Synthesis and fungicidal activities of novel bis(trifluoromethyl)phenyl- based strobilurins

Article abstract of DOI:10.1021/jf800651z

Strobilurins have become one of the most important classes of agricultural fungicides. To search for novel strobilurin compounds with unique biological activities, novel bis(trifluoromethyl)phenyl-based strobilurin analogues were synthesized by the reacti

Full text of DOI:10.1021/jf800651z

6562 J. Agric. Food Chem. 2008, 56, 6562–6566
Synthesis and Fungicidal Activities of Novel
Bis(trifluoromethyl)phenyl-Based Strobilurins
AIPING LIU,*,† XIAOGUANG WANG,† XIAOMING OU,† MINGZHI HUANG,†
CAN CHEN,† SHUDONG LIU,† LU HUANG,† XINPING LIU,† CHENGLAI ZHANG,†
‡
YONGQUAN ZHENG,‡ YEGUO REN,† LIAN HE,† AND JIANREN YAO
National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410007, China, and Institute of Plant Protection, China Academy of Agricultural
Sciences, Beijing, 100094, China
Strobilurins have become one of the most important classes of agricultural fungicides. To search for
novel strobilurin compounds with unique biological activities, novel bis(trifluoromethyl)phenyl-based
strobilurin analogues were synthesized by the reaction of 1-bis(trifluoromethyl)phenyl based metha-
none oxime with corresponding strobilurin pharmacophores in the presence of bases such as
potassium hydroxide, potassium carbonate, or sodium hydride. (E)-Methyl 2-(2-((((Z)(1-(3,5-bis(tri-
fluoromethyl) phenyl)-1-methoxymethylidene)amino)oxy)methyl)phenyl)-3-methoxyacrylate and (Z)-
methyl-N-(E)-2-((E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(methoxyimino)methyl)benzyloxy-3,5-bis(triflu-
oromethyl)benzimidate were more effective against Erysiphe graminis and sphaerotheca fuligine than
commercial strobilurin fungicides metominostrobin, azoxystrobin, and trifloxystrobin.
KEYWORDS: Strobilurins; fungicide; bis(trifluoromethyl)phenyl; structure-activity relationships
INTRODUCTION
showed remarkable fungicidal, insecticidal, and/or acaricidal activi-
ties. Compounds 5f [(E)-methyl 2-(2-((((Z)(1-(3,5-bis(trifluoro-
methyl)phenyl)-1-methoxymethylidene)amino)oxy) methyl)phenyl)-
3-methoxyacrylate] and 5h [(Z)-methyl-N-(E)-2-((E)-(5,6-dihydro-
1,4,2-dioxazin-3-yl)(methoxyimino)methyl)benzyloxy-3,5-
bis(trifluoromethyl)benzimidate] (Figure 4) possess commercial
levels of fungicidal activity comparable to those of commercial
strobilurin fungicides such as metominostrobin, azoxystrobin, and
trifloxystrobin; 5f also exhibits potent insecticidal activities, and
5a [(E)-methyl-2-(2-((((Z)(1-(3,5-bis(trifluoromethyl)phenyl)-
1-methylthiomethylidene)amino)oxy)methyl)phenyl)-3-meth-
oxyacrylate] gave good control against adults, larva, and eggs
of various acarids and possesses a level of acaricidal activity
comparable to those of commercial acaricides such as fluacryp-
rim, tebufenpyrad, and chlorfenapyr.
Strobilurins and oudemansins are naturally occurring ꢀ-meth-
oxyacrylate fungicides. Their primary mechanism of action is
the inhibition of mitochondrial respiration. Since 1996, thou-
sandsofanaloguesofdiversestructureshavebeensynthesized(1–8)
leading to over 10 commercialized products including metomi-
nostrobin, azoxystrobin, and trifloxystrobin (Figure 1).
Strobilurins have become one of the most important classes
of agricultural fungicides due to their positive attributes such
as a novel action mode, broad fungicidal spectrum, lower
toxicity toward mammalian cells, and environmentally benign
characteristics. However, a short period of repeated field
application of strobilurin fungicides has led to the development
of resistance in a range of important plant pathogens (9, 10).
