Synthesis and bioactivities of novel N-(4-(2-Aryloxythiazol-5-yl)but-3-yn- 2-yl)benzamides

Article abstract of DOI:10.1002/cjoc.201200824

A series of novel N-(4-(2-aryloxythiazol-5-yl)but-3-yn-2-yl)benzamide derivatives were designed and synthesized. Their structures were identified by ¹H NMR and elemental analyses. Preliminary bioassays indicated that some title compounds provided >80% control of Sclerotinia sclerotiorum at 50 μg/mL and >70% herbicidal activities against B. campestris at 100 μg/mL. Their structure-activities relationships were also discussed. A series of novel N-(4-(2-aryloxythiazol-5-yl)but-3-yn-2-yl)benzamide derivatives were designed and synthesized. Some of them provided >80% control of Sclerotinia sclerotiorum at 50 μg/mL and >70% herbicidal activities against B. campestris at 100 μg/mL. Copyright

Full text of DOI:10.1002/cjoc.201200824

FULL PAPER
DOI: 10.1002/cjoc.201200824
Synthesis and Bioactivities of Novel N-(4-(2-Aryloxythiazol-
5-yl)but-3-yn-2-yl)benzamides
Youquan Zhu,* Pei Liu, Danyang Wang, Jin Zhang, Jie Cheng,
Yuan Ma, Xiaomao Zou,* and Huazheng Yang
State Key Laboratory of Elemento-organic Chemistry, Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
A series of novel N-(4-(2-aryloxythiazol-5-yl)but-3-yn-2-yl)benzamide derivatives were designed and synthe-
1
sized. Their structures were identified by H NMR and elemental analyses. Preliminary bioassays indicated that
some title compounds provided ＞80% control of Sclerotinia sclerotiorum at 50 µg/mL and ＞70% herbicidal ac-
tivities against B. campestris at 100 µg/mL. Their structure-activities relationships were also discussed.
Keywords fungicides, benzamide, ACCase, aryloxythiazole, herbicide
Introduction
resistance of other fungicides.
The crystal structures of the CT domain of yeast
ACCase in complex with commercial herbicides[9-12]
(Figure 2a－2c) and their interactions between them
were reported.[13-17] These facts further suggested that
the CT domain may be a suitable target for discovering
small-molecule inhibitors against ACCase. By docking
A with the CT domain of yeast ACC, similar mode of
interaction was observed (Figure 2d). It was also no-
ticed that many compounds, containing the moiety of
substituted benzamide, exhibited excellent fungicidal
activities [boscalid,[18] fluopicolide,[19] fluopyram[19] and
zoxamide[20] (Figure 1)]. To find potent lead compounds,
compounds B were designed and synthesized (Scheme
1). Their fungicidal activities were evaluated.
Acetyl-coenzyme A carboxylases (ACCase) were
key enzymes in fatty acid biosynthesis in both eukaryo-
tes and prokaryotes[1-3] and attractive targets for drug
discovery.[4-6] Recently, N-(3-(2-aryloxythiazol-5-yl)-
prop-2-ynyl)acetamide (A) (Figure 1) was reported as a
new kind inhibitor against recombinant human ACCase
to provide a safer therapeutic approach for chronic
treatment of obesity, diabetes, and other symptoms of
the metabolic syndrome.[7,8] Since the human and yeast
carboxyl-transferase (CT) domains shared 50% overall
amino acid sequence identity, and the sequence conser-
vation was even higher (ca. 90%) in the active site re-
gion,[5] the further research of A’s fungicidal activities
may result in the discovery of a new kind of fungicides
targeting ACCase and would be helpful to resolve the
CF3
O
Cl
Cl
O
Cl
Cl
O O
HN
Cl
NH
O
N
S
N
H
H3C
O
H
R
N
N
N
CF3
Cl
CF3
Cl
Fluopyram
Fluopicolide
O
A1: R = 4-OCH2(Cyclopentyl)
A
Zoxamide
O
N
O
N
HN
Cl
N
O
O
N
N
O
O
N O
F3C
Cl
O
COO
OH
Cl
Faloxyfop
Tepraloxydim
Boscalid
CP-640186
Figure 1 The structures of A and some commercial products.
*
E-mail: zyq8165@nankai.edu.cn
Received August 13, 2012; accepted October 18, 2012; published online December 17, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200824 or from the author.
Chin. J. Chem. 2013, 31, 173—181
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
173

Zhu et al.
FULL PAPER
G1998'
O
V1705
V2001'
V2002'
V2024'
I1974'
a
V2002'
HO
b
Y1738
O
NH
L2025'
V2004'
W1924'
O
F
O
O
F
F
V2001'
NH
O
O
NH
G1998'
O
HO
N
O
N O
S1708
V1975'
V1967'
Cl
Cl
L1705
O
F1956'
L1742
A1712
HO
O
O
OH
S1708
O
NH
HN
O
O
HN
HN
NH
O
H
L1968'
A1627
N
A1627
O
G1734
L1756
I1735
Y1738
G1734
I1735
c
G1958'
O
d
I1974'
V2002'
T1757
K1764
H2N
Y1738
HO
I1762
HO
A1761
HN
N
O
W1924'
V1967'
S
V2004'
O
L1766
M1765
NH
V2001'
G2032'
HN
O
O
NH
G1998'
O
O
O
N
S
N
N
HO
O
H
N
I2033'
H2N
L1705
S1957'
F1956'
HO
O
O
S1708
R1954'
HN
O
H
O
O
O
N
NH
Q2028'
H
L1968'
L1756
HN
N
N
A1627
P1920'
O
V1923'
G1734
O
L2025'
H2N
NH2
E2026'
I1735
Figure 2 Schematic drawing of the interactions between the CT domain and haloxyfop (a), tepraloxydim (b), CP-640186 (c) and A1 (d),
respectively.
