Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide moiety: Design, synthesis and bioactive evaluation against phytopathogenic fungi in vitro and in vivo

Article abstract of DOI:10.1016/j.cclet.2019.03.038

A series of novel 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety were designed, synthesized and evaluated for their antifungal activities against Rhizoctonia solani (Rs), Fusarium graminearum (Fg), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The in vitro antifungal bioassays indicated that most of title compounds displayed good selectivity and specificity aganist Rs relative to Fg, Bc and Cc. Strikingly, the title compound N'-(4-chlorophenyl)-2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl)acethydrazide (5b) obviously inhibited the Rs growth in vitro with the EC₅₀ value of 0.24 μg/mL, which is approximately 2-folds more effective than the commercialized fungicide carbendazim (0.55 μg/mL). The in vivo anti-Rs effects of title compound 5b were further evaluated on rice leaves with control efficacies of 98.58% at 200 μg/mL and 61.27% at 100 μg/mL. The above researches provide a significant reference for the further structural optimization of 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety as potential fungicides.

Full text of DOI:10.1016/j.cclet.2019.03.038

Accepted Manuscript
Title: Novel 1,3,5-thiadiazine-2-thione derivatives containing
a hydrazide moiety: Design, synthesis and bioactive
evaluation against phytopathogenic fungi in vitro and in vivo
Authors: Xiaobin Wang, Xincan Fu, Min Chen, An Wang,
Jinghua Yan, Yudong Mei, Mengqi Wang, Chunlong Yang
PII:
DOI:
Reference:
S1001-8417(19)30133-0
https://doi.org/10.1016/j.cclet.2019.03.038
CCLET 4874
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
20 February 2019
20 March 2019
21 March 2019
Please cite this article as: Wang X, Fu X, Chen M, Wang A, Yan J, Mei Y, Wang M,
Yang C, Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide moiety:
Design, synthesis and bioactive evaluation against phytopathogenic fungi in vitro and
in vivo, Chinese Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.03.038
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Communication
Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide
moiety: Design, synthesis and bioactive evaluation against
phytopathogenic fungi in vitro and in vivo
Xiaobin Wanga,b, Xincan Fua, Min Chena,b, An Wanga, Jinghua Yana, Yudong Meia, Mengqi Wanga,
Chunlong Yanga,b,*
aJiangsu Key Laboratory of Pesticide Science, Nanjing Agricultural University, Nanjing 210095, China
bDepartment of Chemistry, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
Graphical abstract
A series of novel 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety were designed, synthesized and evaluated
for their biological activities against phytopathogenic fungi. The antifungal bioassays indicated that the title compound 5b
impressively displayed the obvious selectivity and specificity aganist Rhizoctonia solani (Rs) in vitro and in vivo. The above
researches provide a significant reference for the further structural optimization of 1,3,5-thiadiazine-2-thione derivatives bearing
a hydrazide moiety as potential fungicides.
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
Available online
ABSTRACT
A series of novel 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety were designed, synthesized and evaluated for their antifungal activities
against Rhizoctonia solani (Rs), Fusarium graminearum (Fg), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The in vitro antifungal bioassays
indicated that most of title compounds displayed good selectivity and specificity aganist Rs relative to Fg, Bc and Cc. Strikingly, the title compound N'-(4-
chlorophenyl)-2-(5-phenyl-6-thioxo-1,3,5-thiadiazinan-3-yl)acethydrazide (5b) obviously inhibited the Rs growth in vitro with the EC50 value of 0.24 µg/mL,

which is approximately 2-folds more effective than the commercialized fungicide carbendazim (0.55 µg/mL). The in vivo anti-Rs effects of title compound 5b
were further evaluated on rice leaves with control efficacies of 98.58% at 200 µg/mL and 61.27% at 100 µg/mL. The above researches provide a significant
reference for the further structural optimization of 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety as potential fungicides.
Keywords:
1,3,5-Thiadiazine-2-thione
Hydrazide
Crop protection
Antifungal activity
Rhizoctonia solani
Grains, vegetables and fruits are important food sources that are tremendously threatened by the infection of plant pathogenic fungi
[1]. These pathogenic fungi, such as Rhizoctonia solani (Rs), Fusarium graminearum (Fg), Botrytis cinerea (Bc) and Colletotrichum
capsici (Cc), not only lead annually to agricultural yield reductions of at least 10% [2], but also pose huge risks to food security and
human health by generating hazardous mycotoxins in infected crops [3]. Nowadays, the rational application of commercialized
fungicides is regarded as the most effective approach to alleviate agricultural disease outbreaks caused by phytopathogenic fungi[4,5].