As a consequence, new types of fungicides must be continually
developed to overcome this problem.
In our previous work, a series of novel sulfur-containing
oxime-ethers (Figure 1) had shown remarkable insecticidal
activity, but their fungicidal activity was weak (11–14). To
search for novel strobilurin compounds with unique biological
activities, an optimization program was carried out by introduc-
ing the essential pharmacophore T (Figure 2) of the com-
mercialized strobilurin fungicides to oxime-ethers (Figure 3).
Compounds containing the bis(trifluoromethyl)phenyl moiety
This paper reports the synthesis, fungicidal activity, and the
structure-activity relationships of the target bis(trifluorometh-
yl)phenyl-based strobilurins (Figure 3).
MATERIALS AND METHODS
Unless otherwise noted, reagents and solvents were used as received
from commercial suppliers. 1H NMR spectra were obtained with a
Varian INOVA-300 spectrometer using tetramethylsilane (TMS) as the
internal standard and deuterochloroform (CDCl3) as the solvent. Mass
spectra (MS) were obtained with both Hewlett-Packard 6890-5973 GC/
MS and Agilent 1100 Series LC/MSD. Uncorrected melting points were
taken on a WRS-1A digital melting points apparatus.
Synthesis. The general synthetic methods for compounds 5a-5v are
shown in Figure 5. Representative procedures are given below. Yields
were not optimized. All reactions were carried out under a protective
atmosphere of dry nitrogen or utilizing a calcium chloride tube.
* To whom correspondence should be addressed. Fax: 8673 1595
9000. E-mail: lapliu@yahoo.com.
† Hunan Research Institute of Chemical Industry.
‡ China Academy of Agricultural Sciences.
10.1021/jf800651z CCC: $40.75  2008 American Chemical Society
Published on Web 07/04/2008

Synthesis and Fungicidal Activities of Strobilurins
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6563
Figure 1. Structures of metominostrobin, azoxystrobin, trifloxystrobin, and oxime-ethers in our previous work.
Figure 2. Structures of T-1 to T-5: the essential pharmacophores of
commercialized strobilurin fungicides.
Figure 4. Structures of 5f and 5h.
(Z)-3,5-Bis(trifluoromethyl)benzaldehyde Oxime (2). 3,5-Bis(trifluo-
romethyl)benzaldehyde (1) (24.2 g, 0.10 mol) was added dropwise to
a solution of hydroxyamine hydrochloride (7.30 g, 0.105 mol) in
methanol (100 mL), and the reaction mixture was refluxed for 4-5 h.
The reaction was cooled to room temperature and poured into
ice-water. Precipitates formed, which were filtered and washed with
cool methanol, then dried under vacuum to yield compound 2 as a
white solid: 23.4 g (91.0%), mp 91.2-91.3 °C (lit. (15) 92-93 °C);
1H NMR (CDCl3) δ (ppm) 7.88 (s, 1H, 4-Ph-H), 8.03 (s, 2H, 3,5-
Ph-H), 8.22 (s, 1H, CHd); GC-MS (EI, 70Ev) (m/z 258 (M+).
N-Hydroxy-3,5-bis(trifluoromethyl)benzimidoyl Chloride (3). tert-
Butylhypochlorite (5.5 g, 0.05 mol) was added dropwise to a solution
of compound 2 (12.85 g, 0.05 mol) in methanol (200 mL) at -5 to 0
°C over 0.5 h, and the reaction mixture was then stirred at the same
temperature for an additional 1.0 h. Reaction solvent was evaporated
under reduced pressure to give compound 3 as an oil: 13.08 g, 90.0%
(GC), GC-MS (EI, 70Ev) (m/z 291 (M+). Without further purification,
compound 3 was used in the next reaction.
