Design and synthesis of novel coumarin analogs and their nematicidal activity against five phytonematodes

Article abstract of DOI:10.1016/j.cclet.2016.01.029

The presence of hydroxyl groups at the C4 and C7 positions in coumarin backbone has been proposed as a potential modification site for providing excellent bioactivity according to previous studies. A series of novel coumarin derivatives were rationally designed and synthesized by use of a complex catalytic system for a targeted modification at the above sites. These derivatives were assayed for nematicidal activity. As predicted, the derivatization enhanced the activity of the coumarins against five nematodes. Compounds 7b, 9a, 10c and 11c showed significant strong nematicidal broad spectrum activity against all tested nematodes. Compound 10c was the most effective with the lowest LC₅₀ values against Meloidogyne incognita (5.1 μmol/L), Ditylenchus destructor (3.7 μmol/L), Bursaphelenchus mucronatus (6.4 μmol/L), Bursaphelenchus B. xylophilus (2.5 μmol/L) and Aphelenchoides besseyi (3.1 μmol/L), respectively. A brief investigation on the structure-activity relationships (SAR) revealed that the targeted modification by a C7 hydroxyl was optimum compared with that of a C4 hydroxyl and that the coupling chain length was crucial for the nematicidal activity.

Full text of DOI:10.1016/j.cclet.2016.01.029

G Model
CCLET-3557; No. of Pages 5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Design and synthesis of novel coumarin analogs and their nematicidal
activity against five phytonematodes
a,b
a
c
a
a
a,
Le Pan , Xiu-Zhuang Li , Di-An Sun , Hui Jin , Hong-Ru Guo , Bo Qin *
a
Key Laboratory of Chemistry of Northwestern Plant Resources of CAS and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b
University of Chinese Academy of Sciences, Beijing 100049, China
c
Institute of Medical Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The presence of hydroxyl groups at the C4 and C7 positions in coumarin backbone has been proposed as a
potential modification site for providing excellent bioactivity according to previous studies. A series of
novel coumarin derivatives were rationally designed and synthesized by use of a complex catalytic
system for a targeted modification at the above sites. These derivatives were assayed for nematicidal
activity. As predicted, the derivatization enhanced the activity of the coumarins against five nematodes.
Compounds 7b, 9a, 10c and 11c showed significant strong nematicidal broad spectrum activity against
all tested nematodes. Compound 10c was the most effective with the lowest LC50 values against
Received 26 June 2015
Received in revised form 15 November 2015
Accepted 8 January 2016
Available online xxx
Keywords:
Coumarin analogs
Targeted design
Meloidogyne incognita (5.1
mmol/L), Ditylenchus destructor (3.7
mmol/L), Bursaphelenchus mucronatus
(
6.4 mol/L), Bursaphelenchus B. xylophilus (2.5
m
m
mol/L) and Aphelenchoides besseyi (3.1 m
mol/L),
Synthesis
respectively. A brief investigation on the structure–activity relationships (SAR) revealed that the
targeted modification by a C7 hydroxyl was optimum compared with that of a C4 hydroxyl and that the
coupling chain length was crucial for the nematicidal activity.
Nematicidal activity
Structure–activity relationships
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
1
. Introduction
Plant-parasitic nematodes have been one of the most notorious
Coumarins are widely available promising natural compounds
for modification due to their broad bioactivities [10–12]. Some
simple coumarins, furocoumarines and dicoumarolums, display
excellent nematicidal activity and their skeletons have drawn
interest for the development of efficient nematicides [13,14]. In
our previous study, 7-hydroxycoumarin was isolated from
Stellera chamaejasme and had been discovered to show nematici-
dal activity against Bursaphelenchus xylophilus and Bursaphe-
lenchus mucronatus. In recent years, the structure–activity
relationships (SAR) of hydroxycoumarin derivatives have been
intensively conducted and indicated that C4 and C7 position
modifications in the backbone could enhance their tumor
cytotoxicity, termiticidal and bactericidal activities [15–18].
