Synthesis and bioactivities evaluation of L-pyroglutamic acid analogues from natural product lead

Article abstract of DOI:10.1016/j.bmc.2018.07.041

A series of L-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of L-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC₅₀ values of 1.44 and 1.21 μg mL^?1, which were about seven times that of commercial azoxystrobin (7.85 μg mL^?1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.

Full text of DOI:10.1016/j.bmc.2018.07.041

Accepted Manuscript
Synthesis and bioactivities evaluation of L-pyroglutamic acid analogues from
natural product lead
Fang-li Gang, Feng Zhu, Xiao-ting Li, Jie-lu Wei, Wen-jun Wu, Ji-wen Zhang
PII:
S0968-0896(18)31104-0
https://doi.org/10.1016/j.bmc.2018.07.041
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DOI:
Reference:
Bioorganic & Medicinal Chemistry
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Please cite this article as: Gang, F-l., Zhu, F., Li, X-t., Wei, J-l., Wu, W-j., Zhang, J-w., Synthesis and bioactivities
evaluation of L-pyroglutamic acid analogues from natural product lead, Bioorganic & Medicinal Chemistry (2018),
doi: https://doi.org/10.1016/j.bmc.2018.07.041
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Graphical Abstract
Synthesis and bioactivities evaluation of L-
pyroglutamic acid analogues from natural
product lead
Leave this area blank for abstract info.
Fang-li Ganga, †, Feng Zhua, †, Xiao-ting Lia, Jie-lu Weia, Wen-jun Wub, and Ji-wen Zhanga,b,
a College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest
A&F University, Yangling, Shaanxi, 712100, P. R. China
b Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi, 712100, P. R. China

Bioorganic & Medicinal Chemistry
Synthesis and bioactivities evaluation of L-pyroglutamic acid analogues from natural
product lead
Fang-li Ganga, †, Feng Zhua, †, Xiao-ting Lia, Jie-lu Weia, Wen-jun Wub, and Ji-wen Zhanga,b,
a College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University, Yangling, Shaanxi, 712100,
P. R. China
b Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi, 712100, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of L-pyroglutamic acid analogues from natural product lead were designed and
synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic
activities, antibacterial activities and anti-inflammatory activities are described. The bioassays
and SAR study showed that the majority of L-pyroglutamic acid esters have a significant
antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with
EC50 values of 1.44 and 1.21 μg·mL-1, which were about seven times that of commercial
azoxystrobin (7.85 μg·mL-1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory
activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in
NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and
2j are potential drugs to control P. infestans.
Available online
Keywords:
L-pyroglutamic acid
Structure-activity-relationship
Anti-inflammatory activity
Antifungal activity
2009 Elsevier Ltd. All rights reserved.
Neuritogenic activity
1. Introduction
In recent years, complex compounds contained L-
pyroglutamic acid analogues, which exhibited human
farnesyltransferase inhibitory activity16, anti-HIV-1 and anti-
HCV activity17, antioxidant activity18, Gram-negative
antibacterial activity19-21, anti-colitic activity22, anti-inflammatory
activity on RAW 264.7 macrophages23, antidepressant-like
activity24 and antiplatelet efficacy (in vitro) 25, have received
great attention from chemists and biologists.
Plant is a natural molecular manufacturing factory and a
superb organic chemist. There is no doubt that natural products
are a treasure trove of drug development, giving a constant
stream of inspiration to human drug design. Many plant-derived
biologically active natural compounds origin possess
insecticidal,1-2 antibacterial,3 anti-microbial,3-4 anti-tumor,5 anti-
malarial,6 anti-tuberculosis7 or nematocidal8 activities, and can be
considered as ideal lead in the development of agricultural or
medical chemicals.9-14 Moreover, some of the secondary
metabolites in plants are formed in order to resist stress damage
during the long-term survival competition. Typically, they are
unique new structures; tend to have very good biological activity;
better compatibility with the environment. All these advantages
make pesticide scientists, medical experts and toxicologists pay
more attention on the traditional herbal.
Motivated by the above findings and to continue our efforts in
studying the structure−activity relationships of L-pyroglutamic
acid (1) toward exploring lead compounds for botanical
medicines,26 we herein designed and synthesized 42 L-
pyroglutamic acid analogues, and their biological activity was
systematically evaluated. To the best of our knowledge, this is
the first report on antifungal activity against P. infestans,
neuritogenic activity and anti-inflammatory activity of this series
of pyroglutamic acid derivatives.
