Oxygenated chalcones and bischalcones as potential antimalarial agents

Article abstract of DOI:10.1016/S0960-894X(00)00409-1

Oxygenated chalcones (3a,b) and bischalcones (4a-j) have been synthesized and evaluated for antimalarial activity against chloroquine sensitive and resistant strains of Plasmodium berghei in mice. Some of the screened compounds, 3a, 4c, 4e, 4f and 4i, have shown significant activity at 100 mg/kg dose against sensitive strain. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00409-1

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2159±2161
Oxygenated Chalcones and Bischalcones as Potential
Antimalarial Agentsy
Vishnu J. Ram,a,* Abhishek S. Saxena,a Shalini Srivastavab and Subhash Chandrab
aMedicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
bParasitology Divisons, Central Drug Research Institute, Lucknow 226001, India
Received 29 February 2000; accepted 31 May 2000
AbstractÐOxygenated chalcones (3a,b) and bischalcones (4a±j) have been synthesized and evaluated for antimalarial activity
against chloroquine sensitive and resistant strains of Plasmodium berghei in mice. Some of the screened compounds, 3a, 4c, 4e, 4f
and 4i, have shown signi®cant activity at 100 mg/kg dose against sensitive strain. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
indeed displayed signi®cant activity for lead generation.
Synthesis
The future of antimalarial chemotherapy appears bleak
because of increasing cross-resistance to drugs, which
are neither structurally similar nor pharmacologically
related to those in clinical use. The main reason for this
dangerous situation is the availability of a limited number
of antimalarial drugs in clinical use. Thus the need for
structurally di€erent ecacious antimalarial drugs is self-
evident. The problem of drug resistance can be cir-
cumvented either by identifying new targets which are
critical to the disease process or essential for the survival
of parasites. The other possible way could be to design
and synthesize a new ecacious chemical entity with the
least side e€ects. Natural products are known as the chief
source of identi®cation of lead structures. The structural
modi®cation of such compounds results in highly e€ec-
tive agents with reduced toxicity and side e€ects. Recently,
licochalcone A, isolated from Chinese liquorice roots, has
been reported1,2 highly e€ective in an in vitro screen
against chloroquine sensitive (3D7) and chloroquine
resistant (Dd2) isolate of Plasmodium falciparum. The
ecacy of this product is also con®rmed against Plas-
modium yoelii in mice. Thus, this provided a lead to
design and synthesize chalcones and bischalcones as
new antimalarials.
Chalcones (3a,b) and bischalcones (4a±j) were synthe-
sized3,4 by base catalyzed condensation of bisketones5
(1) with aromatic aldehyde. To our surprise, a con-
densation of bisketones (1) with 3,4-methylenedioxy-
benzaldehyde always yielded chalcones (3a,b) under
di€erent reaction conditions. However, condensation of
bisketones (1) with 3,4-dimethoxy-, 2,4-dimethoxy- and
3-methoxybenzaldehyde easily yielded bischalcones.
Some of the bischalcone 4c and 4f on condensation±
cyclization reactions6 with 6-amino-1,3-dimethyluracil
in sodium ethoxide solution led to bis-5-diazalumazines
(5a,b) as shown in Scheme 1.
All the synthesized chalcones (3a,b) and bischalcones
(4a±j) were evaluated for antimalarial activity against
chloroquine sensitive and resistant strains of Plasmodium
berghei in mice and some of the synthesized compounds
Scheme 1. Reagents and conditions: (i) K2CO3/acetone/re¯ux; (ii)
piperonal/alc. KOH/rt; (iii) aryl aldehyde/alc. KOH/rt; (iv) NaOEt/
6-amino-1,3-dimethyluracil/re¯ux.
yC.D.R.I. Communication No. 6028.
*Corresponding author.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00409-1