Methyl-N-hydroxy-3,5-bis(trifluoromethyl)benzimidate (4). Com-
pound 3 (90.0%, 4.70 g, 14.5 mmol) was added dropwise to a solution
of sodium methoxide in methanol (8.0 wt.%, 30.5 g, 45.0 mmol) at
15-20 °C. The reaction mixture was then stirred at the same tem-
perature for an additional 1.0 h after which the reaction was poured
into ice-water and extracted with ethyl ether (3 × 100 mL). The
combined ether extracts were washed with water, dried (anhydrous
magnesium sulfate), and filtered, and the solvent was removed under
reduced pressure to yield compound 4 as a white viscous solid: 4.08 g,
GC-MS (EI, 70Ev) (m/z 287 (M+). Without further purification,
compound 4 was used in the next reaction.
were washed with water, dried (anhydrous magnesium sulfate), and filtered,
and the solvent was removed, The residue material was separated by silica-
gel column chromatography with petroleum ether-ethyl acetate (15:1/
10:1 by volume) as eluant to yield 5f as a white solid: 1.01 g (27.9%), mp
1
86.3-86.6 °C; H NMR (CDCl3) δ (ppm) 3.69 (s, 3H, OCH3), 3.83 (s,
3H, OCH3), 4.15 (s, 3H, OCH3), 5.06 (s, 2H, OCH2), 7.17-8.18 (m, 8H,
PhH + CHd); GC-MS (EI, 70Ev) (m/z 491 (M+); LC-MS (APCI, Pos)
(m/z 492 (M+ + 1); calcd for C22H19F6NO5: C, 53.77; H, 3.90; N, 2.85;
found: C, 53.91; H, 3.83; N, 2.88.
5a, 5c-5e, and 5h-5t could be synthesized by the method similar
to that described in the synthesis of 5f.
(Z)-Methyl-N-2-((E)-1-(methoxyimino)-2-(methylamino)-2-oxoethyl)-
benzyloxy-3,5-bis(trifluoro methyl)benzimidothioate (5b). Compound
5a (1.52 g, 3 mmol) was added to a solution of methylamine in
methanol (30 wt.%, 5 mL). The reaction mixture was stirred at 20 °C
for 15 h after which the reaction was continued as described in the
synthesis of 5f to yield compound 5g as a white solid: 0.96 g (63.3%),
1
mp 132.1-133.9 °C; H NMR (CDCl3) δ (ppm) 2.15 (s, 3H, SCH3),
2.87 (d, J ) 5.1 Hz, 3H, NCH3), 3.95 (s, 3H, OCH3), 5.18 (s, 2H,
OCH2), 6.76 (s, 1H, NH), 7.19-7.95 (m, 7H, Ph-H); LC-MS(APCI,
Pos) (m/z 508 (M+ + 1); calcd for C21H19F6N3O3S: C, 49.70; H, 3.77;
N, 8.28; found: C, 49.86; H, 3.81; N, 8.16.
5g could be synthesized by the method similar to that described in
the synthesis of 5b.
(E)-Methyl-2-(2-(((Z)(1-(3,5-bis(trifluoromethyl)phenyl)-1-methyl-
sulfinyl)methylideneaminooxy) methyl)phenyl)-3-methoxyacrylate (5u).
Hydrogen peroxide (30 wt.%, 5 g) was added dropwise to a solution
of 5a (0.51 g, 1 mmol) in methanol (10 mL) and acetic acid (2 mL).
The reaction mixture was stirred at 20 °C for 20 h after which the
reaction was continued as described in the synthesis of 5f to yield 5u
as an oil: 0.31 g (58%); 1H NMR (CDCl3) δ (ppm) 2.92 (s, 3H, SOCH3),
3.69 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 5.24 (s, 2H, OCH2), 7.18-8.18
(m, 8H, Ph-H + CHd); LC-MS(APCI, Pos) (m/z 524).
5v could be synthesized by the method similar to that described in
the synthesis of 5u.
Structures of 5a-5v were supported by spectroscopic data shown
in Tables 1 and 2.
(E)-Methyl-2-(2-((((Z)(1-(3,5-bis(trifluoromethyl)phenyl)-1-meth-
oxymethylidene)amino)oxy) methyl)phenyl)-3-methoxyacrylate (5f). A
solution of compound 4 (70.5%, 2.85 g, 7.0 mmol) in N,N-dimethyl-
formamide (DMF) (5 mL) was added dropwise over 0.5 h to a solution
of potassium hydroxide (0.56 g, 10 mmol) in DMF (15 mL) at -5 to
0 °C. The mixture was stirred at the same temperature for 0.5 h then
a solution of (E)-methyl-2-(2-(bromomethyl)phenyl)-3-methoxyacrylate
(2.58 g, 9.0 mmol) in DMF (10 mL) was added dropwise. The mixture
was stirred at 20-25 °C for 10-12 h. The reaction was poured into
ice-water and extracted with ethyl ether. The combined ether extracts
Figure 3. Design strategy of the target compounds containing bis(trifluoromethyl)phenyl.

