Environmental Chemistry Letters (2020) 18:433–458

https://doi.org/10.1007/s10311-019-00959-w

REVIEW

Chalcone synthesis, properties and medicinal applications: a review

Aluru Rammohan1,2 · Julakanti Satyanarayana Reddy3 · Gundala Sravya1 · Chittluri Narasimha Rao2 ·
Grigory V. Zyryanov1,4

Received: 17 November 2019 / Accepted: 27 November 2019 / Published online: 6 January 2020
© Springer Nature Switzerland AG 2020

Abstract
Chalcone is an aromatic ketone that forms the central core of many important biological compounds, which are known as
chalcones. Chalcones are the biogenetic precursors of flavonoids and isoflavonoids, which are abundant in plants. Chalcones
are active lead molecules in medicinal chemistry for the discovery of new drugs. Here, we review properties, biosynthesis
and structural diversity of natural chalcones. Then, we present the synthesis of chalcones and their biological activities with
focus on structure–activity relationships. Pharmaceutically important and patented chalcones are also discussed.

Keywords Antidiabetic activity · Chalcones · Chemopreventors · Claisen–Schmidt condensation · Fluorescent material ·

Witting reaction

Introduction produce a new class of organic compounds such as azachal-

Chalcone is an aromatic ketone that forms the central core
of many important biological compounds, which are known
as chalcones. Chalcones are the biogenetic precursors of fla-
vonoids and isoflavonoids, which are abundant in plants.
The chalcone core is composed of two aromatic rings that
are linked through a three carbon-α, β-unsaturated carbonyl
system, i.e., 1,3-diphenyl-2-propen-1-one derivative. Chal-
cones are structurally one of most diverse group of flavo-
noids and easily allow to cyclize forming flavonoid structure
which is isomeric key step for the skeletal modification of
chalcones. The chemistry of chalcones is still an attrac-
tion among the organic chemists from ancient days, due to
open-chain model and the feature of skeletal modification to
* Aluru Rammohan
rammohan4ever@gmail.com
1
Department of Organic and Biomolecular Chemistry,
Ural Federal University, 19 Mira, Yekaterinburg,
Russian Federation 620002
2
Department of Chemistry, Sri Venkateswara University,
Tirupati, Andhra Pradesh 517502, India
3
National Health Research Institute, 37 Keyan Road,
Zhunan 35053, Miaoli County, Taiwan
4
Ural Division of the Russian Academy of Sciences,
I. Ya. Postovskiy Institute of Organic Synthesis, 22
S. Kovalevskoy Street, Yekaterinburg, Russian Federation
cones (Downs et al. 2005), isoxazoles (Prakash et al. 2005),
pyrazoles (Prasad et al. 2005) and indole grounded chal-
cones (Gupta et al. 2018). Chalcone derivatives exhibit a
wide range of therapeutic activities (Fig. 1), such as anti-
cancer, antioxidants (Anto et al. 1995), anti-inflammatory
(Ballesteros et al. 1995), antihypertensive (Won et al. 2005),
antimalarial (Dominguez et al. 2005), antiulcer (Kyogoku
et al. 1979), antiviral (Ishitsuka et al. 1982), antiprotozoal
(Chen et al. 1993), cardiovascular activity (Chen et al. 2001)
and mutagenic properties (Rashid et al. 1986). Stereochemi-
cally, chalcone can exist both trans (E) and cis (Z) isomers,
but the Z conformer is most unstable due to steric effects
of ring A with carbonyl group. In chalcones, two aromatic
rings and the electrophilic α, β-unsaturated carbonyl sys-
tem are in continuous conjugation. It may be the reason for
their low redox potential, stability, electron transfer reactions
and more importantly for its promising biological activi-
ties (Gaonkar and Vignesh 2017). Thus, chalcones are an
innovative class of compounds with significant therapeutic
potential against various diseases.
Nomenclature
The common IUPAC acceptable consistent naming of chal-
cone is 1,3-diphenyl-2-propen-1-one, which is considered as
phenyl styryl ketone. The crucial difference in the number-
ing of positions of the chalcone nucleus inverted to that of

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Vol.:(0123456789)
434 Environmental Chemistry Letters (2020) 18:433–458

Fig. 1  Chalcone derivatives

occur in plants and can be
synthesized. Chalcones have
applications such as antican-
cer, antioxidants, antidiabetic,
anti-inflammatory, antimicro-
bial, antiviral and fluorescent
materials

flavonoid structure. The aryl rings are existing in chalcone
designated as rings A and B: ring A designated with primed
numbers and the B ring as non-primed numbers shown in
Fig. 2. In general, the naturally occurring chalcones are com-
mon with substitutions such as hydroxyls, methylation and
prenylation, but they also exist as dihydrochalcones, dimers
(bichalcones) and glycosides. The numbering system used to
distinguish the position of the fused ring prenyl substituents
such as furano and pyrano groups is also indicated in Fig. 2.
Biosynthesis of chalcones
Several reports were published on the biosynthesis of chal-
cones, and the most reliable approach described by Andersen
and Markham (2006) is described here. In biosynthetic
approach, formation of chalcone is a convergence of two
biogenesis pathways: ring A of chalcone is usually phloro-
glucinol ­(C6 Unit) type derived from acetate pathway and
the ring B originates from phenylpropanoid precursor (­ C9
Unit) synthesized through shikimate pathway. A phenylpro-
panoid CoA (p-coumaroyl CoA) is undergoing sequential
condensation with three molecules of malonyl coenzyme A
(malonyl-CoA), resulting in a tetraketide precursor. Further,
this tetraketide may be believed to undergo cyclization in
two different paths (Fig. 3). In the primary way, tetraketide
undergoes cyclization in the presence of chalcone synthase
(acts as a catalyst) and gives a chalcone tri-oxygenation in
ring A (chalconaringenin). In the second method, the tetra-
ketide undergoes a reduction in the presence of NADPH and
then cyclization in the presence of chalcone synthase gives
a 6′-deoxychalcone (isoliquiritigenin). Thus, the NADPH
reductase of either tri- or tetraketide is the evidence for the
formation of many 6′-deoxychalcone in Leguminosae.

