Novel carboxylated pyrroline-2-one derivatives bearing a phenylhydrazine moiety: Design, synthesis, antifungal evaluation and 3D-QSAR analysis

Article abstract of DOI:10.1016/j.bmcl.2020.127519

Aiming to discover novel high-efficient antifungal leads that possess an innovative action mechanism, twenty-three carboxylated pyrroline-2-one derivatives, bearing a phenylhydrazine moiety, were rationally designed and firstly prepared in this letter. The in vitro bioassays showed that most of the compounds possessed excellent antifungal effects with the EC₅₀ values of less than 1 μg/mL against the phytopathogenic fungi Fusarium graminearum (Fg), Botrytis cinerea (Bc), Rhizoctonia solani (Rs) and Colletotrichum capsici (Cc). The further bioassays showed that the compound 6u showed the comparable in vivo control effect with carbendazim against fusarium head blight and rice sheath blight. The 3D-QSAR model revealed the pivotal effects of a bulky electron-donating group at the 1-position of pyrrole ring, a bulky electron-withdrawing group at the 4-position of phenyl ring and a small alkyl at the carbonate group on the anti-Rs activities of target compounds. The abnormal mycelial morphology and delayed spore germination were observed in the treatments of compound 6u. Given the excellent and broad-spectrum antifungal effects the target compounds have, we unfeignedly anticipated that the above finding could motivate the discovery of high-efficient antifungal leads, which might possess an innovative action mechanism against phytopathogenic fungi.

Full text of DOI:10.1016/j.bmcl.2020.127519

Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel carboxylated pyrroline-2-one derivatives bearing a phenylhydrazine
moiety: Design, synthesis, antifungal evaluation and 3D-QSAR analysis
a
a,b
a
a
a
a
a,⁎
Min Chen , Lizhi Zhang , Aimin Lu , Xiaobin Wang , Weijie Si , Jinghua Yan , Chunlong Yang
b
a
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing, China
Institute of Synthesis, CHIA TAI Tianqing Pharmaceutical Group Co., Ltd, Nanjing, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Aiming to discover novel high-efficient antifungal leads that possess an innovative action mechanism, twenty-
three carboxylated pyrroline-2-one derivatives, bearing a phenylhydrazine moiety, were rationally designed and
firstly prepared in this letter. The in vitro bioassays showed that most of the compounds possessed excellent
antifungal effects with the EC50 values of less than 1 μg/mL against the phytopathogenic fungi Fusarium gra-
minearum (Fg), Botrytis cinerea (Bc), Rhizoctonia solani (Rs) and Colletotrichum capsici (Cc). The further bioassays
showed that the compound 6u showed the comparable in vivo control effect with carbendazim against fusarium
head blight and rice sheath blight. The 3D-QSAR model revealed the pivotal effects of a bulky electron-donating
group at the 1-position of pyrrole ring, a bulky electron-withdrawing group at the 4-position of phenyl ring and a
small alkyl at the carbonate group on the anti-Rs activities of target compounds. The abnormal mycelial mor-
phology and delayed spore germination were observed in the treatments of compound 6u. Given the excellent
and broad-spectrum antifungal effects the target compounds have, we unfeignedly anticipated that the above
finding could motivate the discovery of high-efficient antifungal leads, which might possess an innovative action
mechanism against phytopathogenic fungi.
Pyrroline-2-one
Phenylhydrazine
Lead optimization
Antifungal activity
3
D-QSAR
The exploding population looming nine billion by 2050 will chal-
pyrroline-2-one or pyrrolidine-2,4-dione derivatives possessing sig-
nificant antifungal activities were synthesized and documented during
1
lenge the world in feeding overfull people with limited arablelands.
1
8–24
Without the existing agricultural management practices, especially the
wide use of pesticides, crops would face 50% to 82% losses, in which
pathogens were responsible for the 8% to 21% losses. Even in the
modern using of pesticides, weeds, animal pests and phytopathogenic
microorganisms still caused the huge crop losses of at least 10% every
the last decades.
