Antimalarial Activity of Newly Synthesized Chalcone Derivatives In Vitro

Article abstract of DOI:10.1111/j.1747-0285.2012.01383.x

Twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC₅₀ (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-1-one with IC₅₀ of 1.1μg/mL, while that of the natural phytochemical, licochalcone A is 1.43μg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy-substituted chalcones. Furthermore, 3, 4, 5-trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity.

Full text of DOI:10.1111/j.1747-0285.2012.01383.x

ª 2012 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2012.01383.x
Chem Biol Drug Des 2012; 80: 340–347
Research Letter
Antimalarial Activity of Newly Synthesized
Chalcone Derivatives In Vitro
Neesha Yadav1, Sandeep K. Dixit1, Amit
Bhattacharya2, Lokesh C. Mishra2, Manish
Sharma2, Satish K. Awasthi1,* and
Virendra K. Bhasin2,*
derivatives are now the only drugs available for effective cure of
malariab. Synthesis of artemisinin is difficult and expensive. Resis-
tance to artemisinin and its derivatives will also emerge sooner or
later. Thus, there is an urgent need for alternate synthetic, stable,
affordable, and potent antimalarial compounds, which could be
developed as antimalarial drugs for mass administration.
1Department of Chemistry, University of Delhi, Delhi 110007, India
2Department of Zoology, University of Delhi, Delhi 110007, India
*Corresponding author: Virendra K. Bhasin,
virendrabhasin@hotmail.com, Satish K. Awasthi,
awasthisatish@yahoo.com
Naturally occurring chalcones (1,3-diaryl-2-propen-1-one) are the key
intermediates for various plant metabolites. They are biologically
active compounds with known antibacterial (2,3), antifilarial (4), an-
tiviral (5,6), antileishmanial (7), and cytotoxic (8,9) activities. Licoch-
alcone A, a natural compound isolated from Chinese licorice roots,
has shown potent antiplasmodial activity (10). The simple structure
and low-cost synthesis of chalcones have attracted the attention of
chemists to develop different analogs of this novel scaffold for vari-
ous infectious diseases including malaria. In continuation to our ear-
lier work with potent antimalarial chalcone derivatives (11–13), we
have further synthesized 27 chalcones with new substituents on the
basic scaffold and evaluated their antiplasmodial activity against
human malaria parasite P. falciparum in vitro.
Twenty-seven novel chalcone derivatives were
synthesized using Claisen-Schmidt condensation
and their antimalarial activity against asexual
blood stages of Plasmodium falciparum was deter-
mined. Antiplasmodial IC50 (half-maximal inhibi-
tory concentration) activity of
a
compound
against malaria parasites in vitro provides a good
first screen for identifying the antimalarial poten-
tial of the compound. The most active compound
was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimeth-
oxy-phenyl)-propen-1-one with IC50 of 1.1 lg/mL,
while that of the natural phytochemical, licochal-
cone A is 1.43 lg/mL. The presence of methoxy
groups at position 2 and 4 in chalcone derivatives
appeared to be favorable for antimalarial activity
as compared to other methoxy-substituted chal-
cones. Furthermore, 3, 4, 5-trimethoxy groups on
chalcone derivative probably cause steric hin-
drance in binding to the active site of cysteine
protease enzyme, explaining the relative lower
inhibitory activity.
Methods and Materials
Compounds 1–27 (Table 1) were synthesized by base-catalyzed Cla-
isen-Schmidt condensation (14,15) using appropriate substituted
acetophenone with commercially available methoxy benzaldehyde
(Figure 1). Theoretically, E and Z geometric isomers are equally
formed during the reaction. However, NMR analysis showed the
presence of E form only in all compounds. Yields were variables
with approximately in between 50% and 70% and were not opti-
mized. Melting points were recorded by classical approach using
Key words: antimalarial activity, Chalcone synthesis, in vitro, Plas-
modium falciparum
1
capillary methods and were reported uncorrected. H NMR spectra
given were recorded on Brucker AMX300, Brucker AMX400, Jeol
AMX 500 spectrometer; chemical shifts are expressed in d (ppm)
relative to tetra methyl silane. All spectra were recorded in CDCl3.
Infrared (IR) spectra were recorded on Perkin Elmer Fourier trans-
form (FT-IR) in KBr pellets and are expressed in per centimeter. All
mass were recorded on Macromass G. Elemental analysis was per-
formed on Elementar analysensysteme GmbH VaroiE (CHNSO Labo-
ratory, University Science Instrumentation Centre, University of
Delhi). Results were within €0.4% of predicted values for all com-
pounds. Analytical thin-layer chromatography (TLC)s were run on
commercially precoated plates (Merck, silica gel 60 F254, Merck
specialities Pvt. Ltd., Mumbai, India) and visualized under UV lamps
(254 nm). The progress of the reactions was monitored by TLC with
CHCl3 and CH3OH as eluent. Initially, we synthesized the following
Received 28 September 2010, revised 14 January 2012 and accepted
for publication 7 March 2012
Malaria is a public health concern in countries that are endemic to
this disease. These countries constitute over one-fifth of the world
population. Approximately 1 million people die annually owing to
Plasmodium falciparum malaria infections, majority of them in
resource poor settingsa (1). Chloroquine, a synthetic 4-aminoquino-
line, is inexpensive, and till recently widely recommended for its
effective malaria treatment. Emergence of chloroquine-resistant
strains of P. falciparum has caused a major setback to en masse
treatment for malaria and control programs. Artemisinin and its
340