Fig. 2  Systematic numbering of

simple and fused ring prenyl-
substituted chalcones

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Environmental Chemistry Letters (2020) 18:433–458
Fig. 3  The biosynthesis of
chalcones through tetraketide
cyclization in the presence of
chalcone synthase as well as
reduction of tetraketide in the
presence of NADPH reductase
Physical and chemical properties
Chalcones occur not only in flowers but also in leaves, fruits,
roots, stems and all parts of the plant kingdom. The naturally
occurring chalcones are generally crystalline solids, and
they possess different colors including yellow, orange and
brown. Chalcones are more stable than relative flavonoids
and isoflavonoids. Chalcones are well soluble in alcohols,
aqueous acidic and alkaline solutions, as well as in organic
solvents, such as acetone, chloroform and dichloromethane.
In alkaline solutions, they exhibit deep red or orange red
colors. All chalcones are positive to Wilson test, i.e., pink
colorization with conc. H­ 2SO4. Also, chalcones treated with
alcoholic ferric chloride solution resulted in violet coloriza-
tion; this indicates the presence of free phenolic hydroxyl
groups. Chalcones undergo isomerization reactions to give
flavonoids (Andersen and Markham 2006; Harborne et al.
1975) shown in Fig. 4.
435
• Chalcones on heating with traces of iodine in dimethyl-
sulfoxide for 2 h give the corresponding flavones.
• Flavanones can be easily achieved through cyclization of
chalcones treated with hydrobromic acid in glacial acetic
acid. In this isomerization reaction, partial demethylation
and debenzylation may occur.
• Chalcones were converted into flavonols by their oxi-
dation using hydrogen peroxide in methanolic sodium
hydroxide solution.
• Another important isomerization reaction is known to
be the formation of aurones from the chalcone precur-
sors in the presence of aureusidin synthase (Nakayama
et al. 2001). The initial transformation of the o-dihydroxy
groups of B- ring to an o-diquinone is a significant con-
version because with one or without hydroxyl groups in
ring B are anonymous at present.
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Fig. 4  Isomerization reactions of chalcones such as flavanone, flavonol and aurone
Fluorescent properties of chalcones
Fluorescent materials have much attention because of their
promising applications like chemical probes, electrochro-
mic materials, fluorescent dyes, sensors, as additive in dye
sensitized solar cells, and more significantly in diagnosis for
the development of new drugs (Da Costa et al. 2019; Kru-
padam 2011; Tomasch et al. 2012; Wantanabe et al. 2018;
Yun et al. 2014; Zhou et al. 2016). At present, fluorescent
chalcones have been used to detect several diseases through
emission color changes in living cells (Tomasch et al. 2012).
These fluorescent chalcones provide new opportunities for
using non-radioactive substitutes (Yun et al. 2014). Also, at
present fluorescent chalcones are beneficial to investigat-
ing the cellular targets as well as chemical probes for their
mechanistic investigations (Zhou et al. 2016). Watanabe
et al. (2018) had reported novel fluorescent chalcone ana-
logues for the inhibition of formation of β-amyloid plaques,
which is the current therapeutic approach used to treat the
Alzheimer’s disease (AD). In another attempt, heteroaryl
chalcones with both electron donor and acceptor groups
were reported (Pannipara et al. 2015) by changing the polar-
ity of aprotic solvents which enhances the quantum yields
and fluorescence intensity through inter molecular charge
transfer (ICT). Pasricha et al. (2017) studied the interaction
of bovine serum albumin with naphthylchalcone derivatives
using key parameter florescence quenching.
Chalcones with appropriate substituents (electron pull
functional groups) on both aryl rings had been reported
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as intrinsically fluorescent (Fig. 5). The key parameters
involved in the study of fluorescence are absorption (Abs
λnm) and emission (Emi λnm) wavelengths, extinction coef-
ficient (ε) and quantum yield (ϕ). These physical parameters,
in turn, depend on electron density across the molecule to
display intrinsic fluorescence. Based on the previous experi-
mental analysis, the chalcone to be worthy fluorescent mate-
rial, it must possess some structural features.
• The molecular must be planar.
• In ring A, weak electron-donating groups such as meth-
oxyl groups result in promising quantum yields instead
of electron-withdrawing groups like nitro, nitrile groups
which illustrate lesser quantum yields.
• In ring B, the presence of a disubstituted amino group
such as dimethylamino, diethylamino, diarylamino or
piperazine, piperidine groups is of abundant significance
for the higher extinction coefficient, greater quantum
yields and fluorescence with lower ionization potential.
• If there is the extension of the conjugation of α,
β-unsaturated system with additional bonds, fluorescence
will be decreased and cause a redshift of maximum emis-
sion.
Spectral properties
The ultraviolet and visible absorption spectroscopy is an
imperative technique from ancient times, to identify the
number and position of functional groups in flavonoids
Environmental Chemistry Letters (2020) 18:433–458
Fig. 5  Some of the earlier reported nominal fluorescent chalcones and their structural studies
Fig. 6  Classification of UV absorption bands in chalcones. The major
band I is due to cinnamoyl group absorption, and band II absorbtion
is due to benzoyl chromophore of chalcone
and chalcones. The UV spectrum of chalcones consists of
two major absorption maxima: one prominent band which
occurs in the range 340–390 nm (a band I) and the other
relatively minor band in the range 200–270 nm (band II).
In general, the band II absorption maxima originated from
the ring A benzoyl system and the band I from the B- ring
cinnamoyl system (Harborne et al. 1975), (Fig. 6). Occasion-
ally, chalcone band I appears in visible region as similar to
437
anthocyanins, which may be the belief for their variety of
color solutions (De Freitas and Mateus 2006). Also, another
non-prominent shoulder like absorption peak appears in the
UV spectrum of chalcones at 300–320 nm, which is most of
times not detectable.
In chalcones on increasing the number of free hydroxyl
groups, the bathochromic shifts of both UV absorption
bands occur, but particularly in band I it is more significant.