6564 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Liu et al.
Figure 5. Synthetic pathways for the novel bis(trifluoromethyl)phenyl-based strobilurins.
Table 1. Chemical Structures, Physical Characteristics, Yield, and Preventive Activities against Erysiphe graminis (7d) of Compounds 5a-5v
chemical structure
yieldb (%)
compd
Ta
X
R
formula
mp (°C)
500 ppm
100 ppm
6.2 ppm
3.1 ppm
1.5 ppm
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
T-1
T-2
T-3
T-4
T-5
T-1
T-2
T-3
T-4
T-5
T-1
T-4
T-1
T-4
T-1
T-4
T-1
T-4
T-1
T-4
T-1
T-1
S
S
S
S
S
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C22H19F6NO4S
C21H19F6N3O3S
C22H19F6N3O4S
C21H18F6N2O4S
C20H18F6N2O4S
C22H19F6NO5
C21H19F6N3O4
C22H19F6N3O5
C21H18F6N2O5
C20H18F6N2O5
C22H20F6N2O4
C21H19F6N3O4
C21H18F6N2O4
C20H17F6N3O4
C23H21F6NO5
C22H20F6N2O5
C23H21F6NO4S
C22H20F6N2O4S
C24H23F6NO4S
C23H22F6N2O4S
C22H19F6NO5S
C22H19F6NO6S
79.6-80.1
28.9
63.3
26.6
27.4
26.2
27.9
55.1
28.2
29.6
25.8
29.9
32.1
23.6
25.2
31.6
36.5
28.9
38.8
22.8
32.7
48.8
54.6
100
100
100
100
90
100
100
100
80
90
100
98
40
20
93
25
10
75
a
132.1-133.9
oil
oil
oil
65
100
30
100
86.3-86.6
100
90
98
156.5-157.4
oil
100
100
100
100
100
100
30
100
100
85
100
100
100
100
100
95
100
100
80
90
93
96
98
60
65
90
75
95
80
10
25
70
40
O
O
71.6-73.7
oil
oil
89.6-89.9
113.5-114.7
viscous solid
oil
oil
oil
oil
oil
oil
oil
oil
NH
NH
NH
NH
O
O
S
S
S
90
H
CH3CH2
CH3CH2
CH3CH2
CH3CH2
(CH3)2CH
CH(CH3)2
CH3
100
100
90
80
60
50
35
15
85
85
85
70
5s
5t
5u
5v
S
SO
SO2
CH3
70
metominostrobin
azoxystrobin
trifloxystrobin
100
100
100
100
100
100
95
85
100
85
80
98
65
62
75
a See Figure 2. b Yield after purification by column chromatography on silica gel.
Biological Assay. Test Compounds. Stock solution of every test
triplicate, and the biological effect was reported as the average of
the triplicates. Biological data were analyzed as in the test of
preventive activity against Sphaerotheca fuligine or Erysiphe
graminis.
compound was prepared in DMF at a concentration of 1.0 g L-1 and
then diluted to the required test concentrations (0.10-200 mg L-1
)
with water containing Tween 80 (0.4 mg L-1).
PreVentiVe ActiVity against Sphaerotheca fuligine or Erysiphe
graminis. Cucumber plants or wheat plants were grown under green-
house conditions (T ) 22 °C, 60 ((5)% relative humidity and a 12 h
light cycle). Plants were maintained in plastic pots (6 cm diameter ×
10 cm). Test compound solutions were sprayed over the plants. One
day later, plants were inoculated by a spore suspension of Sphaerotheca
fuligine or Erysiphe graminis (1.0 × 105 spores mL-1). One or two
weeks later, the symptoms were examined. Each bioassay was
conducted in triplicate, and the biological effect was reported as the
average of the triplicates. The dose-response data were analyzed by
probit analysis as described by Finney (16), and the activities were
evaluated as EC50 and EC90 values (95% FL).