These modified tetramic acids with antifungal
bioactivities tend to have two important structural features. To some
extent, one molecular characteristic could be concluded as the presence
1
8–21
of a bulky polar fragment at the 3-position of the pyrrole skeleton,
the other is the introduction of a moderate lipophilic moiety into the 4-
2
7,22–24
year. Concurrently, the heavy use of agrochemicals has brought a
position of the pyrrole nucleus.
series of problems including environmental pollutions, food safeties,
Hydrazine, not only the important intermediate in the synthesis of
the nitrogen heterocyclic ring but also a bioactive group, was usually
taken consideration in the optimization of new biological com-
3
pesticide resistances, and so on. Therefore, it is an urgent need for
agricultural productions to develop novel pesticide ingredients with
efficient, broad-spectrum and eco-friendly features.
2
5–27
pounds.
For example, the commercial fungicide famoxadone is the
28
Tetramic acids, bearing a unique pyrroline-2-one or pyrrolidine-2,4-
dione scaffold, are largely existent in the secondary metabolites that are
representative compound containing the hydrazine group (Fig. 1).
Concurrently, our previous work found that introducing a moderate
hydrazine fragment could effectively improve the antifungal effects of
4
,5
generated by natural microorganisms. For the remarkable bioactiv-
ities they displayed, tetramic acids were well reported in the discovery
of novel natural products, the synthesis methods, and the screening of
2
6,29
synthetic compounds (Fig. 1).
As another important fragment ex-
isting in commercial fungicides, carboxylic ester frequently appears in
the lipophilic moieties that effectively regulate the molecular penetr-
6
–9
pharmacological activities.
The natural tetramic acids present di-
10 11,12
30
verse biological activities, such as herbicidal, antifungal,
17
anti-
effects.
ability within living organisms. For instance, the commercial fungi-
1
3,14
15
16
bacterial,
antitumor,
antiviral,
and antioxidative
cides azoxystrobin and pefurazoate contain the carboxylic ester in their
structures (Fig. 1). Meanwhile, our previous work documented that
Based on the molecular structures of natural tetramic acids, many
⁎
Corresponding author.
E-mail address: ycl@njau.edu.cn (C. Yang).
https://doi.org/10.1016/j.bmcl.2020.127519
Received 7 July 2020; Received in revised form 20 August 2020; Accepted 21 August 2020
Available online 27 August 2020
0960-894X/ © 2020 Elsevier Ltd. All rights reserved.

M. Chen, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Fig. 1. Design strategy of target tetramic acid derivatives.
Scheme 1. Synthesis route of target compounds 6a-6w. Reagents and conditions: (i) SOCl
2
, MeOH, r.t., 1 h then reflux 4 h; (ii) MeONa, MeOH, neutralization; (iii)
diketene, r.t., 10 h; (iv) MeONa, MeOH, reflux 4 h; (v) 20% HCl, acidification to pH = 2–3; (vi) Et
3
N, EtOH, reflux, TLC monitoring; (vii) Et
3
N, CHCl , 0–4 °C, 30 min.
3
some bioactive molecules containing a carboxylic ester moiety showed
2
2,31
obvious inhibition effects against phytopathogenic fungi.
Based on the structural features of tetramic acid derivatives ex-
hibiting antifungal bioactivities, phenylhydrazine, carboxylic ester and
carbonate fragments were respectively introduced into the 3- and 4-
positions of pyrrole skeleton to tactfully conceive twenty-three novel
2
1
pyrroline-2-one derivatives (Scheme 1). Using N-substituted glycines
(
1a–1g) as raw materials, pyrrolidine-2,4-dione analogues (4a–4g)
were successfully synthesized by three successive steps including es-
2
9
terification, acylation and cyclization (Scheme 1). Subsequently,
substituted phenylhydrazines were introduced into the 3-position of
compounds 4a–4g to prepare the key intermediates pyrrolidine-2,4-
3
0
diones bearing a phenylhydrazine moiety (5a–5q). Finally, the in-
termediates 5a–5q reacted with different chloroformates to con-
veniently generate the target compounds (6a–6w) with synthetic yields
ranged from 49% to 80% (Table S1 in Supporting information). The
1
structures of all target compounds were confirmed by FT-IR, H NMR,
Fig. 2. ORTEP diagram of compound 6d showing intramolecular hydrogen
13
C NMR and HRMS. The structure of compound 6d was further con-
bonds (red dotted lines).
firmed by the single crystal X-ray analysis (Fig. 2).
2

M. Chen, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Table 1
a.
In vitro antifungal EC50 values (μg/mL) of target compounds 6a–6w.
