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European Journal of Medicinal Chemistry 43 (2008) 1530e1535

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Short communication

Synthesis of novel substituted 1,3-diaryl propenone derivatives

and their antimalarial activity in vitro
Nidhi Mishra a, Preeti Arora a, Brajesh Kumar a, Lokesh C. Mishra b,
Amit Bhattacharya b, Satish K. Awasthi a,*, Virendra K. Bhasin b,**
a
Chemical Biology Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
b
Department of Zoology, University of Delhi, Delhi 110007, India

Received 5 May 2007; received in revised form 7 September 2007; accepted 13 September 2007
Available online 29 September 2007

Abstract

The synthesis of novel 1,3-diaryl propenone derivatives and their antimalarial activity in vitro against asexual blood stages of human malaria
parasite, Plasmodium falciparum, are described. Chalcone derivatives were prepared via ClaiseneSchmidt condensation of substituted aldehydes
with substituted methyl ketones. Antiplasmodial IC50 (half maximal inhibitory concentration) activity of these compounds ranged between 1.5
and 12.3 mg/ml. The chloro-series, 1,2,4-triazole substituted chalcone was found to be the most effective in inhibiting the growth of P. falcipa-
rum in vitro while pyrrole and benzotriazole substituted chalcones showed relatively less inhibitory activity. This is the first report on antiplas-
modial activity of chalcones with azoles on acetophenone ring.
Ó 2007 Elsevier Masson SAS. All rights reserved.

Keywords: Chalcones; Synthesis; Antimalarial activity; Plasmodium falciparum; In vitro

1. Introduction alternate synthetic and inexpensive medicines for malaria.

Malaria continues to be one of the major public health
problems in many tropical countries causing extensive mor-
bidity and loss of life [1]. Annual malaria mortality due to
Plasmodium falciparum costs 1e2.7 million lives in Africa
alone, comprising of mainly young children [2]. Artemisinin
(Fig. 1), contained in the decoction prepared from the aerial
parts of a plant Artemisia annua, used for over thousand years
for fever resolution has been re-discovered as the most potent
antimalarial drug [3]. Resistance to this drug has not been clin-
ically encountered so far [4,5]. Chloroquine (Fig. 1), the only
synthetic antimalarial drug which cured malaria for decades,
rather than centuries, has fallen to resistance [6]. With the de-
mise of chloroquine there is renewed interest to look for
* Corresponding author. Tel.: þ91 11 27662104.
** Corresponding author. Tel.: þ91 11 27667989; fax: þ91 11 27667524.
E-mail addresses: awasthisatish@yahoo.com (S.K. Awasthi),
virendrabhasin@hotmail.com (V.K. Bhasin).
Synthesis of artemisinin is commercially unviable at present.
One of the strategies adopted by malariologist to delay the
emergence of resistance to artemisinin and its derivatives is
to use them in combination with other novel antimalarial(s).
Artemisinin based combination therapies (ACTs) instead of
artemisinin monotherapy are being advocated and supported
by WHO. Currently used ACTs are in demand and by no
means the ideal combinations [5,7]. There is scarcity of arte-
misinin globally. Thus there is a need to search for novel, in-
expensive antiplasmodials as suitable synergistic partners for
artemisinin to reduce dependence on artemisinin for malarial
treatment.
Chalcone, a biosynthetic product of shikimate pathway, is
a class of privileged structure that has a wide range of biological
properties. Chalcones are precursors of various flavones and key
intermediates for combinatorial assembly of different heterocy-
clic scaffolds. Chalcone (1,3-diaryl propenone or 1,3-diphenyl-
2-propen-1-one) constitutes an important group of natural
products, and some of them possess a wide range of biological

0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.09.014
 N. Mishra et al. / European Journal of Medicinal Chemistry 43 (2008) 1530e1535 1531

Table 1
H
Antimalarial activity of chalcone derivatives
O
H
HN NEt2 O HO OH Compounds R R1 R2 R3 Mean IC50  SEa (mg/ml)
O
O 1 H Cl H 2.93  0.08
N
Cl O O O
Chloroquine Artemisinin Licochalcone A
N
Fig. 1. Structure of chloroquine, artemisinin and licochalcone A. 2 H Cl H 2.5  0.27
N
N

activities, such as anti-bacterial [8,9], anti-fungal [10], anti- 3 N H Cl H 7.76  0.42