L-pyroglutamic acid (1), according to our previous study, is a
biologically active substance that has been isolated from
2. Results and discussion
Disporopsis aspersa (HUA
)
ENGL
.
ex DIELS against
Pseudoperonospora cubensis and Phytophthora infestans.15
Significantly, L-pyroglutamic acid showed excellent antifungal
activity against P. infestans and P. cubensis with EC50 values of
9.48, 10.82 μg/mL, respectively. In addition, 1 also exhibited
dual effect of protection and treatment against P. cubensis in
2.1. Chemistry
Synthesis of the target compounds 1a-h, 2a-k, 3a-j, 4a-k, and
5a-5b was performed as illustrated in Scheme 1. Briefly, various
precursor L-pyroglutamic acid derivatives were obtained from L-
pyroglutamic acid and the different substituted alcohols/phenols/
amines as the starting materials in one-pot with satisfactory
vivo.
———
 Corresponding author. Tel.: +86-029-87092191; e-mail: author@university.edu (Jiwen Zhang)
† These two authors contribute equally to this work.

yields (55% to 95%). Of these, 32 compounds were synthesized
for the first time. In addition, during the reaction, the
stereochemistry of these products did not change, and still
maintained the same configuration as L-pyroglutamic acid.
(S)-Prop-2-yn-1-yl 5-oxopyrrolidine-2-carboxylate: (1g)
1
Yield: 87%, yellowish oil. [α]2D4 –8.2° (c 1.0, DMSO). H NMR
(500 MHz, DMSO-d6) δ 8.02 (s, 1H), 4.78 (d, J = 1.4 Hz, 2H),
4.26 (dd, J = 9.1, 4.1 Hz, 1H), 3.51 (t, J = 2.4 Hz, 1H), 2.49 –
2.33 (m, 1H), 2.29 – 2.07 (m, 2H), 2.05 – 1.99 (m, 1H).13C NMR
(125 MHz, DMSO-d6) δ 177.7, 172.7, 78.3, 75.0, 55.1, 52.9, 29.3,
+
24.9. MS (ESI, MeOH) m/z calcd for C8H9NO3 (M + H) :
168.06; found 168.06.
Scheme 1. Synthesis of L-pyroglutamic acid analogues.
2.2. Antifungal activity against P. infestans
In this study, the target 43 compounds were evaluated for
their antifungal activity against P. infestans via inhibition of
zoospore release assay27-28 at concentrations of 100 μg/mL
(Figure 1). The results of the preliminary bioassays exhibited
that compounds 1, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 2j, 2h and 2k have
excellent antifungal activities against P. infestans, and similar to
the positive control with inhibition rate as 99.23%. As can be
seen in Table 1, most of L-pyroglutamic acid esters (1a-1h, 2a-
2k) showed good
except 1g and 2e, which were
superior to the activities of L-pyroglutamines (3a-3j, 4a-4k, and
5a-5b). Moreover, the antifungal activities of L-pyroglutamic
acid esters containing fatty chains (1a-f) are slightly lower than
that of phenols (2a-k except 2e).
Table 1 Inhibitory effect of L-pyroglutamic acid derivatives at a concentration of 100 μg/mL on zoospore release of P. infestans
Inhibition rate
Inhibition rate
 SD (%)b
Inhibition rate
 SD (%)b
compound
compound
compound
 SD（%）
azoxystrobin a
2f
2g
2h
2i
3j
4a
4b
4c
4d
4e
4f
99.23  0.88
98.85  2.17
26.10  0.95
95.81  2.01
95.12  1.15
98.95  1.68
36.46  3.10
64.90  0.66
-
48.56  1.49
33.68  2.75
1.17  0.97
-
1
39.75  3.06
1a
98.22  2.12
1b
13.16  1.56
17.76  2.64
1c
2j
98.47  0.90
49.32  3.11
-
1d
2k
3a
3b
3c
3d
3e
3f
98.32  2.51
-
1e
44.26  2.91
-
1f
4g
4h
4i
35.78  1.79
-
-
-
1g
1h
84.19  4.10
98.27  2.04
96.34  1.45
98.39  1.67
98.09  1.33
-
47.52  3.44
-
-
-
-
2a
4j
21.52  2.60
-
2b
4k
5a
5b
2c
3g
3h
3i
13.58  2.14
-
2d
2e
2.37  1.33
aPositive control.
bValues represent the means ± SD based on three independent experiments.

