Design, synthesis and biological evaluation of some novel 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones as antimalarial agents

Article abstract of DOI:10.1007/s00044-011-9694-1

A novel series of 3-cinnamoyl-4-hydroxy-2Hchromen-2-ones were designed, synthesized and screened for antiplasmodial activity. Eleven compounds of the series exhibited micromolar potency against chloroquine sensitive and chloroquine resistant strains. The most potent compound 4-hydroxy-3-(3-(4- nitrophenyl)acryloyl)-2Hchromen-2-one showed inhibitory potency (IC ₅₀) of 3.1 and 4 μg/ml against chloroquine sensitive and chloroquine resistant strains, respectively. A structure activity relationship study was performed by correlating the effect of substituents with the antimalarial activity of the title compounds. The novel 3-cinnamoyl-4-hydroxy- 2H-chromen-2-ones reported here should be good lead for further development of antimalarial agents that can overcome resistance.

Full text of DOI:10.1007/s00044-011-9694-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1780–1784
DOI 10.1007/s00044-011-9694-1
ORIGINAL RESEARCH
Design, synthesis and biological evaluation of some novel
3-cinnamoyl-4-hydroxy-2H-chromen-2-ones as antimalarial
agents
•
Kuldeep Patel Chandrabose Karthikeyan
•
•
N. S. Hari Narayana Moorthy Girdhar Singh Deora
•
•
Viswas Raja Solomon Hoyun Lee Piyush Trivedi
•
Received: 28 January 2011 / Accepted: 8 June 2011 / Published online: 22 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of 3-cinnamoyl-4-hydroxy-2H-
chromen-2-ones were designed, synthesized and screened
for antiplasmodial activity. Eleven compounds of the series
exhibited micromolar potency against chloroquine sensi-
tive and chloroquine resistant strains. The most potent
compound 4-hydroxy-3-(3-(4-nitrophenyl)acryloyl)-2H-
chromen-2-one showed inhibitory potency (IC50) of 3.1
and 4 lg/ml against chloroquine sensitive and chloroquine
resistant strains, respectively. A structure activity rela-
tionship study was performed by correlating the effect of
substituents with the antimalarial activity of the title
compounds. The novel 3-cinnamoyl-4-hydroxy-2H-chro-
men-2-ones reported here should be good lead for further
development of antimalarial agents that can overcome
resistance.
Keywords Antimalarial ꢀ Chalcones ꢀ Coumarin
Introduction
Malaria constitutes the most important infectious disease
problems of humans, affecting third-world countries, with
over 275 million new cases annually and mortality reaching 2
million (Dominguez, 2002; Guerin et al., 2002). The majority
of these cases are pediatric deaths in developing countries
which exemplify the tragedy of the disease caused by this
parasite. There are four species of malaria or the genus Plas-
modium, which include Plasmodium falciparum, P. vivax,
P. ovale and P. malariae. P. falciparum is the foremost killer
and is found primarily on the African continent. There is
increasingly serious problem of malaria parasite resistance to
currently used antimalarials (Macreadie et al., 2000; Neek-
hara et al., 2006a, b) and the emergence of drug-resistant
parasites especiallyP. falciparumposes significantchallenges
to the future of drug discovery efforts (Sahu et al., 2008).
Hence, there is an urgent need to discover new and effective
chemical entities that can combat P. falciparum.
Kuldeep Patel and Chandrabose Karthikeyan contributed equally to
this study.
