Design, synthesis, and bioactivities screening of a diaryl ketone-inspired pesticide molecular library as derived from natural products

Article abstract of DOI:10.1111/j.1747-0285.2011.01082.x

Three natural products, 1,5-diphenylpentan-1-one, 1,5-diphenylpent-2-en-1-one, and 3-hydroxy-1,5-diphenylpentan-1-one, with good insecticidal activities were extracted from Stellera chamaejasme L. Based on their shared diaryl ketone moiety as 'pharmacophores', a series of diaryl ketones were synthesized and tested for insecticidal activity, acetylcholinesterase inhibitory activity, and antifungal activity. All synthesized compounds showed poor insecticidal and acetylcholinesterase inhibitory activities. Compound III with a furyl ring showed strong activities against plant pathogenic fungi. The IC₅₀ of compound (E)-1-(2,4-dichlorophenyl)-3-(furan-2-yl)- -prop-2-en-1-one (III₂) was 1.20mg/L against Rhizoctonia solani, suggesting its strong potential as a novel antifungal drug.

Full text of DOI:10.1111/j.1747-0285.2011.01082.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01082.x
Chem Biol Drug Des 2011; 78: 94–100
Research Article
Design, Synthesis, and Bioactivities Screening of
a Diaryl Ketone-Inspired Pesticide Molecular
Library as Derived from Natural Products
Hong Zhang1,2, Hong Jin3, Lan-zhu Ji1,
natural product guiding (1–5), protein structure, and biologic or
diversity orientation (6–18) to gain access to reveal novel chemical
structures.
Ke Tao4,*, Wei Liu5, Hao-yu Zhao4 and
Tai-ping Hou4,*
1Institute of Applied Ecology, Chinese Academy of Sciences,
Natural products can be regarded as evolutionarily selected ligands
for ligand-sensing cores of proteins. They emerge via biosynthesis
by proteins and often fulfill various biologic functions through inter-
action with multiple proteins (19,20). Their underlying structures
define structural prerequisites for binding to proteins and biologic
activity. Because the entire biologically relevant chemical space
may be larger than the structural space occupied by natural prod-
ucts, their structural scaffolds represent the biologically relevant
and prevalidated fractions of chemical structure space explored by
nature so far. Consequently, compound collections designed to
mimic the structure and property of natural products will have
greater biologic relevance than the libraries obtained on the basis
of chemical feasibility alone. Therefore, natural products–guided
compound library development should follow this guiding principle
for pesticides identification in agrochemical research (1,19–22)
(Figure 1).
Shenyang 110016, China
2Graduate School of the Chinese Academy of Sciences, Beijing,
100049, China
3College of Chemistry, Sichuan University, Chengdu Sichuan 610064,
China
4College of Life Sciences, Sichuan University, Chengdu Sichuan
610064, China
5Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu 610041, China
*Corresponding authors: Tai-ping Hou, houtp@scu.edu.cn; Ke Tao,
taokescu@163.com
Three natural products, 1,5-diphenylpentan-1-one,
1,5-diphenylpent-2-en-1-one, and 3-hydroxy-1,5-
diphenylpentan-1-one, with good insecticidal
activities were extracted from Stellera chamaej-
asme L. Based on their shared diaryl ketone moi-
ety as ’pharmacophores’, a series of diaryl ketones
were synthesized and tested for insecticidal activ-
ity, acetylcholinesterase inhibitory activity, and
antifungal activity. All synthesized compounds
showed poor insecticidal and acetylcholinesterase
inhibitory activities. Compound III with a furyl ring
showed strong activities against plant pathogenic
fungi. The IC50 of compound (E)-1-(2,4-dichlor-
ophenyl)-3-(furan-2-yl)- -prop-2-en-1-one (III2) was
1.20 mg ⁄ L against Rhizoctonia solani, suggesting
its strong potential as a novel antifungal drug.