Therefore, we were prompted to design and develop coumarin-
based nematicides by modification at these positions (Fig. 1). In a
pilot study, we coupled 4-hydroxycoumarin (1) and 7-hydroxy-
plant pathogens worldwide [1,2]. Thousands of crops and trees are
susceptible and the disease caused by the phytonematodes results
in billions of agricultural losses annually [3]. Chemical methods,
combined with agriculture practice, have been the primary way for
the nematode control [4–7]. To lessen environmental toxicity,
pesticide residues and nematode resistance, the development of
new control substitutes has become an urgent and challenging task
[
8]. Natural products and their derivatives provide a promising
treasury for the identification of modern pesticides [9]. As an
alternative to a large screening program for the identification of
new active materials, a rational program of structural modification
of known active compounds can be more efficient and equally
useful.
4
-methylcoumarin (2) with alkyl bromides, and a significant
difference in activity was observed. Based on this, we proposed
to further develop modifications of 4-hydroxycoumarin (1) and
7
-hydroxy-4-methylcoumarin (2) by coupling coumarin with
*
Corresponding author.
E-mail address: bqin@licp.cas.cn (B. Qin).
functional moieties at the C4 and C7 hydroxyls, and five
http://dx.doi.org/10.1016/j.cclet.2016.01.029
1
001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: L. Pan, et al., Design and synthesis of novel coumarin analogs and their nematicidal activity against five
phytonematodes, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.01.029

G Model
CCLET-3557; No. of Pages 5
2
L. Pan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
CH
3
-4), 3.92 (s, 3H, OCH
3
-6), 4.23 (t, 2H, J =6.0 Hz, H-13), 4.63 (t,
0
2H, J =6.0 Hz, H-11), 6.12 (s, 1H, H-3 ), 6.76 (s, 1H, H-3), 6.83 (d, 1H,
0
J =2.4 Hz, H-8 ), 6.87 (dd, 1H, J =8.8 Hz, 2.4 Hz, H-6), 7.14 (d, 1H,
J =2.4 Hz, H-8), 7.25-7.28 (m, 2H, H-7 , H-5), 7.46 (d, 1H, J = 8.8 Hz,
H-5 ). C NMR (100 MHz, CDCl
0
0
13
3
):
d 18.68, 18.89, 28.95, 30.95,
5
1
1
5.97, 65.46, 101.43, 103.39, 111.91, 112.07, 112.73, 113.12,
13.53, 120.26, 125.47, 125.57, 125.93, 128.95, 152.54, 155.29,
Fig. 1. Structures of coumarins and their modification sites.
1
56.04, 160.44, 161.34, 162.07. The H NMR spectrum showed the
two methyl protons and one methoxyl protons. The protons at
d
phytonematodes were applied to evaluate their nematicidal
activities.
6.12–7.46 indicated the moieties of coumarin and quinolone. The
presence of the protons at d 2.32-2.35 (H-12), 4.23 (H-13) and 4.63
(
H-11) revealed the existence of linker between the two moieties.
1
3
1
2
. Experimental
The results of C NMR were in accordance with that of H NMR
spectrum. Therefore, the compound 11b was elucidated as
4-Methyl-7-[3-(6-methoxy-4-methylquinolin-2-on-1-yl)propyloxy]-
benzopyran-2-one.
All starting chemicals were of analytical reagent and used
without purification. Reactions were monitored by precoated TLC
plates (Silica Gel 60 F254. Qingdao Haiyang Chemical Co., Ltd.,
Qingdao, China), and the spots were visualized by ultraviolet (UV)
illumination. Silica gel (200–300 mesh) (Qingdao Haiyang Chemi-
cal Co., Ltd.) was used for column chromatography. Melting points
were tested with a X-4 melting point apparatus (Beijing Tech
2.2. Nematicidal assay
Five prevalent nematodes, Meloidogyne incognita, Ditylenchus
destructor, Bursaphelenchus xylophilus, Bursaphelenchus mucronatus
and Aphelenchoides besseyi, were used to evaluate the nematicidal
spectrum and potential of the synthesized compounds. B.
