Design, synthesis, and bioactivities of novel pyridazinone derivatives containing 2-phenylthiazole or oxazole skeletons

Article abstract of DOI:10.1002/jhet.4118

A series of novel pyridazinone derivatives were designed and synthesized by replacing 4-(tert-butyl)phenyl moiety of pyridaben with 2-phenylthiazole or oxazole fragments via activity substructure connecting approach. The structures of all target compounds were characterized through NMR, MS, and elemental analysis. Bioassay results exhibit that most compounds showed potent bioactivities against Aphis fabae, Tetranychus urticae, Erysiphe graminis, and/or Puccinia polysora. Among the newly synthesized compounds, 2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) displays remarkable insecticidal activity against A fabae. Its LC₅₀ value (2.73 mg/L) is better than that of pyridaben (5.46 mg/L), although inferior to that of imidacloprid (0.51 mg/L). In addition to its extraordinary insecticidal activity, compound 12b also exerts 96.9% fungicidal activities against P polysora at 500 mg/L in vivo, significantly superior to that of pyridaben (50.0%), while slightly lower than that of tebuconazole (100%). This article discusses the synthesis, bioassay results, and structure-activity relationship of this series of novel pyridazinone derivatives.

Full text of DOI:10.1002/jhet.4118

Design, Synthesis and Bioactivities of Novel Pyridazinone Derivatives
Containing 2-Phenylthiazole or oxazole Skeletons
Mingming Danga,b, Minhua Liub,c*, Lu Huangb,d, Xiaoming Oub,c, Chuyun Longb,d, Xingping Liub,c,
Yeguo Renb,c, Ping Zhangb,d, Mingzhi Huangb,c* and Aiping Liub,c *
aDepartment of Resources and Environment, Hunan Nonferrous Metals Vocational and Technical
College, Zhuzhou 412000, Hunan, China
bNational Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410007, China
cHunan Province Key Laboratory for Agrochemicals, Changsha 410014, China
dHunan J & F Test Co., Ltd., Changsha 410014, China
*E-mail: lmh80963@163.com; huang-mz@163.com; lapliu@yahoo.com
Abstract: A series of novel pyridazinone derivatives were designed and synthesized by replacing 4-(tert-butyl)phenyl
moiety of pyridaben with 2-phenylthiazole or oxazole fragments via activity substructure connecting approach. The
structures of all target compounds were characterized through NMR, MS, and elemental analysis. Bioassay results
exhibit that most compounds showed potent bioactivities against Aphis fabae, Tetranychus urticae, Erysiphe graminis,
and/or
Puccinia
polysora.
Among
the
newly
synthesized
compounds,
2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) displays remarkable insecticidal
activity against A. fabae. Its LC50 value (2.73 mg/L) is better than that of pyridaben (5.46 mg/L), although inferior to that
of imidacloprid (0.51 mg/L). In addition to its extraordinary insecticidal activity, compound 12b also exerts 96.9%
fungicidal activities against P. polysora at 500 mg/L in vivo, significantly superior to that of pyridaben (50.0%), while
slightly lower than that of tebuconazole (100%). This article discusses the synthesis, bioassay results, and
structure-activity relationship of this series of novel pyridazinone derivatives.
Keywords: pyridazinone derivatives; design/synthesis; bioactivities; structure-activity relationship study; pyridaben
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which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/jhet.4118
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Introduction
Agriculture pest is a major threat to crop production, and insecticide application is recognized as the most important
tool for pest control. In addition, insecticide also helps to improve crop quality and reduce labor costs [1-6]. Traditional
insecticides are mainly categorized into four classes: diamides, neonicotinoids, pyrethroids and carbamates, as well as
organophosphorus. Wide usage of these traditional insecticides leads to drug resistances [7, 8]. Therefore, the design of
novel insecticides is a top priority in crop protection.
Pyridazinone fragment is not new in agrochemistry. This pharmacophore is commonly found in herbicides in the
market, although there are a few insecticide applications [9-12]. Some pyridazinone agrochemicals are represented in
Figure 1. Among them, 2-(tert-butyl)-5-((4-(tert-butyl)benzyl)thio)-4-chloropyridazin-3(2H)-one (NC-129) developed by
Nissan Chemical under the trade name 'Pyridaben' in 1991 is the most important insecticide of this class [13, 14]. The
product acts as an inhibitor of complex I (NADH: ubiquinone oxidoreductase) [14-17]. This active ingredient shows
excellent inhibition rate against all stages of phytophagous mites on vegetables, citrus fruit, pome fruit, and
ornamentals. More importantly, this ingredient is safe to a range of beneficial insects [10, 13, 18]. Although many
insects, especially phytophagous mites, such as: Auphitetranychus viennensis zache, Tetranychus urticae, and
Panonychus citri have developed moderate or high levels resistance to pyridaben [19-22]. we believe pyridazinone
worth more exploration given its high inseciticidal activity and low toxicity.