1
2
3
Compound
R
R
R
Fg
Bc
Rs
Cc
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
Me
Et
0.71 ± 0.21
0.42 ± 0.11
0.51 ± 0.12
0.33 ± 0.33
0.38 ± 0.49
0.24 ± 0.40
0.30 ± 0.61
1.86 ± 1.76
0.26 ± 0.09
0.77 ± 0.30
0.68 ± 1.02
66.59 ± 7.92
0.31 ± 0.17
176.33 ± 9.11
0.80 ± 0.08
2.23 ± 2.66
0.22 ± 0.11
0.30 ± 0.34
0.48 ± 0.11
0.36 ± 0.34
0.28 ± 0.04
0.40 ± 0.35
0.39 ± 0.12
0.49 ± 0.14
/
0.19 ± 0.04
0.14 ± 0.03
0.20 ± 0.21
0.18 ± 0.17
0.22 ± 0.23
0.23 ± 0.24
0.39 ± 0.38
1.14 ± 1.31
0.35 ± 0.27
0.58 ± 0.43
0.67 ± 0.56
2.38 ± 1.91
0.27 ± 0.28
3.85 ± 3.02
0.49 ± 0.51
0.65 ± 0.79
0.21 ± 0.33
0.16 ± 0.23
0.13 ± 0.14
0.13 ± 0.16
0.11 ± 0.12
0.26 ± 0.36
0.19 ± 0.31
/
0.09 ± 0.15
0.12 ± 0.13
0.14 ± 0.21
0.24 ± 0.23
0.12 ± 0.19
0.17 ± 0.24
0.14 ± 0.51
1.67 ± 2.31
1.08 ± 1.32
2.08 ± 1.54
1.21 ± 1.38
2.23 ± 2.47
0.73 ± 0.95
2.05 ± 2.45
1.09 ± 1.71
0.82 ± 0.67
0.60 ± 0.42
0.14 ± 0.29
0.07 ± 0.65
0.23 ± 0.32
0.11 ± 0.16
0.12 ± 0.31
0.09 ± 0.15
0.54 ± 0.42
/
0.55 ± 0.45
0.53 ± 0.37
0.47 ± 0.41
0.26 ± 0.20
0.37 ± 0.41
0.51 ± 0.60
0.54 ± 0.44
1.24 ± 1.04
0.62 ± 2.74
1.66 ± 1.47
1.29 ± 0.48
1.39 ± 1.53
0.29 ± 0.34
2.07 ± 1.48
0.53 ± 0.57
0.90 ± 0.87
0.31 ± 0.92
0.23 ± 1.43
0.22 ± 2.87
0.16 ± 1.02
0.22 ± 0.54
0.28 ± 0.73
0.29 ± 0.53
/
H
H
n-Pr
i-Pr
n-Bu
i-Bu
Bn
H
H
H
g
h
i
H
H
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-pr
i-Pr
i-Pr
/
H
4-Me
3,4-di-Me
4-OMe
2-F
j
H
k
l
H
H
m
n
o
p
q
r
H
4-F
H
2-Cl
3-Cl
2,4-di-Cl
4-Br
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
/
H
H
H
Me
s
Et
t
acetyl
u
v
w
cyclopropyl
cyclohexyl
Bn
/
Carbendazim
Procymidone
Validamycin A
Azoxystrobin
/
/
/
0.36 ± 0.67
/
/
/
/
/
/
212.15 ± 15.46
/
/
/
/
/
/
/
0.33 ± 0.32
a
Values are the average of three replicates.
The in vitro antifungal activities of compounds 6a–6w against
Fusarium graminearum (Fg), Botrytis cinerea (Bc), Rhizoctonia solani (Rs)
and Colletotrichum capsici (Cc) were assayed at the concentration of
and validamycin A (212.15 μg/mL), which showed remarkable in vivo
32
activity against Rs and has been widely used in Asia.
