Mohammad Asif. 2016. A review on recent advances and potential pharmacological activities of ...

18 Pages·2015·0.59 MB·English

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A review on recent advances and potential pharmacological activities of versatile
chalchone molecule

Mohammad Asif
Department of Pharmacy, GRD(PG) Institute of Management & Technology, 248009, Dehradun, (Uttarakhand), India
*Corresponding author’s E. mail: [email protected]

A R T I C L E I N F O A B S T R A C T
Article type: Chalchone is an aromatic ketone and precursors of open chain flavonoids and
Review article isoflavonoids present in edible plants and their derivatives have attracted
Article history: attention due to many potential pharmacological activities. Chalchone are also
Received April 2015 known as benzalacetophenone and phenyl styryl ketone. Modifications in their
Accepted June 2015 structure have offered diverse pharmacological activities that have proven useful
January 2016 Issue for the development of new medicinal agents having improved potency and
Keywords: lesser toxicity. They are also the intermediates in the Auwer's synthesis of
Chalchone flavanoids and in the biosynthesis of flavanoids. Chalchone can be synthesized by
Flavonoids various method but the two main methods are Aldol condensation method and
Isoflavonoids Claisen Schmidt method. This review provides an overview of the
Pharmacological activities pharmacological activities of natural and synthetic chalchone derivatives.