K. Patel ꢀ C. Karthikeyan ꢀ N. S. Hari Narayana Moorthy ꢀ
G. S. Deora ꢀ P. Trivedi (&)
School of Pharmaceutical Sciences, Rajiv Gandhi Technical
University, Airport Bypass Road, Gandhi Nagar, Bhopal 462036,
M.P, India
e-mail: prof_piyushtrivedi@yahoo.com; piyush.trivedi@rgtu.net
Chalcones are structurally simple compounds of the
flavonoid family and are present in variety of plant species
(Boeck et al., 2006; Begum et al., 2011). Chemically, these
are 1,3-diphenyl-2-propen-1-one and have broad spectrum
activities (Go et al., 2005; Chimenti et al., 2009) which
include antileishmanial, antiinflammatory, antimitotic,
modulation of P-glycoprotein-mediated multidrug resis-
tance, antimalarial, etc. The antimalarial activity of chal-
cones was apparent (2,4-dimethoxy-40-allylchalcone and
2,4-dimethoxy-40-butoxychalcone) after the first report on
licochalcone A with potent in vivo and in vitro antimalarial
activity at micromolar concentrations (Kharazmi et al.,
N. S. Hari Narayana Moorthy
Department of Chemistry & Biochemistry, Faculty of Sciences,
University of Porto, 687, Rua de Campo Alegre, Porto 4169-007,
Portugal
V. R. Solomon ꢀ H. Lee
Tumour Biology Group, Northeastern Ontario Regional Cancer
Program at the Sudbury, Regional Hospital, 41 Ramsey Lake
Road, Sudbury, ON P3E 5J1, Canada
V. R. Solomon ꢀ H. Lee
Department of Biology, Laurentian University, Sudbury,
ON P3E 2C6, Canada
123

Med Chem Res (2012) 21:1780–1784
1781
1997; Narender and Reddy, 2007). Since then, numerous
reports have emerged on the antimalarial activity of chal-
cones, e.g. quinolinyl chalcone analogues (Dominguez
et al., 2001), prenylated chalcones (Frolich et al., 2005),
sulphonamide chalcones (Domıinguez et al., 2005a), phe-
nylsulphonyl urenyl chalcones (Araico et al., 2006), ferr-
ocenyl chalcones (Wu et al., 2002; 2006) in the literature
(Tomar et al., 2010).
Daphnetin (7,8-dihydroxycoumarin), a Chinese herbal
product used for the treatment of coagulation disorders
showed potency against malarial parasite both in vitro and
in vivo (Yang et al., 1992; Huang et al., 2006). In vitro,
3
Daphnetin causes a 50% inhibition (IC50) of H-hypoxan-
thine incorporation by P. falciparum at concentrations
between 25 and 40 lM (Yang et al., 1992). In the light of
aforementioned findings and the growing interest in chal-
cones as potential antimalarials, we hypothesized that a
novel chalcone incorporating coumarinyl moiety will be
worth investigating for its antimalarial potency (Fig. 1).
Hence in this communication, a series of 3-cinnamoyl-4-
hydroxy-2H-chromen-2-ones was synthesized and assessed
for their antimalarial properties in vitro against chloroquine
susceptible and chloroquine resistant strains.
There are multiple mechanisms of action reported for the
antimalarial activity of chalcones. Reported mechanisms
include inhibition of malaria proteases responsible for
hemoglobin digestion, interference with the detoxification
process of hemozoin formation, inhibition of the new per-
meation pathways that uptake essential nutrients, and inhibi-
tion of the Pfmrk cell cycle kinase (Dominguez et al., 2005b;
Go et al., 2004; Ziegler et al., 2004; Geyer et al., 2009).
Coumarin, an organic heterocyclic scaffold constitutes
an important class of compound with versatile biological
activities and can be found in many natural or synthetic
drug molecules (Sun and Cui, 2008). Precedence exists in
literature on antimalarial activity of coumarins for example
Chemistry
The synthesis of the 3-cinnamoyl-4-hydroxy-2H-chromen-
2-ones was accomplished by a two step procedure outlined
Fig. 1 Pharmacophore
similarity of synthesized
2,4-dimethoxy-4´-allylchalcone
Daphnetin
compounds with existing active
compounds (coumarin and
chalcone derivatives)
OCH3
D
OH
B
O
HO
O
O
C
O
OCH3
E
A
OH
O
O
O
C
R
B
A
D
H3CO
E
OCH3, OH, NO2, CH3, Cl
Compounds 1-15
CH2
CH3
CH3
D
OCH3
B
O
D
OH
B
C
O
OCH3
E
HO
C
O
OCH3
E
2,4-dimethoxy-4´-butoxychalcone
Licochalcone A
123

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Med Chem Res (2012) 21:1780–1784
in the Scheme 1. The experimental procedure and spectral
data of the compounds are given in our earlier communi-
cation (Patel et al., 2011). The first step involves synthesis
of the precursor 4-hydroxy-3-acetyl coumarin by reacting
4-hydroxy coumarin with phosphorous oxychloride and
glacial acetic acid and the second step includes Knoeve-
nagel condensation between the 4-hydroxy-3-acetyl cou-
marin and substituted benzaldehydes in chloroform in the
presence of piperidine catalyst.