xylophilus and B. mucronatus, isolated from Pinus massoniana,
were supplied by Dr. Han Zhengmin (College of Forest Resources
and Environment, Nanjing Forestry University). M. incognita,
D. destructor and A. besseyi were provided by Dr. Lin Maosong
1
13
Instrument Co., Ltd., China). The structural H NMR and C NMR
spectra were performed on a Bruker AM-400BB instrument
(Bruker, Karlsruhe, Germany) with TMS as internal standard,
operating at 400 MHz. The chemical shift values are on a scale
d
and the coupling constant values (J) are in Hertz. ESI-HRMS was
recorded using a Bruker micrOTOF-Q II.
(
College of Plant Protection, Nanjing Agricultural University).
2
.1. Synthesis of target compounds (3a–12b)
D. destructor was grown on potato dextrose Agar (PDA) media
containing a strain of Fusarium solani in 9-cm Petri dishes.
M. incognita, B. xylophilus, B. mucronatus and A. besseyi were
cultured on PDA media with Botrytis cinerea Pers. All nematodes
were stored at 28 8C and subcultured before bioassay. With
successive observing under a microscope, J2s were collected and
suspended in distilled water for the experiments. The tested
compounds were dissolved in dimethylsulfoxide (DMSO) to obtain
stock solutions, which were diluted with distilled water containing
The general synthesis is illustrated in Scheme 1. Compounds
a–c were prepared by the reaction of 4-hydroxycoumarin (1) with
, 2-dibromoethane, 1, 3-dibromopropane and 1, 4-dibromobu-
3
1
tane, respectively, in the presence of an alkaline catalyst [19].
Compounds 9a–c were similarly prepared with the dibromides.
6
-Methoxy-4-methylquinolone (5) and 6-hydroxy-4-methylqui-
nolone (6) were synthesized via a Knorr reaction of ethyl
acetoacetate with anisidine in the presence of H SO [20]. The
bromoalkoxy derivatives of 4-hydroxycoumarins (4a–c) and
-hydroxy-4-methylcoumarins (10a–c) were prepared through
2
4
Tween-20 to prepare working solutions. 300 mL of dilutions and
J2s suspension (containing about 60–80 J2s) were added into
24-well plates within 24 h. The final concentrations of DMSO and
Tween-20 were kept under 0.5% and 0.05% of volume in each well,
at which concentration levels, the motility of nematodes exposed
was similar to those of a blank control. Distilled water and a
solution of DMSO and Tween-20, at concentrations equivalent to
those in the treatment wells, was used as a control. Abamectin was
used as a positive control [21]. The plates were covered and
parafilmed to prevent evaporation, and then incubated in the dark
at 28 8C for 72 h. Juveniles were delivered to clean water and
observed with a microscope at 40ꢀ magnification (Shanghai
Optical Instrument Factory, Shanghai, China). Those immotile in a
straight or ‘‘L’’ shape and not recovering in clean water were
defined as dead. (Fig. 2) The experiment was conducted twice with
three replicates. The values were determined as percentage
corrected mortality (ꢁstandard deviation) according to the Schnei-
der-Orelli formula:
7
the bromoalkylation of 4-hydroxycoumarin (1) and 7-hydroxy-4-
methylcoumarin (2) with 1, 2-dibromoethane, 1,3-dibromopro-
pane and 1,4-dibromobutane, respectively. N-Alkylation is classi-
cally realized with halogen derivatives under alkaline condition,
but with simply potassium hydroxide as a catalyst, the coupling
reaction between alkyl bromides, coumarins (4a–c) and 6-
methoxy-4-methylquinolone (5) was unsuccessful. Finally, a
complex catalyst system of KOH, KI and tetrabutyl ammonium
bromide (TBAB) was developed to prepare compounds 7a–c in
high yield. Compounds 11a–c were then prepared by the reaction
between 6-methoxy-4-methyl-quinolone (5) and 7-bromoalkoxy-
4
-methylcoumarins (10a–c). 6-Hydroxy-4-methylquinolone (6)
coupled with appropriate 4-bromoalkoxycoumarins (4a and b) in
the presence of K CO , KI and TBAB to yield compounds 8a and 8b,
2
3
and the reaction with 7-bromoalkoxy-4-methylcoumarins (10b
and c) gave 12a and b. The coumarin analogs were analyzed by H
1
Corrected mortality% = [(mortality% in treatment – mortality%
in control)/(100 – mortality% in control)] ꢀ 100.
