Mosquito larvicidal studies of some chalcone analogues and their derived products: Structure-activity relationship analysis

Article abstract of DOI:10.1007/s00044-010-9305-6

A series of chalcone analogues and some of their derivatives were synthesized and subjected to the mosquito larvicidal study. Chalcones having electron releasing group(s) on either ring A or ring B showed high toxicity. Electron withdrawing group(s), especially at ring B, reduced the activity of chalcones. The activity was abruptly decreased due to replacement of ring A by CH₃, extension of conjugation or blocking of α,β- unsaturated ketone part of chalcones by derivatization. Quantitative structure-activity relationship (QSAR) studies of these compounds were performed using various spatial, electronic and physicochemical parameters. Genetic Function approximation with linear and spline options was used as the chemometric tool for developing the QSAR models.

Full text of DOI:10.1007/s00044-010-9305-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:184–191
DOI 10.1007/s00044-010-9305-6
ORIGINAL RESEARCH
Mosquito larvicidal studies of some chalcone analogues and their
derived products: structure–activity relationship analysis
Naznin A. Begum
Kunal Roy
•
Nayan Roy
•
Rajibul A. Laskar
•
Received: 16 June 2009 / Accepted: 13 January 2010 / Published online: 2 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of chalcone analogues and some of
their derivatives were synthesized and subjected to the
mosquito larvicidal study. Chalcones having electron
releasing group(s) on either ring A or ring B showed high
toxicity. Electron withdrawing group(s), especially at ring
B, reduced the activity of chalcones. The activity was
abruptly decreased due to replacement of ring A by CH3,
extension of conjugation or blocking of a,b-unsaturated
ketone part of chalcones by derivatization. Quantitative
structure–activity relationship (QSAR) studies of these
compounds were performed using various spatial, elec-
tronic and physicochemical parameters. Genetic Function
approximation with linear and spline options was used as
the chemometric tool for developing the QSAR models.
one billion people in the developing countries are at risk.
Mosquito of Culex species is mainly the intermediate host
and vector of Bancroftian filariasis (Kumar and Clark
2005). Diethylcarbamazine (DEC) kills both adult worms
and microfilariae. However, serious allergic responses may
occur as the parasites are killed and particular care is
needed when one is using DEC in areas endemic for loiasis
(lymphatic filariasis) (Kumar and Clark 2005). In Indian
subcontinent, filariasis is quite common and Culex quin-
quefasciatus is the most prevalent species of mosquito in
this region.
One of the primary ways to prevent this deadly disease is
the control of mosquito larvae, for which several insect
growth regulators, e.g., diflubenzuron and methoprene are
used extensively along with other insecticides like organo-
chlorinated compounds, organo-phosphates and carbamate
type of compounds (Yang et al., 2002; Chang et al., 2003;
Frear, 1955). But the constant and repeated applications of
these controlling agents have some grave consequences
toward the agriculture and public health programs including
disruption the natural and biological control system, out-
break of other insect species, wide spread development of
resistance, and undesirable effects toward the nontarget
animals, e.g., acute poisoning and high mammalian toxicity
Keywords Chalcones ꢀ Culex quinquefasciatus ꢀ
Mosquito larvicidal activity ꢀ QSAR
Introduction
Lymphatic filariasis, which may be caused by different
species of filarial worm, e.g., Wuchereria bancrofti, has a
scattered distribution in the tropics and subtropics. Nearly
(Yang et al., 2002; Chang et al., 2003; Frear, 1955). Thus, the
unprecedented environmental persistence of these insecti-
cides forced us to realize that they cannot be used indefinitely
and in exponentially increasing quantities. Hence there is a
tremendous need for new strategies for mosquito larval
control which will be safe, cheaper, and more effective.
Chalcones are structurally simple compounds of the
flavonoid family and are present in variety of plant species
N. A. Begum (&) ꢀ N. Roy ꢀ R. A. Laskar
Bio-Organic Chemistry Laboratory, Department of Chemistry,
Siksha Bhavana, Visva Bharati, Santiniketan 731 235, West
Bengal, India
e-mail: nazninab@gmail.com
K. Roy (&)
Drug Theoretics and Cheminformatics Laboratory, Department
of Pharmaceutical Technology, Jadavpur University, Kolkata
(Agarwala, 1989). Not only that, they can be readily syn-
thesized in laboratory by Claisen-Schmidt reaction which
is very easy and simple to conduct as well as inexpensive.