RESULTS AND DISCUSSION
Synthesis. The synthesis scheme shown in Figure 5 provided
an efficient high yield synthesis of the test compounds. Their
structures were confirmed by spectroscopic and elemental
analysis. Table 1 summarizes the chemical structures, physical
characteristics, and yields of the new compounds 5a-5v. MS
and 1H NMR data are listed in Table 2. The observed molecular
weight for each compound of 5a-5v was as expected in the
MS analysis.
CuratiVe ActiVity against Sphaerotheca fuligine or Erysiphe grami-
nis. Cucumber plants or wheat plants were grown under greenhouse
conditions (T ) 22 °C, 60 ((5)% relative humidity and a 12 h light
cycle). Plants were maintained in plastic pots (6 cm diameter × 10
cm) and were inoculated by a spore suspension of Sphaerotheca
fuligine or Erysiphe 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 in
Fungicidal Activity. Table 1 shows the preventive activities
of the synthesized strobilurins against E. graminis. The
activity of commercial strobilurin fungicides such as me-
tominostrobin, azoxystrobin, and trifloxystrobin are also
presented in Table 1.
As shown in Table 1, all the compounds 5 exhibit remarkable
fungicidal activity against E. graminis, and some compounds 5

Synthesis and Fungicidal Activities of Strobilurins
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6565
Table 2. 1H NMR Data of the Novel Bis(trifluoromethyl)phenyl-Based Strobilurins
compd
MS (m/e)
1H NMR (CDCl3), δ
5a
507
2.17 (s, 3H, SCH3), 3.68 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 5.21 (s,2H,
OCH2), 7.16∼7.98 (m, 8H, Ph-H + CHd)
5b
5c
5d
5e
5f
507
535
508
496
491
491
519
492
480
490
491
476
477
505
2.15 (s, 3H, SCH3), 2.87 (d, J ) 5.1 Hz, 3H, NCH3), 3.95 (s, 3H, OCH3), 5.18
(s, 2H, OCH2), 6.76 (s, 1H, NH), 7.19-7.95 (m, 7H, Ph-H)
2.17 (s, 3H, SCH3), 3.98 (s, 3H, OCH3), 4.16 (t, J ) 4.2 Hz, 2H, CH2), 4.48 (t,
J ) 4.2 Hz, 2H, CH2), 5.22 (s, 2H, OCH2), 7.18-7.98 (m, 7H, Ph-H)
2.15 (s, 3H, SCH3), 3.82 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 5.17 (s, 2H,
OCH2), 7.18∼7.95 (m, 7H, Ph-H)
2.19 (s, 3H, SCH3), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 5.34 (s, 2H,
OCH2), 7.37-7.96 (m, 7H, Ph-H).
3.69 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.15 (s, 3H, OCH3), 5.06 (s, 2H,
OCH2), 7.17-8.18 (m, 8H, Ph-H + CHd)
5g
5h
5i
2.86 (d, J ) 5.1 Hz, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.12 (s, 3H, OCH3), 5.17
(s, 2H, OCH2), 6.80 (s, 1H, NH), 7.21-7.95 (m, 7H, Ph-H)
3.81 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.16 (t, J ) 4.2 Hz, 2H, CH2), 4.48 (t,
J ) 4.2 Hz, 2H, CH2), 5.08 (s, 2H, CH2), 7.15-7.53 (m, 7H, Ph-H)
3.84 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 5.02 (s, 2H,
OCH2), 7.19-8.14 (m, 7H, Ph-H)
5j
3.70 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 5.12 (s, 2H,
CH2), 7.34-8.34 (m, 7H, Ph-H)
5k
5l
2.68 (d, J ) 5.4 Hz, 3H, NCH3), 3.70 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.99
(s, 2H, CH2), 5.30 (br, 1H, NH), 7.16-7.94 (m, 8H, Ph-H + dCH)
2.68 (d, J ) 5.4 Hz, 3H, NCH3), 3.87 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 4.99
(s, 2H, CH2), 5.47 (br, 1H, NH) 7.18-7.92 (m, 7H, Ph-H)
3.72 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.98 (br, 2H, NH2), 5.07 (s, 2H, CH2),
7.16-8.08 (m, 8H, Ph-H + dCH).