Our group is devoted to the discovery, synthesis, and screening of
new pesticides. Stellera chamaejasme L. (Thymelaeaceae) is one
type of toxic Chinese herb. The root is used as 'Langdu' in tradi-
tional Chinese medicine. It displays therapeutic effects on some dis-
eases such as leucocythemia and stomach cancer (23). In recent
years, its insecticidal activity against some pests has drawn wide
attention (24,25). 1,5-diphenylpentan-1-one (compound a), 1,5-diphe-
nylpent-2-en-1-one (compound b), and 3-hydroxy-1,5-diphenylpen-
tan-1-one (compound c) are isolated from S. chamaejasme L.
Laboratory bioassays showed that compounds a and b had strong
contact activities and very good antifeedant activities against Aphis
gossypii and Schizaphis graminum (26). Contact activities (LC50) of
compounds a and b against aphids were 443 and 195 mg ⁄ L,
respectively, and the antifeedant activities (LC50) of compounds a
and b on aphids were 462 and 383 mg ⁄ L, respectively. Moreover,
at a dose of 2 g ⁄ kg per os, the two compounds did not cause any
toxic effects in mice, rats, or rabbits. Furthermore, compound b
showed an 83.6% inhibition against Ca2+-Mg2+-ATPase at
20 lmol ⁄ L and a 70% inhibition against acetylcholinesterase (AChE)
at 5 · 103 mg ⁄ L. Compound c acted on AChE with an inhibition
ratio of 78.5% at 162 mg ⁄ L (27,28).
Received 18 January 2010, revised 30 December 2010 and accepted for
publication 31 December 2010
Key words: antifungal activity, bioactivity, diaryl ketones, pesticide,
synthesis
The identification of efficient pesticides is the central topic of agro-
chemical research. The discovery of novel modulators of protein
function lies in the identification of appropriate starting points in
chemical structure for compound library development, which
could serve as 'leitmotifs' for the synthesis of biologically relevant
compounds. New strategies for library design now are focused on
A systematic study on the diaryl ketone compounds a, b, and c
revealed that the analogs bearing only aryl, no aryl, or no ketone
94

Design, Synthesis, and Bioactivities Screening of Diaryl Ketone
O
O
O
OH
A
B
C
Figure 1: Compounds a, b, and c from Stellera chamaejasme L.
moieties instead of diaryl ketone moiety show poor biologic activity.
Thus, we hypothesized that the diaryl ketone moiety might repre-
sent a 'privileged' pharmacophore structure, which conveyed bio-
logic relevance to compound collections derived thereof. In this
study, a compound collection with a diaryl ketone moiety as the
'pharmacophore' has been synthesized. Their insecticidal and anti-
fungal activities have been examined in an effort to reveal their
potential use in agrochemistry.
immersed in the solutions and allowed to air dry in the petri dishes.
Healthy and apterous aphids were gently dislodged from the under-
sides of leaves onto the treated leaves. Fifty aphids were subjected
to each bioassay, and the entire experiment was replicated three
times. Control leaves were treated only with the solvent. The number
of dead aphids was recorded after 48 h to calculate the mortality rate
(%), which was corrected for control mortality by Abbott's formula.
Enzyme activity
Materials and Methods
The capacity of all compounds I1–46, II1–14, and III1–15 to inhibit
AChE activity was assessed using Ellman's method (30). Acetylcho-
linesterase (E.C. 3.1.1.7, from electric eel), 5,5¢-dithiobis-(2-nitroben-
zoic acid; DTNB, Ellman's reagent), butylthiocholine chloride,
acetylthiocholine chloride, and tarcine hydrochloride were purchased
from Sigma-Aldrich (St. Louis, MO, USA).
Reagents and analysis
All chemicals and solvents purchased from commercial sources
were used without specific purification. 1H NMR spectra were
recorded in a deuterochloroform solution on a Bruker spectrometer
(400 MHz; Bruker, Fallanden, Switzerland), using tetramethylsilane
as an internal standard.
The tested compounds were dissolved in Tween 80 ⁄ MeOH 3:1 (v ⁄ v,
<400 L total volume) and were diluted in 0.1 M KH2PO4 ⁄ K2HPO4
buffer (pH 8.0) to provide a final concentration. Tween 80 ⁄ MeOH
was diluted to a concentration in excess of 1 in 1250, and no inhib-
itory action on AchE was detected in separate prior experiments.
