scheme 1 Ring closure reactions of chalcones

Cyanopyridines, pyrazolines, isoxazoles and pyrimidines having different hetero-

Condensing agents for synthesis

Alkali as condensing agent

Hydrochloric acid as condensing agent

Fig. 2 Numbering as per

Fig. 3 Numbering as per

Other condensing agents

Scheme 2 Chalcones by Claisen-Schmidt condensation

Benzaldehyde Acetophenone Chalcone

Scheme 3 Chalcones by Aldol condensation

means to avoid the disproportionation of aldehyde, the use of benzylidene-diacetate

Aldol condensation reaction

The preparatory material for this reaction is acetophenone and benzaldehyde

Venkatraman and Nagrajan [73] prepared bis-chalcone using dihydroxy-diacetyl-

(I) (II) Chalcone (III) (IV)

Scheme 4 Chalcones by Suzuki coupling

Scheme 5 Chalcones by Heck coupling

Fig. 4 Preparation of bis-halcones

Fig. 5 Preparation of bis-halcones

Several hydroxy-nitrochalcones have been prepared using dry hydrogen chloride

Fig. 6 Preparation of hydroxy-nitrochalcones

Reaction of benzaldehyde with phosphonate carbanion

A typical reaction (Scheme 6) of benzaldehyde (I) with phosphonate carbanion (II)

Reaction of ketones and aromatic aldehyde

Preparation of a chalcone derivative using 2-hydroxy-3-bromo-5-ethyl

Preparation of chalcones using cinnamic acid

Preparation of chalcone using O-iodophenyl acetate and palladium

Palladium-catalyzed synthesis of O-hydroxychalcones and flavanones has been

Preparation of chalcones using Schiff bases

Preparation of chalcones from organometallic compounds

Studies have reported the synthesis of chalcones using organometallic compounds

Scheme 6 Chalcones by benzaldehyde and phosphonate anions

Scheme 7 Chalcones from aromatic aldehydes and ketones

Scheme 8 Chalcones from aromatic aldehydes and ketones

Aq. KOH (40%) R

Fig. 7 Chalcones from 2-hydroxy-3-bromo-5-ethyl acetophenone

ether, phenyl magnesium bromide and cinnamonitrile in the presence of ammonium

Microwave-assisted synthesis of chalcones

Chalcone synthesis using ultrasound irradiation

Heterogeneous catalysts such as potassium carbonate, basic Al2O3, amino-grafted

Solvent-free synthesis of chalcones

One-pot synthesis of chalcones

One-pot synthesis of chalcones [103] was recently performed using CuI/carbon

Fig. 8 Microwave assisted synthesis of chalcones

Scheme 9 Solvent-free synthesis of chalcones

Scheme 10 Synthesis of coumarinyl chalcones

Mechanism of chalcone formation