If 2′-hydroxyl group of chalcone is protected such as methyl,
prenyl and sugar moiety; in this case, 15–20 nm hypochro-
mic shift occurs in band II and other positions show lit-
tle effect. The position of hydroxyl groups was estimated
significantly by using shift reagents such as sodium meth-
oxide (NaOMe), sodium acetate (NaOAc), sodium acetate/
boric acid (NaOAc/H3BO3), aluminum chloride ­(AlCl3)
and aluminum chloride/hydrochloric acid ­(AlCl3/HCl).
The preparation of reagents and their uses were completely
described by Mabry et al. (1970). The proton magnetic reso-
nance (PMR) spectrum of chalcones displays two charac-
teristic signals for ­Hα and ­Hβ in the range δ 6.7–7.4 and
7.3–7.7, respectively, as doublets (J = 15–17 Hz) (Harborne
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438
et al. 1975). Also, the carbon nuclear magnetic resonance
(13C NMR) spectrum shows three characteristic signals
for a chalcone: a typical signal for carbonyl in the range δ
188.6–194.4 and two another prominent signals for C ­ α, and
­Cβ in the range 116.1–128.1 and 136.9–145.4 ppm, respec-
tively (Agrawal 2013). These typical UV and NMR mono-
grams are more useful to detect the chalcones in the natural
products discovery.
Structural diversity of natural chalcones
Chalcones with humble substituents such as hydroxyls,
methoxyls, prenyls and glycosides are common in nature.
However, some of the chalcones with unusual bonding
and substitutions isolated from plant source are described
here (Fig. 7). For example, two unusual β-OH chalcones
are reported from the natural source. Galiposin (7A) is iso-
lated from Galipea granulosa (Rutaceae) and is the first
bis(methylenedioxy) chalcone reported in the literature from
natural source (Lopez et al. 1998). Similarly, 2′β-hydroxy-
4′,6′-dimethoxy-3′-methyl chalcone (7B) is obtained from
Fig. 7  Unique chalcones with unusual bondings and substitutions isolated from various plant sources and listed here
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aerial parts of Leptospermum scoparium (Myrtaceae)
(Mayer 1993). Likewise, a bisdesmosidic triglycoside (7C)
isolated from the roots of Glycyrrhiza aspera (Leguminosae)
is the rare chalcone with unusual bonding of three sugar
moieties so far reported (Kitagawa et al. 1998) in the litera-
ture. Rhuschalcone VI (7D) isolated (Masesane et al. 2000;
Mdee et al. 2003) from Rhus pyroides is a bichalcone formed
through C–C linked two isoliquiritigenin units. This C–C
linked bichalcone is very rare in nature.
Azobechalcone (7E), isolated from Lophira alata
(Ochnaceae), is the uncommon oligomeric chalcone formed
through condensation of six isoliquiritigenin (monomeric
chalcone) molecules (Tih et al. 1999). The isolation and
structure establishment of these molecules are very challeng-
ing devoid of extensive 2D NMR spectral characterization.
Furthermore, significant annotation concerning chalcones
may act as dienophiles in Diels–Alder reactions. Chalcones
also arise in the form of Diels–Alder adducts from natural
source, especially in the plants that belong to the family
Moraceae. Sanggenon R (7F) is the first example reported as
Diels–Alder adduct from the roots of Morus species (Hano
et al. 1995).
Environmental Chemistry Letters (2020) 18:433–458
Synthetic approaches
Chalcones have a modest privileged scaffold and been usu-
ally used as a template in medicinal chemistry which ena-
bles a variety of substitutions with the easy synthesis for
the drug discovery. In general, synthesis of chalcones was
achieved through condensation reactions by using acid or
base catalysis. At present, statistics of synthetic methods
and procedures have been reported due to their remarkable
biological applications. The synthetic techniques, catalysts,
conditions and general methodologies for the synthesis of
chalcones are summarized below.
Claisen–Schmidt condensation
The Claisen–Schmidt reaction is the most familiar reaction
in organic chemistry. This reaction has a simple procedure
for the preparation of chalcone derivatives, in which ace-
tophenone and aldehyde derivatives undergo condensation
in the presence of acid or base catalysts in polar solvents at
50–100 °C for several hours (Gaonkar and Vignesh 2017;
Smith and Paulson 1954) (Scheme 1). The formation chal-
cone in the presence of base takes place from aldol prod-
uct via dehydration of enolate mechanism, whereas in the
case of acid catalysis the product is produced from the enol
Scheme 1  Claisen–Schmidt reaction in the presence of base/acid catalyst
Scheme 2  Claisen–Schmidt reaction in solid-phase medium
439
mechanism. The general base reagents used for this con-
densation are NaOH, KOH and NaH. The main drawbacks
of this method are the slow reaction rate and probability
of by-products; typically, it needs more reaction time and
sometimes unspent starting materials (Gaonkar and Vignesh
2017). However, Claisen–Schmidt condensation is the
most commonly used procedure for the synthesis of chal-
cones due to simple procedure and more yields compared
with other conventional methods. Burmaoglu et al. (2016)
reported a series of fluoro-substituted chalcones with high
yields (90–80%) by employing Claisen condensation of tri-
methoxy acetophenone with respective fluoro-substituted
aldehydes in aqueous base solution. In another attempt, the
authors have prepared a novel prenylated chalcones through
Claisen–Schmidt condensation in LiOH/MeOH with moder-
ate yields (Passalacqua et al. 2015).
In general, Claisen–Schmidt condensation reaction is car-
ried out in the liquid phase, but in some cases solid-phase
condensations are also carried out (Cheng et al. 2000; Wata-
nabe and Imazawa 1982). In this solid-phase condensation
reaction, initially the acetophenone derivative was bounded
to the resin and then treated with derivatives of benzalde-
hydes. Finally, the chalcones were free from the resin by
treating with trifluoroacetic acid (Scheme 2). The best resins
for the solid-phase Claisen–Schmidt condensations are the
complex of Co (II) cross-linking 4-vinyl pyridine styrene
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440
and 2-chlorotritylchloride because these resin-mediated
reactions result in no by-products (Cheng et al. 2000; Wata-
nabe and Imazawa 1982).
Similarly, zinc oxide-supported metal oxide catalysis
Claisen–Schmidt condensation of 2′-hydroxy acetophenone
with aldehydes is also reported under solvent-free condition
(Scheme 3) (Saravanamurugan et al. 2005).
Although base-mediated Claisen–Schmidt condensation