Scheme 1
S
O
OH
S
Br
Br
Br
R1
R1
+
N
N
C
H
CH3
N
O
80%N2H4 H2O
EtOH, 80 oC
H
H
CH3
CH3
NH2 HCl
phthalimide
DEAD, PPh3
OH
O
R3
CH3
NH
R1
R3
COCl
+
R2
CH3
NH2
R3 = H, CH3
H
N
Et3N
C/Pd(PPh3)2Cl2/CuI/Et3N
R2
S
O
O
R2
R3 CH3
O
N
B
D
Experimental
Siemens P4 diffractometer. Yields were not optimized.
Solvents were dried according to standard methods and
distilled prior to use.
Synthetic procedures
1H NMR spectra were obtained on 400 MHz (Varian
Mercury Plus 400 spectrometer) in CDCl3 solution with
tetramethylsilane as the internal standard. Elemental
analyses were determined on a Yanaca CHN Corder
MT-3 elemental analyzer. Melting points were taken on
a Thomas-Hoover melting point apparatus and uncor-
rected. X-ray diffraction analyses were measured on a
General synthetic procedure for C
Compounds C were synthesized as the literature de-
scribed.[9]
Data for C1 (R1＝2-Cl) Yellow liquid, yield 98%;
1H NMR (400 MHz, CDCl3) δ: 7.06 (s, 1H), 7.15－7.19
(m, 1H), 7.25－7.27 (m, 2H), 7.40－7.42 (m, 1H).
174
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 173—181

Synthesis and Bioactivities of Novel N-(4-(2-Aryloxythiazol-5-yl)but-3-yn-2-yl)benzamides
Data for C2 (R1＝3-Cl) Colorless liquid, yield
91%; H NMR (400 MHz, CDCl3) δ: 7.09－7.10 (m,
benzoyl chlorides.[22] D5 (R2＝2-Cl; R3＝4-CH3), m.p.
1
95－96 ℃ (94－96 ℃[22]); D6 (R2 ＝4-Cl; R3 ＝
4-CH3): m.p. 144－145 ℃ (141－143 ℃[22]); D7 (R2
＝2,4-Cl2; R3＝4-CH3): m.p. 109－110 ℃ (108－109
2H), 7.16－7.30 (m, 3H).
Data for C3 (R1＝4-Cl) White solid, yield 94%,
m.p. 49－50 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.09 (s,
1H), 7.14 (d, J＝8.7 Hz, 2H), 7.31 (d, J＝8.7 Hz, 2H).
Data for C4 (R1＝3-F) Colorless liquid, yield
92%; 1H NMR (400 MHz, CDCl3) δ: 6.88－7.00 (m,
3H), 7.11 (s, 1H), 7.27－7.33 (m, 1H).
℃
[22]); D8 (R2＝4-CH3; R3＝4-CH3): m.p. 126－129
℃; 1H NMR (400 MHz, CDCl3) δ: 1.76 (s, 6H), 2.39 (s,
4H, CH3), 6.20 (s, 1H), 7.22 (d, J＝8.1 Hz, 2H), 7.65 (d,
J＝8.1 Hz, 2H).
Data for C5 (R1＝4-F) White solid, yield 95%,
m.p. 45－47 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.01－
7.06 (m, 2H), 7.08 (s, 1H), 7.15－7.19 (m, 2H).
Data for C6 (R1＝4-OCH3) White solid, yield
General synthetic procedure for B
To a degassed solution of C (3 mmol), D (3.3 mmol)
and triethylamine (15 mmol) in 25 mL of dry THF, were
added dichlorobis(triphenylphosphine) palladium (0.015
mmol) and copper iodide (0.006 mmol). After the mix-
ture was refluxed under nitrogen for 3 h, it was cooled
to room temperature and poured slowly into 30 mL of
saturated ammonia chloride solution. The mixture was
extracted with methylene chloride. The organic layer
was dried over anhydrous Na2SO4. The solvent was re-
moved in vacuo, and the residue was purified by flash
column chromatography on silica gel, using ethyl ace-
tate-petroleum ether as the eluent to afford the pure tar-
get product B.
1
72%, m.p. 44－45 ℃; H NMR (400 MHz, CDCl3) δ:
3.74 (s, 3H), 6.86 (d, J＝9.1 Hz, 2H), 7.11 (d, J＝8.7
Hz), 7.07 (s, 1H).
Data for C7 (R1＝3-CF3) Colorless liquid, yield
1
88%; H NMR (400 MHz, CDCl3) δ: 7.07 (s, 1H), 7.38
－7.47 (m, 4H).
Data for C8 (R1＝2,4-Cl2) White solid, yield 91%,
m.p. 76－77 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.16 (s,
1H), 7.30 (s, 2H ), 7.50 (s, 1H).