Table 2 EC50 values of L-pyroglutamic acid derivatives
against P. infestans
R2 (Chi-
square value)
Toxic regression
Compound
EC50 (μg·mL-1)b
equation
Azoxystrobin a
y= 3.23x + 4.04
y= 2.58x + 2.69
y= 3.12x + 1.31
y= 1.67x + 3.17
y= 3.05x + 1.80
y= 2.14x + 2.24
y= 3.71x + 1.54
y= 2.89x + 1.64
y= 1.09x + 4.83
y= 2.28x + 2.23
y= 1.12x + 4.91
y= 1.55x + 4.02
0.995
0.988
0.991
0.975
0.969
0.990
0.989
0.996
0.992
0.993
0.984
0.984
1.98  0.50
7.85  0.58
15.25  0.74
12.43  1.22
11.20  0.65
19.51  0.25
8.58  0.88
14.56  1.02
1.44  0.33
16.42  0.81
1.21  0.67
9.62  0.36
1
1b
1c
1d
2a
Figure 1. Effect on indirect germination (zoospore release from
zoosporangia), zoospore motility, and cystospore germination: I compound
2j; II compound 2d; III L-pyroglutamic acid; IV blank control
2b
2c
To further determine the activity and structure-activity
relationship of the target compounds, the EC50 values of
compounds with activities greater than 90% were determined in
this study. As shown in Table 2, compounds 2d and 2j revealed
better activity against P. infestans with EC50 values of 1.44 and
1.21 μg·mL-1; these values are even better than pyroglutamic
acid (7.85 μg·mL-1) and the positive control azoxystrobin (1.98
μg·mL-1). Moreover, compounds 2b and 2k exhibited relatively
good antifungal activity, comparable to the positive control at the
same magnitude as L-pyroglutamic acid. In addition, the
introduction of straight-chain alcohols (1b, 1c and 1d) and
phenols (2a-2d, 2h, 2j and 2k) on the pyroglutamate ring led to a
significant increase in antifungal activity against P. infestans.
For the effect of substituents on phenols, available data show
that the electron-withdrawing groups were useful for fungicidal
activity increasing.
2d
2h
2j
2k
aPositive control.
bValues represent the means ± SD based on three independent experiments.
2.3. Anti-inflammatory activity
The title compounds were evaluated for their inhibitory
activities against NO production induced by lipopolysaccharide
(LPS) in BV-2 microglial cells using the Griess assays29-31
.
Comparison of the inhibitory effects of L-pyroglutamines,
pyroglutamic acid esters have better activities, and with the
increase of chain growth activity (Figure 2). It is worth noting
that allyl and propargyl are very useful groups for inhibitory
activity against NO production, and the propargyl activity is
higher than the allyl group.
Figure 2. Inhibitory effects of L-pyroglutamic acid derivatives against LPS-induced NO production in BV-2 cells; Data represent the mean ± SD of three
dependent experiments; ** P <0.01 represent differences compared with LPS-induced NO production in BV-2 cells
Table 3 IC50 values of the active compounds against LPS-
induced NO production in BV-2 cells
As illustrated in Table 3, compounds 2e, 2g, 4d and 4e
compound
IC50 (μM) a
4.5 ± 0.9
19.4 ± 1.2
9.1 ± 0.6
6.0 ± 0.8
4.3 ± 0.3
cell viability (%) b
showed anti-inflammatory activities with IC50 values in the range
of 4.5-19.4 μM. Among them, the value of 2e is basically the
same as the positive control quercetin (IC50 = 4.3 μM), a well-
known NO inhibitor29-30. These 4 compounds did not show
significant cytotoxicity with LPS treatment for 24 hours using
SRP assay, which indicates that inhibition activity of the active
compounds and their cytotoxicity independent.
2e
92.6
91.1
95.4
89.5
99.5
2g
4d
4e
quercetin c
aValues represent the means ± SD based on three independent experiments.
bCell viability was expressed as a percentage (%) of control group.
cPositive control.