700 032, India
e-mail: kroy@pharma.jdvu.ac.in; kunalroy_in@yahoo.com
1
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Med Chem Res (2011) 20:184–191
185
Various substitution patterns can easily be incorporated on
the two aromatic rings of chalcone to give large number of
analogues which may have potential activity. Chemically
chalcone is 1,3-diphenyl-2-propen-1-one. Depending on the
substitution pattern on the two aromatic rings, a wide
spectrum of pharmacological activities have been observed
for chalcones (Liu et al., 2001) encompassing anti-malarial
In the present study, a series of chalcones (1–28)
(Table 1) were synthesized by (i) varying the substitution
pattern on ring A and ring B of chalcone (1,3-diphenyl-2-
propen-1-one), (ii) varying the length of the conjugation
in the a,b-unsaturated ketone part, and (iii) by blocking
the a,b-unsaturated ketone part of chalcone by derivati-
zation. Then, these products were evaluated for their
mosquito larvicidal activity. Structure–activity relation-
ship study of these synthesized compounds was also done
based on the relevant physicochemical, spatial, and
electronic parameters for these compounds. This would
be our guiding tool for further exploration and lead
optimization. Genetic function approximation (GFA)
method with linear and spline options was applied as the
chemometric tool to develop the QSAR models which
would give us clear idea about the relationship between
the larvicidal activity and the structural patterns of these
compounds.
(
Liu et al., 2001; Go et al., 2004), anti-leshmanial, anti-
fungal and immunosuppressive (Boeck et al., 2006), anti-
inflammatory (Herencia et al., 1998) and anti-miotic (Ducki
et al., 1998) properties. Though chalcones have been widely
studied, to our knowledge there is a lack of quantitative-
structure–activity relationship study of the mosquito larvi-
cidal activity of chalcones along with their derived prod-
ucts. This made us interested to study the larvicidal
activities of some chalcone-type compounds with varying
substitution pattern along with some of their derived prod-
ucts against the larvae of Culex quinquefasciatus.
Table 1 Larvicidal activities of
Compound
-3
)
LC50 (lmole dm
chalcones and some of the
a
derived products
(
(
(
(
(
2E)-1,3-diphenylprop-2-en-1-one (1)
90.00
55.00
2E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (2)
2E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one (3)
2E)-3-(4-hydroxyphenyl-3-methoxyphenyl)-1-phenylprop-2-en-1-one (4)
2E)-3-(4-hydroxyphenyl-3-methoxyphenyl)-1-(2-hydroxyphenyl)prop-
104.00
1474.00
684.90
2
-en-1-one (5)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
2E)-3-(3-nitrophenyl)-1-phenylprop-2-en-1-one (6)
994.40
526.60
5.00
2E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one (7)
2E)-3-(1,3-benzodioxol-5-yl)-1-phenylprop-2-en-1-one (8)
2E)-3-(1,3-benzodioxol-5-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (9)
2E)-1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-one (10)
2E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (11)
2E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (12)
2E)-1-(4-hydroxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (13)
2E)-1-(2-hydroxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (14)
2E)-3-(4-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (15)
2E)-1-(4-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one (16)
2E)-3-(furan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (17)
3E)-4-phenylbut-3-en-2-one (18)
986.10
238.00
5.00
959.50
91.00
881.60
81.00
89.00
19.00
479.00
2064.40
437.00
1121.10
2134.50
2531.30
465.00
2344.10
2087.90
345.00
2638.20
1E,4E)-1,5-diphenylpenta-1,4-dien-3-one (19)
2E,4E)-1,5-diphenylpenta-2,4-dien-1-one (20)
2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (21)
Phenylhydrazone of 1 (22)
,4-Dinitrophenylhydrazone of 1 (23)
Phenylhydrazone of 18 (24)
,4-Dinitrophenylhydrazone of 18 (25)
2
2
Semicarbazone of 18 (26)
Oxime of 18 (27)
a
A and B indicate ring systems
in the general structure of
chalcones
2
,4-Dinitrophenylhydrazone of 19 (28)
123

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Med Chem Res (2011) 20:184–191
Results and discussion
showed 100% mortality. Its LC is also very low with a
5
0
-
3
value of 19 lmole dm . In this compound, ring B is
replaced by a furan ring. Hydroxychalcones (2, 3, 15, and
Chemical synthesis
16) showed high activity.
Hydroxylated chalcones showed potent activity espe-
Total 28 compounds (chalcones along with some of the
derived products) were synthesized and tested for mosquito
larvicidal activity against the third instar larvae of Culex
quinquefasciatus. Table 1 displays structures as well as the
0
cially when there is –OH group at 2 -position on ring A as
in the cases of compounds (2), (15), and (17). In general, it
was noticed that the larvicidal activity of chalcones was
reduced when there was electron withdrawing group on
ring B, e.g., (6), (7), (12), and (14). Compounds (13) and
-
3
LC50 values (lmole dm ) of these compounds against the
third instar larvae of Culex quinquefasciatus.
Compounds (1–17 and 20–21, except 4 and 5) were
prepared by Claisen-Schmidt reaction in the absence of
solvent. Here the method of Toda et al. (1990) has been
employed with some modifications. In this method, no
organic solvent was used unless in the case of recrystalli-
sation of the crude product. Moreover, it requires no pre-
formed enolate. No heating, stirring, or cooling were
required here.