is successfully carried out for the synthesis of chalcones,
Bronsted acids and Lewis acids also have been employed as
acid catalysis. The acid-catalyzed Claisen–Schmidt conden-
sation reaction (Dhar 1981) was carried out with common
acid HCl in ethanol, but the yields were very poor (10–40%).
Further, the chalcones were synthesized with baron trif-
luoride-etherate ­(BF3-Et2O, Scheme 4) with appreciable
yields 75–95% over less than 3 h reaction time (Narender
and Reddy 2007).
Scheme 3  Metal oxide-cata-
lyzed Claisen–Schmidt reaction
under solvent-free condition
Scheme 4  Lewis acid-catalyzed
Claisen–Schmidt reaction
Scheme 5  Synthesis of chalcones using grinding method
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Grinding method
Grinding method is very simple, environmentally benign,
solvent-free and significant in terms of short reaction time
with quantitative yields. Rateb and Zohdi (2009) used a
facile, solvent-free and eco-friendly approach for the syn-
thesis of chalcones at room temperature. In this method,
various chalcones were prepared by grinding the mixture of
appropriate methyl ketones, aldehydes and sodium hydrox-
ide using pestle in an open mortar. Radhakrishnan et al.
(2016) reported a facile solvent-free synthesis of azacha-
lcones through grinding the reactants. In another attempt,
Arslan et al. (2016) prepared a new series of bischalcones
through diazotization and diazocoupling by applying grind-
ing method with good yields (88–60%, Scheme 5).
Microwave irradiation condition
Microwave irradiation technique is now a well-known tech-
nique in organic synthesis. This method has more advan-
tages over other conventional methods, because it reduces
Environmental Chemistry Letters (2020) 18:433–458
the reaction time, by-products, evaporation of solvents, and
most importantly, it results in enhanced yields (Gupta and
Mahajan 2019). A solvent-free, molecular iodine-impreg-
nated alumina-catalyzed microwave irradiation reaction of
acetophenones with aldehydes was reported (Kakati and
Sarma 2011). The neutral alumina acts as catalytic surface,
and the molecular iodine serves as Lewis acid to activate the
carbonyl group of aldehydes for the nucleophilic attack with
hydroxy aryl ketone (Scheme 6). In this method, polyhy-
droxy chalcones are preparing without using any protecting
groups. Likewise, Ashok et al. (2016) reported a new class
of carbazole-based chalcones using powdered KOH under
solvent-free microwave condition with enhanced products.
Ultrasound irradiation technique
The ultrasound irradiation is another beneficial technique
like microwave-assisted synthesis because it has short reac-
tion time and the high percentage of reaction yields. The
principle involved in this technique is the activation of
catalytic sites by ultrasonic waves that could be related to
an increase in the vibrational state of the lattice that makes
chemical reactions (Tran et al. 2015). The synthesis of
chalcones was also conducted under ultrasound irradiation
procedure using heterogeneous catalysts such as ­K2CO3,
basic ­Al2O3, Ba(OH)2, KF–Al2O3 and amino-grafted zeo-
lite (Chtourou et al. 2010; Fuentes et al. 1987; Li et al. 2002;
Wei et al. 2005). Wei et al. (2005) had reported ultrasound-
irradiated synthesis of chalcones with high yields in the
Scheme 6  Synthesis of chalcones through solvent-free microwave irradiation condition
Scheme 7  Synthesis of dinitrochalcones under ultrasound irradiation
441
presence of ­K2CO3 as catalyst. Similarly, Chtourou et al.
(2010) reported a solvent-free synthesis of chalcones with
outstanding yields (96–80%) using acidic clay (KSF) under
ultrasonic irradiation technique (Scheme 7). Likewise, in
another attempt the authors have prepared different chal-
cones using KOH/EtOH (without catalyst, 52–97%) and KF/
MeOH (with the presence of A ­ l2O3, 83–98%) with ultra-
sonication procedure (Calvino et al. 2006) under moderate
temperature conditions.
Coupling reactions
In the design of a new class of chalcones with various sub-
stituents, using conventional methods sometimes leads to
undesirable products besides with preferred products which
make challenging chromatographic separation. Hence, cur-
rently new strategies such as cross-couplings (Scheme 8)
with transition metal catalysts such as Julia–Kocienski olefi-
nation, Witting and Friedel–Crafts acylation have been used
for the synthesis of potent pharmaceutical molecules includ-
ing chalcones (Díaz Sánchez et al. 2019; Guo et al. 2015;
Zhuang et al. 2017).
Heck coupling
Metal-catalyzed Heck coupling reactions are an efficient
methodology for the synthesis of chalcones through the cou-
pling of aryl boronic acids and aryl vinyl ketones over C–C
bond formation. Aryl vinyl ketones are coupled with aryl
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442
Scheme 8  Various cross-couplings reactions used for the synthesis of chalcones
iodides or aryl boronic acids to produce chalcone derivatives
in outstanding yields (Hird et al. 1993) under catalytic con-
ditions (Pd(OAc)2, ­Ph3P, ­K2CO3, DMF, Scheme 9). Later,
chalcones were prepared using carbonylative vinylation of
aryl halides with styrene in the presence of carbon monoxide
using palladium catalysts (Guo et al. 2015).
Sonogashira isomerization coupling
Sonogashira coupling can be defined as a coupling of termi-
nal alkynes with aryl halides in the presence of palladium
catalyst combined with a co-catalytic amount of CuI in a
boiling mixture of trimethylamine and THF, under inert gas
conditions for 16–24 h (Scheme 10; Muller et al. 2000). In
this condition, several desired chalcones were synthesized
Scheme 9  Chalcone synthesis through Heck coupling
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with moderate to excellent yields. But, Sonogashira coupling
has some limitations, i.e., extended reaction times, quite
excess base and need for electron-deficient aryl halides. To
overcome these shortcomings, Schramm and Mueller (2006)
described a microwave-assisted coupling isomerization reac-
tion (MACIR) for the synthesis of chalcones with less than
half-hour reaction period in worthy yields.
Suzuki–Miyaura coupling
Suzuki coupling was initially introduced by Akira Suzuki
in 1979, and later, Eddarir et al. (2003) applied this cou-
pling for the synthesis of chalcones and it is the first exam-
ple. Suzuki–Miyaura coupling is another more interesting
metal-catalyzed cross-coupling reaction, in which two
Environmental Chemistry Letters (2020) 18:433–458 443

