Synthesis and bioactivities of novel piperazine-containing 1,5-Diphenyl-2-penten-1-one analogues from natural product lead

Article abstract of DOI:10.1016/j.bmcl.2016.01.088

A series of novel 1,5-Diphenyl-2-penten-1-one analogues (7a–h, 8a–h) with piperazine moiety have been designed and synthesized on the basis of natural product 1,5-Diphenyl-2-penten-1-one (I). All the synthesized compounds were evaluated in vitro for anti-plant pathogenic fungi activities and insecticidal activities. The results indicated that most of these analogues exhibited moderate antifungal activities and moderate to good insecticidal activities. Amongst them, the most potent 7c, 7e and 7h keep a mortality of 100% against larva of mosquito at the concentration of 1?mg/L. Initial structure–activity relationship (SAR) analysis showed that, a methyl group can influence the biological activities of these compounds significantly, the compounds with N′-unsubstituted piperazine showed much better antifungal activities and larvicidal activity against mosquito than the compounds with N′-methylated piperazine. In addition, the larvicidal activity against mosquito had sharply decline when the substituent on benzene ring was changed from 4-position to 2 or 3-position.

Full text of DOI:10.1016/j.bmcl.2016.01.088

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and bioactivities of novel piperazine-containing
1,5-Diphenyl-2-penten-1-one analogues from natural product lead
Gaofei Xu a, Xinling Yang a, Biaobiao Jiang a, Peng Lei a, Xili Liu b, Qingmin Wang c, Xuebo Zhang a,
Yun Ling a,
⇑
a Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
b Department of Plant Pathology, College of Agronomy and Biotechnology, China Agricultural University, 100193, China
c State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 1,5-Diphenyl-2-penten-1-one analogues (7a–h, 8a–h) with piperazine moiety have been
designed and synthesized on the basis of natural product 1,5-Diphenyl-2-penten-1-one (I). All the syn-
thesized compounds were evaluated in vitro for anti-plant pathogenic fungi activities and insecticidal
activities. The results indicated that most of these analogues exhibited moderate antifungal activities
and moderate to good insecticidal activities. Amongst them, the most potent 7c, 7e and 7h keep a mor-
tality of 100% against larva of mosquito at the concentration of 1 mg/L. Initial structure–activity relation-
ship (SAR) analysis showed that, a methyl group can influence the biological activities of these
compounds significantly, the compounds with N0-unsubstituted piperazine showed much better antifun-
gal activities and larvicidal activity against mosquito than the compounds with N0-methylated piperazine.
In addition, the larvicidal activity against mosquito had sharply decline when the substituent on benzene
ring was changed from 4-position to 2 or 3-position.
Received 6 November 2015
Revised 20 January 2016
Accepted 30 January 2016
Available online xxxx
Keywords:
1,5-Diphenyl-2-penten-1-one
Stellera chamaejasme L.
Piperazine
Synthesis
Bioactivities
Ó 2016 Published by Elsevier Ltd.
Natural products are often used as lead structures for the
discovery of novel pesticides despite of their low yield, instability,
and limited biological activities.1–3 Meanwhile, there are many
advantages of botanical pesticides produced from natural products,
such as less or slower resistance development and lower
environmental pollution. Therefore, the discovery of new pesti-
cides directly or indirectly originated from natural products has
recently been crucial in the search of agrochemicals and attracted
much research attention.4–6 1,5-Diphenyl-2-penten-1-one (I) and
1,5-Diphenyl-1-pentanone(II) (Fig. 1) were first isolated from
Stellera chamaejasme L. (Thymelaeaceae, used in Chinese tradi-
tional medicine) by Hou et al. in 2001.7 These two natural products
are similar in structure to daphneolone, a nematicidal substance
extracted from Daphne odora.8 Laboratory bioassay showed that
these two compounds had strong contact activity and very good
antifeedant activity against Aphis gossypii and Schizaphis
graminum.9,10 Moreover, compound I exhibited the similar effects
on ATP-ase found in the three membranes amongst which the
plasma membrane Ca2+-Mg2+-ATPase is the primary target.11 After
that, by replacing the two benzene ring of compound I with
different aromatic C6 and C5 aromatic rings or changing the bridge
chain, various analogues with antifungal activity and insecticidal
activity were synthesized by Hou’s group and our group.12–17 How-
ever, by the conservative approach of modification, the improve-
ment of the bioactivity of most analogues was limited. Thus,
further study is required to develop new potential pesticide mole-
cules with enhanced bioactivity and safety to humans and the
environment.