2.4. Neuritogenic activity
2.6. Structure–activity relationship analysis (SAR)
In this study, the
target compounds
Based on the above bioassay experiments, we further discuss
its structure-activity relationship (Scheme 2). Concerning the
presence of L-pyroglutamic acid derivatives involved alcohols or
phenols, the corresponding compounds exhibited good
antifungal activity against P. infestans (Table 1-2), wherein L-
pyroglutamate containing alcohol has a lower antifungal activity,
and significant increase in activities with the growth of the
carbon chain (1d＞1c＞1b＞1a), branched reduced (1d＞1f, 1c
＞ 1e). In particular, for aryl pyroglutamate, the activity of
naphthyl is higher than the phenyl, and electron-withdrawing
group on the aromatic ring has a significant effect on the activity
enhancement (2b, 2c, 2d, 2h and 2k). In addition, alkynyl group
introduced to title compounds (1g and 4e) is unfavorable for
antibacterial activity against P. infestans, which is contrary to
cellular activities (Table 3 and Figure 2-3). Compounds 1g, 2e,
2g and 4d displayed anti-inflammatory against LPS-induced NO
production in BV-2 microglial cells; same as neuritogenic
activity in NGF-induced PC-12 cells. L-pyroglutamic acid
were measured using rat pheochromocytoma (PC-12) cells as a
neuronal differentiation model32-33 and are given in Figure 3.
in combination with NGF (20 ng/mL)
degrees of increase neurite bearing cells compared to positive
control percentage of neurite-bearing NGF-
induced PC-12 cells treated with 20 μM 2e and 4d reached
15.443 ± 0.49% and 14.962 ± 0.36%, respectively. These were
compatible with positive control (11.90 ± 0.25%) and far higher
than negative control (0.77 ± 0.13%). In addition, the vast
majority of test pyroglutamic acid derivatives contained fatty
alcohols or aromatic amines had no effect on neurite outgrowth
in NGF-induced PC-12 cells.
different
derivatives have no significant activity against
B.
thuringiensis, S. aureus, B. cereus, R. solanacearum and E.
carotovora).
In a word, the SAR analysis demonstrated pyroglutamates
derivatives contained naphthol, long-chain alcohol or electron-
withdrawing group have a significant meaning for the design of
drugs against P. infestans, and C3H3/C3H5 or 4–OH/2-CH3-4-Cl
on the phenyl ring of phenols is beneficial for the increase of
anti-inflammatory activity/
(B)
Scheme 2. SAR study of title compounds.
3. Conclusion
In summary, a series of L-pyroglutamic acid derivatives were
synthesized and their antifungal activity against P. infestans,
neuritogenic activity, anti-inflammatory activity and antibacterial
activity were systematically evaluated. From the bioassay results
and the structure–activity relationship (SAR) analysis, most of
L-pyroglutamic acid esters have good antifungal activity against
P. infestans. Notably, compounds 2d and 2j demonstrated the
best activities with EC50 values of 1.44 and 1.21 μg·mL-1,
respectively, which were superior to commercial azoxystrobin.
Moreover, compounds 2e, 2g and 4d displayed anti-
inflammatory against LPS-induced NO production in BV-2
microglial cells; same as neuritogenic activity in NGF-induced
PC-12 cells.
Figure 3. Effects of compounds 1g, 2e, 2g, 2h, 2i, 4d, 4i, 4j and 5b on the
neurite outgrowth in NGF-induced PC-12 cells; (A) Cell morphology (B)
Neurite bearing cells analyze. Data represent the mean ± SD of three
dependent experiments. ** P <0.01 represent differences compared with
NGF-treated PC-12 cells.
2.5. Antibacterial activity
To
B. thuringiensis, S. aureus, B. cereus, R.
solanacearum and E. carotovora),
To the best of our knowledge, this is the first report on the
antifungal, neuritogenic and anti-inflammatoryof L-pyroglutamic
acid derivatives. In particular, compounds 2d and 2j can be used
as a potential drug for controlling P. infestans. Further detailed
mechanism and field experiments are ongoing.
in Supporting Information, Table S.1.