13
NMR, C NMR and HR-ESI-MS. The purity of all test compounds
was above 95% (determined by HPLC). All the compounds were
characterized and the data was listed in Supporting information.
Here, compound 11b was taken as an example to show the typical
structure of coumarin analogs.
The compounds with strong activity were tested further under a
series of concentrations to calculate their LC50 values. Probit
analysis was used to estimate LC50 [22,23].
4
-Methyl-7-[3-(6-methoxy-4-methylquinolin-2-on-1-yl)pro-
pyloxy]benzopyran-2-one (11b): White solid, yield 63%. mp 184-
85 8C. Its molecular formula was determined to be C24
3. Results and discussion
1
H23NO
5
The target coumarin analogs were efficiently prepared in the
presence of the complex catalytic system. Their nematicidal
activity was evaluated under a series of concentration and the LC50
+
1
from the HRESIMS data at m/z 406.2 [M + H] . H NMR (400 MHz,
CDCl
0
3
):
d
2.32-2.35 (m, 2H, H-12), 2.38 (s, 3H, CH
3
-4 ), 2.58 (s, 3H,
Please cite this article in press as: L. Pan, et al., Design and synthesis of novel coumarin analogs and their nematicidal activity against five
phytonematodes, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.01.029

G Model
CCLET-3557; No. of Pages 5
L. Pan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
Scheme 1. Synthesis of coumarin derivatives. Reagents and conditions: (a) K
2
CO
3
/KOH/acetone, reflux; (b) ethyl acetoacetate, reflux; (c) 80% H
2
SO
4
, 95 8C; (d) K
2
CO
3
/acetone,
reflux; (e) KOH/KI/TBAB/methylbenzene, 90 8C; (f) K CO /KI/TBAB/methylbenzene, 90 8C.
2
3
Fig. 2. Representative pictures of five plant-parasitic nematodes immersed in the solution of compound 9a at the concentration of 100
microscope at 100ꢀ magnification).
mmol/L for 72 h (observed with
Please cite this article in press as: L. Pan, et al., Design and synthesis of novel coumarin analogs and their nematicidal activity against five
phytonematodes, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.01.029

G Model
CCLET-3557; No. of Pages 5
4
L. Pan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 1
Nematicidal activity of coumarin analogs against five plant-parasitic nematodes (calculated at 72 h).
Comp.
LC50 values (95% CI)/mmol/L
M. incognita
D. destructor
B. mucronatus
B. xylophilus
A. besseyi
1
2
261.1 (150.0–318.7)
>1000
333.5 (220.2–412.1)
>1000
329.7 (262.3–483.0)
>1000
168.9 (92.1–251.9)
>1000
406.7 (307.0–539.8)
>1000
3
3
3
4
4
4
7
7
7
8
8
9
9
9
1
1
1
1
1
1
1
1
a
>1000
>1000
>1000
>1000
>1000
b
>1000
>1000
>1000
>1000
>1000
c
940.3 (737.0–1043.5)
>1000
286.2 (140.8-351.1)
>1000
>1000
744.9 (612.1-955.4)
>1000
>1000
a
>1000
>1000
b
>1000
>1000
>1000
>1000
>1000
c
>1000
>1000
>1000
>1000
>1000
a
544.4 (195.7–893.2)
64.0 (20.5–127.0)
>1000
436.2 (284.5–663.9)
52.9 (38.8–84.7)
>1000
329.4 (152.6–556.3)
97.9 (72.7–123.2)
>1000
812.9 (464.3–1241.1)
103.2 (112.9–427.3)
>1000
>1000
b
95.2 (29.4–276.9)
>1000
c
a
883.5 (786.8–980.3)
>1000
761.8 (510.5–913.8)
>1000
>1000
913.1 (565.5–1260.8)
>1000
>1000
b
>1000
>1000
a
37.4 (10.9–67.2)
>1000
35.8 (15.7–75.3)
>1000
60.9 (31.3–86.7)
>1000
190.9 (75.9–260.2)
>1000
121.2 (63.9–184.6)
>1000
b
c
>1000
>1000
>1000
>1000
>1000
0a
0b
0c
1a
1b
1c
2a
2b
491.1 (233.1–785.3)
762.6 (432.2–955.1)
5.1 (2.0–9.3)
907 (555.0–1255.2)
593.7 (247.6–912.1)
3.7 (1.2–8.5)
>1000