Scheme 10  Sonogashira isomerization coupling for the synthesis of chalcones (EWG: electron-withdrawing groups)

Scheme 11  Synthesis of chalcones using Suzuki–Miyaura coupling

electronically divergent chemical fragments results chal-

cones through the formation of C–C bond (Scheme 11). A
series of chalcones were synthesized (Haddach and McCa-
rthy 1999) over the coupling of cinnamoyl chloride with var-
ious aryl boronic acids under Pd(PPh3)4, ­Cs2CO3 and anhy-
drous toluene in the argon atmosphere, but the yields are
Scheme 12  Synthesis of chalcones using Julia–Kocienski olefination
found to be moderate. In the same reaction condition, when
the coupling is accompanied by styrylboronic acid with vari-
ous benzoyl chlorides, the reaction results in high yields thiazol-2ylsulfonyl)-1-phenylethanone are the best base and
(Haddach and McCarthy 1999). An assumption concluded Julia reagent pair for the preparation of chalcones through
that the substitution patterns are effects in aryl boronic acid, Julia–Kocienski olefination. Less polar solvents and efficient
which are absent in benzoyl chlorides. base are the key factors which influence the synthesis of
chalcones. Julia–Kocienski olefination results E-chalcones
Julia–Kocienski olefination are the foremost products even at low temperatures also.

Kumar and coworkers (2010) had reported an innovative Witting reactions

application of Julia–Kocienski olefination (Scheme 12) for
the synthesis of chalcones with outstanding yields. A series
of chalcones were synthesized using condensation reaction
of a new Julia coupling reagent, heteroaryl sulfonyl phenyle-
thanone and aromatic aldehydes in basic medium. 1,8-Diaz-
abicyclo [5.4.0] undec-7-ene (DBU) and 2-(benzo[d]
Chalcones are also synthesized via Witting olefina-
tion by considering the basic function of chalcones as α,
β-unsaturated carbonyl derivatives (Scheme 13). Chalcones
were achieved from the triphenylbenzoylmethylene phos-
phorane and benzaldehyde in THF over 30 h at reflux or