L-
pyroglutamines
L-pyroglutamic acid
esters, and
4. Experimental section
in the bacterial bioassay experiments, the title
compound showed relatively high activities against B.
thuringiensis showing lower activities against S. aureus,
B. cereus, R. solanacearum and E. carotovora.
4.1. General

separately. After mixing, they were placed in a 4 oC environment
and cultured in darkness for 4 h. Solvent as negative control and
azoxystrobin as positive control. The zoospore release was
recorded and the inhibition rate was calculated when the control
spore release rate reached 90%. Toxicity bioassay was then
performed the concentration for 50% of maximal effect (EC50) of
compounds with inhibition rate > 50%. Inhibition rate (%)36 was
calculated as equation (1):
4.2. Chemical synthesis
Where P0 is control germination rate; P1 is treated-groups
germination rate
4.2.1 General procedure for the synthesis of L-pyroglutamic acid
esters (1a-1h):
4.4. Anti-inflammatory activity and cell viability
To a solution of L-pyroglutamic acid (10 mmol) in anhydrous
alcohol (30 mL) was added catalytic amount of SOCl2 (1 mmol).
The reaction mixture was stirred at room temperature for 12 h
until no change was observed by TLC. After evaporating the
solvent under reduced pressure, the residue was dissolved in
EtOAc (100 mL), stirred over K2CO3, and dried with MgSO4 to
afford the crude product. Then the residue passed through a flash
column chromatography (MeOH/ CH2Cl2=1/10) on silica gel and
removal of all volatiles were in vacuo to give the pure products.
LPS-induced
as an inflammation model
were plated into a 96-well plate at a density of 1×105 cells/mL.
After 24 h incubation, cells were pretreated with target
compounds at the specified concentration and stimulated with 1
μg/mL LPS for another 24 h. Quercetin was used as positive
control. The cell-free supernatant (50 μL) was mixed with 100
μL Griess reagent, and the absorbance was measured at 540 nm
using a microplate reader. Cell viability was evaluated using an
SRB assay.
4.2.2 General procedure for the synthesis of L-pyroglutamic acid
ester (2a-2k) and L-pyroglutamines (3a-3j):
4.5. Neuritogenic activity
To a round bottom flask with a stirring bar, L-pyroglutamic
acid (10 mmol), phenol/aromatic amine (11 mmol) and DMAP
(1 mmol) in dry CH2Cl2 (30 mL) was stirred for 10 min, followed
by addition of DCC (11 mmol). The mixture was allowed to stir
at room temperature overnight. The reaction was filtered
CH2Cl2
×
dryness. The crude mixture was purified using flash column
chromatography (MeOH/ CH2Cl2=1/30) to give the pure products.
All target compounds were evaluated for their
by rat pheochromocytoma (PC-12) cells as a neuronal
differentiation model. The evaluation was carried out using
morphological analysis and quantification of neurite-bearing
cells. PC-12 cells were seeded in poly-L-lysine-coated 24-well
plates in high serum medium (10% HS and 5% FBS) for 48 h
with a density of 1×104 cells/mL, and then starved for 14 h with
low serum media (1% HS and 0.5% FBS). The hungry cells were
treated with tested compounds (20 μM) in the presence of NGF
(20 ng/mL) in three parallels. NGF-treated cells were used as
positive control; solvent-only cells were used as negative
control. After 48 h incubation, neurite outgrowth of PC-12 cells
was observed under an inverted microscope. Ten images were
selected randomly under the microscope in each well, with at
least 100 cells in each field. A cell that contains one or more
neuritis greater than the length of its body was positive for
neurite outgrowth, and neurite bearing cells (%) was calculated
as:
4.2.3 General procedure for the synthesis of L-pyroglutamines
(4a-4k):
The reaction was conducted with fatty amine (11 mmol), L-
pyroglutamic acid (10 mmol), HOBt (0.25 mmol) and EDC·HCl
(12 mmol) in dry CH2Cl2 (30 mL) was stirred for 6 h at room
temperature.
CH2Cl2
×
dryness. The reaction residues
were purified by flash column chromatography on silica (MeOH/
CH2Cl2=1/2) to provide pure products.
Where Na is the number of neurite bearing cells; Nt is the number
of total cell number
4.2.4 General procedure for the synthesis of L-pyroglutamines
(5a-5b):
4.6. Antibacterial activity
Stirred L-pyroglutamic acid methyl ester (10 mmol) in NH3
[aq] / N2H4 [aq] (50 mL) for 12 h at room temperature. Then the
o
mixture was allowed to stand for one day at -10 C. Next the
crystallization washed with ethanol, ether,
O4,
The crude mixture was purified by flash column chromatography
on silica (MeOH/ CH2Cl2=1/6) to provide pure product as white
solid.