5m
5n
5o
3.85 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 4.95 (br, 2H, NH2), 5.05 (s, 2H, CH2),
7.19-8.09 (m, 7H, Ph-H)
1.34 (t, J ) 7.05 Hz, 3H, CH3), 3.70 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.47
(q, J ) 7.10 Hz, 2H, CH2), 5.06 (s, 2H,CH2), 7.16-8.32 (m, 8H, dCH +
Ph-H)
5p
5q
5r
506
521
522
535
536
523
539
1.34 (t, J ) 7.05 Hz, 3H, CH3), 3.87 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 4.43
(q, J ) 7.0 Hz, 2H, CH2), 5.01 (s, 2H, CH2), 7.15-7.531 (m, 7H, Ph-H)
1.14 (t, J ) 7.35 Hz, 3H, CH3), 2.68 (q, J ) 7.35 Hz, 2H, SCH2), 3.70 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 5.22 (s, 2H, OCH2), 7.16-8.04 (m, 8H, Ph-H)
1.15 (t,J ) 7.35 Hz, 3H, CH3), 2.69 (q, J ) 7.35 Hz, 2H, SCH2), 3.83 (s, 3H,
OCH3), 4.08 (s, 3H, OCH3), 5.17 (s, 2H, OCH2), 7.19-8.00 (m, 7H, Ph-H)
1.20 (d, J ) 6.9 Hz, 6H, 2CH3), 3.48-3.57 (m, 1H, CH), 3.66 (s, 3H, OCH3),
3.82 (s, 3H, OCH3), 5.23 (s, 2H, OCH2), 7.16-8.13 (m, 8H, Ph-H + CHd)
1.18 (d, J ) 6.9 Hz, 6H, 2CH3), 3.42-3.50 (m, 1H, CH), 3.83 (s, 3H, OCH3),
4.05 (s, 3H, OCH3), 5.18 (s, 2H, OCH2), 7.18-8.10 (m,7H, Ph-H)
2.92 (s, 3H, SOCH3), 3.70 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 5.24 (s, 2H,
OCH2), 7.18-8.18 (m, 8H, Ph-H + CHd)
5s
5t
5u
5v
3.18 (s, 3H, SO2CH3), 3.57 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 5.25 (s, 2H,
OCH2), 7.09-8.05 (m, 8H, Ph-H + CHd)
Table 3. Preventive Activities of 5f, 5h, and Azoxystrobin (14 d after Treatment)
Pathogen
Erysiphe graminis
Sphaerotheca fuligine
dose (mg L-1
)
6.25
3.12
1.56
0.78
EC50
EC90
6.25
3.12
1.56
0.78
EC50
EC90
5f
5h
100
100
90
81
98
65
60
75
50
20
30
20
1.2
0.9
1.7
2.8
2.0
7.0
100
100
95
100
100
80
80
75
60
59
55
35
0.8
0.8
1.2
1.5
1.6
4.5
azoxystrobin
Table 4. Curative Activities of 5f, 5h, and Azoxystrobin (14 d after Treatment)
pathogen
Erysiphe graminis
Sphaerotheca fuligine
dose (mg L-1
)
6.25
3.12
1.56
0.78
EC50
EC90
6.25
3.12
1.56
0.78
EC50
EC90
5f
5h
94
100
89
82
90
78
50
70
52
20
35
15
1.5
1.0
1.7
4.8
2.4
5.9
100
100
100
100
100
90
92
80
80
56
60
55
0.8
0.8
0.8
1.4
1.5
2.1
azoxystrobin
show high fungicidal activity. For example, compounds 5a, 5f,
5h, 5i, and 5l have g90% fungicidal activity at 3.1 mg L-1
as metominostrobin, azoxystrobin, and trifloxystrobin only
exhibit e75% fungicidal activity at the same treatment dose.