Heterocycles play important roles in medical chemistry and
agrochemicals, such as pyridine, pyrazole, triazole, thiophene.
Amongst them, piperazine is a very important starting material
in the pharmaceutical industry. Piperazine derivatives have been
experimented extensively by the organic chemists due to the
derivatives’ close association with various types of biological prop-
erties, such as antiviral,18 antibacterial,19 anticancer,20 anti-HIV,21
antimalarial,22 antifungal23 and so on.24,25 Piperazine itself as well
O
O
II
I
Figure 1. The chemical structure of compound I and II, originally isolated from
Stellera chamaejasme L.
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2016.01.088
0960-894X/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Xu, G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.088

2
G. Xu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
O
O
compound
5
followed by
a
condensation reaction with
1-methylpiperazine in the presence of triethylamine.
N
R
A
B
The synthesized 7a–h, 8a–h were evaluated for their fungicidal
activities against five plant pathogenic fungi (Pythium aphanider-
matum, Sclerotinia sclerotiorum, Botrytis cinerea, Alternaria solani
and Bipolaris maydis) first at the concentration of 50 mg/L accord-
ing to the method in the references.28 Difenoconazole, a commer-
cial fungicide, was used as a positive control. The results were
reported in Table 1. Data listed in Table 1 showed that most of
the tested compounds exhibited fungicidal activities at a moderate
level. Some compounds showed superior activities against Pythium
aphanidermatum and Botrytis cinerea than lead compound I.
Amongst them, the inhibitory rates of 7b, 7f and 7g against
Pythium aphanidermatum reached 57.5%, 58.9% and 58.2%, respec-
tively, similar with difenoconazole (58.9%). However, for the rest
plant pathogenic fungi, most compounds did not show better
activities compare with difenoconazole and compound I. Interest-
ingly, The methyl group on N0-position of piperazine has a signifi-
cant influence on their fungicidal activity, especially against
Pythium aphanidermatum, Botrytis cinerea and Alternaria solani
(Fig. 3). After N-methylation of 7a–h, namely compounds 8a–h,
almost all the fungicidal activities declined sharply. One possible
reason maybe the N-methylation changed the Log P of the com-
pounds and ultimately affected their penetrability. Moreover, the
introduction of thiophene group (7e, 8e) is unfavorable to the
fungicidal activity.
Further EC50 value of some compounds (7a, 7b, 7f, 7g, 8a, 8b, 8f,
8g) against Pythium aphanidermatum were then tested (Table 2).
Compound 7g, with a 3-position chlorine substituted phenyl
group, exhibited the highest activity with an EC50 of 0.075 mM,
superior to compound I (0.39 mM). Moreover, same with the above
result, the fungicidal activities of compound with N0-unsubstituted
piperazine (7a, 7b, 7f, 7g) were much better than compounds with
N0-methyl piperazine (8a, 8b, 8f, 8g).
Considering that compound I has insecticidal activities and the
various activities of piperazine moiety, we then tested the insecti-
cidal activities against four kinds of insects (larvae of mosquito
(Culex pipiens pallens), armyworm (Mythimna separate), cotton
bollworm (Helicoverpa armigera) and corn borer (Ostrinia nubilalis))
N
R1
R1 =H, CH3
I
R= Substituted-phenyl or Thien-2-yl
Lead compound
New analogues
Figure 2. Design strategy of titled compounds.
as 1-methylpiperazine are symmetric, commercially available,
inexpensive compounds, which makes their synthetic elaboration
for agrochemicals attractive. However, there are few commercial
pesticides with piperazine moieties in the structure.
In view of the need of potent and environmental friendly agro-
chemicals and in continuation of our earlier interest in this field,15–17
here a series of new analogues were designed by introducing
unsaturated piperazine moiety to replace B-ring of lead compound
I and replacing A-ring with substituted phenyl or thiophene ring
with the aim to obtain new products with simple structure and
good activities (Fig. 2). All the compounds were evaluated for the
activities against five plant pathogenic fungi and four kinds of
insects (larvae of mosquito, armyworm, cotton bollworm and corn
borer). In addition, the initial SAR analysis was also reported in the
present work.