In our previous studies [23-26], we discovered that compounds containing 2-phenylthiazole or oxazole motifs (Ⅰa -
Ⅰe, Figure 2) showed excellent bioactivities. Besides the ones we have discovered, thiazole or oxazole are also
commonly used in a variety of approved agrochemicals (e.g., dicloromezotiaz, thiamethoxam and oxathiapiprolin, et al)
and medicines (e.g., acotiamide, isavuconazole and tivozanib, et al) [27-30]. Therefore, in the process of optimizing
pyridaben, we thought thizazole and oxazole first. We designed and synthesized a series of novel pyridazinone
derivatives by replacing 4-(tert-butyl)phenyl moiety of pyridaben with 2-phenylthiazole or oxazole fragments via
activity substructure connecting approach. The structures of all new compounds were confirmed by NMR, MS and
elementary analysis.
Bioassay results exhibit that the synthesized compounds displayed broad-spectrum biological activities such as
insecticidal,
acaricidal
and/or
fungicidal
activities.
Among
the
target
compounds,
2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) exerts remarkable insecticidal
activity against A. fabae with a LC50 value of 2.73 mg/L, superior to that of pyridaben (5.46 mg/L), though inferior to
that of the commercial insecticide imidacloprid (0.51 mg/L). Meanwhile, compound 12b also shows 96.9% fungicidal
activity against P. polysora at 500 mg/L in vivo, which is significantly superior to that of pyridaben (50.0%), while slightly
lower than that of the commercial fungicide tebuconazole (100%). A detailed synthesis, biological evaluation, and
structure–activity relationships (SAR) study of this series of novel pyridazinone derivatives are as discussed below.
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RESULTS AND DISCUSSION
Chemistry. The synthetic routes of all target compounds and intermediates are shown in Figure 3 [26, 31-33]. The
structures of all synthesized compounds were characterized by NMR, MS and elemental analysis. The chemical
structures, MS data, physical properties, and biological activities of all target compounds 12a-l are illustrated in Table 1.
Elemental analysis and NMR data are presented in Table 2.
Target compounds 12a-l were prepared by reacting intermediate 10 or 11 with intermediate 5 or 6 in a solvent of
N,N-dimethylformamide and potassium carbonate (route 1). Because a bimolecular by-product was formed when
synthesizing intermediate 10, we took an alternative method: intermediate 9 with benzyl chloride 5 or 6 was directly
transformed into target compounds in the presence of thiourea (route 2). Route 2 avoids by-product and reduces
overall steps compared to route 1.
Table 1
Chemical structures, MS, physical properties, and bioactivities (%) against A. fabae, T. urticae, E. graminis and P.
polysora of target compounds 12a-l.
AF
TU
EG
PP
No.
X
W
R
R1
R2
Formula
MS
Mp(℃)
500
50
500
50
500
500
mg/L mg/L mg/L mg/L mg/L mg/L
5-O
5-S
S
S
S
S
S
S
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
H
H
C18H18ClN3O2S
C18H18ClN3OS2
C18H19ClN4OS
C19H20ClN3OS2
C19H20ClN3OS2
C31H24N4OS4
375 113.0-115.2 100
391 92.2-93.3 100
70.1
100
/
11.2
88.9
25.0
92.9
72.3
15.7
/
33.1
/
80.0
0.0
83.5
96.9a
40.0
60.0
55.0
62.3
12a
12b
12c
12d
12e
12f
5-NH
5-S
374 159.2-160.5 63.9
0.0
Brown mucous
405
100
100
89.9
/
16.2
/
80.0
80.0
0.0
2-CH3
4-CH3
H
5-S
405 110.8-111.0 100
5-S
PhCH2 4-SQ
596 120.2-124.6 33.4
/
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5-S
4-S
5-S
5-S
5-S
5-S
O
O
O
O
O
O
t-Bu
t-Bu
Ph
4-Cl
5-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
C18H18ClN3O2S
C18H18ClN3O2S
C20H14ClN3O2S
C19H20ClN3O2S
C18H17Cl2N3O2S
375 128.5-130.3 81.1
/
54.3
0.0
/
85.0
15.0
20.0
80.0
65.0
30.0
40.0
60.0
85.0
45.0
60.0
50.0
75.0
50.0
12g
12h
12i
12j
12k
12l
Pyr
Brown mucous
H
375
7.6
/
/
/
H
395 149.4-151.8 29.7
389 90.1-90.8 100
409 112.8-113.2 100
/
39.7
89.8
70.3
17.9
100
t-Bu
t-Bu
t-Bu
100
98.6
43.0
100
84.5
/
2-CH3
2-Cl
2,6-diF C18H16ClF2N3O2S 411 93.6-95.3
93.7
100
/
100
Imi
/
/
100
/
/
/
/
/
/
Teb
/
100
100b
Q: 2-phenylthiazole-4-methyl; AF: Aphis fabae; TU: Tetranychus urticae; EG: Erysiphe graminis; PP: Puccinia polysora;
Pyr: Pyridaben; Imi: Imidacloprid; Teb: Tebuconazole; “ / ” means no test; “ a ”: 63.8% at 50 mg/L; “ b ”: 95.9% at 50
mg/L.