(5 μL, 2 mg/mL) w
in three parall
s used as positive control;
4.3. Antifungal activity against P. infestans
solvent-only was used as negative control. The air-dried filter
paper is affixed to the culture medium. After 4-10 h incubation at
,
A zoosporangia suspension (5×104 zoosporangia/mL) was
used to evaluate the effects on title compounds against
P. infestans. Sporulation has taken gently from P. infestans to
prepare spore suspension with a concentration of each field 60-
70 best. Next, spore suspension (0.1 mL) and compounds
solution (0.1 mL, 0.2 mg/mL) were added to 0.5 mL EP tube

Zoumpoulakis, P.; Mavromoustakos, T.; Hadjipavloulitina, D.
Bioorg. Med. Chem. 2011, 19, 2888-2902.
Acknowledgments
19. Tan, S. W.; Chai, C. L.; Moloney, M. G. Org. Biomo.l Chem.
2017, 15, 1889–1912.
20. Angelov, P.; Chau, Y. K.; Fryer, P. J.; Moloney, M. G.;
Thompson, A. L.; Trippier, P. C. Org. Biomol. Chem. 2012, 10,
3472–85.
21. Tan, S. W.; Chai, C. L.; Moloney, M. G.; Thompson, A. L. J. Org.
Chem. 2015, 80, 2661–75.
22. Kiyono, T.; Wada, S.; Ohta, R.; Wada, E.; Takagi, T.; Naito, Y.;
Yoshikawa, T.; Sato, K. Journal of Functional Foods. 2016, 27,
612–621.
23. Hirai, S.; Horii, S.; Matsuzaki, Y.; Ono, S.; Shimmura, Y.; Sato,
K.; Egashira, Y. Life Sci. 2014, 117, 1–6.
24. Yamamoto, Y.; Mizushige, T.; Mori, Y.; Shimmura, Y.;
Fukutomi, R.; Kanamoto, R.; Ohinata, K. Neuropeptides. 2015,
51, 25–9.
25. Misra, A.; Anil Kumar, K. S.; Jain, M.; Bajaj, K.; Shandilya, S.;
Srivastava, S.; Shukla, P.; Barthwal, M. K.; Dikshit, M.; Dikshit,
D. K. Eur. J. Med. Chem. 2016, 110, 1–12.
26. Benoit, R. J. Heterocyclic Chem. 1988, 25, 49–57.
27. Mitani, S.; Araki, S.; Yamaguchi, T.; Takii, T.; Ohshima, T.;
Matsuo, N. Pestic. Biochem. Phys. 2001, 70, 92-99.
28. Pasteris, R. J.; Hanagan, M. A.; Bisaha, J. J.; Finkelstein, B. L.;
Hoffman, L. E.; Gregory, V.; Andreassi, J. L.; Sweigard, J. A.;
Klyashchitsky, B. A.; Henry, Y. T.; Berger, R. A. Bioorg. Med.
Chem. 2015, 24, 354-361.
29. Dong, Z.; Gu, Q.; Cheng, B.; Cheng, Z.; Tang, G.; Sun, Z.; Zhang,
J.; Bao, J.; Yin, S. RSC Adv. 2014, 4, 55036–55043.
30. Huang, Z.; Zhu, Z.; Li, Y.; Pang, D.; Zheng, J.; Zhang, Q.; Zhao,
Y.; Ferreria, D.; Zjawiony, J. K.; Tu, P-F, Li, J. J. Nat. Prod.
2015, 78, 2276−2285.
31. Zhang, C.; Wang, S.; Zeng, K.; Li, J.; Ferreira, D.; Zjawiony, J.
K.; Liu, B-Y.; Guo, X-Y.; Jin, H-W.; Jiang, W.; Tu, P-F. J. Nat.
Prod. 2016, 79, 213−223.
32. Bai, R.; Zhang, C.-C.; Yin, X.; Wei, J.; Gao, J.-M. J. Nat. Prod.
2015, 78, 783-788.
33. Zhang, C.; Yin, X.; Cao, C.; Wei, J.; Zhang, Q.; Gao, J.-M.
Bioorg. Med. Chem. Lett. 2015, 25, 5078-5082.
34. Hu, Y.; Qiao, J.; Zhu, R.; et al. Medicinal Plant. 2010, 90, 47-54.
35. Zhang, W.; Wei, S.; Zhang, J-W.; Wu, W-J. Molecules. 2013, 18,
2763-2768.