The synthetic route of title compounds 7a–h, 8a–h is shown in
the Scheme 1. Initially, substituted cinnamic acids 2 were synthe-
sized by a knoevenagel reaction of substituted benzaldehydes 1
with malonic acid in the presence of piperidine in pyridine, accord-
ing to the method in the literature.26 Next, following the procedure
described in the literature,27 substituted cinnamic acids 2 were
reduced by lithium aluminium hydride to afford substituted
phenylpropanol 3. Then 3 were oxidised by PCC, leading to the cor-
responding substituted benzenepropanal 4. (E)-5-(Substituted
phenyl) pent-2-enoic acid 5 were obtained through the same pro-
cess as compound 2. Finally, target compounds 7 were prepared by
the acylchlorination of compound 5 followed by a condensation
reaction with piperazine in acetic acid as solvent. While target
compounds
8
were synthesized by the acylchlorination of
O
O
HOOC
COOH
LiAlH4,
OH
H
R
OH
R
R
THF, reflux
piperidine
3a-h
CH2Cl2
1a-h
pyridine,
85 oC
2a-h
PCC
R.T.
O
O
HOOC
COOH
OH
H
R
R
piperidine
pyridine
85 o
5a-h
4a-h
C
CHCl3
reflux
SOCl2
DMF
HN
HN
O
O
O
N
NH
CH3
N
N
Cl
R
R
R
N
N
AcOH
35 o
R1
R1
TEA
CH2Cl2
R.T.
C
6a-h
8a-h
R1= CH3
7a-h
R1= H
Scheme 1. Synthetic route for 1,5-Diphenyl-2-penten-1-one analogues 7a–h, 8a–h.
Please cite this article in press as: Xu, G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.088

G. Xu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
The in vitro antifungal activities of title compounds 7a–h, 8a–ha
Compd
R
R1
CLog Pc
Inhibitory %
P. aphanidermatum
S. sclerotiorum
B. cinerea
A. solani
B. maydis
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
Ph
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
1.36
1.84
1.38
1.74
1.17
1.80
2.08
2.13
1.72
2.20
1.75
2.10
1.54
2.16
2.44
2.49
30.8
57.5
23.6
26.8
10.9
58.9
58.2
22.5
8.1
16.3
8.4
8.4
7.7
8.1
25.0
19.3
20.9
21.3
8.6
21.7
11.5
7.4
27.5
16.0
34.8
26.6
32.8
32.8
26.2
27.5
24.6
13.0
9.9
32.5
21.0
46.7
22.8
15.7
0.0
15.2
5.5
0.0
0.0
0.0
28.1
16.5
0.0
16.5
13.8
20.5
19.6
14.7
12.4
7.9
10.2
13.8
0.0
0.0
0.0
18.6
27.5
17.1
15.6
6.3
35.4
20.6
24.5
9.2
20.6
9.2
22.0
5.8
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
Ph
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
36.3
28.5
42.8
8g
8h
3-Cl-Ph
4-Cl-Ph
16.0
11.3
0.0
0.0
0.0
Compound I
/
/
/
/
/
/
27.5
58.9
50.0
96.7
14.3
73.4
27.7
95.5
44.7
94.6
DZb
a
b
c
Were measured at concentration of 50 mg/L.
DZ means difenoconazole, used as the positive control.
LogP means octanol-water partition coefficient, which is equal to the logarithm of the ratio of concentrations of an unionized compound between octanol and water.
ClogP is a calculated logP value in silico method.