© 2016 International Scientific Organization: All rights reserved.
Capsule Summary: The recent advances and potential pharmacological activities of versatile chalchone molecule are
reviewed in this article.
Cite This Article As: M. Asif. 2016. A review on recent advances and potential pharmacological activities of versatile
chalchone molecule. Chemistry International 2(1) 1-18.
derivatives of chalchone are used as drugs, sunscreen agents
INTRODUCTION and sweeteners (Li et al., 2002; Karthikeyan, et al., 2007). In
the synthesis of heterocyclic compounds chalchone are the
A group of compounds having different substitution patterns well-known intermediate (Rateb, 2007; Forkmann et al.,
on the two aromatic rings of 1,3- diphenyl-2-propen-1-one 1999). Synthesis of the chalchone is the one step reaction and
which is known as chalchone and it is linked by a three the synthesis of the alpha beta unsaturated compounds is the
carbon α, β-unsaturated carbonyl system. It is an important main structural component in natural occurring and
class of natural product and belongs to the flavonoid family biological essential substance. There are several strategies
which have been reported a wide spectrum of biological for the synthesis of these based on the formation of the
activities (Matos et al., 2015; Wang et al., 2015; Jantan et al., carbon-carbon bond directly reported to the Aldol
2014; Abdellatif et al., 2014; Lee et al., 2014; Singh et al., Condensation and Claisen-Schmidt Condensation occupies
2014; Drutovic et al., 2014; Lahsasni et al., 2014; the important position (Bukhari et al., 2012; Wang et al.,
Thillainayagam et al., 2014; Mohamed et al., 2012; Dimmock 2012; Tran et al., 2012; Zhang et al., 2012; Luo et al., 2012;
et al., 1999; Go et al., 2005; Nowakowska and Kedzi. 2008). Kerher et al., 2003; Yarishkin, 2008). There are various
They are also defined as the product of condensation of methods to synthesize chalchones. Most widely used method
substituted or simple aromatic with substituted or simple is base catalyzed and acid catalyzed method. In base
acetophenone in the presence of alkali. Some of the catalyzed such as potassium hydroxide, barium hydroxide,
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lithium hydroxide and sodium hydroxide are used whereas in Chalchones (1,3-diaryl-2-propen-1-ones) and their
acid base catalyzed it includes aluminium trichloride, dry heterocyclic analogues, belong to the flavonoid family, which
hydrochloric acid, titanium trichloride and ruthenium possess a number of interestingbiological properties.
trichloride. The most important catalyst were used are solid Chalchones are one of the major classes of naturally
sodium hydroxide and aqueous sodium hydroxide. Palleros occurring compounds. A large number of synthetic routes
was introduced the first solid sodium hydroxide method in have been reported for the synthesis of chalchones, the most
2004 (Anderson. 2001). It is an aromatic ketone that forms a classical and general being the Claisen-Schmidt condensation.
variety of biological compounds. Some chalchones are able to Chalchones and their derivatives have a huge importance in
block the voltage-dependent potassium channel (Patil et al., medicinal chemistry, displaying a wide range of important
2009). They are also the intermediate in the biosynthesis of pharmacological activities. Several chalchones have been
flavonoid. It is also an intermediate in the synthesis of approved for clinical use or tested in humans. Clinical trials
Auwers Synthesis (Prakash et al., 2005). Now the Auwers have shown that these compounds reached reasonable
synthesis is a series of organic synthesis of forming flavonol plasma concentration and are well-tolerated. For this reason
from coumarins. they are an object of continuously growing interest amongst
Chalchones (trans-1,3-diaryl-2-propen-1-ones) (1), a the scientists. However, much of the pharmacological
biosynthetic product of the shikimate pathway, belonging to potential of chalchones is still not utilized (Singh et al., 2011;
flavanoid family are precursors of open chain flavonoids and Rahman, 2011).
isoflavonoids, which are abundant in edible plants. In this reaction the first step is acid catalyzed aldol
Chalchones are also key precursors in the synthesis of many condensation between 3-oxypentanone and benzaldehyde to
biologically important heterocycles such as benzothiazepine, form ohydroxy chalchone. Alkenes product is brominates to
pyrazolines, 1,4-diketones, and flavones. Thus the synthesis give dibromo adduct which re-arranges flavonol by the
of chalchones has generated vast interest to organic as well reaction with potassium hydroxide. Chalchones are found
as for medicinal chemists. There are also some reports of abundant in edible plants and it is considered to be precursor
acid-catalyzed aldol condensations, e.g. AlCl , BF , dry HCl, of iso-flavonoid and flavonoid (Prasad et al., 2005). It is also
3 3
ZrH /NiCl and RuCl (for cyclic and acyclic ketones). considered as the precursor of biologically important
2 2 3
Chalchones and its derivatives have attracted increasing heterocycles such as pyrazolines (Raghavan and Anuradha,