Antimalarial Activity of Novel Chalcone Derivatives
Table 1: Antimalarial activity of chalcones.
R2
O
2'
5'
β
(E)
1
R3
R4
3'
4'
1'
α
6
6'
R4'
R5
S. No.
R4¢
R2
R3
R4
OCH3
R5
H
Mean IC50 € SEa (lg ⁄ mL)
1
H
H
6.92 € 0.25
1''
N
6''
5''
2''
3''
4''
2
H
H
OCH3
H
6.9 € 0.15
1"
N
N
2''
6''
5''
3''
4''
CH3
3
4
OCH3
OCH3
H
H
OCH3
OCH3
H
H
2.37 € 0.22
7.68 € 0.15
1"
N
5"
2"
3"
4"
1''
N
6''
5''
2''
3''
4''
5
OCH3
H
OCH3
H
2.95 € 0.21
1"
N
6"
5"
2"
3"
O
4"
6
7
8
OCH3
OCH3
OCH3
H
H
H
OCH3
OCH3
OCH3
H
H
H
5.98 € 0.22
6.7 € 0.21
3.38 € 0.06
1"
N
N
N
5"
2"
2"
2"
4"
3"
1"
5"
4"
N
3"
1"
N
5"
N
3"
4"
Chem Biol Drug Des 2012; 80: 340–347
341

Yadav et al.
Table 1: Continued
S. No.
R4¢
R2
R3
H
R4
R5
H
Mean IC50 € SEa (lg ⁄ mL)
9
OCH3
OCH3
1.1 € 0.06
7''
1''
N
6''
2''
N
5''
4''
7''
3''
10
OCH3
H
OCH3
H
7.22 € 0.29
1''
N
N
6''
5''
2''
N
4''
3''
11
12
OCH3
OCH3
H
H
H
H
OCH3
OCH3
5.53 € 0.24
6.13 € 0.18
1"
N
N
5"
4"
2"
3"
1''
6''
5''
2''
3''
4''
N
13
OCH3
H
H
H
H
OCH3
10.1 € 0.31
1"
2''
6''
5''
3''
N
CH3
4''
14
OCH3
OCH3
3.26 € 0.29
1"
N
6"
5"
2"
3"
O
4"
15
16
OCH3
OCH3
H
H
H
H
OCH3
OCH3
6.36 € 0.12
1"
N
5"
2"
4"
7''
3"
12.73 € 0.32
1''
N
N
N
6''
5''
2''
4''
3''
17
H
OCH3
OCH3
H
2.91 € 0.08
1"
N
5"
4"
2"
3"
342
Chem Biol Drug Des 2012; 80: 340–347