Table 2
NMR and Elemental analysis data
1H NMR (CDCl3, 300 MHz), 13C NMR (CDCl3, 75 MHz) δ and elemental analysis
No.
1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 5.49 (s, 2H, CH2), 7.41 (s, 1H, Ar H), 7.45-7.47 (m, 3H, Ar H),
7.93 (s, 1H, Ar H), 7.94-7.97 (m, 2H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 27.8, 66.4, 68.0, 117.1,
12a
117.2, 125.2, 126.5, 129.0, 130.4, 133.1, 151.3, 153.6, 158.9, 169.1. Elemental anal. (%): Calcd
for C18H18ClN3O2S: C, 57.52; H, 4.83; N, 11.18; Found: C, 57.50; H, 4.82; N, 11.19.
1H NMR (CDCl3) 1.64 (s, 9H, 3CH3), 4.44 (s, 2H, CH2), 7.27 (s, 1H, Ar H), 7.44-7.46 (m, 3H, Ar H),
7.85 (s, 1H, Ar H), 7.94-7.98 (m, 2H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 27.8, 31.3, 66.2, 116.5,
12b
116.6, 126.5, 129.0, 130.3, 130.4, 133.1, 140.5, 151.8, 156.0, 169.0. Elemental anal. (%): Calcd
for C18H18ClN3OS2: C, 55.16; H, 4.63; N, 10.72; Found: C, 55.17; H, 4.62; N, 10.71.
1H NMR (CDCl3) 1.64 (s, 9H, 3CH3), 4.68 (dd, J1 = 0.9 Hz, J2 = 6.0 Hz, 2H, CH2), 5.32-5.37 (m, 1H,
NH), 7.13 (s, 1H, Ar H), 7.44-7.47 (m, 3H, Ar H), 7.62 (s, 1H, Ar H), 7.92-7.94 (m, 2H, Ar H). 13C
12c
NMR (CDCl3, 75 MHz) δ: 28.1, 43.5, 65.5, 114.9, 115.0, 123.6, 126.5, 129.0, 130.4, 133.2, 143.1,
153.5, 157.9, 169.3. Elemental anal. (%): Calcd for C18H19ClN4OS: 57.67; H, 5.11; N, 14.94;
Found: C, 57.68; H, 5.12; N, 14.93.
1H NMR (CDCl3) 1.64 (s, 9H, 3CH3), 2.56 (s, 3H, CH3), 4.45 (s, 2H, CH2), 7.31-7.41 (m, 4H, Ar H),
7.69 (m, 1H, Ar H), 7.92 (s, 1H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 21.5, 27.8, 31.3, 66.2, 117.0,
117.1, 126.1, 129.7, 129.9, 130.4, 131.6, 132.4, 136.6, 140.6, 151.3, 156.0, 168.7. Elemental
anal. (%): Calcd for C19H20ClN3OS2: C, 56.21; H, 4.97; N, 10.35; Found: C, 56.23; H, 4.98; N, 10.36.
1H NMR (CDCl3) 1.64 (s, 9H, 3CH3), 2.40 (s, 3H, CH3), 4.42 (s, 2H, CH2), 7.22 (d, J = 4.5 Hz, 2H, Ar
H), 7.26 (s, 1H, Ar H), 7.80 (d, J = 8.1 Hz, 2H, Ar H), 7.84 (s, 1H, Ar H). 13C NMR (CDCl3, 75 MHz)
δ: 21.4, 27.8, 31.3, 66.2, 116.0, 116.1, 126.4, 129.6, 129.7, 130.3, 130.4, 140.6, 140.8, 151.6,
12d
12e
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169.2. Elemental anal. (%): Calcd for C19H20ClN3OS2: C, 56.21; H, 4.97; N, 10.35; Found: C, 56.23;
H, 4.98; N, 10.36.
1H NMR (CDCl3) 4.24 (s, 2H, CH2), 4.62 (s, 2H, CH2), 5.30 (s, 2H, CH2), 6.65 (s, 1H, Ar H), 6.86 (s,
1H, Ar H), 7.30-7.42 (m, 11H, Ar H), 7.73 (s, 1H, Ar H), 7.83-7.84 (m, 4H, Ar H). 13C NMR (CDCl3,
75 MHz) δ: 32.0, 55.8, 116.0, 116.1, 116.2, 116.3, 126.5, 127.9, 128.6, 128.7, 128.8, 128.9,
130.0, 130.2, 132.9, 133.2, 133.5, 136.1, 146.1, 152.1, 153.5, 157.4. Elemental anal. (%): Calcd
for C31H24N4OS4: C, 62.39; H, 4.05; N, 9.39; Found: C, 62.38; H, 4.05; N, 9.38.
12f
1H NMR (CDCl3) 1.64 (s, 9H, 3CH3), 4.23 (s, 2H, CH2), 7.45-7.50 (m, 3H, Ar H), 7.69 (s, 1H, Ar H),
7.79 (s, 1H, Ar H), 8.00-8.06 (m, 2H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 27.1, 27.8, 66.3, 126.5,
128.8, 130.0, 130.1, 130.8, 136.1, 136.2, 137.5, 140.2, 155.9, 162.3. Elemental anal. (%): Calcd
for C18H18ClN3O2S: C, 57.52; H, 4.83; N, 11.18; Found: C, 57.53; H, 4.84; N, 11.19.