Pythium aphanidermatum
Botrytis cinerea
Alternaria solani
50
40
30
20
10
0
30
20
10
0
80
R1=H
R1=CH3
R1=H
R1=H
R1=CH3
R1=CH3
60
40
20
0
0
0
0
0
0
0
0
0
0
0
0
l
l
l
h
h
h
h
h
h
h
h
h
h
h
h
h
h
h
-y
2
-
P
P
P
Ph
P
P
Ph
-
l
-y
-y
Ph
P
P
Ph
l-
3-
P
Ph
-
l
P
Ph
P
P
P
P
l-
-
-
-P
l-
l-
-
-P
-
2
-
2
-
H3
l-
l
l-
3
3
O-
O
n
C
C
C
O-
O
O-
O-
H3
2H5
2
3
4
C
C
C
-
-
-
n
e
C
-
C
C
H3
H5
i
2-
4-
-
H3
H5
2
3-
4-
e
C
en
CH
CH
-
-
4
C2
T
C2
T
C
h
4
hi
C
C
4
Thi
-
-C
4-
4-
4
4
4-
4-
R-Group
R-Group
Figure 3. The effect of methyl on the fungicidal activities of title compounds.
R-Group
Table 2
The EC50 value of some title compounds against Pythium aphanidermatum
instance, the activities of 7c, 7e, 7h had a 100% morality at the
concentration of 1 mg/L, whereas the activities of 8e, 8h were
20% and 60%, respectively, and 8c had no activity at the same
concentration.
Compd
EC50 (mM)
Compd
EC50 (mM)
7a
7b
7f
0.48
0.14
0.10
0.075
8a
8b
8f
>2
>2
0.82
0.85
The positions of the substituents on the benzene ring also had a
significant influence on the larvicidal activity against mosquito. For
instance, compound 7h and 8h, with chlorine substituent on the
4-position, exhibited obvious activities (100% and 60%, respectively,
at 1 mg/L). However, compound 7f, 7g, 8f and 8g, with chlorine
substituent on the 3-position or 2-position, had no activity at the
concentration of 5 mg/L). Moreover, unlike fungicidal activity,
when R is thiophene ring, the compounds (7e, 8e) exhibited higher
larvicidal activity against mosquito than those compounds with
unsubstituted phenyl ring as R-ring (7a, 8a).
Some of these synthesized compounds also showed moderate
to good insecticidal activities against cotton bollworm (Helicoverpa
armigera), corn borer (Ostrinia nubilalis) and armyworm (Mythimna
separate) at the concentration of 600 mg/L (Table 4). Amongst
them, 8b and 8c, which contain 4-position methyl substituted phe-
nyl group and 4-position methoxy substituted phenyl group
respectively, showed better activities (60%, 55%, respectively)
against H. armigera than that of lead compound I (15%). 7b, 7e,
7g
8g
Compound I
Difenoconazole
0.39
0.075
/
/
/
/
of all the titled compounds using reported methods.29 The results
were listed in Tables 3 and 4.
Data in Table 3 showed that most of the compounds exhibited
good to excellent larvicidal activity against mosquito (Culex pipiens
pallens) at given concentrations (10, 5, 2, 1, 0.5 mg/L), and the most
potent compounds 7c, 7e and 7h still keep a mortality of 100%
when the concentration reduced to 1 mg/L, which is much better
than that of lead (I). Just like fungicidal activity, when the R-ring
is same, the larvicidal activity of all the compounds with
N0-unsubstituted piperazine were obviously higher than that of
the compounds containing N0-methyl piperazine moiety. For
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G. Xu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 3
Larvicidal activity against mosquito of title compounds
Compd
R
R1
% mortality at given concentration
10 mg/L
5 mg/L
2 mg/Lꢀ1
1 mg/L
0.5 mg/L
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
Ph
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
100
100
100
100
100
70
100
100
100
100
100
—
—
100
0
20
0
100
100
—
—
100
60
100
100
100
100
—
—
100
—
—
—
60
100
—
—
—
—
50
—
20
—
—
10
—
—
—
—
—
—
—
—
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
Ph
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
60
100
60
100
—
—
100
—
—
—
—
20
—
b
70
100
100
100
100
100
100
50
8g
8h
3-Cl-Ph
4-Cl-Ph
40
100
—
100
—
60
Compound I
/
/
/
/
100
100
0
0
—
—
—
—
—
—
Diflubenzurona
a
Diflubenzuron was used as the positive control.
