CHALCONE

Introduction:

Chalcone is an important secondary metabolite, belonging to the family of flavonoids and

isoflavonoids. Chalcones are found in many plant derivatives and have various
cytoprotective And modularity functions. They are found in flowers, fruits, leaves, stems,
and all the other parts of the plant, Initially, chalcones were manufactured in the research
lab in the late 1800s. Chalcone is a privileged structure composed of two aromatic rings that
are linked through a three-carbon-alpha beta-unsaturated carbonyl system i.e., 1,3-
diphenyl-2-propen-1-one derivative.
Chalcones have a wide variety of therapeutic activities like anticancer,anti-ulcer,
antimalarial, antibiotics, antihypertensive, etc. Stereochemically, Chalconecan exists in both
trans (E) and cis (Z) isomers, but the Z conformer is most unstable due to the steric effects of
ring A with the carbonyl group. In chalcones, two aromatic rings and the electrophilic α,β-
unsaturated carbonyl system are in continuous conjugation.
The chalcone scaffold also known as chalconoid, exists in cis and trans isomers of which
trans isomer is thermodynamically more stable. Chalcones with few structural modifications
can exhibit fluorescent properties.

SYNTHESIS OF CHALCONE:

1.Claisen-schmidt reaction
Chalcone is synthesized by Claisen-Schmidt condensation, which involves the cross-aldol
condensation of aldehydes and ketones with a base or acid catalyst followed by a
dehydration reaction. In the laboratory, we can synthesize using the Claisen-Schmidt
reaction by reacting acetophenone compounds or their derivatives with benzaldehyde or
their derivatives using strong bases such as NaOH, KOH, Ba(OH)2, LiOH.2H2O, or NaH as
catalysts in polar solvents. Other catalysts that can also be used are sodium phosphate and
aluminum-magnesium hydroxide hydrate. Whereas acid catalysts are usually used such as
HCl, AlCl3, BF3-Et2O, TiCl4, and RuCl3.[1] It is possible to synthesize a wide range of
chalcone derivatives by treating aromatic aldehydes with aryl ketones in the presence of an
appropriate amount of condensing agents.[2]
2. Meyer-Schuster Rearrangement
Mayer-Schuster rearrangement is also employed to synthesize chalcones from different
reactants such as propargyl alcohol, propargyl acetate, and siloxypropyne with different
mechanistic arrangements. The simple 1,3-shift of hydroxy functional group in propargylic
alcohols is quite different from Rupe rearrangement. It employed various bases namely
trimethylamine, and KOH [95], and the catalyst was also used such as 1,2,3-triazole-
coordinated PPh3-Au (TA-Au).

3. Oxidation of Benzylic alcohol

The synthesis of chalcone can be done via the conversion of benzylic alcohols into
the corresponding ketone in the presence of an oxidant such as hydrogen peroxide.[3]

4. Coupling reactions
The design of a new class of chalcones with various substituents using conventional
methods sometimes leads to undesirable products besides preferred products which makes
challenging to chromatographic separation. Hence, currently, new strategies such as cross-
couplings (Scheme 8) with transition metal catalysts such as Julia-Kocienski olefination,
Witting, and Friedel-Crafts acylation have been used for the synthesis of potent
pharmaceutical molecules including chalcones.[4]

5. Debromination of Vicinal Dibromides

This method involved the elimination reaction (E2) of vicinal halogen such as bromide.
Debromination of vic-bromides to form of α, β-unsaturated compounds of chalcone with
Hantzsch ester and white light irradiation LED to acquire the 80% yield. In the absence of
the Hantzsch ester, base, and light irradiation, their action never gave the desired product.
[3]

6. Friedel-Crafts acylation
Highly substituted chalcones were prepared by using this technique but, it is a very
infrequently used
method. Acylation of aromatic ethers with cinnamoyl chloride in the presence of strong
Lewis acid catalyst AlCl3 yields the chalcones.[4]

UV spectrum of chalcone.
Generally, it is known that the chalcones absorb light in the UV region and transmit to the
remaining region (56-59). The UV spectrum of chalcones consists of two essential
absorption bands: band I and relatively a minor band, band II. In chalcones, a band I usually
appears in 340-390 nm, although a minor inflection or peak often occurs at 300-320 nm.
Band II appears in 220-270 nm. Increasing oxygenation generally causes bathochromic
shifts, particularly in the band I. The addition of an unsubstituted 2’-hydroxyl group to the
chalcone causes a marked effect on the spectrum e.g. 2’,4’,4-trihydroxychalcone (λmax 370
nm), 4’,4-dihydroxychalcone (λmax 348 nm). Glycosylation or methylation of 2’-position
leads to 15-20 nm hypsochromic shift.[5]

Fluorescent property of chalcone

Because of its conjugated system, chalcones with proper electron-pulling and electron-
pushing functional groups on the benzene ring(s) can be fluorescent making them potential
chemical probes for mechanistic investigations and imaging/diagnosis.[6] Chalcones with
appropriate substituents have been reported to be intrinsically fluorescent, potentially
avoiding such a disadvantage as fluorescent probes. The fluorescence of the chalcones is
highly sensitive to structural and environmental factors. Environmental factors influencing
fluorescence included solvent polarity, pH, and the interactions of the chalcones with
proteins and detergents.[7]
PHARMACOLOGICAL ACTIVITY OF CHALCONE:
1. Antimicrobial properties of chalcone
The antibacterial activity of natural chalcones is well documented. The antibacterial effects have
been related to the ability of the a, unsaturated ketone moiety of the compounds to react with
cellular nucleophiles like the accessible thiol groups in essential proteins.