For example, carbendazim, penthiopyrad and azoxystrobin were developed as the highly-efficient and broad-spectrum fungicides that
were widely used to reduce the losses of agricultural economies in last decades. However, the long-term application of existing
agricultural fungicides not only leads to the rapid deterioration of fungal resistance [6], but also generates the harmful influences on
the environment and non-target organisms [7,8]. Therefore, it remains a challenge in agricultural sciences to develop highly-efficient
and broad-spectrum fungicides with a novel molecular structure [9,10].
Featuring high lipid solubilities and desirable enzymatic hydrolyzation within living organisms [11,12], 1,3,5-thiadiazine-2-thione
derivatives were documented to possess various bioactivities including anti-proliferative [13], antibacterial [14], antiepileptic [15],
antifungal [16], antileishmanial [17], antimalarial [18], antitubercular [19], trypanocidal [20], antioxidant [21] and herbicidal [22]
properties. Recent practical studies on 1,3,5-thiadiazine-2-thione derivatives showed that this type of nonaromaic heterocycles
exhibited desirable inhibition effects against phytopathogenic fungi, bacteria and nematodes. As the important bioactive molecules
bearing a 1,3,5-thiadiazine-2-thione fragment, milneb and dazoment (Fig. 1) were respectively developed as agricultural fungicide and
acaricide over the last three decades [23,24]. Meanwhile, Mao et al. conducted the antibacterial evaluation of dazoment against
Ralstonia solanacearum in field trials and found dazoment could be used as an alternative bactericide to control ginger bacterial wilt
[25]. Subsequently, Hwang et al. also found that dazoment could effectively manage agricultural diseases caused by the soil-borne
fungal pathogens Plasmodiophora brassicae, Fusarium avenaceum, Pythium ultimum and Rhizoctonia silani [26]. However, to the
best of our knowledge, 1,3,5-thiadiazine-2-thione derivatives except milneb and dazoment were rarely reported on their structural
modifications and agricultural bioactivities.
Fig. 1. Design strategy of title compounds.
Scheme 1. Synthesis route of title compounds.
Hydrazide derivatives are significant nitrogenous compounds that exhibit herbicidal [27], anticancer [28], antimalarial [29], anti-
inflammatory [30], antiviral [31], antibacterial [32], antifungal [33], anticoagulant [34] and insecticidal [35] bioactivities. Among these

bioactive hydrazide derivatives, arylhydrazide derivatives have recently attracted tremendous interests from biologists and chemists
due to their excellent inhibition effects against various phytopathogenic fungi. For example, ethyl 2-phenylhydrazine-1-carboxylate
named miexiuyihao (Fig. 1) was developed as the systemic fungicide that was mainly applied in effectively controlling wheat stripe
rust [36]. Recently, Wang et al. reported that arylhydrazide derivatives bearing a 1,2,3-triazole moiety exhibited fine systemic
conductions and effectively inhibited the energy generation of various plant fungi [37]. In addition, our previous studies also found
that 2-(4-oxoquinazolin-3(4H)-yl)-N'-phenylacetohydrazide derivatives exhibited the impressive anti-phytopathogenic effects against
Rs and Fg in vitro [38].
Based on the above-mentioned outstanding fungicidal activities and excellent properties of 1,3,5-thiadiazine-2-thione and hydrazide
derivatives, the aims of this work are to: (i) construct novel bioactive molecules by combinating the 1,3,5-thiadiazine-2-thione fragment
with the hydrazide substructure, as shown in Fig. 1, which could enhance the molecular lipid solubility within organisms and improve
the combining capacity with receptor proteins; (ii) generate a series of novel 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide
moiety (Scheme 1) and evaluate their antifungal activities in vitro against Rs, Fg, Bc and Cc; and (iii) investigate their in vivo anti-Rs
effects and perform their structure-activity relationship (SAR) analysis against the above tested fungi.