(16) showed high activity though there is –NO group at 4
2
and 3 positions, respectively, on ring B. But in addition
to –NO2 group, there is also one –OH group at the
0
4 -position on ring A; which may be the cause of their
enhanced activity. But when there is a –NO group on ring
2
0
B and at the same time there is a –OH group at 2 -position
on ring A, low activity was observed as in the case of (7)
and (14). It was observed that when there is a chlorine
substituent at the 4-position of ring B, activity is enhanced,
e.g., (11). Another trend was observed: when there was
electron releasing group on both rings A and B, the activity
of chalcones was abruptly decreased as in the case of (2E)-
3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one
Mosquito larvicidal activity
On the basis of larvicidal assay, we have divided these
compounds into three main categories:
(
4) and (2E)-3-(4-hydroxy-3-methoxyphenyl)-1-(2-hydroxy-
phenyl)prop-2-en-1-one (5). Activity was also reduced when
ring A is replaced by a methyl group or C H –CH=CH–
(
(
(
1) Compounds showing 100% mortality of mosquito
-
3
larvae at 100 lg cm
concentration at 30 ± 2°C
after 24 h. There are five compounds under this
6
5
group, e.g., 4-phenyl-but-3-en-2-one (18) and 1,5-diphe-
nyl-penta-1,4-dien-3-one (19). Larvicidal activity was also
reduced when ring B was replaced by C H –CH=CH–
category; which are (1), (2), (3), (17), and (15).
2) Compounds, which showed no mortality of mosquito
-
3
6 5
larvae at 100 lg cm
after 24 h. There are three compounds under this
concentration at 30 ± 2°C
group, e.g., compounds (20) and (21). But it was observed
that when ring B is replaced by a furan ring, the activity
was highly enhanced as in the case of compound (17).
However, compound (18) showed higher activity than (19),
category; which are (23), (25), and (28).
3) Compounds which showed variations of % mortality
-
3
of mosquito larvae at 100 lg cm concentration at
0 ± 2°C after 24 h are included in this category.
These are (4), (5), (6), (7), (8), (9), (10), (11), (12),
13), (14), (16), (18), (19), (20), (21), (22), (24), (26),
(
20), and (21). Actually in (19), (20), and (21), there was an
3
extension of conjugation of the a,b-unsaturated ketone part
of chalcone and this might be the cause of their lower
larvicidal activity. When the a,b-unsaturated ketone part
was blocked by derivatization, activity was drastically
reduced as in the case of compounds (22), (23) (25), and
(
and (27). Total 20 compounds are included in this
category. These twenty compounds showed % mor-
tality ranging from a very low value (*10%) to a
very high value (*90%).
(28), though some toxicity was noticed in case of (27). This
result was in agreement with a previous report (Das et al.,
Present toxicity study showed that chalcones having
2005).
electron releasing group on either ring A or on ring B
showed high activities. Analysing the % mortality and
LC50 values for all the compounds, it is evident that the
lead compounds were (2E)-3-(4-chlorophenyl)-1-phenyl-
prop-2-en-1-one (11), i.e. 4-chlorochalcone, which has a
chlorine substituent at 4 position of ring B and (2E)-3-(1,3-
benzodioxol-5-yl)-1-phenylprop-2-en-1-one (8) with a
methylenedioxy group at 3,4-position of ring B. Both of
these two compounds showed potent larvicidal activity
Structure–activity relationship study
Biological activity of a compound depends on the types
and magnitude of interactions between the target site and
the molecule. Various structural attributes of the drug
molecule like electronic distribution, steric feature, etc., are
the determining factors regulating the interactions. Quan-
titative structure activity relationship (QSAR) studies (van
de Waterbeemd, 1995a, b) are based on the notion that
biological activity is function of structure and/or property.
-
3
having LC50 value of 5 lmole dm . On the other hand,
2E)-3-(furan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one (17),
(
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Med Chem Res (2011) 20:184–191
187
The goals of QSAR studies include better understanding of
the modes of actions, prediction of new analogues with
better activity, and optimization of the lead compound to
reduce toxicity and increase selectivity. In order to have a
clear understanding about the relationship between the
larvicidal activity and structures of the synthesized chal-
cones, we have performed a preliminary QSAR study using
structural (numbers of rotatable bonds, hydrogen bond
donors, and acceptors and chiral centers), physicochemical
pLC50 ¼ 19:913ðꢃ4:722Þ ꢁ 0:025ðꢃ0:005ÞJurs PPSA 1
ꢁ
6:784ðꢃ2:125ÞJurs RPCG þ 0:692ðꢃ0:312ÞHOMO
2 2
n ¼ 28; R ¼ 0:590; R ¼ 0:538; F ¼ 11:5ðdf3; 24Þ;
a
2
s ¼ 0:529; Q ¼ 0:455; PRESS ¼ 8:9
ð1Þ
The standard errors of the regression coefficients are
shown within parentheses. All regression coefficients are
significant at 95% level. Equation 1 could explain 53.8%
of the variance of the larvicidal activity while the predicted
variance was found to be 45.5%.
[
lipophilicity (AlogP98) and molar refractivity (MolRef)],
spatial (radius of gyration, Jurs descriptors, shadow indi-
ces, area, density, and molar volume) and electronic
Equation 1 contains two Jurs descriptors and one elec-
tronic parameter, which is energy of the highest occupied
molecular orbital (HOMO). Jurs descriptors combine shape
and electronic information to characterize the molecules.