Among natural chalcones, pinocembrin chalcone, a compound from Helichrysum trilineatum,

showed to have antibacterial activity against the human pathogen Staphylococcus aureus
Licochalcone A—a retrochalcone isolated from Glycyrrhiza species—showed an antibacterial effect
against Gram-positive bacteria, especially against Bacillus species. For example, it inhibited in vitro
the vegetative cell growth of B. subtilis in a concentration-dependent manner, which become
complete at 3 microgram/ml concentration. Licochalcone A showed in vitro inhibitory effects on
human pathogenic Mycobacteria and Legionella species. For instance, M. tuberculosis, M. bovis and
BCG were inhibited by 20 mg/l, while L. bozemanii, L. dumoffii, and other species were inhibited at
1–4 mg/l concentrations. This data indicates that licochalcone A might be of interest as a new class
of antibacterial drug in the treatment of severe lung infections.

The dihydrochalcones isolated from Piper aduncum, asebogenin, and piperanduncin B displayed the
greatest activity towards Bacillus subtilis and Micrococcus luteus.

Some more examples are:

Compounds isolated from DaleVersicolor exhibited direct or synergistic activity toward S. aureus and
the opportunistic pathogen Bacillus cereus. Prenyl- or geranyl-substituted chalcones from A. keiskei
[isobavachalcone, 4-hydroxyderricin, xanthoangelol, and xanthoangelol] were found to inhibit Gram-
positive bacteria. . Panduratin A, a dihydrochalcone from Boesenbergia pandurata possesses high in
vitro activity against biofilm-producing clinical Enterococcus strains, including organisms resistant to
other antimicrobials.

2. Antifungal properties of chalcone:

chalcones have demonstrated toxicity not only towards bacteria but fungi as well. Compounds
isobavachalcone and isolated from Maclura tinctoria showed inhibitory activity against Candida
albicans (with IC50 of 3 and 15 lg/ml, respectively). Isobavachalcone also showed an antifungal effect
on Conccus neoformans (IC50 of 7 lg/ml). The crude methanolic extract of Zuccagnia punctata
consisting of compounds 3 and 10 was active toward the fungal pathogens of soybean (Phomopsis
longicolia and Colletotrichum truncatum).  The antimicrobial property of chalcones is due to the
presence of a reactive unsaturated keto function in the molecule while antifungal properties
are present in some phenolic synthetic chalcones. Chalcones inhibit β(1,3)-glucan and chitin
synthases, enzymes, that catalyze the biosynthesis of β(1,3)-glucan and chitin polymers of
the fungal cell wall, respectively.[8]

Antimycotic activity of natural and synthetic chalcones is also frequently associated with the
inhibition of the conversion of tubulin into microtubules. Compounds isolated from M. Philippines—
exhibited antifungal activity against C. neoformans and Aspergillus fumigatus, respectively.
Antimicotic activity of natural and synthetic chalcones is also frequently associated with inhibition of
conversion of tubulin into microtubules.

3. Antiviral properties of chalcone:

Alkyl-substituted chalcones from A. keiskei were found to be reversible noncompetitive inhibitors of

the influenza virus neuraminidase (NA) enzyme. 2-hydroxychalcone barely inhibits the tomato
ringspot virus (ToRSV) replication in Chenopodium quinoa. Hydroxy and methoxy substituted
chalcone derivatives had been investigated against ToRSV infection.  This study demonstrated that
the antiviral activity was activated by hydroxylation of the A-ring at 2‘,3‘, and 4‘ positions and B-ring
at C-4‘, suppressed by hydroxylation at C-5‘, and reduced by methoxylation of the B-ring.
Another attention-grabbing reality was that licochalcones A and B, similarly to 3,4-tetrahydroxy-2-
methoxychalcone suppressed the 12-o-tetra-decanoyl phorbol-13-acetate (TPA)-
induced HIV promoter. These antiviral effects were thought to result from multiple biological
effects similar to the inhibition of poly(ADP-ribose) glycohydrolase PARG and superoxide radical-
scavenging. xanthohumol was an effective and selective inhibitor of HIV-1 and may represent a novel
promising therapeutic agent for HIV-1 infection.[9]

xanthohumol
 4. Tumor cell cytotoxic activity of chalcone derivatives.