attention due to numerous pharmacological applications. 2002), 1,4-diketones (Bohn, 1998), benzothiaepiene (Sogawa
They have displayed a broad spectrum of pharmacological et al., 1994) and flavones. Chalchone are also obtained from
activities, among which antimalarial (Motta et al., 2006; the natural source, whereas some of its derivatives have been
Awasthi et al., 2009; Cheng et al., 2000; Lim et al., 2007), found to inhibit several enzymes in cellular system, such as
anticancer (Achanta et al., 2006; Romagnoli et al., 2008; protein tyrosine kinase and xanthine oxidase (Nerya et al.,
Echeverria et al., 2009; Szliszka et al., 2010; Ilango et al., 2004). Biosynthetically chalchone can be synthesized by
2010), antiprotozoal (antileishmanial and antitrypanosomal) these methods which are as follows: chalchone synthase,
(Lunardi et al., 2003), anti-inflammatory (Yadav et al., 2010; chalchone isomerase, Naringenin-chalchone synthesis and
Zhang et al., 2010), antibacterial (Hamdi et al., 2010; Bhatia aurones. Chalchone synthase a class of organic compound
et al., 2009), antifilarial (Awasthi et al., 2009), antifungal (Bag that is synthetically found as intermediate, such as in the
et al., 2009; Lahtchev et al., 2008), antimicrobial (Yayli et al., production of pigments and mainly found in the plants as
2006), larvicidal (Begum et al., 2010), anticonvulsant natural defense mechanism. Cloning of chalchones synthase
(Kaushik et al., 2010), antioxidant (Vasil’ev et al., 2010; from the moss revealed an important transition from the
Sivakumar et al., 2010; Vogel et al., 2008) activities have been chalchone synthase present in microorganisms to those
reported. They have also shown inhibition of the enzymes, present in higher plants (Nerya et al., 2004). Petunia plants, a
especially mammalian alpha-amylase (Najafian et al., 2010), chalchone synthase gene is famous for being the first gene in
cyclo-oxygenase (COX) (Zarghi et al., 2006) and monoamine which RNA interference phenomena were exist. Pigments
oxidase (MAO) (Chimenti et al., 2009). They have shown were produced in light pink or violet colour flowers
antimitotic activity too (Romagnoli et al., 2008). Chalchones produced or introduced a transgene for the chalchone
are α,β-unsaturated ketones consisting of two aromatic rings synthase. Both native and transgenic gene, express the
(ring A and B) having diverse array of substituents. Rings are enzyme and results in more deeply coloured flower known as
interconnected by a highly electrophilic three carbon α,β- phenotype. Plants which are transgenic were mottled with
unsaturated carbonyl system that assumes linear or nearly white flower led to the introduction of transgene had down
planar structure (Awasthi et al., 2009; Lim et al., 2007). They regulated or silenced chalchone synthase expression (Jiang et
contain the ketoethylenic group (–CO–CH=CH-) (Ilango et al., al., 2006). Further investigation indicates that the down
2010). Chalchones possess conjugated double bonds and a regulation is due to the post transcriptional inhibition for
completely delocalized π-electron system on both benzene chalchone synthase gene expression and increase the rate of
rings. They can be readily synthesized by the Claisen-Schmidt the messenger RNA degradation (Napoli et al., 1990).
reaction which is very easy and simple to conduct as well as In aurones, a chalchone group is enclosed with 5
inexpensive (Siddiqui et al., 2010). membered rings instead of 6 membered rings. Aurones are
the plant flavonoid which provide yellow colour to the
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ornamental plants, such as cosmos and snapdragon. There groups like 2-amino was about 40 times more active the
are two isomers of aurones i.e. E and Z configurations. Most chalchone without 2-amino group such as 3'-methooxy-4, 5-
of the aurones are in Z configuration which is most stable methylenedioxychalchone. Another amino chalchone i.e., 3-
then E configuration (Nakayama, 2002). (3-amino-4-methoxyphenyl)-1-(2,3,4-
trimethoxyphenyl)prop-2-en-1-one exhibit potent activity
Chalchone isomerase against murine melanoma B16 cells while its nitro derivative
or precursor had no activity. It was suggested that nitro
Chalchone isomerase in enzymology is an enzyme which chalchone were potentially useful for bioreductive prodrugs.
catalyzes the chemical reaction. This enzyme is also known as
chalchone-flavanone isomerase which converts chalchone Preparation of chalchones
into flavanone. The name of this enzyme is flavanone lyase or
decyclizing. It participates in the biosynthesis of flavonoid. Preparation of chalchone by aldol condensation reaction: In
Class of this enzyme is intramolecular lyase and it belongs to aldol condensation reaction the most important synthetic
the family of isomerases (Van Blokland et al., 1994). route is that it gives the large molecules by the formation of
carbon-carbon double bonds. In this the first step involves
Naringenin-chalchone synthesis the acidbase reaction mechanism between the hydrogen
located at alpha position carbonyl group and the strong base