As shown in Scheme 1, the nucleophilic reaction of the primary amide 1 (aniline, para-fluoroaniline or benzylamine) with carbon
disulfide in sodium hydroxide solution generated the substituted potassium carbamodithioate 2 that directly reacted with formaldehyde
to synthesize the substituted N-hydroxymethyl-S-hydroxymethyl carbamodithioate 3. The substituted 2-(6-thioxo-1,3,5-thiadiazinan-
3-yl)acetic acid 4 was conveniently synthesized by the nucleophilic substitution of an intermediate 3 with glycine in phosphate buffer
(pH 7.8). Using O-(benzotriazol-1-yl)-N,N,N',N′-tetramethyluroniumtetrafluoroborate (TBTU) as the catalyst and triethylamine as the
acid binding agent, the intermediates 4 reacted with substituted phenylhydrazines to obtain the target compounds 5–7 with good yields
ranging from 31% to 88%. The obtained 1,3,5-thiadiazine-2-thione derivatives bearing a hydrazide moiety were confirmed via
corresponding FT-IR, 1H NMR, 13C NMR, 19F NMR and HRMS. The relevant spectroscopic data of synthesized compounds 5–7 were
collected and presented in Supporting information.
Using the agricultural fungicides carbendazim, penthiopyrad and azoxystrobin as positive controls, the in vitro antifungal effects of
title compounds against Rs, Fg, Bc and Cc were evaluated by a mycelium growth rate method [5,10,37–43]. As shown in Table 1, the
title compounds 5b, 6a–6c and 7a–7c exhibited impressive anti-Fg effects in vitro, with the corresponding EC50 values of 2.11, 2.34,
2.17, 2.82, 1.49, 1.19 and 1.73 µg/mL. Meanwhile, the title compounds 5a–5e, 5g, 6a–6c, 6g and 7a–7c obviously inhibited Bc in vitro
with the EC50 values of 1.38, 0.85, 0.66, 2.57, 2.26, 2.08, 2.03, 1.43, 2.13, 2.62, 1.75, 1.10 and 1.44 µg/mL, respectively. In addition,
Table 1 also showed that the title compounds 5d, 5g, 5h, 5j, 6d, 6g and 7d had obvious anti-Cc effects, with the corresponding EC50
values of 2.29, 2.88, 0.70, 2.12, 0.70, 1.59 and 1.41 µg/mL. Strikingly, the anti-Rs EC50 values of title compounds 5b, 5c, 6d, 7b, 7c
and 7d reached 0.24, 0.44, 0.25, 0.28, 0.35 and 0.46 µg/mL, respectively, which are better than that of carbendazim (0.55 µg/mL).
Table 1 showed that most of title compounds displayed good selectivity and specificity in vitro aganist Rs relative to Fg, Bc and Cc.
Impressively, the title compound 5b obviously inhibited the Rs growth in vitro with the EC50 value of 0.24 µg/mL, which is
approximately 2-folds more effective than the commercialized fungicide carbendazim (0.55 µg/mL). Aiming to further investigate the
application values of title compounds as agricultural fungicides, the in vivo anti-Rs effects of title compound 5b, carbendazim and
hymexazol were evaluated on rice leaves by a detached leaf assay [44]. As shown in Table 2 and Fig. 2, the in vivo anti-Rs control
efficacy of title compound 5b at 100 µg/mL was 61.27%, which is inferior to that of carbendazim at 100 µg/mL (98.08%). Meanwhile,
the in vivo bioassay results in Table 2 also presented that the title compound 5b obviously inhibited the Rs growth on rice leaves at 200
µg/mL with an impressive control efficacy of 98.58%, which is obviously better than hymexazol at the same concentration of 200
µg/mL (54.90%). The in vivo bioassay research provides a significant reference for the practical application of 1,3,5-thiadiazine-2-
thione derivatives bearing a hydrazide moiety in agricultures.
Table 1
In vitro antifungal EC50 values of title compounds 5–7 (µg/mL).a
Compd.