The descriptors are calculated by mapping atomic partial
charges on solvent-accessible surface areas of individual
atoms. Both Jurs descriptors present in Eq. 1 show negative
coefficients while the HOMO energy shows positive
contribution.
(
principal moment of inertia, dipole moment, energies of
highest occupied and lowest unoccupied molecular orbi-
tals, and superdelocalizability) parameters. For the QSAR
-
3
work, the larvicidal concentration data (lg cm ) were first
converted into the molar scale and then the negative log-
arithm of the inverse of concentration [pLC (M)] was
5
0
used as the response variable.
Genetic function approximation with linear and spline
options was used as the chemometric tool for developing
the QSAR models. GFA (Rogers and Hopfinger, 1994)
involves a combination of multivariate adaptive regression
splines (MARS) algorithm with genetic algorithm to
evolve a population of equations. In the GFA technique, an
initial population of equations is first generated by random
selection of descriptors followed by random crossover
between pairs of equations chosen from the population
whereby new progeny equations are formed. The fitness of
the equations formed is measured by the ‘‘lack of fit’’
Jurs_PPSA_1 is partial positive surface area, which is
the sum of the solvent-accessible surface areas of all pos-
itively charges atoms. Jurs_RPCG is the partial charge of
the most positive atom divided by the total positive charge.
The negative coefficients of these terms indicate that
compounds with higher positively charged surface areas
(because of presence of electron withdrawing substituents)
will have less larvicidal activity.
HOMO is the energy of highest occupied molecular
orbital of a molecule. It is crucially important in governing
molecular reactivity and properties. Molecules with high
HOMO energies are more able to donate their electrons and
are hence relatively reactive compared to molecules with
low-lying HOMOs; thus descriptor HOMO should measure
the nucleophilicity of a molecule. The positive coefficient
of HOMO in Eq. 1 indicates that electron withdrawing
substituents are not favorable for the activity.
(
LOF) value. The equations with lower LOF value show
higher significance. The LOF is given by:
LSE
LOF ¼
;
À
Á
2
cþdꢂp
1
ꢁ
M
where LSE is the least square error, c is the number of
basis functions, d is the smoothing parameter which was
set at the default value of 1, p is the number of
descriptors, and m is the number of observations in the
training set. GFA builds models not only with linear
functions, but also use higher order polynomials, splines,
etc. The spline option enables nonlinear modeling of
activity as the function of the different variables. For
example, \f(x) - a[ is equal to zero if the value of
GFA with spline option gave the following best equation:
pLC ¼ 4:068ðꢃ0:326Þꢁ24:477ðꢃ4:145Þ
50
h1:120ꢁDensityiþ7:687ðꢃ1:667Þ
hJurs FNSA 2þ0:697iꢁ0:001ðꢃ0:0:001ÞJurs PPSA 2
2
2
n ¼ 28;R ¼ 0:709;R ¼ 0:672;F ¼ 19:5ðdf3;24Þ;
a
2
s ¼ 0:446;Q ¼ 0:633;PRESS ¼ 6:0
ð2Þ
\f(x) - a[ is negative, else it is equal to f(x) - a. The
constant ‘a’ is called the knot of the spline.
Note that on using spline option, there has been con-
siderable increase in statistical quality in comparison to
Eq. 1. The predicted variance of Eq. 2 is 63.3% compared
to 45.5% in case of Eq. 1.
Descriptor calculation and model development was done
using Cerius2 software (http://www.accelrys.com/) running
on a Silicon Graphics O2 workstation. The values of
important descriptors are shown in Table 2.
Density is a 3D spatial descriptor, which is defined as
the ratio of molecular weight to molecular volume. The
density reflects the types of atoms and how tightly they are
Genetic function approximation with 5,000 iterations
and linear terms generated the following best equation:
123

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Med Chem Res (2011) 20:184–191
Table 2 Values of important descriptors and observed and calculated larvicidal activity of synthesized chalcones
Sl. No.
Descriptors
Larvicidal activity [pLC50]
a
b
Jurs-PPSA-1
Jurs-PPSA-2
Jurs-RPCG
Density
HOMO
Jurs-FNSA-2
Obs.
Calc.
Calc.