1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 4.53 (s, 2H, CH2), 7.42-7.43 (m, 3H, Ar H), 7.51 (s, 1H, Ar H),
7.61 (s, 1H, Ar H), 7.96-7.98 (m, 2H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 27.4, 27.8, 66.1, 126.3,
128.3, 130.4, 133.7, 133.8, 135.8, 137.5, 138.7, 158.7, 161.7. Elemental anal. (%): Calcd for
C18H18ClN3O2S: C, 57.52; H, 4.83; N, 11.18; Found: C, 57.53; H, 4.84; N, 11.19.
12g
12h
1H NMR (CDCl3) 4.31 (s, 2H, CH2), 7.38-7.43 (m, 1H, Ar H), 7.44-7.51 (m, 5H, Ar H), 7.57-7.61 (m,
2H, Ar H), 7.73 (s, 1H, Ar H), 8.02-8.06 (m, 2H, Ar H), 8.09 (s, 1H, Ar H). 13C NMR (CDCl3, 75 MHz)
δ: 27.2, 125.1, 126.5, 126.8, 128.4, 128.8, 130.4, 130.8, 132.8, 136.1, 136.2, 137.3, 141.1, 141.5,
155.1, 162.4. Elemental anal. (%): Calcd for C20H14ClN3O2S: C, 60.68; H, 3.56; N, 10.61; Found: C,
60.67; H, 3.55; N, 10.63.
1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 2.65 (s, 3H, CH3), 4.23 (s, 2H, CH2), 7.25-7.38 (m, 3H, Ar H),
7.69-7.70 (m, 1H, Ar H), 7.94-7.97 (m, 2H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 21.9, 27.0, 27.8,
66.2, 125.8, 126.0, 128.7, 130.3,130.4, 131.6, 135.4, 135.5, 137.3, 137.6, 140.4, 155.9, 162.5.
Elemental anal. (%): Calcd for C19H20ClN3O2S: C, 58.53; H, 5.17; N, 10.78; Found: C, 58.55; H,
5.16; N, 10.79.
12i
12j
1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 4.26 (s, 2H, CH2), 7.34-7.43 (m, 2H, Ar H), 7.50-7.53 (m, 1H,
Ar H), 7.76 (s, 1H, Ar H), 7.89 (s, 1H, Ar H), 7.96-7.99 (m, 1H, Ar H). 13C NMR (CDCl3, 75 MHz) δ:
27.0, 27.8, 66.3, 125.8, 126.9, 130.2, 130.9, 131.3, 131.4, 132.6, 136.4, 136.5, 137.5, 140.2,
155.9, 160.1. Elemental anal. (%): Calcd for C18H17Cl2N3O2S: C, 52.69; H, 4.18; N, 10.24; Found:
C, 52.66; H, 4.17; N, 10.25.
1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 4.28 (s, 2H, CH2), 7.02-7.09 (m, 2H, Ar H), 7.41-7.50 (m, 1H,
Ar H), 7.79 (s, 1H, Ar H), 7.81 (s, 1H, Ar H). 13C NMR (CDCl3, 75 MHz) δ: 27.1, 27.8, 66.4, 109.7,
112.1 (d, J = 24.1 Hz), 128.6, 130.1, 132.2 (t, J = 10.8 Hz), 137.0, 137.8, 138.0, 140.3, 141.6,
163.1. Elemental anal. (%): Calcd for C18H16ClF2N3O2S: 52.49; H, 3.92; N, 10.20; Found: C, 52.46;
12k
12l
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H, 3.92; N, 10.21.
Biological activity. All new compounds were evaluated for initial activities against Aphis fabae, Tetranychus urticae,
Erysiphe graminis and Puccinia polysora at 500 mg/L by typical assay (Table 1). For target compounds with high
insecticidal activity against A. fabae , median lethal concentration (LC50) value was calculated by further assay with five
to six different concentrations as listed in Table 3. The activities of pyridaben are also shown in Table 1 and 3,
respectively.
Insecticidal/acaricidal activity. The mortality data of 12a-l against A. fabae and T. urticae are exhibited in Table 1. All
target compounds 12a-l have excellent insecticidal activity against A. fabae at 500 mg/L, while some compounds even
display potential insecticidal activity at lower test concentration. For example, compounds 12b, 12d and 12j show 100%
insecticidal activity against A. fabae at 50 mg/L, which is equal to that of pyridaben and imidacloprid.
Compound 12b and 12j have LC50 values against A. fabae of 2.73 mg/L and 3.63 mg/L, respectively. These data are
better than that of pyridaben ( 5.46 mg/L), though not as good as that of imidacloprid (0.51 mg/L, Table 3).