Synthesis
General procedure for synthesis of diaryl
ketones
In vitro AChE assay. All the assays were carried out under 0.1 M
KH2PO4 ⁄ K2HPO4 buffer, pH 8.0, using a Shimadzu UV-2450 spectro-
photometer (Kyoto, Japan). Enzyme solutions were prepared to give
2.0 units ⁄ mL in 2 mL aliquots. The assay medium (1 mL) contained
phosphate buffer (pH 8.0), 50 mL of 0.01 M DTNB, 10 mL of
enzyme, and 50 mL of 0.01 M substrate (Acetylthiocholine chloride
solution). The substrate was added to the assay medium containing
the compound solution, enzyme, buffer, and DTNB with inhibitor
after a 15-min incubation. Activity was determined by measuring
the increase in absorbance at 412 nm at 1 min intervals at 37 ꢀC.
Calculations were performed according to the equation in Ellman
et al. Each concentration was assayed in triplicate.
An appropriately substituted acetophenone (10 mmol) was added to
equimolar quantities of appropriate aryl aldehyde, furfural, or cin-
namaldehyde in EtOH (10 mL). Then, an aqueous solution of NaOH
(2%, 3 mL) was added, and the reaction mixture was stirred for 5 h
and then refrigerated overnight. The product crystals were filtrated
and washed carefully with water and cold EtOH. The resulting prod-
uct was purified by recrystallization.
Bioactivity
Insecticidal activity examination
The aphid colony was reared on cotton plants in the greenhouse.
They were maintained at 22–23 ꢀC with a 14:10 h (light:dark) pho-
toperiod. Vigorous and apterous aphids (4-day-old aphids) were
used in the experiments. To obtain 4-day-old aphids, adult cotton
aphids were transferred to cotton plants and allowed to deposit
nymphs overnight, and then the adult aphids were removed. Four
days later, the resulting aphids were collected for the bioassays.
Antifungal activity
All synthesized small molecule compounds I1–46, II1–14, and III1–15
were screened for their in vitro antiplant pathogenic fungi activity.
Preliminary antifungal screening activities on Rhizoctonia solani,
Gibberella zeae, Bipolaris maydis, Sclerotia sclerotium, and Botrytis
cirerea were carried out by the plate growth rate method (31). The
results were compared with the activity of a commercial agriculture
fungicide,carbendazim, which was used as a positive control. Fungi
were obtained from the Institute of Pesticide and Crop Protection,
Sichuan University.
Bioassays of fungicidal activity were performed following products
as previously described (29). Bioassays were carried out at room
temperature (20–21 ꢀC) in petri dishes (15 cm diameter). Solutions
of the test products and omethoate (standard) were separately pre-
pared in acetone:water:polysorbate 80 (1:9:0.01% by volume) with
varied compound concentrations. Fresh cotton leaves were
The tested compounds were dissolved in acetone and added
to a sterile agarized Czapek–Dox medium at 45 ꢀC. In primary
screenings, compounds were used at a concentration of 200 mg ⁄ L.
Chem Biol Drug Des 2011; 78: 94–100
95

Zhang et al.
The control sample contained only one equivalent of acetone. The
media were poured onto 8-cm petri dishes (10 mL for each dish)
and after 2 days were inoculated with 4 mm potato dextrose agar
(PDA) disks of overgrown mycelium. Petri dishes were incubated at
26 ꢀC in the dark. Two or seven days after inoculation, the diame-
ters of the cultures were measured. The percentage inhibition of
fungal growth was determined by comparison between the develop-
ment of fungi colonies on media containing compounds and on the
control. Three replicates of each test were carried out. Results
were examined statistically using analysis of variance.
rithm of the concentration. Comparative studies involving carbenda-
zim were carried out under the same conditions using solutions in
acetone, and the concentrations of the fungicide were related to its
active component.
Results and Discussion
Synthesis of diaryl ketone building blocks
Different diaryl ketone derivatives were synthesized in alkaline solu-
tion by the Claisen–Schmidt condensation reaction as shown in
Scheme 1 (32).
In the secondary screening, only three compounds that showed bet-
ter fungal growth inhibition were used. In these experiments, the
media contained five different concentrations of the compounds.