The in vivo antifungal effects of the compound 6u against Rs and Fg
2
9
1
0 μg/mL. As illustrated in Table S4 (Supporting information), all
were further evaluated, and the corresponding results were vividly
2
7
compounds showed remarkable antifungal activities, in which, seven-
teen compounds exhibited the inhibition rates over 80% against the
four phytopathogenic fungi mentioned above. Delightedly, the com-
pounds 6a, 6c, 6d, 6m, 6q, 6s, 6t, 6u and 6w displayed up to 90%
inhibitory effects against all tested fungi, and the compounds 6a, 6b,
presented in Fig. 3–5. As can be seen from Fig. 3, the control effi-
ciency of the compound 6u against fusarium head blight (FHB) reached
44.7% at 200 μg/mL, which was comparable to that of carbendazim
(41.7%). Meanwhile, the compound 6u showed 45.0% control effi-
ciency against rice sheath blight (RSB) on the rice leaves at 200 μg/mL
(Fig. 4) with the referenced comparisons carbendazim (52.8%) and
validamycin A (84.7%). Similar with the results observed on rice leaves,
the control efficiency of compound 6u against RSB on rice plants ex-
hibited 69.8% at 200 μg/mL (Fig. 5), whereas carbendazim and vali-
damycin A showed control efficiencies of 82.1% and 91.3%, respec-
tively. All the tested results mentioned above indicate that the
compound 6u had obvious in vivo antifungal effects against Fg and Rs.
Aiming to deeply understand the structure–activity relationships of
designed compounds against the fungus Rs, a comparative molecular
field analysis (CoMFA) was successfully constructed. The calculated
statistical parameters relevant to the above CoMFA model are provided
6
c, 6e and 6f could completely inhibited the mycelial growth of Fg.
Thereafter the EC50 values of target compounds against the four fungi
were tested and presented in Table 1. As shown in Table 1, the anti-Fg
EC50 values of 6b, 6d–6g, 6i, 6m, 6q–6w (0.11–0.48 μg/mL) were
equivalent or obviously better than that of carbendazim (0.49 μg/mL).
For the fungus Bc, the compounds 6a–6f, 6i, 6m and 6q–6w had in-
hibition effects with the EC50 values ranging from 0.11 μg/mL to
0
.35 μg/mL, which were better than the control fungicide procymidone
(
0.36 μg/mL). Meanwhile, the compounds 6d, 6m and 6q–6w ex-
hibited lower anti-Cc EC50 values (0.16–0.31 μg/mL) than the control
fungicide azoxystrobin (0.33 μg/mL). Furthermore, the antifungal EC50
values of 6a (0.09 μg/mL), 6b (0.12 μg/mL), 6e (0.12 μg/mL), 6s
3
3
in Table S9 (Supporting information). The cross-validated coefficient
2
(
0.07 μg/mL), 6u (0.11 μg/mL), 6v (0.12 μg/mL) and 6w (0.09 μg/mL)
q , optimum number of components, non-cross-validated correlation
2
against Rs were obviously superior to that of carbendazim (0.54 μg/mL)
coefficient r , standard error of estimate and F-test value were
Fig. 3. In vivo control efficacy of compound 6u against Fg at 200 μg/mL.
3

M. Chen, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Fig. 4. In vivo control efficacy of compound 6u against Rs on rice leaves at 200 μg/mL.
Fig. 5. In vivo control efficiency of compound 6u against Rs on rice plants at 200 μg/mL.
1
2
position of a pyrrole ring (R ) and the 4-position of phenyl ring (R ),
indicated that steric bulky substituents in these positions is associated
with greater anti-Rs activities of target compounds. As predicted by the
above model, compounds 6r–6w bearing alkyl or acetyl substituents at
1
the R position had better EC50 values than compound 6d bearing a
1
hydrogen atom at the R position. Concurrently, the target compounds,
2
bearing substituents at the 4-position of phenyl ring (R ), exhibited
better anti-Rs effects than the unsubstituted compound 6h, no matter
the substituted groups were electron-donating (6i and 6k) or electron-
withdrawing (6d, 6m and 6q) groups. The yellow blocks (Fig. 7A),
3
nearby the alkyl section of carbonate group (R ) and the 2-position of
2
the phenyl ring (R ), indicated that steric bulky substituents in these
positions is associated with worse anti-Rs activities. For example, the
compounds 6l and 6n, bearing substituents at the 2-position of the
2
phenyl ring (R ), have lower EC50 values than the unsubstituted com-
pound 6h. In the electrostatic map of CoMFA (Fig. 7B), the red and blue
blocks meant the electron-withdrawing and electron-donating groups in
these regions might increase the anti-Rs activity. In fact, both the
electron-withdrawing group substituted compounds, such as 6d
Fig. 6. Correlation between experimental and predicted pEC50 values in CoMFA
model.