Furthermore, as depicted in Table 1, some target compounds exhibit good acaricidal activity against T. urticae at 500
mg/L. For instance, the mortalities of 12b, 12d and 12j against T. urticae at 500 mg/L are 88.9%, 92.9% and 89.8%,
respectively. Compounds 12e and 12k have greater than 70.0% acaricidal activity against T. urticae at the same
concentration. However, only compounds 12j exerts 84.5% acaricidal activity against T. urticae at 50 mg/L, inferior to
that of pyridaben (100%).
Table 3 The LC50 values of target compounds with high insecticidal activity against A. fabae
Compound
Regression equation
y=2.4422+1.7992x
Correlation
0.9997
LC50 (mg/L)
26.40
12a
12b
12d
y=4.4737+1.2063x
y=3.4887+1.1574x
y=-1.1864+4.7352x
y=4.1921+1.4434x
y=3.6259+1.5129x
y=1.8891+4.2181x
y = 5.5894 + 2.0180x
0.9307
0.9780
0.9848
0.9782
0.9722
0.9247
0.9661
2.73
20.22
20.25
3.63
8.10
12e
12j
12k
Pyridaben
Imidacloprid
5.46
0.51
Fungicidal activity. According to Table 1, some of target compounds show high fungicidal activities against E.
graminis and/or P. polysora at 500 mg/L. For example, 12a, 12d, 12e, 12g, 12j and 12k exhibit 80%, 80%, 80%, 85%, 80%
and 65.0% fungicidal activity against E. graminis in vivo at 500 mg/L, respectively. As a reference, pyridaben has 40%
and tebuconazole has 100%. The mortalities of 12a, 12b and 12h against P. polysora in vivo at 500 mg/L are 83.5%, 96.9%
and 85.0%, respectively, higher than pyridaben (50.0%). 12b also shows 63.8% fungicidal activity against P. polysora at
50 mg/L, although lower than that of tebuconazole (95.9%).
Preliminary structure–activity relationship study.
The general structure of target compounds 12a-l was optimized through the X, W, R, R1 and R2 groups, and the
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choices of substituents can significantly affect bioactivities (Table 1).
When W, R, R1 and R2 are kept constant, the bioactivities of the synthesized compounds are influenced by the nature
of the X group. When X group is changed from oxygen or nitrogen to sulfur atom, the bioactivities of the corresponding
compound are dramatically increased. For example, activity order against A. fabae, T. urticae and P. polysora: 12b > >
12a, 12c; However, for activity order against E. graminis: 12a > > 12b, 12c, the best group of X is oxygen atom.
When X, R, R1 and R2 are kept constant, the bioactivities of target compounds are influenced by the nature of the W
group. Modification of the W group from sulfur to oxygen atom shows the different level of bioactivities. As an example,
activity order against A. fabae, T. urticae and P. polysora: 12g < 12b. But, for activity order against E. graminis: 12g >>
12b, the best group of X is oxygen substituent. Interstingly, the corresponding compounds have similar biological
activities when R2 is 2-methyl group.
When X, W, R1 and R2 are kept constant, the bioactivities of new compounds are influenced by the nature of the R
group. Optimizations of the R group from t-Bu to Ph or benzyl substituents result in a remarkable drop in activity. For
example, activity order against A. fabae, T. urticae, E. graminis and P. polysora: 12f, 12i << 12g.
When X, W, R and R2 are kept constant, the bioactivities of target compounds are influenced by the nature of the R1
group. When R1 group are changed from 5-chloro or 4-S(2-phenylthiazole-4-methyl) to 4-chloro substituents, the
bioactivities of the corresponding compound have a remarkable boost. dramatical improvement. For instance, activity
order against A. fabae, T. urticae and E. graminis: 12g >> 12h; But, for activity order against P. polysora: 12h > 12g, the
best substituent of X is 5-chloro group.
When X, W, R and R1 are kept constant, the bioactivities of the synthesized compounds are influenced by the nature
of the R2 group. Modifications of the R2 group from hydrogen to 2-methyl, 4-methyl, 2-chloro, 2,6-difluoro substituents
show the different level of bioactivities. When W is sulfur atom, the activity order against A. fabae, T. urticae and P.
polysora of the corresponding compound is 12b > 12d > 12e. It suggests that compounds with R2 = hydrogen (12b)
exhibits excellent bioactivity against A. fabae, significantly superior to that of pyridaben. However, for activity order
against E. graminis of the corresponding compounds is 12d, 12e >> 12b. When W is oxygen atom, the activity order
against A. fabae, and T. urticae of the corresponding compound is 12j > 12k > 12l > 12g. Furthermore, when R2 is
hydrogen group, the fungicidal activity against E. graminis of corresponding compound is better than that of
compounds with other substituents. Nevertheless, when 2,6-difluoro groups is replaced by other substituents, the
fungicidal activity against P. polysora of corresponding compound declines.
In general, the preliminary structure−activity relationships of target compounds can be summarized as follows:
Activity order against A. fabae, T. urticae and P. polysora of X: S >> O, NH; Activity order against E. graminis of X: O >> S,
NH.
Activity order against A. fabae, T. urticae and P. polysora of W: S >> O; Activity order against E. graminis of X: O >> S;
and Activity order against all tested targets of W (R2 = 2-CH3): S ≈ O.