In order to compare fungicidal activities of compounds 5 with
that of the commercial strobilurin fungicide azoxystrobin, the
,
compounds 5f and 5h still have g95% fungicidal activity at
1.5 mg L-1, while the commercial strobilurin fungicides such

6566 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Liu et al.
preventive and curative activities of the more active compounds
5f, 5h, and azoxystrobin against E. graminis and S. fuligine are
presented in Tables 3 and 4, respectively.
T-2 > T-3 > T-4 > T-5 (X ) S, R ) CH3) and T-1 ≈ T-3 >
T-4 > T-5> T-2 (X ) O, R ) CH3). Further studies on the
biological activity and structure-activity relationships of this
series compounds are in progress.
The results in Tables 3 and 4 show that 5f and 5h have high
preventive and curative activities against Erysiphe graminis and
Sphaerotheca fuligine, respectively. For example, compound 5f
has EC90 (mg L-1) values of 2.8 and 1.5 in preventive treatment
and 4.8 and 1.4 in curative treatment against Erysiphe graminis
and Sphaerotheca fuligine, respectively; compound 5h has EC90
(mg L-1) values of 2.0 and 1.6 in preventive treatment and 2.4
and 1.5 in curative treatment against Erysiphe graminis and
Sphaerotheca fuligine, respectively. Both EC50 and EC90 values
of compounds 5f and 5h are better than that of the commercial
strobilurin fungicide azoxystrobin.
Apparent Structure-Activity Relationship. In the general
formula for compounds 5 (Figure 5), structural optimization
was carried out with three primary substructures: the R, X, and
T moieties. Variances among R, X, and T can greatly effect
fungicidal activity against Erysiphe graminis (Table 1).
When X and T are kept constant, the fungicidal activities of
the synthesized compounds are influenced by the nature of the
R group. Modification of the R group from a hydrogen atom to
a methyl group maintains or increases the fungicidal activity
(e.g., the fungicidal activity of 5l is better than that of 5n, while
5k has a similar level of fungicidal activity to 5m). When the
methyl group is changed to ethyl or isopropyl, the fungicidal
activity of the corresponding compound decreases; for example,
the fungicidal activities are correlated as follows: 5o < 5f, 5p
< 5i, 5q ) 5s < 5a, and 5r ) 5t < 5d. This suggests that the
dealkylation of the alkyl moiety could be an activation process
for this group of compounds.
When R and T are kept constant, the fungicidal activity of
the synthesized compounds is influenced by the nature of the
X group. When X is changed from O to S, NH, SO, and SO2,
the fungicidal activity of the corresponding compound decreases;
for example, fungicidal activities are correlated as follows: 5f
> 5a > 5k > 5u ) 5v and 5i > 5l > 5d. When X equals O,
all of the compounds (5f, 5h-5j, 5o-5p), except for 5g, show
high fungicidal activity.
When R and X are kept constant, the fungicidal activity of
the synthesized compounds is influenced by the nature of the T
group (Figure 2). When R is kept as methyl, X is S, the
fungicidal activity of the T-1 derivative 5a is the highest. When
T is changed from T-1 to T-2, T-3, T-4, and T-5, the fungicidal
activity of the corresponding compound decreases; for example,
fungicidal activities are correlated as follows: 5a > 5b > 5c >
5d > 5e. When R is methyl, X is O, the fungicidal activity of
the T-1 and T-3 derivatives are almost equal and higher than
other T-2, T-4, and T-5 derivatives; for example, fungicidal
activities are correlated as follows: 5f ≈ 5h > 5i > 5j > 5g.
In general, for the synthesized compounds 5: (1) The activity
order of R is CH3 > H > CH2CH3 > CH(CH3)2. This suggests
that the metabolic dealkylation of alkyl to H is an important
process. Compounds in which R equals methyl could be
profungicides. (2) Activity order of pharmacophore T is T-1 >
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Received for review March 20, 2008. Revised manuscript received May
8, 2008. Accepted May 9, 2008. We gratefully acknowledge support of
this work by both the National Natural Science Foundation of China
(No. 20572019), the Hunan Provincial Natural Science Foundation of
China (No. 06JJ20054), and National tenth-five Key Project of China
(No. 2004BA308A24-4).
JF800651Z