652.8 (385.8–819.6)
256.6 (221.2–535.9)
6.4 (2.4–9.2)
>1000
910.5 (486.6–1334.5)
731.6 (386.7–944.0)
2.5 (0.3–6.2)
>1000
893.7 (618.8–1168.5)
907.9 (555.0–1293.7)
3.1 (1.0–7.3)
>1000
>1000
114.5 (98.8–196.3)
42.4 (19.8–70.2)
385.0 (343.3–447.8)
335.9 (279.5–430.4)
0.50 (0.15–1.08)
214.2 (126.8–301.5)
68.0 (41.2–86.9)
380.6 (343.2–433.9)
275.3 (233.1–335.3)
0.62 (0.12–1.36)
367.6 (302.6–432.5)
77.8 (42.1–101.4)
430.0 (385.9–497.6)
330.6 (288.8–391.5)
0.38 (0.12–0.94)
410.2 (333.6–566.4)
145.5 (72.6–232.1)
381.8 (322.2–495.1)
393.3 (315.2–561.3)
0.47 (0.11–0.94)
384.5 (337.8–453.9)
120.7 (65.4–201.2)
441.6 (400.3–502.5)
>1000
a
Abamectin
0.26 (0.14–1.22)
a
Abamectin was used as a positive control.
values were calculated (Table 1). As predicted, the modification on
the hydroxyl at C4 and C7 positions led to the identification of
promising lead compounds. Among the derivatives, compounds
among quinolone coupled 7-hydroxy-4-methylcoumarins (11a–c).
Thiswasnotobservedamongcompounds10a-c, buttheyallshowed
strong activities with four carbon chains. The chain length had little
influence on the activity expression of compounds 12a and b. It was
worth noting that brombutyl substituted 7-hydroxy-4-methylcou-
marin (10c) exerted outstanding nematicidal activity, whereas
bromopropyl (10b) and bromoethyl (10a) derivatives showed weak
activity, which suggested that the four-carbon chain length was the
mostactive.About mono-coumarinanalogsandbi-coumarinones, it
was found that, as a mono-coumarin analog, brombutyl coumarin
(10c) exhibitedbetteractivities thanitsbi-coumarinanalog(9c), but
the different results were observed between bromoethyl analog
(10a) and bi-coumarin one (9a). This indicated that the better
activity of compound 10c was determined by the combination of
coumarin moiety, bromo atoms and butyl chain. Taken together, the
length of the alkyl chain was a key factor for the activity, but the
optimumlengthwasnotfixedandwasdependeduponthemoietyto
which it was linked.
7
b, 9a, 10c and 11c showed significant strong nematicidal activity,
with a broad spectrum against all tested nematodes. Compound
0c was the most effective with lowest LC50 values against
1
M. incognita (5.1
B. mucronatus (6.4
m
m
mol/L), D. destructor (3.7
mmol/L) and
mol/L), B. xylophilus (2.5 mol/L) and A.
m
besseyi (3.1
mmol/L) respectively. The rest of the derivatives
exhibited moderate or weak nematicidal activity. Clearly, the
type and position of the substituents were intensively responsible
for the activity expression. Different substituents resulted in varied
activity. When the coumarin moiety was replaced with that of a
quinolone, a change of activity occurred. For the C4 position,
substitution of the coumarin moieties with quinolone groups
significantly increased (7b) or decreased (7a and c) the nematicidal
activity. For the C7 position, compounds 9a–c showed significantly
different activity compared with their quinolone derivatives (11a–
c). Beside the effect of a particular functional group, the position
effect was also significant. Most 7-hydroxy-4-methylcoumarin
derivatives showed improved nematicidal activity, whereas only
one among all the 4-hydroxycoumarin derivatives (7b) exhibited
better activity. Thus, the C7 hydroxyl is more likely to be a better
modification site for the preparation of promising compounds.