2
2
2
(
R = 4-Cl), 6m (R = 4-F) and 6q (R = 4-Br), as well as the electron-
2
donating group substituted compounds, such as 6i (R = 4-CH
3
) and 6k
2
calculated as 0.795, 9, 0.988, 0.081 and 89.687, respectively. The q
2
(
R
= 4-OCH ), had better anti-Rs activity than the unsubstituted
3
2
2
and r values mentioned above met the validation criterion (q > 0.5
compound 6h. However, the compounds 6d, 6m and 6q had better
EC50 values than the compounds 6i and 6k. This reflects the fact that
the red blocks were more than blue blocks in number and size near the
2
and r > 0.8), which indicated the generated CoMFA model had good
internal predictive ability and reliability. In the CoMFA model, all
synthesized compounds were randomly divided into two sections in-
cluding a training set and a test set (Table S10 in Supporting in-
formation). The predicted anti-Rs pEC50 values predicted by the ob-
tained CoMFA model and the corresponding experimental pEC50 values
are also summarized in Table S10 (Supporting information), and their
correlation is vividly presented in Fig. 6.
4
-position of phenyl ring (Fig. 7B). Besides that, a blue block located at
1
the R position reflected the fact that the compounds 6r, 6s and 6u–6w
1
1
(
R
R
= electron-donating groups) had better anti-Rs activities than 6d
1
(
= H) and 6t (R = acetyl, an electron-withdrawing group).
The effects of compound 6u against Fg and Rs on mycelial
morphologies were observed by an optical electron microscope and
In the steric map of CoMFA (Fig. 7A), green blocks, around the 1-
34
were illustrated in Fig. 8. As shown in Fig. 8A and 8D, the mycelia of
4

M. Chen, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Fig. 7. CoMFA contour maps showing compound 6u. (A) Steric fields: green and yellow blocks mean steric-bulk favored and steric-bulk disfavored regions, re-
spectively; (B) Electrostatic fields: red blocks mean electron-withdrawing group favored regions and blue blocks represent electron-donating group favored regions.
Fig. 8. Mycelial morphology of Fg and Rs treated with compound 6u. (A) Negative control of Fg; (B and C) Fg treated with compound 6u at 1 μg/mL; (D) Negative
control of Rs; (E and F) Rs treated with compound 6u at 1 μg/mL.
were subsequently investigated at different time intervals, and the ob-
tained results were vividly shown in Fig. 9. As shown in Fig. 9, the
germination rates of each treatment gradually increased as time goes
on. Compared with the negative control, the fungal spores treated with
compound 6u were inhibited in germination rates with the inhibition
effects gradually increased over the concentration of compound 6u.
According to the germination curves, we inferred that compound 6u
could delay the germination of Fg spores but not completely inhibit.
In summary, a series of novel carboxylated pyrroline-2-one deriva-
tives bearing a phenylhydrazine moiety were rationally designed and
firstly prepared. The structures of these synthesized compounds were
well characterized using spectroscopic analyses and single crystal X-ray
diffraction. Fourteen target compounds showed excellent in vitro anti-
fungal effects with the EC50 values of less than 1 μg/mL against the
tested four pathogenic fungi (Fg, Bc, Rs and Cc). The compound 6u
showed the comparable in vivo control effect with carbendazim against
Fg and Rs. The constructed 3D-QSAR model revealed that the antifungal
Fig. 9. Influences of compound 6u on spore germination rates against Fg.
activities of target compounds would conducively improve by in-
troducing a bulky electron-donating group at the 1-position of a pyrrole
1
ring (R ), a bulky electron-withdrawing group at the 4-position of a
both Fg and Rs in the negative controls were regular and smooth. After
treatment by compound 6u at the concentration of 1 μg/mL, the my-
celia showed difference in morphologies compared with the negative
control, such as the abnormal hyperplasia at tips (Fig. 8B, 8E and 8F),
the shrinkage and collapse of mycelium (Fig. 8C and 8E), and the
blurring effects on mycelium outline (Fig. 8B, 8C and 8E). It was ob-
vious that the mycelial growth and the cytoderm integrity of fungus cell
were greatly damaged after the treatment with compound 6u.
2
3
phenyl ring (R ) and a small alkyl at the carbonate group (R ). The
abnormal mycelial morphology and delayed spore germination were
observed in the treatments of compound 6u. Given the excellent and
broad-spectrum antifungal effects of target compounds that is firstly
constructed in our present work, we unfeignedly anticipated that the
above finding could motivate the discovery of high-efficient antifungal
leads, which possess an innovative action mechanism against phyto-
pathogenic fungi.