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444
Scheme 13  Synthesis of chal-
cones using Witting olefination
Scheme 14  Synthesis of
chalcones using Friedel–Crafts
acylation
Scheme 15  Synthesis of
chalcones via photo-Fries rear-
rangement
Scheme 16  Synthesis of chalcones cis-chalcones
3 days in benzene at reflux in moderate yields (Ramirez
and Dershowitz 1957). Further, Xu et al. (1995) reported
a microwave-assisted synthesis of chalcones in outstand-
ing yields using Witting olefination over 5–6 min reaction
time. This innovative attempt reduces the reaction time with
enhancing the reaction rates to get excellent yields.
Friedel–Crafts acylation
Highly substituted chalcones were prepared by using this
technique, but it is the very infrequently used method. Shot-
ter et al. (1978) synthesized chalcones using Friedel–crafts
acylation in the presence of Lewis acid catalyst. Acylation
of aromatic ethers with cinnamoyl chloride in the presence
of strong Lewis acid catalyst ­AlCl3 yields the chalcones
(Scheme 14).
Photo‑Fries rearrangement
Photo-Fries rearrangement reactions are either ortho or
para directory products based on temperature and solvents.
Phenyl cinnamates are irradiated with a high-pressure
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mercury-arc lamp in benzene solvents under nitro-
gen to acquire 2′- hydroxy chalcones in very poor yields
(Scheme 15; Obara et al. 1969). Further, Ramakrishnan and
Kagan (1970) reported an another photo-Fries rearrange-
ment reaction of chalcones in alcohols and chloroform with
the enhancement of yields up to 50%. The photo-Fries rear-
rangement reactions of chalcones were not used generally
because of its low yields, extended reaction times and com-
plications to handle the reaction procedures.
Synthesis of cis‑Chalcones
Most of the chalcones reported from either natural origin or
synthetic region are in trans- diastereomers only, because
the cis form of chalcones is thermodynamically not stable.
In general, the possible approach for the synthesis of cis-
chalcones is photoisomerization of the corresponding trans-
chalcones, but it results in very low yields. Yoshizawa and
Shioiri (2006) reported a novel method of synthesis of cis-
chalcones using siloxypropynes (Scheme 16). When aryl
siloxypropynes had treated with the catalytic quantity of
potassium tert-butoxide under very mild conditions gives
Environmental Chemistry Letters (2020) 18:433–458
an intermediates siloxyallenes, which were on treated with
conc. ­H2SO4 in 1.2-dimethoxyethane to produce cis-chal-
cones in excellent yields with more enantioselectivity (up
to 99/1: cis/trans ratio).
Hybrid chalcones
Chalcones are versatile molecules and easily allow to cyclize
forming a flavonoid structure which is an isomeric step for
Scheme 17  Recent approaches have been used for the synthesis of hybrid chalcones in different reaction media
445
skeletal modification in the biosynthetic pathway. Based
on the feature of structure modification, several synthetic
attempts have been made to produce a new class of organic
compounds such as azachalcones, isoxazoles, pyrazoles,
indole grounded chalcones and coumarinyl-quinolinyl chal-
cones (Scheme 17), owing to broad-spectrum pharmacologi-
cal potentials.
13
446
Radhakrishnan et al. (2015) reported a series of azacha-
lcones as a tyrosinase enzyme inhibitory (depigmenting)
agents. In another attempt, novel chalcones bearing isoxa-
zole moieties were reported (Niu et al. 2016) with a strong
activator of tyrosinase enzyme. Prasad et al. (2005) reported
pyrazoline derivative with antidepressant activity through
condensation of chalcone moiety with phenylhydrazine
hydrochloride. Potent antiproliferative active indole chal-
cones were prepared, by reflux of mixture of chalcones,
indole derivatives and malononitrile in acetonitrile for 6-h
reaction period (Gupta et al. 2018). These indole chalcones
are the promising lead molecules for the drug development
against colorectal cancer. Abonia et al. (2018) reported
new class of coumarinyl-quinolinyl chalcone hybrids using
Claisen–Schmidt condensation of 3-acetyl-4-hydroxy-2H-
chromene-2-one and 2-butoxyquinoline-3-carbaldehyde in
methanol in the presence of a base.
Medicinal applications of chalcones
The chalcones and their derivatives have enormous impor-
tance in medicinal chemistry even in the twenty-first century
because of their broad spectrum of the therapeutic potential
and pharmacological properties. The chalcones derivatives
show a variety of biological activities including anticancer,
antibacterial, anticonvulsant, anti-HIV, antihyperglycemic,
anti-inflammatory, antileishmanial, antimicrobial, antioxi-
dant, antiprotozoal, antitubercular and antiviral, anti-ulcer-
ative. A concise study about the biological importance of
chalcones with examples is summarized below.
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Chalcones as chemopreventors
A number of chalcones were isolated from natural
source, and a few were documented as chemopreventors.
(+)-Tephrosone (1) (Chang et al. 2000) and tephropurpu-
rin (2) (Chang et al. 1997) were isolated from Tephrosia
purpurea (Leguminosae) and identified as chemopreventive
agents using cell-based quinone reductase induction assay.
Munsericin (3) is another natural chemopreventive chalcone,
isolated from Mundulea sericea (Leguminosae) (Luyengi
et al. 1994). Xanthohumol (4) is a versatile chemopreven-
tive agent (Stevens and Page 2004), which exhibits three
properties: (1) inhibition of metabolic activation of procar-
cinogens, (2) induction of carcinogen-detoxifying enzymes
and (3) early-stage inhibition of tumor growth.
Anticancer activity
Some chalcones from synthetic as well as natural origin
were acknowledged as active against tumor cells along with
antioxidant principles, by inhibiting superoxide production
and lipid peroxidation. Wu et al. (2013) reported an anti-
cancer chalcone, Millepachine (5) is isolated from Millet-
tia pachycarpa. Licochalcone A (6), isolated from Glycyr-
rhiza inflate, is another anticancer chalcone which exhibited
toxicity toward L1210 leukemia and B16 melanoma cells
(Shibata et al. 1991). A new class of chalcone (7) proposed
as an antimitotic agent by increasing the survival of mice
inoculated with L1210 leukemia with doses range of 2.65-
5.0 mg/kg (Edwards et al. 1990). Butein (8) is another natu-
ral chalcone which can suppress the several human cancers
including breast cancer, colon carcinoma, osteosarcoma and
hepatic stellate cells in vitro (Wang et al., 2005; Yit and Das
1994).
Environmental Chemistry Letters (2020) 18:433–458
Antimicrobial activity
Antimicrobial activity of chalcones is believed owing to α,
β-unsaturated carbonyl function. Isobavachalcone (9) and
bavachalcone (10) are two important chalcones isolated
from Psoralea corylifolia reported as antibacterial agents
from the natural source (Oh et al., 2010; Qiu et al. 2011).
A synthetic scaffold, 3-(carboxyalkyl) rhodanine (11) is an
antimicrobial chalcone which displays potent inhibition at
447