Concentrations that would give 50% growth inhibition (IC50) were
calculated by linear regression between the activity and the loga-
The optimization of the diaryl ketones as 'leitmotifs' starts in two
aspects. On the one hand, diaryl was preserved, and the carbon
chain was changed to change the spatial configuration and electron
O
R1
R2
I1~34
iii
O
O
O
i
ii
R2
R1
R1
R1
O
III1~15
II1~14
Scheme 1: Reagents and conditions: (i) aromatic aldehyde, NaOH ⁄ EtOH, rt, 24 h; (ii) furfural, NaOH ⁄ EtOH, rt, 24 h; (iii) Cinnamaldehyde.
Table 1: Mortality of compound I1–34 against Myzus persicae in 1000 mg ⁄ L and inhibition of compound I1–34 for acetylcholinesterase in
50 mg ⁄ L
O
R2
R1
Mortality
(%)
Enzyme
activity (%)
Mortality
(%)
Enzyme
activity (%)
No.
R1
R2
No.
R1
R2
I1
H
4-F
4-Cl
4-Br
4-CH3
4-OCH3
4-NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
36.1
0.0
29.4
50.0
0.0
25.0
0.0
34.1
50.0
0.0
25.0
0.0
30.0
0.0
0.0
33.3
0.0
33.6
39.1
36.0
26.1
36.5
31.2
27.7
20.5
26.6
26.5
43.1
39.5
30.4
33.5
14.8
16.8
12.6
I18
I19
I20
I21
I22
I23
I24
I25
I26
I27
I28
I29
I30
I31
I32
I33
I34
3,5-F2
3,5-(CF3)2
4-OPh
4-Ph
H
4-F
H
H
H
H
0.0
0.0
25.0
0.0
0.0
0.0
40.6
0.0
22.2
45.8
0.0
0.0
0.0
25.0
0.0
0.0
40.6
27.5
27.2
42.0
66.4
96.0
73.1
94.1
38.6
88.9
79.0
69.9
28.7
43.1
29.0
40.6
77.8
I2
I3
I4
I5
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
I6
I7
4-Cl
4-Br
I8
3-NO2
I9
2,4-Cl2
2,5-Cl2
4-F,3-NO2
4-Cl,3-NO2
4-Br,3-NO2
4-CH3,3-NO2
4-OCH3,3-NO2
3-CF3
4-CH3
4-OCH3
4-NO2
3-NO2
2,4-Cl2
2,5-Cl2
3-CF3
4-OPh
3,5-F2
I10
I11
I12
I13
I14
I15
I16
I17
4-CF3
0.0
96
Chem Biol Drug Des 2011; 78: 94–100

Design, Synthesis, and Bioactivities Screening of Diaryl Ketone
density of the parent compounds, so compounds I1–34 were synthe-
Acetylcholinesterase inhibitory activities were measured and summa-
sized with one carbon–carbon double bond addition in comparison
with the parent compounds. Meanwhile, compounds II1–14 were
synthesized via the shortage of the carbon chain. On the other
hand, two parent phenyls were changed, one of which was substi-
tuted by a furan ring owing to its good biologic activity; this was
how compounds III1–15 were synthesized (33).
rized in Tables 1, 2, and 3. At concentrations of 50 mg ⁄ L, most of
the compounds showed poor inhibitory activities. Compounds I1–34
,
I22, I24, I25, I27, I28, I29, and I34 had better inhibitory activities
(enzyme activity > 50%), and enzyme activity of compound I25 was
the highest, reaching 94.1%. However, among compounds II1–14
,
only the enzyme activity of compound II11 was over 50% (reaching
63.4%). In line with this, among compounds III1–15, only two com-
pounds, III3 and III13, showed better activities (57.3% and 87.4%).
The present data show that these structure-optimized compounds
have weak enzyme activity in inhibiting AChE. We have detected a
similar pattern among all compounds; the increase in mortality
against M. persicae is proportional with their ability to inhibit AChE.
Evaluation of insecticidal activities and AChE
inhibitory activities
As shown in Tables 1, 2, and 3, at the concentration of 1000 mg ⁄ L,
most compounds showed poor activities (mortality < 50%) against
Myzus persicae, the mortality of some compounds was even zero.