substituted compounds, nitro substitution on the phenyl ring
(7) showed highest antimalarial potency (IC50 \ 5 lg/ml)
against both chloroquine sensitive and resistant strains and
the potency decreases in the order NO2 [ Cl [ CH3
[ OCH3 [ N(CH3)2. It is also interesting to note that there
is only a moderate difference in activity values on moving
from a more a polar nitro group (7) to a less polar methyl
group (9). In case of meta position in the phenyl ring,
chloro group seems to be a substituent of choice as indi-
cated by low IC50 values (\5 lg/ml). In contrast to para
substituted compounds, nitro substitution in meta position
of phenyl ring did not favour antimalarial activity. Fur-
thermore, the methoxy group alone in the para position
(10) and along with ortho and/or meta position (12, 13) of
the phenyl ring also show significant activity at lower
concentrations. The replacement of methoxy group with
hydroxyl group (11) in the para position decreased the
activity two fold than the methoxy substitution (12). The
dimethylamino substitution in the para position of the ring
(8) has antimalarial activity five times lower than the nitro
group containing compound. The methoxy group in the
para, meta and meta0 position (14) is devoid of antimalarial
activity. Replacement of furan ring in place of phenyl ring
(15) resulted in loss of activity ([50 lg/ml). It is also
worth mentioning that most of compounds (3, 4, 7 and 9)
which showed significant inhibitory activity against chlo-
roquine sensitive strain 3d7 also exhibited comparable
potencies against chloroquine resistant strain. Cytotoxicity
studies conducted on K562 cell line suggest that the studied
compounds are devoid of any significant toxicity. Only two
of the 10 compounds (Compound 4 and 13) exhibit cyto-
toxicity at less than 50 micromolar concentration. The most
potent anti malarial compound of the studied series (7) did
not show any toxicity against K562 cell line even at con-
centrations greater than 100 lg/ml. Altogether, the results
of SAR studies establish the 3-cinnamoyl-4-hydroxy-2H-
chromen-2-one nucleus as a chemical structure endowed
with antiplasmodial properties.
Results and discussions
The antiplasmodial efficacy of the synthesized 3-cinna-
moyl-4-hydroxy-2H-chromen-2-ones was ascertained by
conventional in vitro parasite culture method (Trager and
Jensen, 1976; Nivsarkar et al., 2005), using chloroquine
sensitive (3D7) and chloroquine resistant strain (W2) of
P. falciparum. In addition to antiplasmodial properties, the
in vitro toxicity of 10 representative compounds of the
series towards K562 cell line was also evaluated by fol-
lowing Sulphorhodamine B (SRB)-based protocol (Skehan
et al., 1990; Vichai and Kirtikara, 2006; Solomon et al.,
2009). Chloroquine di phosphate was used as the reference
drug. The antimalarial activity and cytotoxicity shown by
the synthesized compounds is summarized in Table 1.