1
2
3
4
5
6
7
8
9
262.683753
269.847858
278.61443
252.79364
333.418953
335.396975
464.497803
545.563021
380.533502
440.421277
397.922957
483.985482
310.793236
220.090305
380.923501
432.003539
458.484168
292.431791
424.237472
356.834536
251.365425
305.957081
320.504267
406.075985
541.029735
964.70279
0.192591
0.176666
0.181327
0.148406
0.125165
0.345244
0.296288
0.132566
0.130606
0.182561
0.196353
0.345318
0.302637
0.296341
0.179342
0.302582
0.158154
0.192591
0.167687
0.170505
0.16049
1.02629
-11.996
-0.39215
-0.50744
-0.47318
-0.5438
4.046
4.26
3.669
3.642
3.542
3.12
3.755
3.686
3.898
3.47
1.064626
1.062644
1.075214
1.100116
1.119427
1.14441
-11.9302
-11.7095
-11.2893
-11.4136
-12.4616
-12.4428
-11.2293
-11.1764
-11.9079
-11.9415
-12.5628
-12.3171
-12.435
3.983
2.831
3.164
3.002
3.25
315.655653
312.68571
-0.68522
-0.88399
-1.05295
-0.57585
-0.69747
-0.52502
-0.47314
-0.87586
-1.02922
-1.01143
-0.60603
-1.04386
-0.54441
-0.40197
-0.4523
3.267
3.134
3.518
4.053
3.978
3.867
4.427
3.056
3.551
3.285
4.403
3.71
2.871
3.497
3.41
230.122828
228.571569
284.61765
1.114274
1.142259
1.06047
5.301
3.006
3.623
5.301
3.018
4.041
3.055
4.092
4.051
4.721
3.32
4.279
3.345
3.483
5.464
3.499
3.423
3.383
4.334
3.434
4.563
3.713
2.976
2.956
2.781
2.505
2.626
3.13
289.581378
259.968908
233.168295
230.417008
229.016357
237.997626
240.260772
224.849464
258.536841
261.199661
287.961821
294.884399
298.560574
384.279004
331.850475
352.729549
305.38771
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
a
1.120704
1.119554
1.146881
1.147448
1.149717
1.145965
1.1135
-11.8843
-12.2394
-10.5769
-11.996
4.99
1.027586
1.016621
1.015957
1.049525
1.026731
1.147253
1.003391
1.152992
1.045263
1.040324
1.132231
3.707
3.339
3.485
3.503
2.349
2.585
2.864
3.109
3.263
3.36
-11.7946
-11.3031
-11.2413
-10.0302
-10.9925
-10.1393
-11.0301
-10.8069
-11.0415
-10.7025
2.685
3.359
2.95
-0.44996
-0.56303
-0.50007
-1.47362
-0.37092
-1.23996
-0.46336
-0.41403
-1.50889
0.135005
0.197215
0.165455
0.21472
2.67
2.597
3.333
2.63
405.185612
815.398821
440.25256
2.85
301.907006
292.272598
355.694528
0.227714
0.225437
0.189501
2.68
3.392
3.827
2.46
321.939157
1076.11087
3.462
2.579
2.236
From Eq. 1
b
From Eq. 2
packed in a molecule. The negative coefficient of the term
1.120-Density[ indicates that the larvicidal activity
and negative coefficients of the terms \Jurs_FNSA_2 ?
0.697[ and Jurs_PPSA_2 indicate that there should be
optimum charge distribution over the molecular surface for
the optimum activity. The calculated activity values
obtained from Eqs. 1 and 2 are shown in Table 2.
\
increases when the value of Density is more than 1.120.
The positive coefficient of \Jurs_FNSA_2 ? 0.697[
indicates that the value of Jurs_FNSA_2 should be less
negative than -0.697. Jurs_FNSA_2 is fractional charged
partial negative surface area which is obtained by dividing
total charge weighted negative surface area (partial nega-
tive solvent-accessible surface area multiplied by total
negative charge) by the total solvent-accessible surface
area.
Conclusion
Present investigation has clearly shown that certain chal-
cone analogues had potent mosquito larvicidal activity.
Most of the hydroxyl chalcones showed toxicity against the
third instar larvae of Culex quinquefasciatus. The favorable
chemical structures were found to be a hydroxyl substituent
Jurs_PPSA_2 is total charge weighted positive surface
area which is obtained by multiplying partial positive sol-
vent-accessible surface area with total positive charge. The
negative coefficient of Jurs_PPSA_2 indicates that it has
negative contribution on the larvicidal activity. The positive
0
in ring A at 2 -position which may be hydrogen bonded
with the electron pair on a,b-unsaturated ketone moiety,
1
23

Med Chem Res (2011) 20:184–191
189
thereby decreasing the electrophilicity of this part. Pres-
0
as the starting materials; except in the case of compounds
(17), (20) and (21). For compound (17), the starting
materials were o-hydroxyactetophenone and furfuralde-
hyde. Compound (20) was prepared by this solid phase
aldol condensation reaction between acetophenone and
cinnamaldehyde. For compound (21), o-hydroxyactetoph-
enone and cinnamaldehyde were the starting materials.
Compounds (4) and (5) were synthesized by the method
of Liu et al. (2001) with slight modification. Vanillin
ence of hydroxyl group at 2 -position of ring A and
replacement of ring B (phenyl) by furan ring also increased
the larvicidal activity. Besides that 3-chlorine substitution
in ring B was also another feature of favorable activity.
Presence of methylenedioxy group at 3,4 positions of ring
B also enhanced the larvicidal activity of chalcone-type
compound. However, extension of conjugation and block-
ing of a,b-unsaturated ketone part of chalcones had bad
effects toward the activity of these compounds. In con-
clusion, QSAR analysis suggests that charge distribution
on molecular surface and surface area are important
determinants of the larvicidal activity. The derived models
suggest that for the good larvicidal activity positively
charged surface areas of the compounds should be limited.