A variety of chalcone derivatives exhibited cytotoxicity towards a number of different tumor cell
lines. Isoliquiritigenin is one of the most frequently tested compounds. Isoliquiritigenin and butein
markedly suppressed the growth of B16 melanoma cells and induced cell death. In cells treated with
the chalcones condensation of nuclei and fragmentation of nuclear DNA, typical phenomena of
apoptosis were observed. Xanthohumol and dehydrocycloxanthohumol caused a dose-dependent
decrease in the growth of human breast cancer (MCF7), colon cancer, and ovarian cancer cells in s
an antiproliferative agent, xanthohumol may have potential chemopreventive activity
against breast and ovarian cancer in humans.

Isoliqiritigenin

Butein

Flavokawain B, a chalcone from the plant genus pricei, significantly suppressed the

expansion of carcinoma cells. It exerted its apoptotic action through ROS generation and GADD153
up-regulation, which result in mitochondria-dependent programmed cell
death characterized by unharness of cytochrome c and translocation of Bak.

Flavokawain

Based on the studies, chalcones are highly multifunctional and their targets cover the majority of the
actions of tumor cells, as well as growth, proliferation, invasion, and metastasis.
 5. Chemopreventive properties of natural chalcones
Chemoprevention is an approach that seeks to arrest or reverse the process of carcinogenesis
through the use of pharmacological agents. The chemopreventive role of chalcones may be in
connection with various actions, such as antioxidant properties influencing metabolic enzymes and
anti-inflammatory effects. Antioxidants are important for human health protection. They can reduce
or prevent oxidative stress, which is involved in aging, inflammation, cancer, diabetes,
atherosclerosis, ischemic injury, and neurodegenerative diseases. Free radicals are involved in
different stages of carcinogenesis .
Structure-activity relationship (SAR) has shown that the presence of hydroxy and methoxy groups in
the rings A and B appear to be important structural features in the antioxidant activities of
chalcones.
SAR studies on the antioxidant effect of dihydrochalcones showed that the antioxidant activity of the
compounds depends on the presence of a hydroxyl group at the C2 and C4 positions and that there
is a correlation between ionization potential and O–H-bond dissociation enthalpy and peroxynitrite
scavenging activity and lipid peroxidation.
Broussochalcone A was found to suppress production in a concentration-dependent manner in
lipopolysaccharide (LPS)-activated macrophages. It also showed strong inhibition of arachidonic
acid (AA)-induced platelet aggregation.

Broussochalcone A
Xanthohumol effectivelymodulated activity of enzymes involved in carcinogenesis, metabolism and
detoxification. It was able to scavenge reactive oxygenspecies, including hydroxyl and peroxyl
radicals, and to inhibit the production of superoxide anion radical and nitric oxide by suppressing
expression of inducible NOsynthase
Flavokawain A , a major constituent of chalcones derived from kava extracts, indicated anti-
inflammatory activity by suppressing LPS-induced expression of pro-inflammatory mediators via
blockage of NF-jB—AP-1—JNK/p38 MAPK signaling pathways in murine macrophages.

6. Antidaibetic property of chalcone

Several synthetic chalcones have shown an antihyperglycemic effect comparable to the antidiabetic
drug tolbutamide. 4-hydroxyderricin and xanthoangelol chalcones from the Japanese herb A. keiskei
showed strong insulin-like activities via a pathway independent of peroxisome proliferator-activated
receptor activation.

4-Hydroxyderricin

Xant
hoangelol

Conclusion:

The article presents an overview of naturally occurring chalcones focusing on their plant sources and
biological activities. Several chalcone-containing plants have been used in traditional medicine
throughout the world, this phytochemical and pharmacological investigation resulting identification
of chalcones as biologically active compounds provides and supports the use of these plants in
ethnomedical practice.
References:

1.https://aip.scitation.org/doi/pdf/10.1063/5.0042002#:~:text=Chalcone%20is%20synthesized
%20by%20Claisen,in%20flavonoid%20biosynthesis%20%5B2%5D.

2. https://pubs.acs.org/doi/10.1021/acsomega.2c01779

3. Recent Synthetic Methodologies for Chalcone Synthesis (2013-2018)

Author(s): Saba Farooq and Zainab Ngaini*

Volume 6, Issue 3, 2019Page: [184 - 192]DOI: 10.2174/2213337206666190306155140

4. Article in Environmental Chemistry Letters · January 2020

DOI: 10.1007/s10311-019-00959-w

5.https://www.researchgate.net/publication/290975602_Spectral_properties_of_chalcones_II

6.Chem Rev. 2017 June 28; 117(12): 7762–7810. doi:10.1021/acs.chemrev.7b00020.

7. Characterization of the Fluorescence Properties of 4-Dialkylaminochalcones and Investigation of

the Cytotoxic Mechanism of Chalcones Bo Zhou 1, Peixin Jiang 2, Junxuan2, Chengguo Xing 1
Affiliations expand PMID: 27214789 DOI: 10.1002/ardp.201500434

8.: Gupta D, Jain DK. Chalcone derivatives

as potential antifungal agents: Synthesis, and antifungal activity.

J Adv Pharm Technol Res 2015;6:114-7.

9.Pharmacia 67(4): 325-337

doi: 10.3897/pharmacia.67.e53842 [https://pharmacia.pensoft.net/article/53842/list/8/].