General synthetic procedure for D1－D4
Data for 2-chloro-N-(4-(2-(2-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B1)
A mixture of 2-(but-3-yn-2-yl)isoindoline-1,3-dione
(10 mmol)[21] and 80% hydrazine monohydrate (15
mmol) in 80 mL ethanol was refluxed for 3.5 h. The
mixture was cooled, acidified with concentrate hydro-
chloride and filtered. The filtrate was concentrated to
give crude 2-(but-3-yn-2-yl)isoindoline-1,3-dione used
for next step without further purification. It was further
transformed into compound D by reaction with different
aroyl chlorides.
1
Yield 44%, m.p. 114－116 ℃; H NMR (400 MHz,
CDCl3) δ: 1.45 (s, 6H), 5.64 (s, 1H), 7.04 (s, 1H), 7.10
－7.14 (m, 1H), 7.20－7.29 (m, 3H), 7.32－7.42 (m,
3H), 7.80－7.83 (m, 1H). Anal. calcd for C21H16Cl2N2-
O2S: C 58.48, H 3.74, N 6.49; found C 58.28, H 3.67, N
6.46.
Data for 4-chloro-N-(4-(2-(2-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B2)
1
Data for D1 (R2＝2-Cl; R3＝H) White solid, total
yield 84%, m.p. 91－94 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.55 (d, J＝6.9 Hz, 3H), 2.32 (d, J＝2.3 Hz,
1H), 4.95－5.11 (m, 1H), 6.41 (s, 1H), 7.31－7.42 (m,
3H), 7.67－7.69 (m, 1H).
Yield 59%, m.p. 183－185 ℃; H NMR (400 MHz,
CDCl3) δ: 1.50 (s, 6H), 5.74 (s, 1H), 7.12 (s, 1H), 7.22
－7.26 (m, 1H), 7.32－7.42 (m, 2H), 7.46 (d, J＝8.6 Hz,
2H), 7.49－7.51 (m, 1H), 7.99 (d, J＝8.6 Hz, 2H). Anal.
calcd for C21H16Cl2N2O2S: C 58.48, H 3.74, N 6.49;
found C 58.49, H 3.84, N 6.43.
Data for D2 (R2＝4-Cl; R3＝H) White solid, total
1
Data for 2-chloro-N-(4-(2-(3-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B3)
yield 85%, m.p. 112－114 ℃; H NMR (400 MHz,
CDCl3) δ: 1.53 (d, J＝6.9 Hz, 3H), 2.32 (d, J＝2.1 Hz,
1H), 4.93－5.08 (m, 1H), 6.35 (s, 1H), 7.41 (d, J＝8.4
Hz, 2H), 7.72 (d, J＝8.4 Hz, 2H).
1
Yield 43%, yellow liquid; H NMR (400 MHz, CDCl3)
δ: 1.55 (s, 6H), 5.74 (s, 1H), 7.17 (s, 1H), 7.19－7.22 (m,
2H), 7.31－7.40 (m, 3H), 7.43－7.47 (m, 1H), 7.50－
7.52 (m, 1H), 7.90 (dd, J＝1.7, 7.7 Hz, 1H). Anal. calcd
for C21H16Cl2N2O2S: C 58.48, H 3.74, N 6.49; found C
58.38, H 3.91, N 6.37.
Data for D3 (R2＝2,4-Cl2; R3＝H) White solid,
total yield 87%, m.p. 102－104 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.54 (d, J＝6.9 Hz, 3H), 2.32 (d, J＝2.1 Hz,
1H), 4.91－5.09 (m, 1H), 6.46 (s, 1H), 7.32 (dd, J＝8.3,
1.6 Hz, 1H), 7.42 (d, J＝1.6 Hz, 1H), 7.64 (d, J＝8.3 Hz,
1H).
Data for 4-chloro-N-(4-(2-(3-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B4)
1
Data for D4 (R2＝4-CH3; R3＝H) White solid,
total yield 75%, m.p. 126－129 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.51 (d, J＝6.9 Hz, 3H), 2.30 (d, J＝2.3 Hz,
1H), 2.39 (s, 3H), 4.93－5.08 (m, 1H), 6.36 (s, 1H),
7.22 (d, J＝8.0 Hz, 2H), 7.68 (d, J＝8.0 Hz, 2H).
Yield 43%, m.p. 118－120 ℃; H NMR (400 MHz,
CDCl3) δ: 1.51 (s, 6H), 5.75 (s, 1H), 7.17 (s, 1H), 7.20
－7.26 (m, 2H), 7.33－7.37 (m, 2H), 7.46 (d, J＝8.5 Hz,
2H), 7.98 (d, J ＝8.5 Hz, 2H). Anal. calcd for
C21H16Cl2N2O2S: C 58.48, H 3.74, N 6.49; found C
58.43, H 3.48, N 6.42.
General synthetic procedure for D5－D8
Data for 2,4-dichloro-N-(4-(2-(3-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B5)
Compounds D5－D8 were synthesized by reacting
2-methylbut-3-yn-2-amine with different substituted
1
Yield 54%, yellow liquid; H NMR (400 MHz, CDCl3)
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Zhu et al.
FULL PAPER
δ: 1.80 (s, 6H), 6.43 (s, 1H), 7.16－7.18 (m, 1H), 7.23－
7.27 (m, 1H), 7.28－7.36 (m, 4H), 7.39 (s, 1H), 7.60 (d,
J＝8.3 Hz, 1H). Anal. calcd for C21H15Cl3N2O2S: C
54.15, H 3.25, N 6.01; found C 54.05, H 3.30, N 6.09.
Data for 2-chloro-N-(4-(2-(4-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B6)
found C 60.99, H 3.74, N 6.76.