Antimalarial Activity of Novel Chalcone Derivatives
Table 1: Continued
S. No.
R4¢
R2
H
R3
R4
R5
H
Mean IC50 € SEa (lg ⁄ mL)
18
OCH3
OCH3
4.96 € 0.56
1"
N
N
2''
6''
5''
3''
4''
CH3
19
H
OCH3
OCH3
H
5.16 € 0.32
1"
N
6"
5"
2"
3"
O
4"
20
21
22
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
6.28 € 0.09
7.34 € 0.27
5.85 € 0.07
1"
N
5"
2"
2"
2"
4"
3"
1"
N
5"
4"
N
3"
1"
N
N
5"
N
3"
4"
7''
23
24
H
H
OCH3
OCH3
OCH3
OCH3
H
H
5.04 € 0.31
1''
N
6''
2''
N
5''
4''
7''
3''
3.5 € 0.23
1''
N
N
6''
5''
2''
N
4''
3''
25
H
H
OCH3
OCH3
OCH3
4.7 € 0.21
7.6 € 0.67
343
1"
N
2''
6''
5''
3''
N
4''
CH3
26
OCH3
OCH3
OCH3
7''
1''
N
6''
5''
2''
N
4''
3''
Chem Biol Drug Des 2012; 80: 340–347

Yadav et al.
Table 1: Continued
S. No.
R4¢
R2
H
R3
R4
R5
Mean IC50 € SEa (lg ⁄ mL)
27
OCH3
OCH3
OCH3
8.15 € 0.95
7''
1''
N
N
N
6''
5''
2''
4''
3''
aStandard error (N = 3).
Figure 1: General procedure
for the synthesis of chalcone
derivatives.
nine substituted acetophenones, which served as intermediate for
the synthesis of 27 chalcone derivatives, and the biological activi-
ties of these 27 novel compounds are presented in Table 1.
to draw closer to room temperature and stirred for 18–20 h.
Appearance of off-white to yellow solids in solution within few
minutes to several hours indicated successful synthesis of chalcone.
The product was filtered and washed with ice-cold water
(3 · 10 mL). The title compound was purified by column chromatog-
raphy using chloroform, methanol as eluent and characterized by
NMR. The remaining substituted 1,3-diarylpropenone was prepared
by the similar method using appropriate reactants.
Procedure for the synthesis of 4-benzimidazole
acetophenone
To a solution of 4-fluoroacetophenone (2.58 mL, 20 mmol) in 5 mL
dry DMF, benzimidazole (2.36 g, 20 mmol) and K2CO3 (3.45 g,
25 mmol) were added. The reaction mixture was refluxed for 18 h
at 110 ꢀC. On the completion of the reaction, as checked by TLC,
the DMF was evaporated in vacuo and redissolved into water
(50 mL). The aqueous solution was extracted with chloroform
(3 · 50 mL), and the combined organic solution was dried over
anhydrous Na2SO4 and evaporated in vacuo to yield crude 4-benz-
imidazole acetophenone. The intermediate was purified by column
chromatography using silica gel (2:98 v ⁄ v MeOH-CHCl3) and charac-
terized by Macromass G and NMR prior to use in the next step.
The remaining intermediates were prepared by the similar method.
In vitro antimalarial assay
Stock culture of a chloroquine-sensitive malaria parasite P. falcipa-
rum 3D7 strain and a chloroquine-resistant P. falciparum RKL 303
strain was continuously maintained in vitro using the candle jar
method of Trager and Jensen (16). The P. falciparum strains 3D7
and RKL 303 were obtained from International Center for Genetic
Engineering and Biotechnology (ICGEB), New Delhi, and National
Institute of Malaria Research (NIMR), New Delhi, respectively. Com-
plete culture medium contained RPMI-1640 (with glutamine but
without bicarbonate), HEPES buffer, 40 mg of gentamycin, sterile
5% sodium bicarbonate and was finally supplemented with 10%
pooled B+ serum. The parasites were maintained on B+ human red
blood cells. The culture parasitemia was kept between 1% and 5%
with hematocrit of 5%.
Procedure for the synthesis of (4-benzotriazole
-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-
1-one
NaOH pellet (100 mg) was added to a stirred solution of substituted
4-benzotriazole acetophenone (237.09 mg, 1 mmol) and 2,4-dimeth-
oxybenzaldehyde (166.17 mg, 1 mmol) in minimum amount of meth-
anol (3–5 mL) at ice-cooled flask. The reaction mixture was allowed
All the newly synthesized chalcones were individually dissolved in
DMSO (Sigma-Aldrich, St. Louis, Mo, USA) to obtain stock solution
344
Chem Biol Drug Des 2012; 80: 340–347