It is notable that the length of linkers between two terminal
moieties was intensively responsible for the activity. For the linkers
between two 4-hydroxycoumarins (1), the change of chain length
hadlittleimpact ontheactivity ofcompounds(3a–c), with3aand 3b
exhibiting none activity and 3c just showing weak nematicidal
activity to specific species. Three-carbon chain lengths (7b) were
most active among the linkers between 4-hydroxycoumarin (1) and
quinolone, and four-carbon atom lengths (7c) induced the loss of
activity. For the coupling of two 7-hydroxy-4-methylcoumarins (2),
the chain length of two carbon atoms (9a) was optimum, and chain
lengths of three carbon atoms (9b) or four (9c) resulted in the great
loss of activity. However, concerning to compounds 10–12, it was
found a positive correlation between linker lengths and activities
4. Conclusion
In summary, a series of coumarin-based compounds were
designed and synthesized with a targeted derivatization of the C4
and C7 hydroxyl groups. Their activity against five prevalent
nematodes was systematically investigated to reveal structure–
activity relationship (SAR). The results showed that the expression
of activity was determined by a combination of carbon chain link
lengths and functional moieties, and that an optimum link chain
length has been established. Compounds 7b, 9a, 10c and 11c
exhibited the most efficient broad spectrum activity and could be
promising for development as novel nematicides.
Acknowledgments
We thank Dr Frank Stermitz for his valuable help in English
editing. The authors are thankful to the National Natural Science
Foundation of China (Nos. 31070386, 21302195 and 31300290),
Please cite this article in press as: L. Pan, et al., Design and synthesis of novel coumarin analogs and their nematicidal activity against five
phytonematodes, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.01.029

G Model
CCLET-3557; No. of Pages 5
L. Pan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
5
[
9] D.J. Chitwood, Phytochemical based strategies for nematode control, Annu. Rev.
Phytopathol. 40 (2002) 221.
1
35 Key Cultivation Program of the Chinese Academy of Sciences,
and the Province-Academy Cooperation Program of Henan
Province of China (No. 102106000021) for financial support.
[
10] M.E. Riveiro, N. De Kimpe, A. Moglioni, et al., Coumarins: old compounds with novel
promising therapeutic perspectives, Curr. Med. Chem. 17 (2010) 1325–1338.
11] B.R. Vijay Avin, P. Thirusangu, V. Lakshmi Ranganatha, et al., Synthesis and tumor
inhibitory activity of novel coumarin analogs targeting angiogenesis and apopto-
sis, Eur. J. Med. Chem. 75 (2014) 211–221.
12] M.E. Riveiro, D. Maes, R. V a´ zquez, et al., Coumarins: old compounds with novel
promising therapeutic perspectives, Bioorg. Med. Chem. 17 (2009) 6547–6559.
13] H. Cui, H. Jin, Q. Liu, et al., Nematicidal metabolites from roots of Stellera
chamaejasme against Bursaphelenchus xylophilus and Bursaphelenchus mucronatus,
Pest. Manag. Sci. 70 (2014) 827–835.
[
Appendix A. Supplementary data
[
[
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2016.01.029.
[14] Z. Yang, Z. Yu, L. Lei, et al., Nematicidal effect of volatiles produced by Trichoderma
sp, J. Asia-Pac. Entomol. 15 (2012) 647–650.
References
[
15] K. Takaishi, M. Izumi, N. Baba, et al., Synthesis and biological evaluation of
alkoxycoumarins as novel nematicidal constituents, Bioorg. Med. Chem. Lett.