It is also an enzyme which catalyzes the chemical reaction. such as hydroxide ion which lead to the formation of enolate
There are two substrate of this enzyme are 4-coumaroyl- CoA ion. And in the second step this enolate ion attacks carbonyl
and malonyl–CoA, whereas its 3 products are naringen group of another molecule of the same ketone and aldehyde
chalchone, CoA and carbon dioxide. Name of this class of or the other reagent present in it. Take equimolar quantity of
enzyme is 4-coumaroyl-CoA malonytransferase/cyclizing and substitute acetophenone and benzaldehydein adequate
malonyl-CoA. Other name is flavonoid synthase, chalchone quantity of ethanol. Place the reaction mixture on the
synthase, chalchone synthase, CHS and DOCS. It also magnetic spin vane for 3-5 min to make sure that the reaction
participates in the biosynthesis of flavonoid (Moustafa and mixture is thoroughly mixed and no solid remains. If solid is
Wong, 1967). remain then heat the mixture to dissolve it. Next add to the
mixture of 10 ml of a concentrate sodium hydroxide solution
Aurones drop wise by the help of burette. Stir the mixture on the
magnetic vane for 25-30 minutes. Cloudiness appears before
It is a flavonoid and a heterocyclic chemical compound the solidification of the mixture and this cloudiness disappear
(Ayabe et al., 1988). Its molecule consist of benzylidiene with an obvious precipitation which led to the formation of
linked at position 2 and a benzofuronone associated with it. chalchone, which can be sep``arated out by the filtration and
They are naturally occurring compounds mainly found in the recrystallized in ethanol (Ducki, 2007).
species of Glycyrrhiza, Humulus, Scutellaria and Angelica.
The substitution patterns or specific functional groups on the Chemical synthesis
chalchone template with particular activity profile. Mainly
functional groups exert their strong influence on the Chalchones were synthesized by the substituted
physiochemical properties of the molecule. By the great acetophenone and benzaldehyde in the presence of NaOH in
extent of functionalities present in the moiety properties like ethanol and reaction is called the Claisen- Schmidt
lipophilicity and hydrogen bonding characteristics gave good condensation. The methyl group of the substituted
activity of the compound and is associated with optimization acetophenone was deprotonated in the presence of to give
of these properties. Some functional groups are associated the enolate, which attacked the electron deficient carbonyl
with the inherent reactivities like radical quenching carbon group of benzaldehyde by the nucleophilic addition
associated with phenolic group. Addition of heteroaryl group reaction. In reaction the loss of water results in the formation
at position 5 of ring B in chalchone increased the liphophilic of chalchone. Synthesis of chalchones was synthesized by
character of the compound. Replacement of carboxylic group reacting the aldehyde and acetophenone in the presence of
in chalchone 1 by boronic group. Boronic acid is a weak and aqueous NaOH. In this reaction, in the presence of base the
exist in a unionized state at pH 7.4. Boronic moiety disrupts methyl group of acetophenone was deprotonated and forms
the salt bridge in the same way as carboxylic acid. Boronic the enolate ion which attacked on the electron deficient
chalchones were demonstrated anti-proliferative activities carbonyl carbon of aldehyde by the nucleophilic addition
and more selective against cancer cells. Chalchones having reaction which led the loss of water from the reaction and
toluenesulfonylamino side chains were identified a new class resulted in the formation of chalchone (Pavia et al., 1990).
of á-glycosidase inhibitors. Á-glycosidase enzymes play an
important role in processing glycoprotein and glycolipid Microwave assisted synthesis
inhibitors of this enzyme and are useful in anti-diabetic and
anti-obesity agents. Amino chalchone showed the The Claisen Schmidt condensation reaction was also
antiproliferative activity. Substituted chalchone with basic successfully carried out under microwave condition at the
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temperature 130° C for 3 min. the better reason for the high inhibitory activity. It is not only a conjugated linker
synthesis outcome is thermal or kinetic effects associated between A and B aromatic substituents, but it keeps
with microwave assisted synthesis. Specific microwave extended the molecular conformation. In this way, the drug
effects are also defined as the “accelerations of chemical molecule seems to bind much better to the active site, which
transformations in the microwave field that cannot be resembles a cleft on the surface of falcipain; (ii) Substitutions
achieved or duplicated by conventional heating, but on the bridge portion of the chalchone series caused a
essentially are still thermal effects”. pronounced decrease in the inhibitory activity, probably due
to steric interactions; (iii) Chloro or fluoro substitution on the
Synthesis of chalchone ring B and electron-donating substitution on the ring A
increased the antimalarial activity; (iv) Quinolinyl group in