Antimalarial Activity of Novel Chalcone Derivatives
of 1 mg ⁄ mL. The stock solution was diluted with antibiotic-free
complete medium on the day of experiment to obtain the desired
concentrations for each test compound. The final concentration of
DMSO present in the experiment had no effect on parasite growth.
We synthesized various substituted chalcones using Claisen-Schmidt
condensation method (Table 1). Fluoro function in 4-fluoroacetophe-
none was substituted systematically with pyrrole, imidazole, benz-
imidazole, benzotriazole, pyrrolidine, morpholine, piperidine, and N-
methyl piperazine. These various substituted acetophenones were
condensed with methoxy-substituted aldehyde to give rise to vari-
ous chalcones. Moreover, to broaden our studies, we included all
possible combination of methoxy at different positions in benzalde-
hyde. We chose five series, viz. 4-methoxy; 2, 4-dimethoxy; 2, 5-di-
methoxy; 3, 4-dimethoxy; and 3, 4, 5-trimethoxy benzaldehyde. All
compounds were analyzed by 1H NMR, 13C NMR, mass spectros-
copy, and FT-IR for their authenticity prior to their antiplasmodial
evaluation (Details provided as Supporting Information). IC50 values
of all the compounds were determined against chloroquine-sensitive
strain (3D7) of P. falciparum (Table 1). Ten compounds showed IC50
values <10 lg ⁄ mL.
Fifty percent inhibitory concentration (IC50) of individual compound
against P. falciparum was determined using dose–response assay in
24-well tissue culture plates (BD Falconꢁ) in triplicates (17). Syn-
chronous parasites were prepared (18) and challenged to graded
concentration of compounds by the modified 48-hour test (19). Med-
ium of each well was changed after 24 h with or without com-
pound. At the end of 48 h, Giemsa stained slides were prepared
from each test-well and examined for number of parasites in ran-
dom adjacent microscopic fields, equivalent to about 3000 erythro-
cytes at 1000· magnification. Percentage inhibition of parasitemia
in relation to control was calculated. Semilog concentration–
response graph of percent parasitemia inhibition was plotted for
each individual compound to determine IC50 values using Microsoft
Excel. Figure 2 shows the dose–response curve of Licochalcone A,
and compound 9 against P. falciparum strain (3D7).
In 4-methoxy series, we evaluated two compounds with piperidine
and N-methyl piperazine having reasonably good activity. Earlier, we
have reported efficient antiplasmodial activity of both pyrrole and
methoxy substituents on acetophenone and benzaldehyde with IC50
of 1.6 lg ⁄ mL, comparable to phytochemical licochalcone A (IC50 of
1.43 lg ⁄ mL) against chloroquine-sensitive 3D7 strain (12). In vitro
sensitivity of P. falciparum RKL 303 strain to licochalcone A
was 1.82 lg ⁄ mL.
Results and Discussion
Plasmodium is an intracellular parasite for most part of its life cycle
in the vertebrate host. The intraerythrocytic parasite grows and
reproduces asexually by converting the toxic heme (ferriprotoporphy-
rin IX) molecules released from hemoglobin catabolism into nontoxic
hemozoin (b–hematin) within the acidic food vacuole (20). Inhibition
of hemoglobin degradation process proves fatal for the parasite.
Clinical manifestations are produced as the merozoites or hemozoin
crystals are released into the blood circulation with the rupture of
infected erythrocytes. It is predicted that malarial aspartic proteases
(plasmepsin) and cysteine proteases (falcipain) mediate the hemo-
globin degradation to release amino acids that are required for in-
traerythrocytic parasite growth and multiplication (20–22). These
proteases form an attractive antimalarial drug target (21). Structure-
based studies predict antimalarial chalcone derivatives inhibition on
trophozoite cysteine protease as the most likely mode of action
(14,23). Availability of continuous cultivation of human malaria para-
site, P. falciparum, (16) provides an interesting in vitro system for
initial screening to identify antiparasitic action of compounds in the
absence of immune components.
In 2, 4-dimethoxy series, we evaluated eight different substituents
on acetophenone rings while keeping 2, 4-dimethoxy substituent
constant on aldehyde and found noteworthy IC50 values between
1.1 and 7.68 lg ⁄ mL. The compound 9 containing benzimidazole
substituent was found to be most active with IC50 of 1.1 lg ⁄ mL.
Thus, the compound 9 was found to be the most potent of about
50 chalcones evaluated by us till now (11,13). In the same series,
three compounds (compounds 3, 5, and 8) having pyrrolidine, mor-
pholine, and 1, 2, 4-triazole substituents have also showed profound
effect on parasites, with IC50 2.37, 2.95, and 3.38 lg ⁄ mL, respec-
tively, while piperidine, pyrrole, imidazole, and benzotriazole substit-
uents showed moderate antiplasmodial activity with IC50 between
5.98 and 7.22 lg ⁄ mL. Moreover, in this series, we observed very
interesting results, when we compared IC50 values of benzimidazole
and benzotriazole derivative. In 2, 5-dimethoxy series, we evaluated
six compounds. Interestingly, morpholine substituent showed good
inhibitory activity with IC50 of 3.26 lg ⁄ mL, while pyrrolidine, piperi-
Figure 2: Log dose–response
curve of Licochalcone A and newly
synthesized compound 9 against
blood stages of Plasmodium falci-
parum (3D7 strain).
Chem Biol Drug Des 2012; 80: 340–347
345