Activity order of R: t-C4H9 > > Ph, benzyl.
Activity order against A. fabae, T. urticae and E. graminis of R1: 4-Cl >> 5-Cl, 4-S(2-phenylthiazole-4-methyl); Activity
order against P. polysora of R1: 5-Cl > 4-Cl.
Activity order against A. fabae, T. urticae and P. polysora of R2 (W = S): H > 2-CH3, 4-CH3; Activity order against E.
graminis of R2 (W = S): 2-CH3, 4-CH3 >> H; Activity order against A. fabae and T. urticae of R2 (W = O): 2-CH3 > 2-Cl >
2,6-diF > H; Activity order against E. graminis of R2 (W = O): H > 2-CH3, 2-Cl, 2,6-diF; Activity order against P. polysora of
R2 (W = O): 2,6-diF > H, 2-CH3, 2-Cl.
Furthermore, further structure-activity relationships of this series of compounds are in progress.
CONCLUSION
In summary, a series of novel pyridazinone derivatives were designed and synthesized by replacing
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4-(tert-butyl)phenyl moiety of pyridaben with 2-phenylthiazole or oxazole fragments via activity substructure connecting
approach. Bioassay results show that target compounds exhibited broad-spectrum bioactivities. Among the new
compounds, 2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) exerts potent
insecticidal activity against A. fabae. Its LC50 value (2.73 mg/L) is superior to that of pyridaben (5.46 mg/L), though
inferior to that of imidacloprid (0.51 mg/L, Table 3). Additionally, compound 12b displays also 96.9% fungicidal activity
against P. polysora in vivo at 500 mg/L, which is better than that of pyridaben (50.0%), while slightly lower than that of
tebuconazole (100%, Table 1). Thus, 12b can be used as potential lead compound for further structural optimization.
EXPERIMENTAL
Liquid chromatography-mass spectrometry (LC-MS) was recorded with an Agilent 1260/6120 Series and gas
chromatography-mass spectrometry (GC-MS) was recorded with an Agilent 7890-5975C Series. NMR spectra was
obtained with a Varian INOVA-300 spectrometer using tetramethylsilane (TMS) as the internal standard and
deuteriochloroform (CDCl3) as the solvent. Uncorrected melting points were taken in a WRS-1B digital melting points
apparatus made in shanghai physical optics instrument plant. Elemental analyses were obtained with a Vario EL III from
Elementar. Unless otherwise noted, all the reagents and solvents used were purchased from commercial suppliers.
Synthesis. The general synthetic methods for target compounds 12a-l are shown in Figure 3. Representative
procedures are given below and yields are not optimized. All reactions were carried out under a protective atmosphere
of utilizing a calcium chloride tube or dry nitrogen.
The synthesis of intermediates.
General procedure for the preparation of intermediates 2. Thionyl chloride (200 mmol) in 1,2-dichloroethane (30 mL)
was added dropwise to a solution of intermediates 1 (100 mmol) in 1,2-dichloroethane (100 mL) at room temperature
(rt). The reaction mixture was refluxed for 3-5 hr and then cooled and concentrated under reduced pressure. The crude
product was used directly to the next step without purification.
General procedure for the preparation of intermediates 3. 25% ammonium hydroxide (220 mmol) was added
dropwise to a solution of intermediates 2 (100 mmol) in dry toluene at 0°C. After 1 hr of stirring, The reaction mixture
was allowed to warm to rt and stirred for 1 hr. A formed precipitate of benzamide 3 was filtered off, washed with cold
toluene and water, and dried in air. The crude product was carried on to the next step with no purification.
General procedure for the preparation of intermediates 4. Benzamide 3 (31.11 mmol) was dissolved in
tetrahydrofuran (THF, 20 mL) and then phosphorus pentasulfide (37.33 mmol) was added in batches. The reaction
mixture was refluxed for 3 hr and then cooled to rt and poured in 10% sodium bicarbonate solution (100 mL), and
stirred for 0.5 hr. The resulting solid was filtered, dried and recrystallized from ethyl acetate (EA) to get compounds 4.
General procedure for the preparation of compounds 5. A mixture of 3 (0.02 mol) and 1,3-dichloroacetone (0.02
mol) was heated at 130°C for 1-2 hr. After the mixture was cooled to rt, the saturated sodium bicarbonate solution (20
mL) was added, and the mixture was extracted with EA (2*30 mL). The extract was washed twice with water (2*30 mL)
and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then the crude
product was recrystallized with petroleum ether (PE) and EA.
General procedure for the preparation of compounds 6. 1,3-Dichloroacetone (0.30 mol) was added to a solution of
intermediates 4 (0.30 mol) in a mixture ethanol (140 mL) and THF (60 mL) at rt. The reaction mixture was refluxed for 6
hr. The solvents were removed in a vacuum, and the residue was dissolved in EA. The organic phase was washed with
10% sodium bicarbonate solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated
under reduced pressure. The crude product was carried on to the next step without purification.