A solution mixture of aldehyde (2 mmol) in methanol (5ml) the ring B resulted in increased activity (Motta et al., 2006).
was added drop wise in a stirred mixture of acetophenone (1 Several chalchone analogues were evaluated as inhibitors of
mmol) dissolved in 3% NaOH in methanol (20 ml). Solution malaria parasite. Inhibitory activity was determined in vitro
mixture was stirred at 28 C for 12 hours and alternatively the against a chloroquine-sensitive P. falciparum strain of
reagents of the solution was reacted under the microwave at parasites. The chalchone ‘3-(4-methoxyphenyl)-1-(4-pyrrol-
130 C for 3 min. residue was dissolved in 1M HCl and extract 1-yl-phenyl)prop-2-en-1-one’ (4) was found to be the most
it with ether after removing the solvent under reduced active with 50% inhibition concentration (IC ) of 1.61μg/ml.
50
pressure. The aqueous layer was alkaline with saturated This inhibitory concentration was comparable to a prototype
Na CO solution which gives the precipitate. This precipitate phytochemical chalchone, licochalchone, with an IC of
2 3 50
was filter out and washed with water. The product is then 1.43μg/ml. The study suggested that small lipophilic nitrogen
recrystallized in methanol and water (Ducki, 2007). heterocyclic at ring B together with small hydrophobic
functionality at ring A can enhance antimalarial activity. The
Pharmacological activities of chalchones results suggested that chalchones are a class of compounds
that provides an option of developing inexpensive, synthetic
It is an effective diuretic which removes the toxic waste from therapeutic antimalarial agents in the future (Awasthi et al.,
the body. Smooth bowel movement enhances detoxification. 2009). In order to accelerate the development of relatively
It helps to protect the organ from the destructive free radical inexpensive antimalarials that are effective against
and slows down the process of aging in human. It helps in chloroquine-resistant strains of P. falciparum, a methodology
cleansing of blood an promote blood circulation which is then for the solid phase synthesis of chalchone analogues in
helps in as follows: Reduces blood pressure, improves vision, reasonably high yields. The chalchone derivatives with
regulates blood sugar, regulates cholesterol level, improves hydroxyl functionality on one of the aromatic rings and with
memory, enhances liver and kidney functions, aids in weight some other appropriate substitutions on the other ring will
control, suppresses gastric acid secretion, beautifies skin and be even more potent as antimalarials. They found that the
hair, relieves smooth muscle spasms in the arteries and chalchone ‘1-(2-chloroquinolin-3-yl)-3-(3-
bronchial tube, functions as an antibacterial and antiviral, hydroxyphenyl)prop-2-en-1-one’ (5) was prepared (Cheng et
strengthens the immune system, reduces allergy and sinus al., 2000). A search for novel antimalarial agents from plants
problems, prevents cancer, prevents osteoporosis and also or via chemical synthesis, twenty derivatives of flavonoids
various other useful functions (Nakayama et al., 2001). and chalchones, four derivatives for each of flavones,
flavanones, chalchones, dihydrochalchones, and 3'-
Antimalarial activity chlorochalchones, and evaluated for in vitro antimalarial
activity against P. falciparum strain FCR-3 and cytotoxicity
Malaria is globally recognized as a serious problem of public against FM3A cells (a mouse mammary tumor cell). The aim
health, mainly in the tropical and subtropical regions of the was to derive predictive structure activity relationships to
world. The increase of resistant malarial parasite strains guide lead compound design. Among the chalchones tested,
represents the largest obstacle to antimalarial chemotherapy. the most active compound was 3-(3,4-dimethoxyphenyl)-1-
A series of chalchone derivatives (1,3-Diphenyl-2-propen-1- (2-hydroxy-4-methoxy-phenyl)propan-1-one (6) showing
one) as act as anti-Plasmodium falciparum agents 100% inhibition against P. falciparum at the final
(antimalarial agents) and inhibitory activity of chalchone concentration of 5.4 μg/ml (EC = 1.0 μg/ml). The compound
50
derivatives on P. falciparum cysteine protease. The observed also showed strong cytotoxicity against FM3A cells, a model
values of biological activity, high adjustment level, statistical of the host, with relatively low EC values (>3.3 μg/ml) and
50
significance and good predictive capacity, hydrophobic and low selectivity index (>3.3) indicating that the compound
steric properties seemed to play an important role in the have non-selective antimalarial activity (Lim et al., 2007).
activity. The results also indicated that molar refractivity and
molecular length have positive contributions to the activity Anticancer activity
against chloroquine-resistant (W2) Plasmodium falciparum
strains, while molecular weight against mefloquine-resistant A series of boronic chalchones were tested for their
(D6) strains as, (i) The C2–C3 double bond is essential for anticancer activity and mechanisms of action.
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O