Yadav et al.
dine, and pyrrole showed moderate antiplasmodial activity. Further
compound 13 and compound 16 having N-methyl piperazine and
benzotriazole substituents on ring B showed weak activity with IC50
10.1 and 12.73 lg ⁄ mL, respectively.
Acknowledgments
SKA is thankful to University Grants Commission, New Delhi, India
(UGC Project Scheme No: 37-410 ⁄ 2009 ⁄ SR), for financial support.
This work was also supported in part by the Department of Biotech-
nology (DBT), Ministry of Science and Technology, Government of
India, and University of Delhi. NY received fellowship from CSIR,
New Delhi. AB received support from Ramjas College, University of
Delhi. LCM received support from Hans Raj College, University of
Delhi. SKA is also thankful to Prof. R Gurunath, Chemistry Depart-
In 3, 4-dimethoxy series, we evaluated eight different substituents.
The compound 17 and compound 24 containing pyrrolidine and
benzotriazole substituents showed good activity with IC50 2.9 and
3.5 lg ⁄ mL, respectively, while rest of compounds showed moder-
ate activity with IC50 range from 7.34 to 4.96 lg ⁄ mL where piperi-
dine substituent was found to be least active. Interestingly, in 3,
4-dimethoxy series, benzotriazole was potentially effective with
IC50 3.5 lg ⁄ mL. We presumed that the position of two methoxy
groups at position 3 and 4 might be able to accommodate benzo-
triazole on active site, which was not possible in the case of 2, 4
dimethoxy having weaker activity. Better understanding of the
binding mechanism could possibly be revealed by obtaining crystal
structures.
1
ment, Indian Institute of Technology, Kanpur, for H-NMR analysis.
Conflict of Interest
Authors have no conflict of interest.
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Supporting Information
Additional Supporting Information may be found in the online ver-
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