Moreover, there should be a balanced distribution of
positive and negative charges on the molecular surfaces of
the compounds.
3
(10 mmol) was dissolved in 10 cm methanol. A metha-
3
nolic solution of NaOH (1% w/v, 10 cm ) was added to it
and the reaction mixture was stirred at 0–5°C for 30 min. A
methanolic solution of acetophenone [in case of (5),
3
o-hydroxyactetophenone] (10 mmol, 10 cm ) was added
drop wisely and the reaction mixture was stirred at ice cold
condition for 3 h. Orange red colored solution was
obtained; which was diluted with water, neutralized with
HCl and then extracted with ether. The organic layer was
dried with anhydrous Na SO and removed by evaporation
2
4
under reduced pressure to yield bright yellow precipitate of
(4) and (5). In both case, the crude product was recrystal-
lized from ethanol. Yields were in the range of 61–62%.
In compounds (18) and (19), ring A of chalcone has
been replaced by –CH group and C H –CH=CH– group,
Experimental
General experimental procedure
3
6 5
Melting points were determined using an electrothermal
apparatus and were uncorrected. All reagents used were of
A.R. Grade and supplied by E. Merck. All the synthesized
products were purified by recrystallization from ethanol
and their purity was routinely checked by thin layer chro-
matography. Thin layer chromatography of the compounds
was carried out in silica gel GF 254 precoated plates using
CHCl or CHCl and petroleum ether (60–80°C) mixture
respectively. These two compounds were prepared by
Claisen–Schmidt reaction between acetone and benzalde-
hyde in different proportion in dilute alkali medium fol-
lowed by recrystalization in ethanol medium (Furniss et al.,
1984), yield: 77.0%. M.p. of (18) was found to be 42°C
[literature m.p. 42°C (Furniss et al., 1984)]. In case of (19),
the yield was 92.19% and m.p. of (19) was found to be
112°C [literature m.p. 112°C (Furniss et al., 1984)]. For the
preparations of compounds (22–28), standard methods with
slight modifications were followed (Furniss et al., 1984).
The yield was in the range of 70.00–80.00%; the structures
of these compounds were confirmed by comparing their
m.p. data with literature data (Pollock and Stevens, 1965;
Furniss et al., 1984).
3
3
(
5:2 or 4:1) as eluting solvents. The structures of the
compounds were confirmed on the basis of melting point
1
1
and H NMR data. H NMR spectra were recorded at
00 MHz in a Varian-400 spectrometer in CDCl3 or
4
MeOH-d solutions using tetramethylsilane as an internal
4
1
standard. H NMR spectra revealed that all the chalcones
were geometrically pure and configured E (JHa-Hb
5–16 Hz).
=
1
Spectroscopic data for the synthesized compounds
Chemical synthesis
(2E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (2):
1
H NMR (400 MHz, CDCl ): d 12.79 (bs, 1H, OH), 7.89
3
For compound (1), a slurry mixture of benzaldehyde
(d, 1H, J = 16.10 Hz, H ), 7.63 (d, 1H, J = 16.10 Hz,
b
0
(
(
10 mmol), acetophenone (10 mmol), and solid NaOH
10 mmol) were ground together by pestle in a mortar at r.t.
H ), 7.03 (dd, 1H, J = 1.20 Hz, 8.4 Hz, H-3 ), 7.93 (dd,
a
0
0
1H, J = 1.20 Hz, 8.40 Hz, H-6 ), 7.49–7.51 (m, 1H, H-4 ),
0
for 2–3 min whereby the reaction mixture turned into pale
yellow solid. The solid was washed with aq. acid solution
and recrystallised from ethanol. The yield was 91.2%. M.p.
6.91–6.95 (m, 1H, H-5 ), 7.41–7.49 (m, 3H, H-3, H-4, H-
5), 7.64–7.67 (m, 2H, H-2, H-6); yellow crystals; Yield
88.0%; m.p. 88–89°C.
(2E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one
5
8°C [literature m.p. 58°C (Pollock and Stevens, 1965)].
The same procedure was also adopted for the synthesis
1
(3): H NMR (400 MHz, CDCl ): d 6.58 (bs, 1H, OH),
3
of other substituted chalcones (2–3, 6–17, and 20–21) using
appropriately substituted acetophenone and benzaldehydes
8.17 (d, 1H, J = 16.40 Hz, Hb), 7.71 (d, 1H,
0
J = 16.40 Hz, H ), 6.90 (d, 1H, J = 8.00 Hz, H-6 ),
a
123

1
90
Med Chem Res (2011) 20:184–191
7
4
3
.55–7.59 (m, 2H, H-4, H-5), 6.94 (t, 1H, J = 8.00 Hz, H-
OH), 7.69 (d, 1H, J = 15.20 Hz, H ), 7.56 (d, 1H,
b
0
0
0
), 7.28 (d, 1H, J = 8.00 Hz, H-2 ),7.47–7.51 (m, 2H, H-
0
J = 15.20 Hz, H ), 7.92 (dd, 1H, J = 1.20 Hz, 8.20 Hz,
a
0
0
, H-5 ), 8.01–8.03 (m, 2H, H-2, H-4, H-5), greenish
H-6 ), 6.94 (dd, 1H, J = 1.20 Hz, 8.20 Hz, H-3 ),
6.99–7.01 (m, 2H, H-3, H-5), 6.53 (dd, 1H, J = 1.80 Hz,
yellow crystals; yield 80.0%; m.p. 150°C.