36. Wang, G.; Chen, X.; Deng, Y.; Li, Z.; Xu, X. J. Agric. Food
Chem. 2015, 63, 6883−6889.
We gratefully acknowledge the National Key R&D Program
of China (2017YFD0200506).
References and notes
1.
2.
3.
4.
5.
6.
7.
Wang, D.; Xie, N.; Yi, S.; Liu, C.; Jiang, H.; Ma, Z.; Feng, J.;
Yan, H.; Zhang, X. Pest Manag. Sci. 2018, 74, 210-218.
Zhao, X.; Xi, X.; Hu, Z.; Wu, W-J.; Zhang, J-W. J. Agric. Food
Chem. 2016, 64, 1503-1508.
Lin, Q.; Zhang, L.; Yang, D.; Zhao, C. J. J. Med. Food. 2014, 17,
714-722.
Da, R.; Maraschin, M.; Di, P. R. Int. J. Food Microbiol. 2015,
215, 64-70.
Chen, Z.; Cao, R.; Shi, B.; Guo, L.; Sun, J.; Ma. Q.; Fan, W. X.;
Song, H. C. Eur. J. Med. Chem. 2011, 46, 5127–5137.
Onguéné, P. A; Ntie, F.; Lifongo, L.; Ndom, J. C.; Sippl, W.;
Mbaze, L. M. Malaria Journal. 2013, 12, 449-474.
Grzelak, E-M.; Hwang, C.; Cai, G.; Nam, J. W.; Choules, M. P.;
Gao, W.; Lankin, D. C.; McAlpine, J. B.; Mulugeta, S. G.;
Napolitano, J. G.; Suh, J. W.; Yang, S. H.; Cheng, J. H.; Lee, H.;
Kim, J. Y.; Cho, S. H.; Pauli, G. F.; Franzblau, S. G.; Jaki, B. U.
Acs. Infect. Dis. 2016, 2, 294-301.
8.
9.
Dong, J.; Li, R.; Zhang, K. Plant Protection, 2005, 31, 9-15.
Harvey, A. L.; Clark, R. L.; Mackay, S. P.; Johnston, B. F. Expert
Opin. Drug Dis. 2010, 5, 559-568.
10. Sparks, T. C.; Lorsbach, B. A. Pest Manag. Sci. 2017, 73, 672-
677.
11. Elangovan, M.; Haneen, A.; Noor, H.; Chandrabose, K.; Aubry,
F.; Hari, N.; Moorthyc, P.; Trivedic, A. Eur. J. Med. Chem. 2017,
133, 365-378.
12. Yutaka, S.; Mariko, S.; Kota, F.; Shotaro, K.; Mikio, O.; Daiju, I.;
Maiko, M.; Noriyuki, Y.; Genji, I.; Fumiyuki, K.; Yutaka, H.
Bioorg. Med. Chem. Lett. 2017, 27, 4558–4563.
13. Lauren, D.; Anthony, D.; Wrightb, K.; Younga, J. Sakoffc.; Adam,
M. Bioorg. Med. Chem. 2014, 22, 1690–1699.
14. Horst, P.; Guido, K.;Tim, S.; Peter, E.;Alex, B.; Meir, G.; Ina, D.;
Frank, P.; Dimitrios, E. L. Bioorg. Med. Chem. 2017, 25, 921–
925.
15. Zhu, F.; Yuan, C. S.; Gang, F. L.;, Yang, C. F.; Wu, W. J.; Zhang,
J.
W.
Chemistry
&
Biodiversity.
2018,
doi:
10.1002/cbdv.201800090.
16. Homerin, G.; Lipka, E.; Rigo, B.; Farce, A.; Dubois, J.; Ghinet,
A. Org. Biomol. Chem. 2017, 15, 8110–8118.
Supplementary Material
17. Martínez M. S.; Fernández, S.; Sanghvi, Y. S.; Theodorakis, E.
A.; Detorio, M. A.; Mcbrayer, T. R.; Whitaker, T.; Schinazi, R.
F.; Gotor, V.; Ferrero, M. Bioorg. Med. Chem. 2012, 20, 6885-
6893.
18. Moutevelisminakakis, P.; Papavassilopoulou, E.; Michas, G.;
Georgikopoulou, K.; Ragoussi, M. E.; Neophytou, N.;
Supporting information associated with this article
(antibacterial activity, characterization data of products and
NMR spectra of all products) can be found at
http://dx.doi.org/10.1002/MS-number.