N
viral [11,12], anti-inflammatory [13], anti-tumor [14,15], anti-
oxidant [16], insect anti-feedent [17], and act as tyrosinase N
4 H Cl H 6.01  0.13
inhibitors [18]. Interest in chalcones as antimalarials was initi-
ated by the discovery of antiplasmodial activity of licochalcone
A (Fig. 1), an oxygenated chalcone isolated from the roots of the N
Chinese licorice during routine screening [19]. Computational 5 H Cl H 9.1  0.10
structural analysis also identified chalcones as potential plasmo- O
dial cysteine protease inhibitors consistent with the experimen-
tal data [20,21]. The model proposed [21] is presented in Fig. 2. N
6 H Cl H 8.26  0.06
Since then attempts have been made to find new synthetic N
antimalarial analogues [22,23].
In our earlier work we have evaluated novel artemisinin N
7 N H Cl H 1.52  0.04
based combinations that target multiple sites in the parasite
N
as antiplasmodial agents [24]. In diversifying our work we
have designed and synthesized new chalcone derivatives and
8 N H Cl H 5.15  0.07
evaluated their antiplasmodial ability in vitro, with an aim to
use the potent chalcones in combination with artemisinin
subsequently.
9 N H OMe H 12.33  0.88
N
2. Chemistry
N
10 H OMe H 6.8  0.11
The ClaiseneSchmidt condensation method [20] was em- N
N
ployed for the synthesis of 14 chalcone derivatives (com-
pounds 1e14, Table 1). Two step synthesis protocols, as
11 N OMe OMe OMe 7.16  0.10
depicted in Fig. 3, were used to prepare the compounds. The
first step involved treatment of 4-fluoroacetophenone with var-
ious cyclic amines in dimethylformamide (DMF) and potas-
sium carbonate at 110  C for 18 h to yield substituted 12 N
N
OMe OMe OMe 6.0  0.05
acetophenone as either liquid (compounds 1, 2, 3, 6) or solid
(compounds 4, 5, 7). In the next step, the substituted acetophe-
none was condensed with a suitable aldehyde using solid so- N
13 OMe OMe OMe 4.6  0.15
dium hydroxide as catalyst in methanol at room temperature
O
to yield chalcone [18]. These conditions were found to be
N
14 N OMe OMe OMe 8.03  0.2
N
H O H O
a
+ SE, standard error (n ¼ 3).
R' N C R R' N C R