2E)-3-(3-nitrophenyl)-1-phenylprop-2-en-1-one (6):
H NMR (400 MHz, CDCl ): d 7.84 (d, 1H, J = 16.00 Hz,
0
0
(
3.60 Hz, H-4), 7.45–7.49 (m, 2H, H-4 , H-5 ); deep yellow
1
crystals; yield 68.0%; m.p. 102–103°C.
(2E,4E)-1,5-diphenylpenta-2,4-dien-1-one (20):
3
1
H ), 7.67 (d, 1H, J = 16.00 Hz, H ), 7.92 (d, 1H,
b
H
a
J = 7.60 Hz, H-6), 8.23–8.51 (m, 2H, H-2, H-4), 7.51–7.60
0
NMR (400 MHz, CDCl ): d 7.64 (d, 1H, J = 15.8 Hz, H ),
a
3
0
0
0
0 0
7.97–7.98 (m, 3H, H-2 , H-6 , H ), 7.49–7.64 (m, 7H, H-2,
b
(
m, 4H, H-5, H-3 , H-4 , H-5 ), 8.02–8.05 (m, 2H, H-2 ,
0
0
0
0
H-6 ), white crystals; yield 88.0%; m.p. 162–163°C.
H-3, H-5, H-6, H-3 , H-4 , H-5 ), 7.33–7.40 (m, 3H, H-c, H-
d, H-4); greenish yellow crystals; yield 89.0%; m.p.
99–100°C.
(
2E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-
1
1-one (7): H NMR (400 MHz, CDCl ): d 12.60 (bs, 1H,
OH), 7.94 (d, 1H, J = 15.60 Hz, H ), 7.78 (d, 1H,
3
(2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-
b
1
J = 15.60 Hz, H ), 8.28–8.53 (m, 2H, H-2, H-4), 7.05 (dd,
a
1-one (21): H NMR (400 MHz, CDCl ): d 12.88 (bs, 1H,
3
0
1
H, J = 0.80 Hz, 8.40 Hz, H-3 ), 7.65 (dd, 1H,
0
OH), 7.84 (d, 1H, J = 15.60 Hz, H ), 7.69 (d, 1H,
b
0
J = 0.80 Hz, 8.40 Hz, H-6 ), 6.95–6.99 (m, 1H, H-5 ),
0
J = 15.60 Hz, H ), 7.74 (dd, 1H, J = 1.60 Hz, 8.00 Hz,
a
0
0
7
.50–7.52 (m, 1H, H-4 ), 7.53–7.55 (m, 2H, H-5, H-6);
H-6 ), 7.01 (dd, 1H, J = 1.60 Hz, 8.00 Hz, H-3 ),
0
yellow crystals; yield 52.0%; m.p. 164°C.
2E)-3-(1,3-benzodioxol-5-yl)-1-phenylprop-2-en-1-
7.47–7.51 (m, 3H, H-4 , H-2, H-6),7.33–7.36 (m, 5H, H-3,
0
(
H-4, H-5, H-5 ), 6.93 (t, 1H, J = 12.10 Hz, 10.10 Hz, H-
c), 6.98 (d, 1H, J = 12.10 Hz, H-d); deep yellow crystals;
yield 88.3%; m.p. 156–157°C.
1
one (8): H NMR (400 MHz, CDCl ): d 7.74 (d, 1H,
3
J = 15.60 Hz, H ), 7.37 (d, 1H, J = 15.60 Hz, H ), 6.01
b
a
(
s, 2H, –O–CH –O–), 6.84 (d, 1H, J = 8.00 Hz, H-5),
2
0
0
7
.09–7.15 (m, 2H, H-2, H-6), 7.46–7.57 (m, 3H, H-3 , H-4 ,
0
Method of mosquito larvicidal assay
H-5 ); pale yellow crystals; yield 92.0%; m.p. 121–122°C.
(
2E)-3-(1,3-benzodioxol-5-yl)-1-(2-hydroxyphenyl)
1
Larvae of Culex quinquefasciatus were reared at 30 ± 2°C
with a photo period of 12 h light and 12 h dark and at
70 ± 10% relative humidity. Fifteen percentage yeast
suspension was used as the growth medium. Larvicidal
tests of the pure compounds (1–28) were performed on the
third instar larvae of Culex quinquefasciatus in water
medium according to the procedure of WHO (Rahuman
et al., 2008) with some modification and as per the method
of Cheng et al. (2004). Then, 0.5% alcoholic solution of
each compound was added in thin stream with gentle
stirring into the beaker containing 25 third instar larvae in
the degassed distilled water, so that the final concentration
prop-2-en-1-one (9): H NMR (400 MHz, CDCl ): d
2.88 (bs, 1H, OH), 7.85 (d, 1H, J = 15.60 Hz, H ), 7.497
b
3
1
(
(
d, 1H, J = 15.60 Hz, H ), 6.03 (s, 2H, –O–CH –O–), 7.90
a 2
0
dd, 1H, J = 1.60 Hz, 8.20 Hz, H-6 ), 7.15 (dd, 1H,
0
J = 1.60 Hz, 8.20 Hz, H-3 ), 6.90–6.94 (m, 3H, H-2,H-5,
0
0
H-6), 7.15–7.17 (m, 1H, H-5 ), 7.45–7.47 (m, 1H, H-4 );
yellow crystals; yield 50.0%; m.p. 133–134°C.