5a
5b
5c
5d
5e
Rs
Fg
Bc
Cc
0.76 ± 1.05
0.24 ± 0.16
0.44 ± 0.27
0.81 ± 0.35
4.14 ± 2.29
19.06 ± 5.60
1.86 ± 0.56
10.03 ± 3.86
3.35 ± 0.79
1.53 ± 0.32
2.10 ± 0.76
0.62 ± 0.51
0.77 ± 0.56
0.82 ± 0.32
0.25 ± 0.39
1.81 ± 1.11
4.98 ± 1.29
0.86 ± 0.39
0.82 ± 0.18
3.16 ± 1.54
2.11 ± 1.12
3.66 ± 2.51
8.43 ± 5.58
5.16 ± 1.68
10.48 ± 1.59
10.68 ± 0.53
72.67 ± 8.62
9.44 ± 7.11
17.81 ± 7.14
54.31 ± 8.67
2.34 ± 0.72
2.17 ± 1.27
2.82 ± 0.97
7.84 ± 1.47
4.53 ± 1.94
7.11 ± 2.78
5.13 ± 1.93
1.49 ± 0.27
1.38 ± 0.91
0.85 ± 0.50
0.66 ± 0.41
2.57 ± 0.74
2.26 ± 0.63
11.10 ± 6.02
2.08 ± 0.82
48.00 ± 7.02
9.14 ± 6.16
7.88 ± 4.78
48.13 ± 9.15
2.03 ± 0.71
1.43 ± 0.43
2.13 ± 1.18
4.12 ± 1.54
6.39 ± 1.42
6.50 ± 3.05
2.62 ± 0.96
1.75 ± 0.30
8.09 ± 0.79
3.75 ± 0.87
4.31 ± 0.87
2.29 ± 0.50
35.42 ± 5.34
86.45 ± 8.67
2.88 ± 0.92
0.70 ± 0.21
45.28 ± 4.20
2.12 ± 0.51
7.99 ± 2.62
3.31 ± 0.88
4.44 ± 1.84
3.44 ± 1.07
0.70 ± 0.27
19.06 ± 4.93
25.62 ± 7.94
1.59 ± 0.67
16.04 ± 6.66
5f
5g
5h
5i
5j
5k
6a
6b
6c
6d
6e
6f
6g
7a

7b
7c
7d
0.28 ± 0.16
0.35 ± 0.33
0.46 ± 0.41
0.55 ± 0.61
-
1.19 ± 0.49
1.73 ± 1.08
9.02 ± 2.73
0.54 ± 0.56
-
1.10 ± 0.25
1.44 ± 0.23
3.78 ± 1.71
-
0.82 ± 0.86
-
8.03 ± 3.05
11.78 ± 2.04
1.41 ± 0.70
-
Carbendazim
Penthiopyrad
Azoxystrobin
-
-
-
0.44 ± 0.48
aValues are the average of three replicates.
Table 2
In vivo anti-Rs control efficacies of bioactive compounds on rice leaves.a
Compd.
Treatment
(µg/mL)
100
200
200
Lesion
(cm)
length Control efficacy
(%)
5b
5b
3.83 ± 2.48
0.14 ± 0.47
4.46 ± 2.76
0.19 ± 0.52
9.89 ± 5.32
61.27
98.58
54.90
98.08
-
Hymexazol
Carbendazim
Blank control
100
-
aValues are the average of 10 replicates.
Fig. 2. In vivo anti-Rs effect photographs of bioactive compounds on rice leaves. (A) Blank control; (B) 5b at 100 μg/mL; (C) 5b at 200 μg/mL; (D) Hymexazol
at 200 μg/mL; (E) Carbendazim at 100 μg/mL.