The influences of compound 6u against Fg on spore germination
5

M. Chen, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127519
Declaration of Competing Interest
7. Wang S, Bao L, Song D, et al. Eur J Med Chem. 2019;179:567–575.
8
9
.
.
Kauhl U, Andernach L, Weck S, et al. J Org Chem. 2016;81:215–228.
Schobert R, Schlenk A. Bioorg Med Chem. 2008;16:4203–4221.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
10. Zhou B, Wang H, Meng B, et al. Pest Manag Sci. 2019;75:2482–2489.
1
1
1
1. Lang G, Blunt JW, Cummings NJ, et al. J Nat Prod. 2005;68:810–811.
2. Healy AR, Vinale F, Lorito M, et al. Org Lett. 2015;17:692–695.
3. Cherian PT, Cheramie MN, Marreddy RKR, et al. Bioorg Med Chem Lett.
2
018;28:3105–3112.
1
1
1
4. Matiadis D, Tsironis D, Stefanou V, et al. Bioorg Med Chem Lett. 2020;30:127107.
5. Aoki S, Higuchi K, Ye Y, et al. Tetrahedron. 2000;56:1833–1836.
6. Sun YL, Wang J, Wang YF, et al. Tetrahedron. 2015;71:9328–9332.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (31772209) and the Fundamental Research Funds
for the Central Universities of China (KYTZ201604 and KJSY201607).
17. Hoshino S, Wakimoto T, Zhang H, et al. Bioorg Med Chem Lett. 2015;25:3953–3955.
18. Zhu X, Huang L, Wang X, et al. Chin. J Org Chem. 2009;29:1784–1789.
1
2
2
9. Wang XF, Si TF, Li QB, et al. ARKIVOC. 2010;ii:31–48.
0. Lu GH, Chu HB, Chen M, et al. Chin Chem Lett. 2014;25:61–64.
1. Zhang L, Ren Z, Lu A, et al. Chem Res Chin Univ. 2015;31:228–234.
Appendix A. Supplementary data
22. Xu WQ, Chen M, Wang KY, et al. Molecules. 2016;21:355.
2
2
2
3. Wang X, Ren Z, Wang M, et al. Chem Cent J. 2018;12:83.
4. Wang X, Ren Z, Mei Y, et al. J Heterocycl Chem. 2019;56:165–171.
5. Li LX, Jiao J, Wang XB, et al. Molecules. 2018;23:746.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.127519.
26. Wang X, Fu X, Chen M, et al. Chin Chem Lett. 2019;30:1419–1422.
2
2
7. Wang X, Dai ZC, Chen YF, et al. Eur J Med Chem. 2017;126:171–182.
8. Chrysayi-Tokousbalides M, Kastanias MA, Philippoussis A, et al. Crop Prot.
References
2
007;26:469–475.
2
3
3
3
9. Hu Y, Wang J, Lu A, et al. Bioorg Med Chem Lett. 2014;24:3772–3776.
0. Lee CK, Uchida T, Kitagawa K, et al. J Pharm Sci. 1994;83:562–565.
1. Wang JJ, Si WJ, Chen M, et al. J Pestic Sci. 2017;42:84–92.
1
2
3
4
5
6
.
.
.
.
.
.
Li D, Zhang S, Song Z, et al. Eur J Med Chem. 2017;136:114–121.
Epstein L. Annu Rev Phytopathol. 2014;52:377–402.
2. Chen X, Lu Y, Fan Y, et al. Validamycin and Its Derivatives: Discovery, Chemical
Synthesis and Biological Activity. Elseiver, 2017;115–164.
Regueiro J, Olguín N, Simal-Gándara J, et al. Environ Res. 2015;140:37–44.
Royles BJL. Chem Rev. 1995;95:1981–2001.
3
3
3. Shao WB, Zheng YT, Liu JM, et al. Bioorg Med Chem Lett. 2020;30:126912.
4. Qu T, Gao S, Li J, et al. Pestic Biochem Physiol. 2017;135:47–51.
Maarisit W, Yamazaki H, Kanno S, et al. Bioorg Med Chem Lett. 2017;27:999–1002.
Henning HG, Gelbin A. Adv Heterocycl Chem. 1993;57:139–185.
6