Data for N-(4-(2-(3-fluorophenoxy)thiazol-5-yl)-
2-methylbut-3-yn-2-yl)-2,4-dichlorobenzamide (B13)
Yield 46%, m.p. 54－56 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.81 (s, 6H), 6.36 (s, 1H), 6.96－7.08 (m, 3H),
7.30－7.41 (m, 4H), 7.63 (d, J＝8.3 Hz, 1H). Anal.
calcd for C21H15ClFN2O2S: C 56.13, H 3.36, N 6.23;
found C 55.98, H 3.25, N 6.18.
1
Yield 40%, m.p. 102－103 ℃; H NMR (400 MHz,
CDCl3) δ: 1.54 (s, 6H), 5.73 (s, 1H), 7.15 (s, 1H), 7.23
(d, J＝8.9 Hz, 2H), 7.37 (d, J＝8.9 Hz, 2H), 7.37－7.39
(m, 1H), 7.43－7.47 (m, 1H), 7.50－7.52 (m, 1H), 7.89
(dd, J＝1.4, 7.7 Hz, 1H). Anal. calcd for C21H16Cl2N2-
O2S: C 58.48, H 3.74, N 6.49; found C 58.31, H 3.80, N
6.46.
Data for N-(4-(2-(3-fluorophenoxy)thiazol-5-yl)-2-
methylbut-3-yn-2-yl)-4-methylbenzamide
(B14)
1
Yield 42%, m.p. 99－102 ℃; H NMR (400 MHz,
CDCl3) δ: 1.51 (s, 6H), 2.42 (s, 3H), 5.73 (s, 1H), 6.93
－6.97 (m, 1H), 7.07－7.11 (m, 2H), 7.18 (s, 1H), 7.28
(d, J＝7.3 Hz, 2H), 7.34－7.37 (m, 1H), 7.94 (d, J＝7.3
Hz, 2H). Anal. calcd for C21H15ClFN2O2S: C 66.99, H
4.85, N 7.10; found C 67.05, H 5.10, N 7.08.
Data for 4-chloro-N-(4-(2-(4-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B7)
1
Yield 47%, m.p. 133－135 ℃; H NMR (400 MHz,
CDCl3) δ: 1.43 (s, 6H), 5.66 (s, 1H), 7.06 (s, 1H), 7.17
(d, J＝8.9 Hz, 2H), 7.30 (d, J＝8.9 Hz, 2H), 7.38 (d,
J＝8.6 Hz, 2H), 7.90 (d, J＝8.6 Hz, 2H). Anal. calcd for
C21H16Cl2N2O2S: C 58.48, H 3.74, N 6.49; found C
58.45, H 3.69, N 6.46.
Data for 2-chloro-N-(4-(2-(4-fluorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B15)
Yield 31%, m.p. 92－94 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.43 (s, 6H), 5.62 (s, 1H), 6.53－6.99 (m, 2H),
7.04 (s, 1H), 7.13－7.16 (m, 2H), 7.22－7.26 (m, 1H),
7.30－7.34 (m, 1H), 7.38－7.40 (m, 1H), 7.79 (dd, J＝
1.4, 7.7 Hz, 1H). Anal. calcd for C21H15ClFN2O2S: C
60.79, H 3.89, N 6.75; found C 61.00, H 3.97, N 6.78.
Data for 4-chloro-N-(4-(2-(4-fluorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B16)
Data for 4-methyl-N-(4-(2-(4-chlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B8)
1
Yield 47%, m.p. 141－142 ℃; H NMR (400 MHz,
CDCl3) δ: 1.51 (s, 6H), 2.43 (s, 3H), 5.72 (s, 1H), 7.14
(s, 1H), 7.25－7.30 (m, 4H), 7.39 (d, J＝8.5 Hz, 2H),
7.93 (d, J＝8.5 Hz, 2H). Anal. calcd for C22H19ClN2O2S:
C 64.30, H 4.66, N 6.82; found C 64.00, H 4.49, N 6.71.
Data for 2-chloro-N-(4-(2-(2,4-dichlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B9)
1
Yield 50%, m.p. 158－159 ℃; H NMR (400 MHz,
CDCl3) δ: 1.42 (s, 6H), 5.64 (s, 1H), 7.00－7.05 (m, 3H),
7.18－7.21 (m, 2H), 7.36 (d, J＝8.5 Hz, 2H), 7.88 (d,
J＝8.5 Hz, 2H). Anal. calcd for C21H15ClFN2O2S: C
60.79, H 3.89, N 6.75; found C 60.70, H 3.74, N 6.72.
Data for 2-chloro-N-(4-(2-(4-methoxyphenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B17)
Yield 54%, m.p. 92－94 ℃; 1H NMR (400 MHz,
CDCl3) δ: 1.47 (s, 6H), 3.74 (s, 3H, OCH3), 5.64 (s, 1H),
6.85 (d, J＝9.0 Hz, 2H), 7.08 (s, 1H), 7.13 (d, J＝9.0 Hz,
2H), 7.27－7.44 (m, 3H), 7.82－7.84 (m, 1H). Anal.
calcd for C22H19ClN2O3S: C 61.89, H 4.49, N 6.56;
found C 61.98, H 4.43, N 6.54.
1
Yield 19%, m.p. 132－134 ℃; H NMR (400 MHz,
CDCl3) δ: 1.47 (s, 6H), 5.66 (s, 1H), 7.03 (s, 1H), 7.19
－7.46 (m, 6H), 7.83－7.85 (m, 1H). Anal. calcd for
C21H15Cl3N2O2S: C 54.15, H 3.25, N 6.01; found C
54.27, H 3.18, N 5.96.