As shown in Table 1, introducing different substituents at R1 and R2 positions greatly influenced the inhibition effects of title
compounds against phytopathogenic fungi. Based on the bioassay results in Table 1, some structure-activity relationships were analyzed
and presented as below. First, all title compounds except 5e, 5f and 5h exhibited better inhibition effects against Rs than that against
Fg, Bc and Cc. Second, most of title compounds bearing a Bn group at R1 position, such as 6a, 6d, 6e, 6f and 6g, displayed better anti-
Rs and anti-Cc effects than those bearing a Ph (5a, 5d, 5e, 5f and 5g) or 4-FPh (7a and 7d) fragment at R1 position. Third, the bioassay
results in Table 1 showed that a presence of 4-FPh group at R1 position overall enhanced the anti-Fg effects of title compounds. For
example, the anti-Fg EC50 values of title compounds 7a, 7b and 7c (R1 = 4-FPh) respectively reached 1.49, 1.19 and 1.73 µg/mL, which
are better than that of title compounds 5a, 5b and 5c (R1 = Ph; 3.16, 2.11 and 3.66 µg/mL) as well as 6a, 6b and 6c (R1 = Bn; 2.34,
2.17 and 2.82 µg/mL). Forth, when R1 was substituted with a Ph group, the anti-Bc EC50 values of obtained compounds 5a–5d were
1.38, 0.85, 0.66 and 2.57 µg/mL, respectively, which are better than that of title compounds 6a–6d (R1 = Bn; 2.03, 1.43, 2.13 and 4.12
µg/mL) and 7a–7d (R1 = 4-FPh; 1.75, 1.10, 1.44 and 3.78 µg/mL). Fifth, introducing a 4-F, 4-Cl or 4-Br group at R2 position greatly
improved the antifungal effects of title compounds against Rs, Fg and Bc. Table 1 showed that the title compounds containing a 4-F
(5a, 6a and 7a), 4-Cl (5b, 6b and 7b) or 4-Br (5c, 6c and 7c) group at R2 position exhibited better inhibition effects against Rs, Fg and
Bc than those molecules bearing a 4-CF3 (5d, 6d and 7d), 4-Me (5e and 6e), 4-OMe (5f and 6f), 2,4-di-Cl (5g and 6g), 2,4,6-tri-Cl (5h),
H (5i), 2-F (5j) or 2-Cl (5k) group at R2 position.
In conclusion, aiming to search for novel bioactive molecules with anti-phytopathogenic effects, a series of novel 1,3,5-thiadiazine-
1
2-thione derivatives bearing a hydrazide moiety were designed and synthesized, and their structures were confirmed by FT-IR, H
NMR, 13C NMR, 19F NMR and HRMS. Antifungal bioassays in vitro indicated that most of target compounds displayed good selectivity
and specificity aganist Rs relative to Fg, Bc and Cc. Strikingly, six title compounds 5b, 5c, 6d, 7b, 7c and 7d exhibited remarkable
antifungal activities against Rs in vitro, with corresponding EC50 values of 0.24, 0.44, 0.25, 0.28, 0.35 and 0.46 µg/mL, which are
obviously better than carbendazim (0.55 µg/mL). The in vivo anti-Rs effects of title compound 5b as a key representative were further
evaluated on rice leaves to investigate the application potentials of title compounds as agricultural fungicides. The in vivo anti-Rs
control efficacies of title compound 5b, which reached 98.58% at 200 µg/mL and 61.27% at 100 µg/mL, indicate that 1,3,5-thiadiazine-
2-thione derivatives bearing a hydrazide moiety may have the research value of further structural optimization.
Acknowledgments
The authors gratefully acknowledge the grants from the National Natural Science Foundation of China (No. 31772209) and the
Fundamental Research Funds for the Central Universities of China (No. KYTZ201604).

References
[1] R.N. Strange, P.R. Scott, Annu. Rev. Phytopathol. 43 (2005) 83–116.
[2] B. Song, Pestic. Biochem. Physiol. 147 (2018) 1–2.
[3] K. Kazan, D.M. Gardiner, J.M. Manners, Mol. Plant Pathol. 13 (2012) 399–413.
[4] Y. Zhang, Y.Z. Zhang, Y. Ma, et al., Chin. Chem. Lett. 29 (2018) 441–446.
[5] X. Wang, Z. Ren, M. Wang, et al., Chem. Cent. J. 83 (2018) 1–12.
[6] T.C. Sparks, B.A. Lorsbach, Pest Manage. Sci. 73 (2017) 672–677.
[7] L.S. Jackson, J. Agric. Food Chem. 57 (2009) 8161–8170.
[8] J.N. Seiber, L.A. Kleinschmidt, J. Agric. Food Chem. 59 (2011) 7536–7543.
[9] X. Qian, P.W. Lee, S. Cao, J. Agric. Food Chem. 58 (2010) 2613–2623.
[10] F. Yu, A. Guan, M. Li, et al., Chin. Chem. Lett. 29 (2018) 915–918.
[11] A.N. El-Shorbagi, Eur. J. Med. Chem. 29 (1994) 11–15.
[12] T. Aboul-Fadl, A.N. El-Shorbagi, Eur. J. Med. Chem. 31 (1996) 165–169.
[13] A.N. El-Shorbagi, M. El-Naggar, H. Tarazi, et al., Med. Chem. Res. 27 (2018) 1103−1110.