The effect of structural variation in the antimalarial
activity exhibited by 3-cinnamoyl-4-hydroxy-2H-chromen-
2-one (1) was explored by varying the substituents on the
aromatic ring as illustrated in Table 1. On perusal of
the table, it is evident that meta and para substitution in the
phenyl ring are mostly favored as shown by the low IC50
values (IC50 \ 10 lg/ml). The unsubstituted 3-cinnamoyl-
4-hydroxy-2H-chromen-2-one (1) has antimalarial activity
at 22.1 lg/ml but substitution with chlorine either in ortho
position of the phenyl ring (2) or in the ortho and para
position of the phenyl ring (5) abolished the antimalarial
activity. However, it may also be observed that compounds
with substitution of chlorine atom in the meta position (3)
and para position (4) have significant activity at low con-
centration. Hence, it can be concluded that ortho substitu-
tion in phenyl ring is not well tolerated for antimalarial
activity shown by the title compounds. Amongst the para
In conclusion, a series of 3-cinnamoyl-4-hydroxy-2H-
chromen-2-ones were synthesized and evaluated for their
antimalarial activity against chloroquine sensitive and
chloroquine resistant plasmodial strain. Compounds 3, 4, 7
and 9 exhibited good antimalarial potency against both
OH
O
OH
OH
O
O
O
R5
R4
R3
a
b
R1
O
O
O
O
R2
4-hydroxy-2H-chromen-2-one
2-acetyl-4-hydroxy-2H-chromen-2-one
Compounds 1-15
Scheme 1 Synthesis of the 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones. Reagents and conditions: a Glacial acetic acid, POCl3, reflux;
b Substituted benzaldehydes, CHCl3, Piperidine (Catalytic), reflux
123

Med Chem Res (2012) 21:1780–1784
1783
Table 1 Chemical structure, antimalarial activity and human cell toxicity of the synthesized compounds
OH
O
R5
R4
R3
R1
O
O
R2
S. R1
no
R2
R3
R4
R5 IC
IC
IC
IC50 (lg/ml)
AACSS AACSS AACRS cytotoxicity against K562/
SI = IC50 SI = IC50 SI = IC50
3D7
50
3D7
80
W2
50
W2
50
K562/
3D7
IC
K562/IC
3D7
IC
50
(lg/ml) (lg/ml) (lg/ml) K562 cell lines
80
1
H
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
22.1
[50
4.2
56.3
ND
9.0
11
99.2
123.5
ND
4.49
ND
1.76
ND
9.02
ND
2
H
H
H
ND
6.2
3
Cl
H
H
H
ND
ND
ND
4
Cl
H
5.1
14.2
ND
25.2
7
6.5
32.1
149
6.29
ND
2.26
ND
4.94
ND
5
H
Cl
H
[50
15.6
3.1
ND
54.1
4
6
NO2
H
H
H
151.7
154
9.72
49.68
9.10
ND
6.02
22.00
7.08
ND
2.80
38.50
2.29
ND
7
NO2
N(CH3)2
CH3
OCH3
H
8
H
H
17.2
6.1
22.1
15
68.2
5.1.
35.8
61.3
22
156.5
ND
9
H
H
10
11
12
H
H
7.2
6.2
ND
ND
ND
ND
OCH3 OH
H
11.2
6.2
27.2
15.1
20.3
ND
ND
ND
ND
ND
ND
OCH3 OCH3
H
71.4
46.6
103.2
ND
11.52
5.48
ND
4.73
2.30
ND
3.25
0.83
ND
13 OCH3 OCH3 OCH3
H
8.5
56.1
ND
ND
14
15
H
OCH3 OCH3
OCH3
[50
[50
ND
ND
ND
OH
O
O
O
O
16 Chloroquine
ND not determined
22.3a
40.1a
230.1a
43.8
1.96
1.09
0.19
AACSS activity against chloroquine sensitive strain
AACRS activity against chloroquine resistance strain
SI selectivity index
a
ng/ml
Singh Deora wishes to thank AICTE, New Delhi for postgraduate
fellowship. One of the authors C. Karthikeyan wishes to thank CSIR,
New Delhi for providing Senior Research Fellowship.
chloroquine sensitive and chloroquine resistant plasmodial
strains. The preliminary structure–activity relationship
study revealed para and meta position in the phenyl rings
are ideal points for structural manipulation for developing
potent antimalarial 3-cinnamoyl-4-hydroxy-2H-chromen-
2-ones. The findings of study successfully establish 3-cin-
namoyl-4-hydroxy-2H-chromen-2-ones as a novel lead for
the development of novel antimalarial agents that can
overcome resistance.
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