Data for 4-chloro-N-(4-(2-(2,4-dichlorophenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B10)
1
Yield 49 %; m.p. 174－175 ℃; H NMR (400 MHz,
CDCl3) δ: 1.44 (s, 6H), 5.67 (s, 1H), 7.02 (s, 1H), 7.18
－7.28 (m, 2H), 7.39 (d, J＝8.6 Hz, 2H), 7.41－7.42 (m,
1H), 7.93 (d, J ＝8.6 Hz, 2H). Anal. calcd for
C21H15Cl3N2O2S: C 54.15, H 3.25, N 6.01; found C
54.36, H 3.40, N 5.97.
Data for 4-chloro-N-(4-(2-(4-methoxyphenoxy)-
thiazol-5-yl)-2-methylbut-3-yn-2-yl)benzamide (B18)
1
Yield 62%, m.p. 117－119 ℃; H NMR (400 MHz,
CDCl3) δ: 1.50 (s, 6H), 3.83 (s, 3H, OCH3), 5.72 (s, 1H),
6.94 (d, J＝9.0 Hz, 2H), 7.24 (d, J＝9.0 Hz, 2H), 7.44
(d, J＝8.5 Hz, 2H), 7.96 (d, J＝8.5 Hz, 2H). Anal. calcd
for C22H19ClN2O3S: C 61.89, H 4.49, N 6.56; found C
62.00, H 4.33, N 6.50.
Data for 2-chloro-N-(2-methyl-4-(2-(3-(trifluoro-
methyl)phenoxy)thiazol-5-yl)but-3-yn-2-yl)benz-
amide (B19) Yield 54%, yellow liquid; 1H NMR (400
MHz, CDCl3) δ: 1.47 (s, 6H), 5.66 (s, 1H), 7.10 (s, 1H),
7.24－7.30 (m, 1H), 7.34－7.49 (m, 6H), 7.80－7.83 (m,
1H). Anal. calcd for C22H16ClF3N2O2S: C 56.84, H 3.47,
N 6.03; found C 56.93, H 3.42, N 5.96.
Data for N-(4-(2-(2-chlorophenoxy)thiazol-5-yl)-
2-methylbut-3-yn-2-yl)-3-fluorobenzamide
(B11)
1
Yield 49%, yellow liquid; H NMR (400 MHz, CDCl3)
δ: 1.45 (s, 6H), 5.65 (s, 1H), 6.81－6.86 (m, 1H), 6.94－
6.99 (m, 2H), 7.09 (s, 1H), 7.22－7.28 (m, 2H), 7.32－
7.36 (m, 1H), 7.39－7.41 (m, 1H), 7.80－7.82 (m, 1H).
Anal. calcd for C21H15ClFN2O2S: C 60.79, H 3.89, N
6.75; found C 60.54, H 3.81, N 6.61.
Data for N-(4-(2-(3-fluorophenoxy)thiazol-5-yl)-
2-methylbut-3-yn-2-yl)-4-chlorobenzamide
(B12)
1
Yield 58 %, m.p. 106－108 ℃; H NMR (400 MHz,
CDCl3) δ: 1.51 (s, 6H), 5.75 (s, 1H), 6.93－6.97 (m, 1H),
7.08－7.12 (m, 2H), 7.18 (s, 1H), 7.34－7.39 (m, 1H),
7.45 (d, J＝8.1 Hz, 2H), 7.98 (d, J＝8.1 Hz, 2H). Anal.
calcd for C21H15ClFN2O2S: C 60.79, H 3.89, N 6.75;
Data for 4-chloro-N-(2-methyl-4-(2-(3-(trifluoro-
methyl)phenoxy)thiazol-5-yl)but-3-yn-2-yl)benz-
amide (B20) Yield 54%, m.p. 131－134 ℃; 1H NMR
(400 MHz, CDCl3) δ: 1.52 (s, 6H), 5.76 (s, 1H), 7.17 (s,
176
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Synthesis and Bioactivities of Novel N-(4-(2-Aryloxythiazol-5-yl)but-3-yn-2-yl)benzamides
1H), 7.46 (d, J＝8.6 Hz, 2H), 7.50－7.61 (m, 4H), 7.98
(d, J＝8.6 Hz, 2H). Anal. calcd for C22H16ClF3N2O2S: C
56.84, H 3.47, N 6.03; found C 56.79, H 3.44, N 5.94.
Data for 4-methyl-N-(2-methyl-4-(2-(3-(trifluoro-
methyl)phenoxy)thiazol-5-yl)but-3-yn-2-yl)benz-
amide (B21) Yield 52%, m.p. 119－120 ℃; 1H NMR
(400 MHz, CDCl3) δ: 1.54 (s, 6H), 2.45 (s, 3H), 5.77 (s,
1H), 7.19 (s, 1H), 7.30 (d, J＝8.0 Hz, 2H), 7.51－7.63
(m, 4H), 7.96 (d, J＝8.0 Hz, 2H). Anal. calcd for
C23H19F3N2O2S: C 62.15, H 4.31, N 6.30; found C 61.93,
H 4.17, N 6.23.
Hz, 2H), 8.48 (d, J＝8.5 Hz, 2H). Anal. calcd for
C20H14ClFN2O2S: C 59.93, H 3.52, N 6.99; found C
59.75, H 3.67, N 7.06.