low concentration (1 µg/mL) against human pathogens and
is documented as antibacterial as well as antifungal agent
(Yanbian university, 2012). Another, ring fused chalcone
(12) is proposed as an antimicrobial scaffold for the treat-
ment of oral infections (Subramanyam et al. 2015). A hybrid
chalcone that comprises pharmacophore fluconazole (13)
showed potent inhibition with 0.12 µg/mL I­ C50 concentra-
tion against Candida albicans and was patented as antifun-
gal agent (Borate et al. 2016).
13
448
Anti‑HIV
Few prominent chalcones were reported from natural and
synthetic origin as active against human immune virus
(HIV). The natural chalcone, xanthohumol (4) isolated
from Hops Humulus exhibits anti-HIV properties (Wang
et al. 2004). Nakagawa and Lee (2006) isolated a unique
β-hydroxy chalcone (14) from the genus Desmos that shows
good anti-HIV activity. Another chalcone (15) isolated from
the leaves of Maclura tinctoria (Moraceae) showed inhibi-
tory activity against pathogens Candida albicans and Cryp-
tococcus neoformans related to AIDS (ElSohly et al. 2001).
An adamantly chalcone (16) was approved as HIV patent
which showed trivial activity against HIV disease (Xiamen
University 2014).
13
Environmental Chemistry Letters (2020) 18:433–458
Antidiabetic activity
Chalcones were reported as potent inhibitors of α-glucosidase,
dipeptidyl peptidase-4 (DPP4), peroxisome proliferator-acti-
vated receptors-γ (PPAR), protein tyrosine phosphatase 1B
(PTP1B) and aldose reductase and are significant agents for
the treating diabetes mellitus (Mahapatra et al. 2015). Isoli-
quiritigenin (17), echinatin (18), licochalcone A (6), lichoch-
alcone C (19) and lichochalcone E (20) were isolated from
Glycyrrhiza inflata, and its synthetic derivatives are reported
as PTP1B which play vital role in treating type II diabetes
and obesity, as a negative regulator of the insulin and leptin
signaling pathway (Yoon et al. 2009). A novel chalcone, abys-
sinone-VI-4-O-methyl ether (21) isolated from the root bark
of Erythrina mildbraedii showed potent antidiabetic activity
by inhibition of PTP1B (Na et al. 2006). Nakai et al. (2005)
reported new sulfonamide chalcones (22–29) as a strong
inhibitor of the α-glucosidase enzyme.
Environmental Chemistry Letters (2020) 18:433–458
Anti‑inflammatory activity
Naringenin-chalcone (30) is a well-known natural compound
which exhibits anti-inflammatory activity by inhibiting the
production of cytokines, a pro-inflammatory agent (Hirai
et al. 2007). Isoliquiritigenin (31) isolated from Nepalese
propolis (Funakoshi et al. 2015) and butein (32) isolated
from Rhus verniciflua (Yang et al. 1998) are another signifi-
cant natural chalcones which exhibit potent anti-inflamma-
tory activity by inhibiting LPS-induced iNOS and COX-2
expression. Zhao et al. (2003) reported a reduced chalcone
(33) identified as anti-inflammatory agent by inhibiting the
production of NO induced by LPS and INF-γ in murine
microphage-like cell lines. Another synthetic heterochalcone
(34) had been reported as a potent cytokine inhibitor used
for the management of anti-inflammatory ailments (Piramal
life Sciences 2011).
449
Antileishmanial activity
Licochalcone A (6) is a renowned natural antiparasitic agent
used to treat various abdominal spasmodic symptoms by
Japanese (Nagai et al. 2007). Kanzonol C (35), isolated from
the licorice roots (Glycyrrhiza eurycarpa, Leguminosae),
showed strong antileishmanial activity (Christensen et al.
1994). Crotaramosmin (36) is another important chalcone
isolated from Crotolaria rosmosissima, which showed potent
antileishmanial activity (Narender et al. 2005). A dihydro-
chalcone (37) synthesized by Hermoso et al. (2003) showed
trivial antileishmanial activity. Rashid et al. (2016) synthe-
sized a new class of dihydropyrimidine derivates, and the
compound (38) displayed antileishmanial activity against
promastigotes of Leishmania major and L. donovani with
the inhibitory concentration of 0.47 µg/mL and 1.5 µg/mL,
respectively.
13
450
Antioxidant activity
Numerous free radicals produced in the human body during
the metabolic process may be capable of damaging the bio-
molecules such as DNA, proteins and lipids through oxida-
tion, which results in several oxidative damage-related dis-
eases such as cancers, non-inflammatory tumors, digestive
ulcers, rheumatoid arthritis and aging. Hatano et al. (1997)
reported a penta-oxygenated chalcone (39) isolated from
Glycyrrhiza uralensis (Leguminosae) exhibits potent DPPH
radical activity and is used as traditional medicine in north-
eastern China. Cedredipronone (40) is another chalcone
(Koorbanally et al. 2003) isolated from the extracts of fruits
and seeds of Cedrelopsis grevei (Ptaeroxylaceae) showed
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strong superoxide scavenging properties. The prenylated
chalcone glycoside (41), isolated from the bark of Maclura
tinctoria (Moraceae), showed the radical scavenging activity
in different antioxidant principles (Cioffi et al. 2003). Doan
and Tran (2011) prepared an allylated chalcones (42–44)
which showed good antioxidant activity than non-allylated
chalcones by inhibiting the free radicals.
Antituberculosis activity
Nardoaristolone A (45) that is a novel terpenoid chalcone
with unusual skeleton, isolated from Nardostachys Chin-
ensis, exhibited promising antituberculosis activity (Fang
2013). Fluorine-substituted synthetic chalcone (46) has
been reported (Guantai et al. 2011) as antitubercular agents
against Mycobacterium tuberculosis strain.
Environmental Chemistry Letters (2020) 18:433–458
Antiviral activity
Naringenin-chalcone (30) is widely distributed in citrus
fruits and described to possess antiviral properties (Kaul
et al. 1985). Another natural chalcone, Myrigalone G (47)
that is isolated from Leptospermum recurvum (Myrtaceae)
exhibits antiviral activity against the herpes simplex virus
(Mustafa et al. 2003). Iryantherin K (48) and L (49) that are
the two antiviral chalones isolated from Iryantheria megis-
tophulla showed strong inhibition against potato virus and
moderate inhibition against acetylcholinesterase (Kyogoku
et al. 1979). The compounds 48 and 49 are C-benzylated
dihydrochalcone-lignan conjugate diastereoisomers, and this
occurrence is very rare in nature.
Antiulcer activity
Kanzonol C (35) is incidence from the natural source as well
as from the synthetic origin. A synthetic derived chalcone
(35) exhibits potent antiulcer activity (Ming et al. 2002).
Sophoradin (50) is a naturally occurring prenylated chal-
cone, and its derivatives displayed antiulcer activity (Sasa-
jima et al. 1978). Synthetic analogues (51–53) of sophoradin
showed highest antiulcer activity as similar potency with
sophoradin.
451
Neuroprotective activity
Alzheimer’s disease is a neurodegenerative disorder due
to aggregation of the beta amyloid peptide and is the most
progressive metabolic disorder people facing worldwide
in huge amount. Acetylcholinesterases (AChE), butyryl-
cholinesterases (BuChE) and memantine inhibitors are the