(
2E)-1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-one
1
(
10): H NMR (400 MHz, CDCl ): d 5.90 (bs, 1H, OH),
3
7
1
.81 (d, 1H, J = 15.60 Hz, H ), 7.54 (d, 1H, J =
b
0
0
5.60 Hz, H ), 7.98–8.00 (m, 2H, H-2 , H-6 ), 7.61–7.63
a
-
3
(
m, 3H, H-3, H-4, H-5), 7.39–7.40 (m, 2H, H-2, H-6),
became 100 lg cm at 30 ± 2°C. In the similar manner,
same amount of alcohol was added to the control. Five
replications were performed for each set. Percent (%)
mortality was calculated after 24 h during which no foods
was given to the larvae. The % mortality was corrected for
control mortality applying Abbott’s formula (Yang et al.,
2002; Abbott, 1925). The % mortality of the larvae was
also measured at different concentrations at 30 ± 2°C and
probit analysis (Finney, 1971) for these compounds were
0
0
6
8
.91–6.93 (m, 2H, H-3 , H-5 ),; pale yellow crystals; yield
8.0%; m.p. 172–173°C.
(2E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one(11):
1
H NMR (400 MHz, CDCl ): d 7.76 (d, 1H, J = 16.00 Hz,
H ), 7.55–7.58 (m, 3H, H-2 , H-6 H ), 7.47–7.51 (m, 3H,
a
3
0
0
b
0
0
0
H-3 , H-4 , H-5 ), 7.98–8.01 (m, 2H, H-3, H-5), 7.37–7.39
m, 2H, H-2, H-6); pale yellow crystals; yield 88.3%; m.p.
(
1
13°C.
2E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (12):
-
3
(
done accordingly to determine their LC50 (lg cm ) val-
ues. Analysis of variance (ANOVA) calculations were
done for those compounds which showed variations of %
1
H NMR (400 MHz, CDCl ): d 7.82 (d, 1H, J = 16.40 Hz,
H ), 7.65 (d, 1H, J = 16.40 Hz, H ), 7.67–7.79 (m, 3H, H-
b
3
a
0
0
0
0
-3
2
, H-6 ), 7.52–7.54 (m, 2H, H-3 , H-5 ), 7.59–7.61 (m, 1H,
0
mortality at 100 lg cm concentration and were appar-
H-4 ), 8.26–8.28 (m, 2H, H-3, H-5), 8.01–8.03 (m, 2H, H-
ently found not to be equivalent. From ANOVA calcula-
tions, the critical difference (CD) values were determined.
The order of toxicity was determined on the basis of CD
and LC50 values.
2
, H-6); white crystals; yield 88.0%; m.p. 164°C.
2E)-3-(furan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-
(
1
one (17): H NMR (400 MHz, CDCl ): d 12.88 (bs, 1H,
3
1
23

Med Chem Res (2011) 20:184–191
191
Acknowledgements The authors are thankful to the University
Grants Commission, India for the financial support (UGC M.R.P.
Grant No. 33-290/2007 (SR) to N.A.B.). Thanks are also due to DST-
FIST and UGC-SAP programmes of Department of Chemistry, Sik-
sha Bhavana, Visva Bharati University, Santiniketan, WB, India. We
would also like to thank Dr. G.K. Das, Reader, Department of
Chemistry, Siksha Bhavana, Visva Bharati University, Santiniketan,
WB, India for his help in statistical analysis. The authors gratefully
acknowledge the help provided by Prof. A. T. Khan, IIT-Guwahati,
Furniss BS, Hannaford AJ, Rogers V, Smith PWG, Tatchell AR
(1984) Vogel’s textbook of practical organic chemistry, 9th edn.
ELBS/Longman, London
Go ML, Liu M, Wilairat P, Rosenthal PJ, Saliba KJ, Kirk K (2004)
Antiplasmodial chalcones inhibit sorbitol induced hemolysis of
Plasmodium falciparum infected erythrocytes. Antimicrob
Agents Chemother 44:3241–3245
Herencia F, Ferrandiz ML, Ubeda A, Dominguez JN, Charris JE,
Lobo GM, Alcaraz MJ (1998) Synthesis and anti-inflammatory
activity of chalcone derivatives. Bioorg Med Chem Lett 8:
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Assam, India in recording the H NMR spectra.
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