2160
V. J. Ram et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2159±2161
Biological Activity
group received chloroquine (15 mg/kg) alone, the third
group received test chemical alone and the fourth group
received no drug and treated as control. Treatment was
given for 4 consecutive days intraperitoneally. The
screening results against sensitive and resistant strains in
terms of % parasitaemia are presented in Table 1 and 2.
Synthesized compounds were screened by suppressive
method of Peters.7 Male mice (Park strain) weighing
(20+2) g were infected intraperitoneally with standard
inoculum of one million parasitized RBC (1Â106
PRBC). The animals were treated with 2±3 h of post
inoculation. The inoculated animals were divided into
two groups with ®ve animals each for treatment. The ®rst
group of ®ve animals received the same dose of a com-
pound and the second group of ®ve animals served as
untreated control. The treatment was given for 4 con-
secutive days intraperitoneally.
Among all the screened chalcones (3) and bischalcones
(4) against chloroquine sensitive strain, only compounds
3a, 4c, 4e, 4f and 4i exhibited signi®cant activity at 100
mg/kg dose on day 5. It is evident from the screening data
(Table 1) that the level of parasitaemia usually increased
with advancement of days. Only compound 4f showed
zero percent parasitaemia even on day 7, increasing slowly
to 2% on day 15. In the case of 4e, percent parasitaemia
also increased at the rate of 1.7% on day 15. The com-
pound 4c was also active but inferior to 4f.
In the case of screening against resistant strain, animals
were divided into four groups of ®ve animals each. Dur-
ing treatment the ®rst group received a combined dose of
test chemical and chloroquine (15 mg/kg), the second
The antimalarial activity of these compounds revealed
that the sites of oxygenated substituents in the phenyl
ring greatly in¯uence the activity pro®le. In general,
chalcones with 3,4-methoxy substituents in the phenyl
ring displayed signi®cant activity compared to 2,4-dime-
thoxy substituents. The importance of methylene chain
length in 3 and 4 cannot be ignored. As is evident, the
activity data of 4e, 4h and 4j, the three-methylene-groups
chain contributes signi®cantly more to the activity than
the four- and six-methylene-groups chain. This obser-
vation was also found true in the case of 3a and 3b.
Table 1. In-vivo activity of chalcones (3a,b) and bischalcone (4a±j)
against chloroquine sensitive strain of P. berghei infection in mice in
terms of percent parasitaemia at 100 mg/kg dose Â4 days (ip)
% Parasitaemia on days
Sample no.
D5
D7
D9
D11
D13
D15
3.85
D17
Da
3a
3b
4a
4b
4c
4d
4e
4f
0
0.35
2.1
5.6
5.0
0.05
4.7
0.52
0
2.0
2.0
0.16
3.4
1.7
4.0
7.25
2.0
0.6
8.0
1.0
0.7
2.4
3.9
1.3
6.8
2.75
6.3
D
D
0.9
D
1.8
1.0
5.2
6.4
2.1
11
3.0
D
1.0
2.8
3.4
0.01
3.2
0
1.5
3.0
The antimalarial activity of these compounds in the
resistant strain was quite surprising, as inactive com-
pounds in the sensitive strain were found signi®cantly
active in the resistant strain. As it is evident from the
screening results (Table 2), only compounds 4a and 4j
displayed zero percent parasitaemia on day 7, slowly
increasing on subsequent days. Two other compounds 3a
1.81
1.5
6.6
19
3.1
D
1.7
2.0
9.5
D
0
4g
4h
4i
1.5
1.5
0
D
D
4.25
4j
2.1
aD, death of animal.
Table 2. E€ect of chloroquine (CQ, 15 mg/kg/day), test compounds (TC, 50 mg/kg/day) for 4 days and their combination thereof on parasitaemia
in resistant strain
% Parasitaemia on days
Sample no.
D5
3.2
0.7
0
2.2
0.02
1.5
0
0.74
0
1.3
1.2
1.75
0.08
1.2
0.002
2.6
0.2
1.9
0.8
0.8
0
D7
D9
D11
D13
D15
D17
D19
D
Control
3a
5.4
1.8
0.04
3.2
2.0
2.3
0
2.4
1.3
2.2
2.3
1.9
1.1
2.5
0.3
3.5
0.6
2.1
3.2
1.6
0.06
3.2
0
8.1
2.2
1.96
4.8
3.2
5.8
0.3
2.0
1.9
4.8
3.76
4.2
3.0
2.5
1.8
3.4
4.0
5.7
2.9
2.0
1.8
7.9
0.14
14.6
6.7
3.0
6.5
3.2
10.2
0.8
5.0
7.6
8.4
7.7
4.2
3.0
5.0
2.7
8.0
4.9
6.6
5.0
4.3
2.3
9.5
2.0
22
Da
11.5
7.0
10
8
D
4.4
D
18
12.5
13.7
13
7.0
13.2
D
8.3
13
13.3
10
15
7.5
D
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
TC+CQ
TC
7.8
5.1
9
D
13
D
3b
4a
4c
4d
4e
4f
5.5
14.3
1.4
10.4
12.2
10.0
9.5
5.4
4.6
6.9
7.5
7.2
7.5
10.8
7.5
7.3
6.0
13
D
11.6
22.6
24
16
18
19
9.5
D
D
D
D
D
13
4g
4h
4i
D
18
D
16
D
D
D
D
TC+CQ
TC
TC+CQ
TC
TC+CQ
11.0
4j
1.8
0
3.6
6.6
11.5
aD, Death of animal.

V. J. Ram et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2159±2161
2161
and 4i, also showed antimalarial activity but were infer-
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found signi®cantly active, compared to 3,4-methylene-
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Acknowledgement
A. S. Saxena and Shalini Srivastava are thankful to
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