Chalcone (1)

O
O
Cl O I
OH (HO)BH
2
Cl
O O
2a 2b

S
OH
HOOC O O
S
OH
O
O H3C
3a 3b

O OH
N Cl
O N
O
4 5

O OH
O O
O

6

Among the eight chalchone derivatives tested, the chalchone accumulation of p53 and p21 proteins and induction of

‘3,5-bis-(4-boronic acid-benzylidene)-1-methylpiperidin-4- apoptosis. Mechanistic studies showed that AM114 treatment
one’ (7) exhibited most potent growth inhibitory activity inhibited the chymotrypsin like activity of the 20S

with IC values of 1.5 and 0.6 μM in the 3-(4,5- proteasome in vitro, leading to a significant accumulation of
50
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ubiquitinated p53 and other cellular proteins in whole cells.

(MTT) assay and colony formation assay respectively. The In vitro studies showed that AM114 did not significantly
cytotoxic activity of AM114 was shown to be linked with the disrupt the interaction of p53 and murine double minute 2

5

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protein. It was noteworthy that AM114 as a single agent was (TRAIL) is a naturally occurring anticancer agent that
preferentially toxic to cells with wild type p53 expression, induces apoptosis in cancer cells and is non-toxic to normal
whereas combination of this compound with ionizing cells. Szliszka et al [8] examined the cytotoxic and apoptotic
radiation significantly enhanced the cell killing activity of effect of five chalchones in combination with TRAIL on
ionizing radiation in both wild type p53 and p53 null cells. prostate cancer cells and evaluated the cytotoxicity by the
Together, these results indicated that the boronic chalchone MTT and Lactate Dehydrogenase (LDH) assays. The
derivative AM114 induced significant cytotoxic effect in apoptosis was determined using flow cytometry with
cancer cells through the inhibition of the cellular proteasome annexin V-FITC. Their study showed that all the five tested
and provided a rationale for the further development of this chalchones: chalchone (1), licochalchone-A (11),
class of compounds as novel cancer chemotherapeutic agents isobavachalchone (12), xanthohumol (13), butein (14)
(Achanta et al., 2006). markedly augmented TRAIL-mediated apoptosis and
A series of chalchone-like agents, in which the cytotoxicity in prostate cancer cells and confirmed the
double bond of the enone system is embedded within a significant role of chalchones in chemoprevention of prostate
thiophene ring, were evaluated for antiproliferative activity cancer. They showed for the first time that chalchones
and inhibition of tubulin assembly and colchicine binding to sensitize prostate cancer cells to TRAIL-induced apoptosis.
tubulin. The replacement of the double bond with a The obtained results suggested that chalchones help
thiophene maintained antiproliferative activity and therefore anticancer immune defense in which endogenous TRAIL
must not significantly alter the relative conformation of the takes part. The TRAIL-mediated cytotoxic and apoptotic
two aryl rings. The synthesized compounds were found to pathways may be a target to the chemopreventive agents in
inhibit the growth of several cancer cell lines at nanomolar to prostate cancer cells and the overcoming TRAIL resistance by
low micromolar concentrations. In general, all compounds chalchones may be one of the mechanisms responsible for
having significant antiproliferative activity inhibited tubulin their cancer-preventive effects (Szliszka et al., 2010). A
polymerization with an IC < 2 μM. Several of these series of chalchones and evaluated them for their in vitro
50
compounds caused K562 cells to arrest in the G2/M phase of cytotoxic activity by microculture Tetrazolium Test Assay
the cell cycle. Turning to the effects of an electron-releasing method using two breast cancer cell lines MCF-7 and T47D.
group (ERG) on the phenyl moiety, they found that a p- The IC50 value was calculated at the 0.1-100 μM
methyl group caused only minor changes in antiproliferative concentration range. The assay was dependent on the activity
activity. Reduced activity occurred when the methyl of mitochondrial dehydrogenase enzymes that reduce yellow
substituent was moved from the para to ortho position. The MTT to a blue formazan product and the activity of enzyme
more active compounds were evaluated for their in vitro that is directly proportional to cell viability. The result
inhibition of tubulin polymerization and for their inhibitory showed significant cytotoxicity against both of the cell lines
effects on the binding of [3H]colchicine to tubulin (in the and value lied between 52-89 μM. All the compounds showed
latter assay, the compounds and tubulin were examined at a good cytotoxic activity and the compound ‘N-(4-hydroxy-3-
concentration of 1 μM with the colchicine at 5 μM). For (3-(2/3/4-nitrophenyl)acryloyl)phenyl) acetamide’ (15)
comparison, the antitubulin agent CA-4 was examined in showed better activity than other compounds, this may be
contemporaneous experiments as a reference compound. due to presence of nitro group in the compound (Ilango et al.,
Compounds ‘3,4,5-trimethoxyphenyl-(5-(thiophen-2- 2010).
yl)thiophen-2-yl)methanone’ (8) and ‘3,4,5-
trimethoxyphenyl-(5-p-tolylthiophen-2-yl)-methanone’ (9) Antiprotozoal activity
were the most active (IC , 0.8 μM), having twice the potency
50
of CA-4 (IC50, 1.4 μM) (Romagnoli et al., 2008). Ten chalchones were tested as leishmanicidal and
A relationship between the structural characteristic trypanocidal agents against in vitro growth of Leishmania
of synthetic chalchones and their antitumoral activity has braziliensis and Trypanosoma cruzi. The results showed that
also been studied. Treatment of HepG2 hepatocellular the positions of the substituents seem to be critical for their
carcinoma cells for 24 h with synthetic 2’-hydroxychalchones antiprotozoal activities. The results also showed that some
resulted in apoptosis induction and dose-dependent substitution-containing chalchones exhibited promising
inhibition of cell proliferation. The calculated reactivity concentration-dependent (i.e., at high concentration)
indexes and the adiabatic electron affinities using the DFT leishmanicidal and trypanocidal activities with no evidence
method including solvent effects, suggested a SAR between of a cytotoxic effect on mouse macrophages. The chalchone
the chalchone structure and the apoptosis in HepG2 cells. The (1), which has no substituent groups, revealed both
absence of methoxy substituents in the ring A of synthetic 2’- pronounced leishmanicidal and trypanocidal activities even
hydroxychalchones, showed the major structureactivity at low concentration with no evidence of a cytotoxic effect on
pattern along the series and because of this, the chalchone ‘1- mouse macrophages (Lunardi et al., 2003).
(2-hydroxyphenyl)-3-phenylprop-2-en-1-one’ (10) was
found to be the most active (Echeverria et al., 2009). Anti-inflammatory activity
Chalchones exhibit chemopreventive and antitumor effects.
Tumor necrosis factor-related apoptosis-inducing ligand
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R R
O 1
R
1
O
R CH2 O
Acetophenone Benzadehyde Chalchone