General procedure for the preparation of compounds 8. A mixture of intermediate 6 (0.05 mol) in
N,N-dimethylformamide (DMF, 60 mL) was added into a solution of potassium phthalimide (0.05 mol) in DMF (40 mL) at
rt. The mixture was stirred at 80°C for 5-6 hr. The reaction mixture was poured into ice water and the precipitate was
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collected by filtration, washed with water, and dried to give intermediate 7 as a brown solid.
Then 7 was mixed with ethanol (200 mL) and hydrazine hydrate (80%, 0.10 mol). After 5 hr under reflux, the
precipitate was separated by filtration and the filtrate was evaporated in a vacuum. The residue mixture was poured
into ice water and the aqueous phase was extracted twice with EA (2*50 mL). The organic layer was washed twice with
water (2*50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 8 was
obtained as brown oil. The product was used in the next reaction without purification.
General procedure for the preparation of compounds 9. tert-Butylhydrazine hydrochloride (50.00 mmol) was added
to a solution of sodium hydroxide (47.50 mmol) dissolved in a mixture toluene (180 mL) and water (20 mL) at rt.
Mucochloric acid (50.00 mmol) was added in batches and stirred for 0.5 hr and then followed by dropwise addition of
acetic acid (47.50 mmol). The reaction mixture was heated to 45-50°C and stirred for 18 hr. The solution was allowed to
cool to ambient temperature and then was diluted with water (80 mL). The organic layer was cooled to 0°C and washed
with 30% sodium hydroxide, followed by concentrated hydrochloric acid and water. The organic solution was
concentrated under a vacuum to yield intermediate 9 as a brown solid.
General procedure for the preparation of compounds 10. The sodium hydrosulfide hydrate (70%, 29.10 mmol) was
added to a solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (14.55 mmol) in ethanol (30 mL) in batches at 0°C.
After the addition was completed, the reaction mixture was stirred at rt for 2 hr. The mixture was poured into ice water
and acidified with concentrated hydrochloric acid (10 mL). The yellow solid was collected, washed, and dried. The crude
product was used directly without purification.
General procedure for the preparation of compounds 11. A mixture of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone
(7.27 mmol), potassium hydroxide (21.81 mmol), and glycol (30 mL) were stirred at 130°C for 5 hr. After cooling, the
reaction mixture was poured into water, and acidified with concentrated hydrochloric acid (10 mL). The white solid was
collected, washed, and dried. The crude product was carried on to the next step without purification.
The synthesis of the target compounds 12.
2-(tert-butyl)-4-chloro-5-((2-phenylthiazol-4-yl)methoxy)pyridazin-3(2H)-one (12a). Potassium carbonate (14.85
mmol)
was
added
to
a
solution
of
4-(chloromethyl)-2-phenylthiazole
(5.74
mmol)
and
2-(tert-butyl)-4-chloro-5-hydroxypyridazin-3(2H)-one (4.95 mmol) in DMF at rt. The reaction mixture was stirred at 80°C
for 4-5 hr and then cooled to rt, poured into ice−water (250 mL) and extracted with EA (2*50 mL). The combined
organic layer was washed with water and dried with anhydrous sodium sulfate. After the solvent was removed, the
crude product was separated by silica-gel column chromatography using PE and EA (3:1 by volume) as eluant to give 98%
(HPLC) 12a as a white solid (3.37 mmol), mp：113.0-115.2°C, yield 68%. GC-MS (EI, 70Ev) (m/z) 340 (M+-Cl), 174 (100%
M+-201); LC-MS(Pos M+) m/z) 375 (M+); calc for C18H18ClN3O2S: C, 57.52; H, 4.83; N, 11.18; Found: C, 57.50; H, 4.82; N,
11.19; 1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 5.49 (s, 2H, CH2), 7.41 (s, 1H, Ar H), 7.45-7.47 (m, 3H, Ar H), 7.93 (s, 1H, Ar H),
7.94-7.97 (m, 2H, Ar H); 13C NMR (CDCl3, 75 MHz) δ: 169.1, 158.9, 153.6, 151.3, 133.1, 130.4, 129.0, 126.5, 125.2,
117.2, 117.1, 68.0, 66.4, 27.8.
2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) Potassium carbonate (27.27
mmol)
was
added
to
a
solution
of
4-(chloromethyl)-2-phenylthiazole
(9.09
mmol)
and
2-(tert-butyl)-4-chloro-5-mercaptopyridazin-3(2H)-one (9.63 mmol) in DMF at rt. The mixture was stirred at 40-50°C for
3-4 hr and then cooled to rt, poured into ice water (200 mL) and extracted with EA (2*50 mL). The combined organic
layer was washed with water (80 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was separated by silica-gel column chromatography using PE and EA (3:1 by
volume) as eluant to give 97% (HPLC) 12b as a brown solid (4.09 mmol), mp：92.2-93.3°C, yield 45%. LC-MS(Pos M+) m/z)
391 (M+); calc for C18H18ClN3OS2: C, 55.16; H, 4.63; N, 10.72; Found: C, 55.17; H, 4.62; N, 10.71; 1H NMR (CDCl3) 1.64 (s,
9H, 3CH3), 4.44 (s, 2H, CH2), 7.27 (s, 1H, Ar H), 7.44-7.46 (m, 3H, Ar H), 7.85 (s, 1H, Ar H), 7.94-7.98 (m, 2H, Ar H); 13C
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NMR (CDCl3, 75 MHz) δ: 27.8, 31.3, 66.2, 116.5, 116.6, 126.5, 129.0, 130.3, 130.4, 133.1, 140.5, 151.8, 156.0, 169.0.