: :
H S: N H S : Nucleophilic
HN N HN .. attack
..
CH2 CH2 satisfactory for the synthesis of chalcones in good yields. In
Cys Cys
CH2 CH2 most cases, products were formed immediately after the addi-
His His tion of sodium hydroxide pellets to the stirred solution of alde-
Enzyme Enzyme hyde and substituted methyl ketone. If the starting material
was insoluble in methanol, tetrahydrofuran (THF) or 1,4-diox-
Fig. 2. Peptide bond cleavage by the enzyme, cysteine protease. ane was used as a co-solvent. To ensure the formation of solid,
1532 N. Mishra et al. / European Journal of Medicinal Chemistry 43 (2008) 1530e1535
R1
O O
R2
F (a) R (b)
(a) c yclic amines, K2CO3, DMF, 18 hrs., 110°C
(b) NaOH, methanol, 16-20 hrs, rt.
Fig. 3. General procedure for the synthesis of chalcones.
a minimal amount of methanol was used. The product, a,b-un-
saturated ketone, is almost always obtained in the trans-alkene
form (E-form). The yields were not optimized and ranged be-
tween 56 and 78%.
The homogeneity of the final compounds was ensured by
column chromatography (silica, mesh size 60e120, CDH) us-
ing chloroform as eluent. The compounds were characterized
by Macromass G and 1H NMR (300 MHz, Brucker), the data
were found consistent with the structures and the microanalyt-
ical results were within 0.4 from theoretical values. The Rf of
all compounds was recorded in 1% methanol in chloroform.
The biophysical parameters of the compounds are presented
in Table 1.
3. Results and discussion
Chalcone is an exceptional chemical template having mul-
tifarious biological activities. Antimalarial property of some
chalcone derivatives is derived from their ability to inhibit
the parasitic enzyme, cysteine protease [20]. The enzyme ca-
tabolizes globin into small peptides within the acidic food vac-
uole of the intra-erythrocytic malaria parasite. Without
cysteine protease action osmotic swelling occurs, food vacuo-
lar functions are impaired, and parasite death ensues. Homol-
ogy-based computer model structure also predicts malaria
blood stage cysteine protease as the most likely target enzyme
of chalcones [25]. The chalcones are conjugates of a,b-unsat-
urated ketones that assume linear or near planar structure. This
structure is stable in acidic food vacuolar environment where
malarial cysteine protease acts, and structural conformation
may fit well into the long cleft of the active site of the enzyme.
Considering these facts we designed and synthesized various
chalcones. Three substituents chosen at aldehyde ring were
4-chloro, 4-methoxy and 3,4,5-trimethoxy functions. In the
acetophenone moiety fluoro group was replaced systematically
with pyrrole, imidazole, benzotriazole, pyrazole, pyrrolidine,
morpholine and piperidine to get new compounds. The anti-
plasmodial IC50 values of these 14 compounds are depicted
in Table 1. Within the chloro-series compounds 1, 2 and 7
showed marked antiplasmodial activity. Compound 7, a tria-
zole substituted chalcone was found to be the most effective
against the parasites, and pyrrole and benzotriazole showed
comparable activities. The morpholine substituent in chloro-
series was found to be the least active (compound 5). In the
monomethoxy series, the benzotriazole group (compound 10)
O
H
O
R1
R3
R R2
R3
i) R1=H, R2=Cl, R3=H
ii) R1=H, R2= -OCH3, R3=H
iii) R1= R2= R3= -OCH3
showed moderate activity while pyrazole showed least activity
(compound 9). In the trimethoxy series, compound 13 having
morpholine substituents unlike in chloro-series showed signifi-
cant activity and it is comparable with compounds 1 and 2 in
chloro-series. Morpholine substituent was found to be the
least effective in chloro-series. Compound 14 containing
1,2,4-triazole in trimethoxy series showed moderate activity,
whereas it was the most active in chloro-series. The activity
can be attributed to the presence of azoles, although reasons
for increased activity are unclear.
Compound 7, containing triazole and chloro substituents,
was found to be the most potent antiplasmodial derivative
evaluated, suggesting that small lipophilic groups containing
single or multiple nitrogen can enhance antimalarial activity
in vitro. Compound 2 showed lower IC50 value compared to
compound 1. In a comparison between compounds 2 and 7,
compound 7 showed more potent antimalarial activity
than compound 2 although both contained three nitrogens.
We assumed that in triazole substituted chalcone, spacing of