current therapeutic approaches used to treat neurodegenera-
tive disorder. Thienylchalcone (54) is a synthesized scaffold
and acts as potent inhibitor of transglutaminase and may
be useful for the prevention or treatment of Alzheimer dis-
eases (Toray industries 2013). Also, some nitro-substituted
chalcones exhibit catechol-O-methyltransferase enzyme
inhibitors activities and are useful in the management of
neurodegenerative disorders like Parkinson’s syndromes
(ICM 2013). Jeon et al. (2016) reported synthetic chalcones
(55) and (56) showed potent inhibition against µ-calpain and
cathepsin B, which may be beneficial to the treatment of
Alzheimer related disorders. In another attempt, a coumarin
chalcone hybrid (57) has been reported (Kang et al. 2018) as
potent AChE inhibitor and may be useful for treating neu-
rogenerative disorder.
13
452
Structure–activity relationship (SAR) studies
In the past decades, several reports have been published on
structure–activity relationship (SAR) studies of chalcones
and are more appropriate to recognize the structural signa-
tures for further design and development of new therapeutic
potent molecules. Chalcones that possess broad-spectrum
pharmacological activities are believed due to their appropri-
ate structural substitutions in rings A and B. Xu et al. (2019)
reported an ample review on the current development of
chalcones and their therapeutic approaches as antibacterial
agents. This review provides a brief impression on structural
activity relationship of chalcone-based drugs against numer-
ous bacterial infections. Introduction of two strong electron-
withdrawing halogen groups at 2, 4-positions of aryl ring of
Fig. 8  Structure–activity rela-
tionship studies of antibacterial
chalcones
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Environmental Chemistry Letters (2020) 18:433–458
chalcone (Fig. 8) may have possessed potent antibacterial
activity while on incorporation of electron-donating groups
such as p-CH3, 2,4- (­ CH3)2, p- or m-OCH3 on aryl groups
suppress the activity (Konduru et al. 2013). In another
report, triazole-integrated chalcones were synthesized and
evaluated for their bacterial activity against S. epidermidis,
B. subtilis, E. coli and P. aeruginosa (Chen et al. 2010).
Strong electron-withdrawing (-F, -NO2) groups on triazole
ring of chalcone influenced largely antibacterial activity.
Likewise, the development of new class of potent antibac-
terial chalcones through replacing one of the aryl rings with
ferrocene moiety were achieved. These novel ferrocene-
based chalcone-linked triazoles-coupled organosilatranes
showed promising antibacterial activities against E. faecalis
and E. coli (Purser et al. 2008). Similarly, sulfone-linked
Environmental Chemistry Letters (2020) 18:433–458
chalcone hybrids showed outstanding antibacterial activity
against both Gram-positive and Gram-negative bacterial
strains having both electron-withdrawing (Cl, Br, N ­ O2) and
electron-donating (OMe) groups on aryl rings (Singh et al.
2019).
Currently, diabetes mellitus is another risky metabolic
disorder from which people suffer worldwide. The univer-
sally accepted molecular targets are aldose reductase (ALR),
α-glucosidase, dipeptidyl peptidase-4 (DPP-4), peroxisome
proliferator-activated receptor-γ (PPAR-γ) and protein tyros-
ine phosphatase 1B (PTP1B) enzyme inhibitors and are the
current therapeutic approaches to treat diabetes even though
they display numerous complications. Chalcones deserve
promising therapeutic potential to control diabetes owing to
their structural substitution pattern. The 2′-hydroxyl group
is an essential feature of natural chalcones that confers sig-
nificant activity by forming hydrogen bonds and sustains
structural stability of chalcone moiety (Fig. 9). Jung et al.
(2006) reported a new series of 2′-hydroxy thiazolidin-
edione chalcone derivatives, as a peroxisome proliferative
activated receptor-γ (PPAR-γ) ligand binding activities. It
is a note to mention that the chalcones which are having
electron-releasing groups such as dimethylamino, alkyl and
amino groups at the C-4 position of either ring A or ring
B flourished extensive activities than heteroaryl chalcones.
Mahapatra et al. (2015) reported the therapeutic approaches
Fig. 9  Structure–activity rela-
tionship studies of antidiabetic
chalcones
Fig. 10  Structure–activity
relationship studies of anti-
inflammatory chalcones and
their structural significance
453
of chalcones and their structural studies in perspective of
diabetes. Chalcones having either 2′- and 4′-hydroxyl pattern
or more hydroxylation in ring B of chalcones exhibit potent
antidiabetic activities. A structural design like 2′-hydroxy-
lation or 2′-, 3′-dihydroxylation, 2,3,4-trihydroxylation and
4-dimethylamino groups in chalcones is more essential and
capable of possessing a wide range of pharmacological
activities including antioxidant activity and antibacterial
activities (Avila et al. 2008; Prasad et al. 2007). Especially,
2′-hydroxylation in chelation with carbonyl group exhibits
promising biological activities.
Inflammation is another risky syndrome related to the
oxidative damage of cellular biomolecules, and abnormal
growth of tissue cells leads to inflammation-associated
tumors. Several chalcones are reported as anti-inflammatory
agents through inhibition of nitric oxide synthase (NOX),
lipoxygenase (5-LOX), cyclooxygenase (COX-1 and COX-
2) enzymes (Fig. 10). Mono- or poly hydroxyls or methoxy-
lated chalcones displayed strong anti-inflammatory activ-
ity by inhibiting lipoxygenase (Kontogiorgis et al. 2008).
The presence of strong electron-donating groups such as
dimethylamino substituents in chalcone showed potent
inhibition of nitric oxide synthase (Herencia et al. 2001).
Broussochalcone A is the another natural chalcone isolated
from Broussonetia papyrifera which acts as potent anti-
inflammatory agent through inhibition of lipopolysaccharide
13
454
(LPS)-induced iNOS protein (Cheng et al. 2001). The activ-
ity of Broussochalcone A is may be believed due to presence
of either prenyl or orthodihydroxyls groups in ring B.
Conclusion
In summary, the present review emphasizes primarily the
novel chalcones with promising applications reported from
the natural source as well as synthetic origin. Furthermore,
this comprehensive review describes the biosynthesis of
chalcones, structural significance of chalcones to be as
fluorescent materials, various synthetic approaches for the
preparation chalcones, therapeutic applications and their
structure–activity relationship studies. It is an interesting
note to mention that the chalcones have a privileged tem-
plate with an α, β-unsaturated carbonyl system and easily
allow for the structural modifications. For this reason, the
researchers make much attention on skeletal modification
of chalcones in the design of new and novel materials with
diverse applications. Hence, chalcone is an innovative scaf-
fold and plays a significant role in the drug discovery.
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