2-(tert-butyl)-4-chloro-5-(((2-(o-tolyl)oxazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12j). Thiourea (11.59 mmol) was
added to a solution of 4-(chloromethyl)-2-(o-tolyl)oxazole (9.66 mmol) in isopropanol (75 mL) at rt. The reaction
mixture was refluxed for 2 hr and then cooled to rt. 2-(tert-butyl)-4,5-dichloropyridazin-3(2H)-one (10.63 mmol) and
potassium hydroxide (28.57 mmol) were added to the mixture, respectively. The solution was stirred at 50 °C for 2 hr
and then cooled to rt, poured into ice water (150 mL) and extracted with EA (2*50 mL). The combined organic layer was
washed with water and dried with anhydrous sodium sulfate, filtered, and concentrated in a vacuum. The crude
product was separated by silica-gel column chromatography using PE and EA (3:1 by volume) as eluant to give 96%
(HPLC) 12j as a white solid (4.15 mmol), mp：90.1-90.8°C, yield 43%. LC-MS(Pos M+) m/z) 389 (M+); calc for
C19H20ClN3O2S: C, 58.53; H, 5.17; N, 10.78; Found: C, 58.55; H, 5.16; N, 10.79; 1H NMR (CDCl3) 1.65 (s, 9H, 3CH3), 2.65 (s,
3H, CH3), 4.23 (s, 2H, CH2), 7.25-7.38 (m, 3H, Ar H), 7.69-7.70 (m, 1H, Ar H), 7.94-7.97 (m, 2H, Ar H); 13C NMR (CDCl3, 75
MHz) δ: 21.9, 27.0, 27.8, 66.2, 125.8, 126.0, 128.7, 130.3, 130.4, 131.6, 135.4, 135.5, 137.3, 137.6, 140.4, 155.9, 162.5.
The syntheses of other tartget compounds with≥96.0% purity (HPLC) were similar to that of the above
representative compound, and their structures are supported by spectroscopic data in Tables 2.
Biological assay
The bioactivity tests of the target compounds were conducted according to our previous studies [26,34-38]. Stock
solution of 1.0 g/L for every test compound was prepared in DMF and then diluted to the required test concentrations
(50-500 mg/L) with water containing Tween 80 (0.4 mg/L).
Activity against A. fabae. These insects were reared in a room maintained at 25 °C, 65 (±5)% relative humidity, and
14:10 hr light/dark. The horse bean seedlings with A. fabae were dipped in the test solution for 5-10 s, then allowed to
dry with a filter paper, transferred to a beaker (100 mL) containing water (10 mL) and kept at 25 °C. The mortality was
determined based on the number and the size of live larvae in the treated bottles relative to that in the untreated
controls after 24 hr. A control experiment was performed under the same conditions. All experiments and the
respective controls were conducted in three replicates, and results were averaged. The dose–response data was
analyzed by probit analysis [39], and the activity for A. fabae was further evaluated as LC50 values.
Activity against T. urticae. Fifty adults of T. urticae were transferred to three horse bean seedlings, and, 24 hr later,
the horse bean seedlings with acarids were dipped in the test solutions for 10 s, then allowed to dry with filter paper,
transferred to a beaker (100 mL) containing water (10 mL) and kept at 25°C. Each assay contained three replications.
Mortality was assessed 72 hr after the treatment. Control groups were tested with water only. The dose-response data
was analysed by probit analysis.
The activity against E. graminis. Wheat plants were grown under greenhouse conditions [T = 22°C, 60 (5)% relative
humidity and a 12 hr lightcycle]. Plants were maintained in plastic pots (6 cm diameter × 10 cm) and were inoculated by
a spore suspension of E. graminis (1.0 × 105 spores mL-1). After one day, test compounds were sprayed over the plants.
After one or two weeks, symptoms were examined. Each bioassay was conducted intriplicate, and the biological effect
was reported as the average of the triplicates. Biological data was analyzed as in the test of preventive activity against E.
graminis.
The activity against P. polysora. The Corn leaves with P. polysora were dipped in the test solutions to wash the spores.
Then filtered with 2-4 layers of gauze, and spore suspension was prepared. The spore suspension was inoculated, and
cultured 24 hr under weak light. Each assay contained three replications. After 24 hr, mortality was recorded. The test
was run three times, and results were averaged.
Acknowledgements. This work was supported by the National Natural Science Foundation of China (21672057),
Changsha Science and Technology Plan Project (kh19022238) and the National Key Research & Development Pillar
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Program of China during the 13th Five-Year Plan Period (Grant No. 2016YFD0300708).
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