nitrogen and the orientation of the molecule on active site of
enzyme are good enough to provide stronger and effective
hydrogen bonding with His 67 of cysteine protease. Therefore,
we propose a possible interaction of compound 7 with the en-
zyme as shown in Fig. 4. Moreover, in the case of benzotria-
zole substituted chalcone, bulky nature or orientation of
benzene ring on enzyme active site gives some kind of steric
hindrance which prevents accessibility of nitrogens for effec-
tive hydrogen bonding or protonation on enzyme active site,
thus making the compound to be less potent than compound 7.
However, the exact reason remains elusive.
Nitrogen containing heterocyclic compounds are generally
known to possess antimalarial activity as seen in the case of
quinolynyl (pKa 4.9) as they tend to concentrate in the acidic
food vacuole (pH 5) of the parasite. The explanation is based
on the crystal structure of cysteine protease showing His 67 at
the active site of the enzyme [20]. We assumed that proton-
ation of triazolyl chalcone under weakly acidic conditions
may enhance their interaction with His 67 in the active sites
of enzyme or vice versa (free His pKa of 6).
4. Conclusion
In vitro antiplasmodial results of 4-chloro, 4-methoxy and
3,4,5-trimethoxy series suggested that small or medium sized
but highly lipophilic groups containing multiple nitrogen or
 N. Mishra et al. / European Journal of Medicinal Chemistry 43 (2008) 1530e1535
:
N H S:
H N
..
CH2
Cys
CH2
His
Enzyme
Fig. 4. Proposed mechanism of compound 2 binding to His 67 in the site S2 of
enzyme.
amine in acetophenone moiety impart antiplasmodial poten-
tial. Such compounds may provide additional hydrogen bond-
ing with histidine residue present at the active site of the
enzyme, cysteine protease. This is the first report in which
chalcones containing small highly polar, lipophilic cyclic
amines are showing antimalarial potential.
More work is needed to obtain second generation version of
these interesting compounds to establish meaningful SAR.
Compounds 1, 2 and 7 could be used as standard precursors
for this purpose. In the meanwhile these compounds are being
evaluated as partners in combination with artemisinin to look
for synergistic action.
5. Experimental protocol
Melting points are determined in an open capillary and are
uncorrected. 1H NMR was recorded on Brucker (AMX-300)
using CDCl3 as solvent. TMS was used as internal reference
for 1H NMR. Mass spectra were recorded on a Macromass
G spectrophotometer. Elemental analysis was performed on
PerkineElmerSeries-II CHN analyzer.
5.1. Procedure for the synthesis of
substituted acetophenone
A solution of 4-fluoroacetophenone (5.1 ml, 40 mmol), pyr-
rolidine (40 mmol) and K2CO3 (11.1 g, 50 mmol) in dry DMF
(20 ml) was refluxed for 18 h at 110  C. The solvent was re-
moved in vacuo and H2O (50 ml) was added to the resultant
residue. The aqueous phase was extracted with diethyl ether
(2  100 ml), dried over anhydrous Na2SO4 and evaporated
in vacuo to yield the desired product. The intermediate was
1533
characterized by mass spectra and used in the next step for
the preparation of chalcones without purification. The remain-
ing intermediates were prepared in the similar way.
5.2. General procedure for the synthesis of substituted
1,3-diaryl propenone derivatives
The title compounds were prepared as follows. A
substituted methyl ketone (3 mmol) and a substituted aldehyde
(3 mmol) were dissolved in a minimum amount of methanol
(normally 5 ml) with stirring. NaOH pellets (300 mg) were
added into it. In most cases off-white to yellow solids were
formed within a few minutes to 18 h. The solid was filtered
and washed three times with cold water. The product was re-
crystalized from appropriate solvents. Column chromatogra-
phy was used to purify the products.
5.2.1. 1-(4-(1H-Pyrrol-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 68%, Rf 0.67, off-white crystals, m.p. 132e134  C,
MS m/z 309.15 (M þ 1), 1H NMR (CDCl3, 300 MHz):
d 7.19e8.0 (m, 14H, Ar).
5.2.2. 1-(4-(1H-Benzo[d][1,2,3]triazol-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 60%, Rf 0.68, off-white crystals, m.p. 154e155  C,
MS m/z 360 (M þ 1), 1H NMR (CDCl3, 300 MHz): d 6.52e
8.15 (m, 14H, Ar).
5.2.3. 1-(4-(1H-Pyrazol-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 74%, Rf 0.67, off-white crystals, m.p. 152e153  C,
MS m/z 309.5 (M þ 1), 1H NMR (CDCl3, 300 MHz):