Not keep tested when mortality was lower than 100%.
b
Table 4
Insecticidal activities against H. armigera, O. nubilalis and M. separata of title compounds
Compd
R
R1
Insecticidal activity (% mortality)
H. armigera
O. nubilalis
M. separata
600 mg/L
600 mg/L
600 mg/L
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
Ph
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
35
50
25
30
50
25
30
35
15
60
55
30
40
10
50
15
45
60
40
50
70
50
50
35
15
35
65
45
70
15
65
15
50
70
10
40
35
5
20
70
50
80
65
25
5
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
Ph
4-CH3-Ph
4-CH3O-Ph
4-C2H5O-Ph
Thiophene-2-yl
2-Cl-Ph
20
65
25
8g
8h
3-Cl-Ph
4-Cl-Ph
Compound I
/
/
/
/
15
65
10
50
20
100
Diflubenzurona
a
Diflubenzuron was used as the positive control.
8c, 8e, 8g, had much higher activities (60%, 70%, 65%, 70%, 65%,
respectively) against Ostrinia nubilalis than that of compound I
(10%). Also, the activities against Mythimna separata of 7b, 7h,
8b, 8c, 8g were 70%, 70%, 80%, 65%, 65%, respectively, obviously
better than the lead compound (20%). What is more, 7b, 8c and
8g, containing a 4-position methyl substituted phenyl group,
4-position methoxy substituted phenyl group and 3-position chlo-
rine-substituted phenyl group, respectively, exhibited broad spec-
trum insecticidal activities against these three kinds of insects,
which is worthy to be further studied.
In conclusion, A series of novel 1,5-Diphenyl-2-penten-1-one
analogues with piperazine moiety have been designed and synthe-
sized on the basis of natural product I from Stellera chamaejasme L.
The bioassay results indicated that some compounds exhibited
fungicidal activities at the concentration of 50 mg/L at a moderate
level. Amongst them, the EC50 value of the compounds 7b, 7f, 7g
against Pythium aphanidermatum were 0.14 mM, 0.10 mM and
0.075 mM, respectively, superior to that of the lead compound I.
What is more, most of these analogues exhibited moderate to good
insecticidal activities. Particularly, the most potent compounds 7c,
7e and 7h, keep a mortality of 100% against larvae of mosquito at
the concentration of 1 mg/L, are promising new agents for preven-
tion and control of mosquito. Initial SAR study showed that, when
the R-ring is same, the antifungal activities and larvicidal activity
against mosquito of the compounds with N0-unsubstituted piper-
azine were better than that of the compounds with N0-methyl
piperazine. In addition, the larvicidal activity against mosquito
had sharply decline when the substituent on benzene ring was
changed from 4-position to 2 or 3-position. These results are wor-
thy for study on new pesticides discovery. Further studies on struc-
tural optimisation are in progress in our laboratory.
Acknowledgments
We thank the financial supports from National Natural
Science Foundation of China (No. 21272266) and the National
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G. Xu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
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References and notes
Bioassay of fungicidal activities: The tested compounds were dissolved in
DMSO to prepare the 10 mg/mL stock solution before mixing with PDA (Potato
Dextrose Agar) medium under 50 °C. The medium containing compounds at a
concentration of 50 mg/L for the initial screening was poured into sterilized
Petri dishes. After the dishes were cooled, the mycelia disks of 7 mm diameter
were inoculated in the center of the Petri dishes and incubated at 25 °C for 2–
3 d. Each experiment was carried out in triplicates. The mixed medium without
sample was used as the blank control. The colony diameter of each strain was
measured by cross bracketing method after 2–3 d of culture. The inhibition
rate was calculated according to the following formula: Inhibition rate (%) =
(C ꢀ T)/(C ꢀ 7 mm) ꢁ 100%. Here, C is the average diameter (in mm) of mycelia
in the blank test. T is the average diameter (in mm) of mycelia on treated PDA
with tested compounds.
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a
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(Helicoverpa armigera), Pyrausta Nubilalis (Ostrinia nubilalis): The stomach
toxicities of the title compounds against oriental armyworm, cotton bollworm,
pyrausta nubilalis were evaluated by foliar application. Individual corn leaves
were placed on moistened pieces of filter paper in Petri dished. The leaves were
then sprayed with the test solution and allowed to dry. The dishes were
infested with 10 fourth-instar larvae. Percentage mortalities were evaluated
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Please cite this article in press as: Xu, G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.088