Data for 2,4-dichloro-N-(4-(2-(3-fluorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl) benzamide (B28) Yield
38%, m.p. 128－129 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.59 (d, J＝6.9 Hz, 3H), 5.12－5.39 (m, 1H), 6.54 (d,
J＝7.9 Hz, 1H), 6.95－7.08 (m, 3H), 7.30－7.43 (m,
4H), 7.64 (d, J ＝8.3 Hz, 1H). Anal. calcd for
C20H13Cl2FN2O2S: C 55.18, H 3.01, N 6.44; found C
54.89, H 3.28, N 6.39.
Data for 2-chloro-N-(4-(2-(3-chlorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl) benzamide (B22) Yield
52%, m.p. 83－85 ℃; H NMR (400 MHz, CDCl3) δ:
1.60 (d, J＝6.8 Hz, 3H), 5.11－5.32 (m, 1H), 6.46 (d,
J＝7.7 Hz, 1H), 7.17－7.26 (m, 2H), 7.32－7.42 (m,
6H), 7.67－7.69 (m, 1H). Anal. calcd for C20H14Cl2N2-
O2S: C 57.56, H 3.38, N 6.71; found C 57.40, H 3.46, N
6.58.
Data for 2,4-dichloro-N-(4-(2-(3-fluorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl) benzamide (B29) Yield
15%, m.p. 99－103 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.58 (d, J＝6.9 Hz, 3H), 2.40 (s, 3H), 5.13－5.38 (m,
1H), 6.32 (d, J＝7.9 Hz, 1H), 6.96－7.01 (m, 1H), 7.03
－7.09 (m, 2H), 7.24 (d, J＝8.1 Hz, 2H), 7.32 (s, 1H),
7.35－7.41 (m, 1H), 7.69 (d, J＝8.1 Hz, 2H). Anal.
calcd for C21H17FN2O2S: C 66.30, H 4.50, N 7.36; found
C 66.08, H 4.64, N 7.59.
1
Data for 4-chloro-N-(4-(2-(3-chlorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl)benzamide (B23)
Yield
Data for 4-methyl-N-(4-(2-(3-(trifluoromethyl)-
phenoxy)thiazol-5-yl)but-3-yn-2-yl)benzamide (B30)
Yield 24%, m.p. 131－133 ℃; H NMR (400 MHz,
CDCl3) δ: 1.58 (d, J＝6.9 Hz, 3H), 2.40 (s, 3H), 5.17－
5.42 (m, 1H), 6.34 (d, J＝7.9 Hz, 1H), 7.24 (d, J＝8.0
Hz, 2H), 7.31 (s, 1H), 7.48－7.58 (m, 4H), 7.70 (d, J＝
8.0 Hz, 2H). Anal. calcd for C22H17F3N2O2S: C 61.39, H
3.98, N 6.51; found C 61.42, H 3.94, N 6.57.
34%, m.p. 113－116 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.57 (d, J＝6.9 Hz, 3H), 4.13－5.38 (m, 1H), 6.61 (d,
J＝7.9 Hz, 1H), 7.16－7.18 (m, 1H), 7.23－7.25 (m,
1H), 7.29－7.36 (m, 3H), 7.39 (d, J＝8.5 Hz, 2H), 7.74
(d, J＝8.5 Hz, 2H). Anal. calcd for C20H14Cl2N2O2S: C
57.56, H 3.38, N 6.71; found C 57.43, H 3.46, N 6.63.
Data for 2,4-dichloro-N-(4-(2-(3-chlorophenoxy)-
1
thiazol-5-yl)but-3-yn-2-yl)benzamide (B24)
Yield
60%, m.p. 107－109 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.60 (d, J＝6.9 Hz, 3H), 5.12－5.39 (m, 1H), 6.50 (d,
J＝8.0 Hz, 1H), 7.17－7.20 (m, 1H), 7.24－7.26 (m,
1H), 7.32－7.38 (m, 4H), 7.43 (d, J＝1.7 Hz, 1H), 7.65
(d, J＝8.3 Hz, 1H). Anal. calcd for C20H13Cl3N2O2S: C
53.17, H 2.90, N 6.20; found C 52.97, H 3.05, N 6.23.
Data for N-(4-(2-(4-chlorophenoxy)thiazol-5-
yl)but-3-yn-2-yl)-4-methyl benzamide (B25) Yield
41%, m.p. 125－128 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.57 (d, J＝6.9 Hz, 3H), 2.40 (s, 3H), 5.17－5.42 (m,
1H), 6.32 (d, J＝7.9 Hz, 1H), 7.22 (d, J＝7.6 Hz, 2H),
7.24 (d, J＝7.8 Hz, 2H), 7.30 (s, 1H), 7.38 (d, J＝7.8 Hz,
2H), 7.69 (d, J ＝7.6 Hz, 2H). Anal. calcd for
C21H17ClN2O2S: C 63.55, H 4.32, N 7.06; found C
63.32, H 4.25, N 7.08.
Bioassays
(1) The antifungal activities of all synthesized
compounds were tested against seven pathogenic fungi,
namely
Phytophthora infestans, Sclerotinia sclerotiorum,
Botrytis cinerea, Thanatephorus cucumeris (Frank)
Donk and Phytophthora capsici by the poison plate
technique.[23]
Alternaria
solani,
Gibberella
zeae,
Compounds B were dissolved in 1 mL acetone before
mixing with 90 mL potato dextrose agar (PDA). The final
concentration of compounds B in the medium was tested
at 50 µg/mL. All kinds of fungi were incubated in PDA at
(27±1) ℃ for 4 d to get new mycelium for antifungal
assay. Then mycelia dishes of approximately 4 mm di-
ameter were cut from culture medium and one of them
was picked up with a sterilized inoculation needle and
inoculated in the center of PDA plate aseptically. The
inoculated plates were incubated at (27±1) ℃ for 5 d.