d 6.53e8.15 (m, 13H, Ar).
5.2.4. 1-(4-(1H-Pyrrolidinl-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 72%, Rf 0.58, light yellow crystals, m.p. 208e210  C,
MS m/z 312 (M þ 1), 1H NMR (CDCl3, 300 MHz): d 3.40 (t,
4H, CH2eNeCH2), d 2.50 (t, 4H, CH2eCH2e), d 7.3e8.0 (m,
8H, Ar H).
5.2.5. 1-(4-(1H-Morpholin-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 68%, Rf 0.56, yellow crystals, m.p. 162e164  C, MS
m/z 349.04 (M þ Na), 1H NMR (CDCl3, 300 MHz): d 3.08 (s,
6H, morpholinyl), d 3.05 (s, 2H, CHeCHe), d 6.68e8.0 (m,
10H, Ar H).
5.2.6. 1-(4-(1H-Imidazol-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 70%, Rf 0.68, yellow crystals, m.p. 160e162  C, MS
m/z 309.12 (Mþ), 1H NMR (CDCl3, 300 MHz): d 7.50 (s, 1H,
imidazolyl eNeCHeNe), d 8.05 (d, 2H, imidazolyl CHeNe
CHe), d 7.18e7.79 (m, 10H, Ar).
1534 N. Mishra et al. / European Journal of Medicinal Chemistry 43 (2008) 1530e1535
5.2.7. 1-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 79%, Rf 0.55, yellow crystals, m.p. 160e162  C, MS
m/z 309.12 (Mþ), 1H NMR (CDCl3, 300 MHz): d 7.31e7.90
(m, 12H, Ar).
5.2.8. 1-(4-(1H-Piperidin-1-yl)phenyl)-
3-(4-chlorophenyl)prop-2-en-1-one
Yield 73%, Rf 0.66, light yellow crystals, m.p. 108e
110  C, MS m/z 326 (Mþ), 1H NMR (CDCl3, 300 MHz):
d 3.39 (t, 5H, piperidine), d 2.04 (t, 5H, piperidine),
d 6.54e8 (m, 10H, Ar).
5.2.9. 1-(4-(1H-Pyrazol-1-yl)phenyl)-
3-(4-methoxyphenyl)prop-2-en-1-one
Yield 44%, Rf 0.46, yellow crystals, m.p. 100e102  C, MS
m/z 305.07 (Mþ), 1H NMR (CDCl3, 300 MHz): d 3.86 (s, 3H,
OCH3), 6.52 (t, 1H, pyrazolyl eCHe), d 7.7 (d, 2H, pyrazolyl
eCHeNeNCH), d 6.93e8.15 (m, 10H, Ar).
5.2.10. 1-(4-(1H-Benzo[d][1,2,3]triazol-1-yl)phenyl)-
3-(4-methoxyphenyl)prop-2-en-1-one
Yield 54%, Rf 0.63, yellowish white crystals, m.p. 124e
128  C, MS m/z 356 (M þ 1), 1H NMR (CDCl3, 300 MHz):
d 3.86 (s, 3H, OCH3), 6.9e7.9 (m, 12H, Ar).
5.2.11. 3-(3,4,5-Trimethoxyphenyl)-
1-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one
Yield 76%, Rf 0.39, orange crystals, m.p. 160e162  C, MS
m/z 381 (Mþ), 1H NMR (CDCl3, 300 MHz): d 3.93 (s, 9H,
OCH3), d 1.67 (s, 6H, CH2eCH2eCH2 of piperidine),
d 3.39 (s, 4H, CH2eNeCH2e), d 6.86e7.98 (m, 12H, Ar).
5.2.12. 1-(4-(1H-Pyrazol-1-yl)phenyl)-
3(3,4,5-trimethoxyphenyl)prop-2-en-1-one
Yield 70%, Rf 0.31, yellow crystals, m.p. 168e170  C, MS
m/z 365 (M þ 1), 1H NMR (CDCl3, 300 MHz): d 3.90 (s, 9H,
OCH3), d 6.54 (s, 1H, pyrazolyl), d 7.45 (d, 2H, pyrazolyl e
CHeNe), d 7.73e8.15 (m, 10H, Ar).
5.2.13. 3-(3,4,5-Trimethoxyphenyl)-
1-(4-morpholinophenyl)prop-2-en-1-one
Yield 76%, Rf 0.34, bright yellow crystals, m.p. 115e
116  C, MS m/z 384 (M þ 1), 1H NMR (CDCl3, 300 MHz):
d 3.92 (s, 9H, OCH3), d 3.09 (s, 6H, morpholinyl), d 3.04 (s,
2H, morpholinyl), d 6.67e8.02 (m, 10H, Ar).
5.2.14. 1-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-
3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one
Yield 68%, Rf 0.56, yellow crystals, m.p. 55e57  C, MS m/
z 365.44 (Mþ), 1H NMR (CDCl3, 300 MHz): d 3.90 (s, 3H,
OCH3), d 3.92 (s, 6H, OCH3), d 6.86e7.94 (m, 10H, Ar),
d 7.97 (s, 2H, triazolyl).
5.3. Measurement of in vitro antiplasmodial activity
Antiplasmodial activity of chalcones was essentially car-
ried out using candle jar method [26]. Briefly, asexual blood
stage parasites of P. falciparum strain 3D7 were challenged
to graded concentration of each compound in multiwell tis-
sue culture plates in triplicates for 48 h at 37  C. The para-
sites were grown in Bþ human erythrocytes in RPMI-1640
medium supplemented with 10% heat inactivated pooled
compatible serum. The percent inhibition of parasitemia in
relation to controls was determined from Giemsa stained
thin blood films. Concentrationeresponse curve was pre-
pared to compute IC50 value of each compound. Stock solu-
tion of each compound at a concentration of 1 mg/ml was
prepared in DMSO. The final concentration of DMSO
used in the culture media was not affecting the parasite
growth. In vitro sensitivity of 3D7 P. falciparum line to
chloroquine was 0.0272 mM.
Acknowledgements
S.K.A. is thankful to Department of Science and Technol-
ogy, India for the financial support. This work was supported
in part by the Department of Biotechnology, Ministry of Sci-
ence and Technology, Government of India. L.C.M. and
A.B. received fellowships from the Council of Scientific and
Industrial Research, New Delhi.
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