However, compound II1 with one fluorine atom and a three carbon
atom chain showed high activity in 1000 mg/L, and its lethal rate
was 72.0% against M. persicae. This study reveals that changes of
structure cannot increase the activities of compounds against
M. persicae.
Evaluation of antifungal activities
In this study, all synthesized compounds I1–34, II1–14, and III1–15
were screened for their in vitro antiplant pathogenic fungi activities.
Their inhibition rates as antifungal agents at 200 mg ⁄ L are summa-
rized in Table 4.
Table 2: Mortality of compound II1–14 against Myzus persicae in 1000 mg ⁄ L and inhibition of compound II1-14 for acetylcholinesterase in
50 mg ⁄ L
O
R2
R1
Mortality
(%)
Enzyme
activity (%)
Mortality
(%)
Enzyme
activity (%)
No.
R1
R2
No.
R1
R2
II1
II2
II3
II4
II5
II6
II7
4-F
4-F
4-F
4-F
4-F
4-F
2,4-Cl2
H
72.0
0.0
0.0
25.0
0.0
0.0
31.2
39.6
32.0
70.1
30.4
24.1
26.8
II8
II9
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
4-OCH3
4-OCH3
4-OCH3
4-OCH3
3-NO2
4-N(CH3)2
4-OCH3, 3-NO2
H
0.0
0.0
0.0
0.0
0.0
0.0
0.0
35.8
48.5
26.5
63.4
20.0
41.9
40.7
3-NO2
4-N(CH3)2
4-OCH3, 3-NO2
2,4-Cl2
4-OCH3
2,4-Cl2
II10
II11
II12
II13
II14
2,4-Cl2
4-OCH3
0.0
Table 3: Mortality of compound III1-15 against Myzus persicae in 1000 mg ⁄ L and inhibition of compound II1–14 for acetylcholinesterase in
50 mg ⁄ L
O
R1
O
Mortality
(%)
Enzyme
activity (%)
Mortality
(%)
Enzyme activity
(%)
No.
R1
No.
R1
III1
III2
III3
III4
III5
III6
III7
III8
4-F
54.5
0.0
25.0
61.0
0.0
43.5
50.0
0.0
18.8
16.0
57.3
40.3
43.7
32.9
42.7
39.7
III9
4-Ph
0.0
0.0
0.0
0.0
0.0
0.0
0.0
43.3
37.5
35.8
44.7
87.4
15.4
8.3
2,4-Cl2
4-OCH3
4-Cl
III10
III11
III12
III13
III14
III15
4-Cl,3-NO2
4-Br,3-NO2
4-CH3,3-NO2
4-OCH3,3-NO2
3,5-F2
4-Br
4-NO2
2,5-Cl2
4-OPh
2-OH
Chem Biol Drug Des 2011; 78: 94–100
97

Zhang et al.
Table 4: Antifungal activity of compounds I1–34, II1–14, and
III1–15: primary screening results at concentrations of 200 mg ⁄ L
Table 4: (Continued)
Inhibition of growth (%)
Inhibition of growth (%)
Rhizoctonia
solani
Bipolaris
maydis
Phytophthora
infestans
Gibberella
zeae
Sclerotia
sclerotium
Rhizoctonia
solani
Bipolaris
maydis
Phytophthora
infestans
Gibberella
zeae
Sclerotia
sclerotium
No.
No.