Acetone in sterile distilled water served as control, while
hymexazole served as positive control. For each treatment,
three replicates were conducted. The radial growth of the
fungal colonies was measured and the data were statisti-
cally analyzed. The inhibiting effects of compounds B in
vitro on these fungi were calculated by the formula: I (%)
＝[(C－T)/(C－0.4)]×100, where C represented the di-
ameter of fungi growth on untreated PDA, and T repre-
sented the diameter of fungi on treated PDA while I
meant inhibition rate. The fungicidal activities were
summarized in Table 1.
Data for 2-chloro-N-(4-(2-(3-fluorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl) benzamide (B26) Yield
24%, m.p. 103－104 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.59 (d, J＝6.8 Hz, 3H), 5.13－5.31 (m, 1H), 6.68 (d,
J＝7.6 Hz, 1H), 6.96－7.08 (m, 3H), 7.29－7.40 (m,
5H), 7.62－7.64 (m, 1H). Anal. calcd for C20H14ClFN2-
O2S: C 59.93, H 3.52, N 6.99; found C 59.65, H 3.77, N
6.86.
Data for 4-chloro-N-(4-(2-(3-fluorophenoxy)-
thiazol-5-yl)but-3-yn-2-yl) benzamide (B27) Yield
50%, m.p. 135－137 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.58 (d, J＝6.9 Hz, 3H), 4.14－5.39 (m, 1H), 6.27 (d,
J＝8.0 Hz, 1H), 6.96－7.01 (m, 1H), 7.03－7.09 (m,
2H), 7.33 (s, 1H), 7.35－7.39 (m, 1H), 7.42 (d, J＝8.5
Chin. J. Chem. 2013, 31, 173—181
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Table 1 The fungicidal activities of compound B (Concentration: 50 μg/mL)
Thanatephorus
cucumeris
(Frank) Donk
Alternaria Gibberella Phytophthora Sclerotinia
Botrytis cine-
Phytophthora
capsici
R1
R2
R3
solani
zeae
infestans
sclerotiorum rea
B1 2-Cl
B2 2-Cl
B3 3-Cl
B4 3-Cl
B5 3-Cl
B6 4-Cl
B7 4-Cl
B8 4-Cl
2-Cl
4-Cl
2-Cl
4-Cl
CH3 23.1
CH3 23.1
CH3 38.5
CH3 26.9
22.2
11.1
36.6
12.2
27.3
36.6
24.4
27.3
31.7
24.4
39.0
24.4
4.5
17.6
11.8
22.2
3.7
16.4
24.6
63.4
21.1
40.8
81.7
14.1
39.5
49.3
35.2
56.3
21.1
39.5
46.1
35.2
28.2
32.8
16.4
57.4
24.6
9.2
14.3
19.0
26.8
17.9
13.7
32.1
26.8
33.3
26.8
17.9
37.5
26.8
23.5
35.3
26.8
17.9
9.5
57.1
57.1
12.7
8.5
12.5
20.8
22.2
27.8
21.4
27.8
36.1
14.3
33.3
27.8
13.9
27.8
28.6
10.7
13.9
27.8
12.5
20.8
25.0
16.7
25.0
21.4
25.0
17.9
14.3
17.9
21.4
14.3
25.0
17.9
2,4-Cl2 CH3 35.7
17.6
29.6
7.4
21.7
14.1
7.0
2-Cl
4-Cl
CH3 46.2
CH3 30.8
4-CH3 CH3 42.9
23.5
3.7
41.3
7.0
B9 2,4-Cl2 2-Cl
B10 2,4-Cl2 4-Cl
CH3 26.9
CH3 26.9
CH3 53.8
CH3 26.9
3.7
7.0
B11 3-F
B12 3-F
B13 3-F
B14 3-F
B15 4-F
B16 4-F
2-Cl
4-Cl
25.9
3.7
9.9
7.0
2,4-Cl2 CH3 35.7
4-CH3 CH3 35.7
35.3
35.3
14.8
3.7
26.1
32.6
0.0
31.8
29.3
14.6
0.0
2-Cl
4-Cl
CH3 34.6
CH3 19.2
CH3 15.4
CH3 23.1
CH3 30.8
CH3 15.4
4.2
B17 4-OCH3 2-Cl
B18 4-OCH3 4-Cl
17.6
11.8
29.4
11.8
11.8
29.4
17.6
17.6
5.9
57.1
14.3
60.7
42.9
17.4
28.3
21.7
21.7
10.9
8.7
5.6
19.0
47.6
19.0
13.7
29.4
25.5
15.7
25.5
23.5
13.7
15.7
32.6
13.7
B19 3-CF3
B20 3-CF3
B21 3-CF3
B22 3-Cl
B23 3-Cl
B24 3-Cl
B25 4-Cl
B26 3-F
2-Cl
4-Cl
16.7
11.1
13.6
27.3
18.2
27.3
27.3
27.3
27.3
4.5
4-CH3 CH3 35.7
2-Cl
H
H
H
H
H
H
H
H
H
28.6
14.3
14.3
21.4
35.7
21.4
28.6
38.5
35.7
72.4
13.2
13.2
11.8
4-Cl
2,4-Cl2
4-CH3
2-Cl
23.5
11.8
5.9
85.5
B27 3-F
4-Cl
10.5
11.8
31.0
13.2
21.7
21.7
22.7
10.9
B28 3-F
2,4-Cl2
4-CH3
4-CH3
B29 3-F
18.8
13.6
33.3
5.9
B30 3-CF3
before being placed on a filter paper in a 6-cm Petri
plate, to which 2 mL of inhibitor solution had been
added in advance. Usually, 15 seeds were used on each
plate. The plate was placed in a dark room and allowed
to germinate for 65 h at 28 (±1) ℃. The lengths of 10
rape roots selected from each plate were measured and
the means were calculated. The percentage inhibition
was used to describe the control efficiency of the com-
pounds.