[14] A.N. El-Shorbagi, Arch. Pharm. 333 (2000) 281−286.
[15] M.H. Semreen, A.N. El-Shorbagi, T.H. Al-Tel, et al., Med. Chem. 6 (2010) 144−149.
[16] C.B. Vicentini, G. Forlani, M. Manfrini, et al., J. Agric. Food Chem. 50 (2002) 4839−4845.
[17] N. Arshad, J. Hashim, Irfanullah, et al., Bioorg. Med. Chem. Lett. 28 (2018) 3251–3254.
[18] J. Coro, R. Atherton, S. Little, et al., Bioorg. Med. Chem. Lett. 16 (2006) 1312–1315.
[19] D. Katiyar, V.K. Tiwari, R.P. Tripathi, et al., Bioorg. Med. Chem. 11 (2003) 4369–4375.
[20] J. Coro, R. Perez, H. Rodriguez, et al., Bioorg. Med. Chem. 13 (2005) 3413–3421.
[21] X. Ji, Z. Zhong, X. Chen, et al., Bioorg. Med. Chem. Lett. 17 (2007) 4275–4279.
[22] C.B. Vicentini, S. Guccione, L. Giurato, et al., J. Agric. Food Chem. 53 (2005) 3848–3855.
[23] W.W. Lam, J.H. Kim, S.E. Sparks, et al., J. Agric. Food Chem. 41 (1993) 1497–1502.
[24] M. Nakamura, S. Noda, M. Kosugi, et al., Food Hyg. Saf. Sci. 51 (2010) 213–219.
[25] L. Mao, H. Jiang, Q. Wang, et al., Crop Prot. 100 (2017) 111−116.
[26] S.F. Hwang, H.U. Ahmed, S.E. Strelkov, et al., Can. J. Plant Sci. 98 (2018) 172–182.
[27] C.W. Huffman, E.M. Godar, K. Ohki, et al., J. Agric. Food Chem. 16 (1968) 1041–1046.
[28] F. Meyer, N. Ueberschaar, H.M. Dahse, et al., Bioorg. Med. Chem. Lett. 23 (2013) 6043–6045.
[29] R.R. Soares, J.M.F. Silva, B.C. Carlos, et al., Bioorg. Med. Chem. Lett. 25 (2015) 2308–2313.
[30] E.B. Park, K.J. Kim, H.R. Jeong, et al., Bioorg. Med. Chem. Lett. 26 (2016) 5193–5197.
[31] L. Yang, P. Wang, J.F. Wu, et al., Bioorg. Med. Chem. 24 (2016) 2125–2136.
[32] S.A. Carvalho, E.F. Silva, M.V.N. Souza, et al., Bioorg. Med. Chem. Lett. 18 (2008) 538–541.
[33] X. Yu, P. Teng, Y.L. Zhang, et al., Fitoterapia 127 (2018) 387–395.
[34] W. Khalid, A. Badshah, A. Khan, et al., Chem. Cent. J. 11 (2018) 1–16.
[35] G. Yu, L. Luo, S. Chen, et al., ChemistrySelect 3 (2018) 10991–10995.
[36] R.R. Pan, Z.Y. Feng, S.Y. Lu, et al., J. Anhui Agric. Sci. 4 (1982) 55–60.
[37] X. Wang, Z.C. Dai, Y.F. Chen, et al., Eur. J. Med. Chem. 126 (2017) 171–182.
[38] X. Wang, M. Wang, J. Yan, et al., ChemistrySelect 3 (2018) 10663–10669.
[39] X.X. Zhang, H. Jin, Y.J. Deng, et al., Chin. Chem. Lett. 28 (2017) 1731–1736.
[40] Y.T. Zheng, T.T. Zhang, P.Y. Wang, et al., Chin. Chem. Lett. 28 (2017) 253–256.
[41] W. Wang, X. Zhang, Y. Zhao, et al., Chin. Chem. Lett. 29 (2018) 1872–1874.
[42] H. Du, Z. Fan, L. Yang, et al., Mol. Diversity 22 (2018) 1–10.
[43] R.J. Wu, K.X. Zhou, H. Yang, et al., Eur. J. Med. Chem. 167 (2019) 472–484.
[44] Z.J. Zhang, Y. Zeng, Z.Y. Jiang, et al., Pest Manage. Sci. 74 (2018) 1736–1746.