Scheme 1: Synthesis of chalchone

O CHO O O
H Br H
CHCl
HCl 3
Br
O C2H5OH O 2 O Br
Cl Cl Cl
KOH
ROH
O
OH
O
Cl

Scheme 2: Auwer’s synthesis

Chalchone derivatives contain α, β-unsaturated carbonyl the phenyl ring greatly influenced the anti-inflammatory
moi ety which is responsible for anti-inflammatory activity. A activity, with an activity order of -4-N(CH3)2>-4-OCH3>-3-
series of five chalchone derivatives and were subjected to OCH -4-OH>-3,4-OCH O->-4-OH>-3,4-(OH) . The potency
3 2 2
anti -inflammatory screening using the carrageenan-induced order of the two Cl-substituted derivatives being 4-Cl>2,4-
rat hind paw edema model. Chalchone derivatives at dose 25 Cl2. the potency order of the two NO -substituted derivatives
2
mg/ kg by oral route inhibited significantly the formation of being 3-NO >2-NO . These results indicated that the
2 2
edema and showing significant anti-inflammatory activity. character of the substitution on the ring A had a significant

The compound ‘4-fluoro/4-chloro chalchone’ (16) showed influence on the anti-inflammatory activity (Zhang et al.,
more activity comparable to standard drug indomethacin due 2010).

to -F/-Cl groups present in the compound. Hence, the anti-
inflammatory activity of chalchone derivatives was increased Antibacterial activity

when electron withdrawing groups (EWG) were present on
the chalchone moiety (Yadav et al., 2010). In an effort to A series of new coumarin derivatives containing a chalchone
develop potent anti-inflammatory agents, a series of moiety and evaluated for possible anti-oxidant and
substituted chalchone derivatives was synthesized and antibacterial activities. The coumarinic chalchone ‘4-

evaluated for anti-inflammatory activity through in vivo hydroxy-3-(3-p-tolylacryloyl)-2Hchromen-2-one’ (18) had
inhibition assay monitoring of their ability to inhibit xylene- been found to be the most active (IC = 2.07 μM). The
50
indu ced ear edema in mice. Some of the tested compounds derivatives were screened in vitro for their antibacterial
exhibited significant activity, and the compound ‘3-(4- activity against Gram +ve bacteria, S. aureus using the paper
chlo rophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one’ disc diffusion method for the antibiotic sensitivity technique.
(17) showed the highest anti-inflammatory activity (68% It showed that the activity against bacteria is moderate, but
inhibition) comparable with or even slightly more potent in addition, it was clearly demonstrated that this kind of

than the reference drug ibuprofen (53%). Furthermore, the compound could be an antibacterial agent. The activity
structure-activity relationship of these substituted chalchone depends on its chemical composition. The moderate active
derivatives demonstrated that the substituted 2’,4’- antibacterial effects observed showed that this kind of
dihydroxychalchone derivatives was stronger than that of 4’- compound could be an antibacterial agent (Hamdi et al.,
hydroxychalchone. The position of the substituted group on 2010).
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ISSN: 2410-9649 Asif / Chemistry International 2(1) (2016) 1-18 iscientic.org.
O
O
O
S S
H OH
O
B N B
OH CH3 H O
7 8

O
R
4
O
S R3
O
R
2
O OH O R1
9 10

OH
OH
HO OH
HO
O
O O
11 12

O
OH OH
HN
H OH
H OH
OH
R
O O
OH O OH O
13 14 15 R=o-/m/p-NO
2

O HO Cl O OH
R
OH O O O
R=4-F/4-Cl 16 17 18

O O
N N
N
N
O O
19 20
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ISSN: 2410-9649 Asif / Chemistry International 2(1) (2016) 1-18 iscientic.org.
O O
NO
2
Br-
S N+
S
21 22

O
Br- O
N+
NO2 OH O
23 24

O O
O O
O
O O
25 26

OH O
OH
O S OH
27 28

OH
OH
HO O
HO O OH
OH
OH O OH O
29 30

O
HO
HO O OH
HO
OH
OH O HO
31 32

O
O
O
S N-
N N+
O H N
33 34

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ISSN: 2410-9649 Asif / Chemistry International 2(1) (2016) 1-18 iscientic.org.