III10
III11
III12
III13
III14
III15
1.79
0
44.35
7.02
82.23
88.43
29.92
38.66
28.03
31.44
57.53
26.36
0
4.10
9.92
11.38
1.00
49.47
37.83
1.45
2.23
6.54
15.67
44.03
38.51
I1
56.18
69.02
12.52
2.09
41.41
38.52
1.00
6.42
53.93
42.70
0
35.42
38.56
44.10
28.04
40.96
40.04
36.72
40.96
35.42
38.56
35.1
20.5
13.8
30.4
6.35
47.05
0
7.54
38.49
6.10
0
9.87
60.86
0
3.60
35.73
41.65
0
25.65
43.73
4.06
0
0
8.23
21.03
0
80.64
30.14
I2
23.06
0
0
0
0
I3
I4
I5
38.75
35.20
10.44
4.20
29.98
18.76
9.48
4.64
6.77
0
I6
I7
0
0
I8
Table 5: IC50 values (mg ⁄ L) of selected compound III1–3
I9
9.39
2.05
22.52
0
0
0
3.62
13.01
0.33
11.37
9.36
0
24.85
0
7.3
I10
I11
I12
I13
I14
I15
I16
I17
I18
I19
I20
I21
I22
I23
I24
I25
I26
I27
I28
I29
I30
I31
I32
I33
I34
II1
II2
II3
II4
II5
II6
II7
II8
II9
II10
II11
II12
II13
II14
III1
III2
III3
III4
III5
III6
III7
III8
III9
Rhizoctonia
solani
Bipolaris
maydis
Gibberella
zeae
Sclerotia
sclerotium
No.
9.79
0
0
0
0
0
III1
III2
7.72
1.20
4.02
4.36
22.66
29.49
38.88
0.76
45.13
104.89
42.03
1.02
43.14
37.84
45.77
0.89
13.32
31.46
67.09
34.51
61.8
0
0
III3
Carbendazim
60.35
0
28.05
0
4.85
0
8.5
7.0
0
4.0
15.1
2.0
7.0
3.3
6.28
0
30.95
2.90
28.82
8.70
6.58
0
0
9.2
0
8.2
0
0
12.0
3.0
7.0
IC50 values are defined as inhibitory concentration at which there is a half
growth.
39.1
0
1.28
0
36.35
0
In our initial experimental design, compounds I1–34 were synthe-
sized based on the fact that the carbon–carbon double bond addi-
tion changed the spatial configuration and electron density of the
parent compounds, thus increasing their biologic activities. However,
as shown in Table 1, these compounds showed poor abilities
against M. persicae. Their abilities against pathogenic fungi were
then examined in this study.
8.9
0
6.3
9.3
5.3
7.6
0
3.0
0
15.3
12.0
6.3
7.6
0
6.3
10.3
0
12.3
0
8.8
0
0
As shown in Table 4, the in vitro bioassay showed that most com-
pounds exhibited poor activities against all six fungi at concentrations
of 200 mg ⁄ L. However, compounds I1, I2, I9, I16, and I18 exhibited
good activities against R. solani, and compound I6 showed the best
performance against Phytophthora infestans. This structure-oriented
increase in antifungal activity urged us to examine another group of
synthesized products (II1–14) where the substituent groups remained
the same but the carbon chains were altered.
14.3
0
9.9
0
6.2
5.3
16.8
1.02
2.3
20.5
18.3
0
8.79
0
0
0
15.1
6.37
6.5
3.3
30.6
86.93
0
62.67
0
0
45.26
20.47
57.40
26.00
50.62
60.30
47.86
75.13
15.35
55.46
6.64
60.17
11.76
66.39
100
49.14
21.21
40.0
15.0
30.17
37.07
18.62
46.03
12.07
18.62
0
48.28
20.17
46.21
81.03
77.59
78.97
59.62
56.01
52.58
80.54
40.72
10.62
56.44
13.86
21.78
15.25
22.18
26.73
21.19
33.67
23.76
29.70
17.23
25.74
21.78
43.96
83.17
69.31
54.85
55.82
54.10
4.50
64.42
17.06
14.15
32.82
0
2.29
0
0
7.33
0
48.55
0
40.0
0
24.73
7.33
28.24
80.15
74.35
83.51
7.46
2.69
1.94
54.18
21.94
22.39
0
Compounds II1–14 showed better antifungal activities in comparison
with the compounds I1–34. This observance supported our hypothe-
sis that a carbon–carbon double bond change may affect biologic
activities. Data S1 also came from another group of compounds
(III1–3) where one furan ring replaced one parental phenyl struc-
ture. These three compounds showed strong antifungal activities
(all reaching 100%) against R. solani at concentrations of
200 mg ⁄ L. In addition, the three compounds also showed better
activities against other plant pathogenic fungi in comparison with
70.75
0
0
0
0
0
46.50
0
70.35
90.50
3.0
73.61
5.01
0
compounds II1–14
.