18 (2008) 5614–5617.
[
[
1] N.G. Ntalli, P. Caboni, Botanical nematicides: a review, J. Agric. Food. Chem. 60
2012) 9929–9940.
2] J.T. Pechacek, T.M. Bargar, M.R. Sabol, Inhibition of nematode induced root
damage by derivatives of methylenecyclopropane acetic acid, Bioorg. Med. Chem.
Lett. 7 (1997) 2665–2668.
(
[16] S. Lee, K. Sivakumar, W.S. Shin, et al., Synthesis and anti-angiogenesis activity of
coumarin derivatives, Bioorg. Med. Chem. Lett. 16 (2006) 4596–4599.
[17] M. Kawase, H. Sakagami, K. Hashimoto, et al., Structure-cytotoxic activity relation-
ships of simple hydroxylated coumarins, Anticancer. Res. 23 (2003) 3243–3246.
[18] M. Adfa, Y. Hattori, T. Yoshimura, et al., Antitermite activity of 7-alkoxycoumarins
and related analogs against Coptotermes formosanus Shiraki, Int. Biodeterior.
Biodegrad. 74 (2012) 129–135.
[19] Y. Chen, S.L. Wang, X.Q. Xu, et al., Synthesis and biological investigation of
coumarin piperazine (piperidine) derivatives as potential multireceptor atypical
antipsychotics, J. Med. Chem. 56 (2013) 4671–4690.
[
[
[
3] D.J. Chitwood, Research on plant-parasitic nematode biology conducted by the
United States Department of Agriculture–Agricultural Research Service, Pest.
Manag. Sci. 59 (2003) 748–753.
4] T.C. Thoden, M. Boppr e´ , J. Hallmann, Effects of pyrrolizidine alkaloids on the
performance of plant-parasitic and free-living nematodes, Pest. Manag. Sci. 65
(2009) 823–830.
5] I.O. Giannakou, I.A. Anastasiadis, S.R. Gowen, et al., Effects of a non-chemical
nematicide combined with soil solarization for the control of root-knot nema-
todes, Crop. Prot. 26 (2007) 1644–1654.
[20] N. Priya, A. Gupta, K. Chand, et al., Characterization of 4-methyl-2-oxo-1, 2-
dihydroquinolin-6-yl acetate as an effective antiplatelet agent, Bioorg. Med.
Chem. Lett. 18 (2010) 4085–4094.
[
[
6] D.J. Chitwood, S.L.F. Meyer, Phytochemically based nematode control: opportu-
nities and challenges, J. Nematol. 46 (2014), 145-145.
7] J. Kearn, E. Ludlow, J. Dillon, et al., Fluensulfone is a nematicide with a mode of
action distinct from anticholinesterases and macrocyclic lactones, Pestic. Bio-
chem. Phys. 109 (2014) 44–57.
[21] Q.L. Dang, W.K. Kim, C.M. Nguyen, et al., Nematicidal and antifungal activities of
annonaceous acetogenins from Annona squamosa against various plant patho-
gens, J. Agr. Food. Chem. 59 (2011) 11160–11167.
[22] P. Caboni, L. Tronci, B. Liori, et al., Tulipaline A: structure-activity aspects as a
nematicide and V-ATPase inhibitor, Pestic. Biochem. Phys. 112 (2014) 33–39.
[23] J.O. Kong, S.M. Lee, Y.S. Moon, et al., Nematicidal activity of plant essential oils
against Bursaphelenchus xylophilus (Nematoda: Aphelenchoididae), J. Asia-Pac.
Entomol. 9 (2006) 173–178.
[
8] S.M. Seo, J. Kim, S.H. Koh, et al., Nematicidal activity of natural ester compounds
and their analogues against pine wood nematode, Bursaphelenchus xylophilus, J.
Agr. Food. Chem. 62 (2014) 9103–9108.
Please cite this article in press as: L. Pan, et al., Design and synthesis of novel coumarin analogs and their nematicidal activity against five
phytonematodes, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.01.029