O Cl HO Cl
OH O OH O
35 36

A series of chalchone derivatives were evaluated for lipophilic or hydrophobic groups containing single or
ant ibacterial activity. All the compounds were screened for multiple nitrogen or oxygen in an acetophenone ring of
their antibacterial activities against four different bacterial chalchone have potent inhibitory effects on motility, viability,
str ains S. aureus, Bacillus subtilis, Escherichia coli, and and GST activity of the parasite, supporting the antifilarial
Pseudomonas aeruginosa. Dimethyl formamide was used as a efficacy of chalchone. The most significant effect on parasites
sol vent, and ciprofloxacin as the standard drug. QSAR was exerted by methoxy-substituted chalchones, suggesting
equation revealed that selected electronic, steric and that these substituents can be used for further studies against

lipophilic parameters had good correlation with antibacterial filariasis (Awasthi et al., 2009).
activity. The findings suggested that the chalchone

framework is an attractive template for structure Antifungal Activity
optimization to achieve higher potency, lower toxicity, and a
wid er spectrum of antibacterial activity. Although more With the aim of developing potential antifungals, a series of
hydrophobic surface areas tend to favor antibacterial activity chalchones incorporating sulfur either as part of a hetero-
and Gram -ve and Gram +ve selectivity, the increase in the aromatic ring (thiophene) or as a side chain (thiomethyl
size of molecules may lead to a decrease in the antibacterial group) and tested for their in vitro activity. Some of the
activity. The hydrophobic surface area should be increased compounds showed appreciable activity against a

without increasing the molecule size. An increase in the fluconazole-sensitive and fluconazole-resistant strain with
dipole and quadrupole moments leads to charge separation the chalchone ‘3-(4-(methylthio)phenyl)-1-(thiophen-2-
wh ich increases biological activity (Bhatia et al., 2009). yl)prop-2-en-1-one’ (21) exhibiting the highest activity.
Maximum activity was obtained with p-fluoro substitution on
Antifilarial activity ring A. Activity was decreased with increasing halogen size.
Presence of p-methoxy or hydroxy groups at the o-, m- or, p-
Chalchone derivatives were evaluated for their antifilarial position also resulted in good activity while the p-nitro group
activity on Setaria cervi using glutathione-S -transferase as well as the bulky p-phenyl substitution decreased activity
(GST) enzyme as a drug target. The compounds ‘1-(4- as compared with the unsubstituted compound. The m- and
benzotriazol-1-yl-phenyl)-3-(4-methoxyphenyl)prop-2-en-1- p- disubstitution with methoxy led to increased activity while
one’ (19) and ‘3-(4-methoxy phenyl)-1-(4-pyrrolidin-1-yl- again the p-phenyl-substituted compounds exhibited
phenyl)prop-2-en-1-one’ (20) showed a significant considerably decreased activity. All compounds with the
suppression in GST activity of adult female parasite extract at bromo thiophene ring in place of ring B exhibited less activity
3 μM concentration in vitro. However, GST activity was compared with those with the unsubstituted thiophene ring.
detected along with depletion in GSH level. More or less, all Bromine substitution on the thiophene ring B decreased
compounds showed a paralyzing effect on the motility and antifungal activity. Compounds with unsubstituted thiophene
viability of parasites, ranging from 25% to 97% inhibition. ring B and thiomethyl substitution at the p- position of ring A,
The compounds ‘1-(4-benzotriazol-1-yl-phenyl)-3-(4- exhibited good antifungal activity. Highest activity was found
methoxyphenyl) prop-2-en-1-one’ and ‘3-(4- when both thiophene ring B and thiomethyl substitution at
methoxyphenyl)-1-(4-pyrrolidin-1-ylphenyl)prop-2-en-1- ring A were present together in the chalchone 3-(4-
one’ exhibited major irreversible effects on viability and (methylthio)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one (Bag
resulted in parasite death and also inhibited the GST activity et al., 2009).
by 84-100% in vitro. They reported for the first time the Aantifungal evaluation and study on substituent
antifilarial activity of chalchones on GST of adult parasites. effects of several chalchones. A lot of genetically defined
This study also strengthened their previous findings where strains belonging to different yeast genera and species,
GST was reported as a potential drug target for antifilarials. namely Saccharomyces cerevisiae, Hansenula polymorpha and
However, this was a preliminary in vivo and in vitro study in Kluyveromyces lactis, were used as test organisms.
which living worms were incubated with chalchones. The Concerning the mode of the antifungal action of chalchones it
results of 4-chloro and 4-methoxy-substituted chalchones was shown that DNA was probably not the main target for
strongly supported that small- and medium-sized highly the chalchones. It was revealed that the yeast’s intracellular
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