100
100
91.74
81.68
11.43
88.43
73.42
66.39
The strong antifungal activities of compounds III1–3 revealed the
importance of the furan ring for antifungal activity enhancement. To
keep the furan ring, compounds III4–15 had been synthesized where
the other phenyl ring had been further modified (Scheme 1). As
shown in Table 4, compounds III4–15, which had strong activities,
revealed the importance of the furan ring in antifungal activities.
0
0
6.72
10.34
98
Chem Biol Drug Des 2011; 78: 94–100

Design, Synthesis, and Bioactivities Screening of Diaryl Ketone
Compared with the antifungal activities of compounds III1, III2, and
Muller G., editors. Chemogenomics in Drug Discovery: A Medic-
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6. Barun O., Sommer S., Waldmann H. (2004) Asymmetric solid-
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3199.
7. Brohm D., Metzger S., Bhargava A., Muller O., Lieb F., Wald-
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III3, the activities of compounds III4–15 were lower. This also
confirmed for us that one compound with substituent groups –F, –
OCH3, and –Cl on the phenyl ring possessed higher antifungal activ-
ities than the other compounds with the other groups, such as –
NO2, –Br, and –Ph.
As shown in Table 4, in comparison with compounds III4–15, com-
pounds III1–3 showed strong activities against a much wider spec-
trum of fungi. In this study, their abilities against fungi were further
examined. As shown in Table 5, compound III2 and compound III3
showed strong activities against R. solani (IC50 = 1.20 mg ⁄ L for III2
and IC50 = 4.02 mg ⁄ L for III3). In comparison with the commercial
agriculture fungicide carbendazim (IC50 = 4.36 mg ⁄ L), these two
compounds show strong potential as a commercial fungicide.
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sity-oriented synthesis. Angew Chem Int Ed;43:46–58.
9. Garcia A.B., Lessmann T., Umarye J.D., Mamane V., Sommer S.,
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product-derived compound collection on a solid phase. Chem
Commun;37:3868–3870.
Conclusion
In conclusion, we have synthesized three series of compounds with
a diaryl ketone moiety as pharmacophores. Preliminary bioassays
and biochemical analyses showed that compounds I1–46, II1–14
,
and III1–15 possessed weak insecticidal activities and AChE inhibi-
tory activities. However, we found that compound III with a furan
ring had strong antifungal activities. Among the examined com-
pounds, the IC50 of compound (E )-1-(2,4-dichlorophenyl)-3-
(furan-2-yl)prop-2-en-1-one (III2) was 1.20 mg ⁄ L against
R. solani suggesting its strong potential as a novel antifungal drug.
To our knowledge, this was the first comprehensive report about
antifungal drug screenings based on natural products from S. cha-
maejasme L. Further structural modifications and antifungal activi-
ties optimization on these analogs will be conducted.
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Acknowledgments
13. Noren-Muller A., Reis-Correa I. Jr, Prinz H., Rosenbaum C., Saxe-
na K., Schwalbe H.J., Vestweber D., Cagna G., Schunk S., Sch-
warz O., Schiewe H., Waldmann H. (2006) Discovery of protein
phosphatase inhibitor classes by biology-oriented synthesis. Proc
Natl Acad Sci USA;103:10606–10611.
This study was supported by the Hi-Tech Research and Develop-
ment of China (No. 2009AA032903), the National Natural Science
Foundation of China (Grant No. 30871657, 20972106), and the Ph.D.
Programs Foundation of Ministry of Education of China (Grant No.
20090181110088).
14. Sanz M.A., Voigt T., Waldmann H. (2006) Enantioselective cataly-
sis on the solid phase: synthesis of natural product-derived tetr-
ahydropyrans employing the enantioselective Oxa-Diels-Alder
reaction. Adv Synth Catal;348:1511–1515.
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Supporting Information
Additional Supporting Information may be found in the online ver-
sion of this article:
Appendix S1. Characterization of all products by 1H NMR.
Please note: Wiley-Blackwell is not responsible for the content or
functionality of any supporting materials supplied by the authors.
Any queries (other than missing material) should be directed to the
corresponding author for the article.
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