(2) The herbicidal activities of compounds B were
determined with Brassica campestris L and Echinochloa
crus-galli (L) Beauv as samples of annual dicotyledo-
nous and monocotyledonous plants, respectively, using
a previously reported procedure.[24-27] For all of the
bioassay tests, each treatment was repeated three times.
Treatment
The emulsions of compounds B were prepared by
dissolving them in 100 μL of N,N-dimethylformamide
with the addition of 2 μL Tween 20. The mixture of the
same amount of water, N,N-dimethylformamide, and
Tween 20 was used as control.
Inhibition of the seedling growth of barnyard grass
(Echinochloa crus-galli (L) Beauv)
Ten E. crus-galli seeds were placed into a 50-mL
cup covered with a layer of glass beads and a piece of
filter paper at the bottom, to which 5 mL of inhibitor
solution had been added in advance. The cup was placed
in a bright room and the seeds were allowed to germi-
Inhibition of the root-growth of rape (Brassica
campestris L)
Rape seeds were soaked in distilled water for 4 h
178
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Synthesis and Bioactivities of Novel N-(4-(2-Aryloxythiazol-5-yl)but-3-yn-2-yl)benzamides
nate for 65 h at 28 (±1) ℃. The heights of the
above-ground parts of the seedlings in each cup were
measured and the means calculated. The percentage in-
hibition was used to describe the control efficiency of
the compounds.
kcal/mol, same site as Tepraloxydim; compound 2 in
3H0J: rmsd＝0.615, ∆G＝−11.87 kcal/mol, same site as
CP-640186). With grid spacing 0.600 Å, compound
B26 was docked into pdb 1UYR. The first three docking
conformation clusters were selected as positive docking
conformation. In first docking cluster, B26 was binding
near the binding site of haloxyfop (Figure 3a), ∆G＝
−11.06 kcal/mol, this conformation suggested that B26
may be trapped in a hydrophobic area; In the second
docking conformation cluster, B26 was binding in the
binding site of haloxyfop (Figure 3b), ∆G＝−10.49
kcal/mol; The third docking conformation cluster shows
that B26 was binding near the binding site of
CP-640186, again trapped in a hydrophobic area with
∆G＝−9.10 kcal/mol (Figure 3c).
In the first docking conformation, B26 was docked
in a hydrophobic site with two hydrophobic zones, con-
structed by residues VAL1733-ILE1735-VAL2001, ILE
1593-ILE2033. In the second docking conformation,
B26 was docked in haloxyftop binding site, which was
constructed by residues LEU1738-TYR1756-PHE1956-
VAL1967-VAL2002, VAL1733-LEU2025. In the third
docking conformation, B26 was docked in another hy-
drophobic site, construct by residues LEU1756-
ILE1762-PHE1956, LEU1777-ILE1782-ILE1903.
The herbicidal activities were summarized in Table
2.
Table 2 Herbicidal activity of compounds B (I/%; concentration:
100 μg/mL)
B. campestris E. crus-galli
B. campestris E. crus-galli
B1 53.3
0
B16 0
0
B3 33.4
B5 6.6
B6 57.3
B10 18.3
B11 70.2
B12 0
0
B17 27.1
B18 0
10.0
52.8
44.5
30.0
20.0
15.0
10.0
10.0
25.0
5.0
5.0
10.0
15.0
5.0
10.0
B19 32.1
B22 20.6
B23 16.9
B25 55.4
B26 29.2
B27 10.3
B13 0
B15 57.7
Results and Discussion
Molecular docking
Synthesis
Autodock 4.2 was used for molecular docking. We
re-docked the cocrystal ligands of three ACCs complex
(pdb ID: 1UYR, 3H0J, 3PGQ) as training set to get ra-
tional docking parameters. Docking experiments were
performed in four sets with different grid spacing: 0.375
Å, 0.500 Å, 0.600 Å, 0.700 Å. Number of points in each
dimension was set to 126. In each set, grid center was
moved for several times to make sure that we got the
atomic potential grid of hole protein. Docking simula-
tions were done using the Lamarckian genetic algorithm
with: GA runs＝100, Population Size＝200, Quaternion
＝30.0°, Torsion＝30.0°. Other parameters are set to
default.[28]
Each ligand can be well re-docked into their own
cocrystal protein with grid spacing 0.375 Å and grid box
size 18.75 Å×18.75 Å×18.75 Å. However, when all
three ligands were docked into 1UYR with grid spacing
0.375 Å and grid box covering all protein, many false
positive results were gotten. Docking with other two
protein conformations in pdb 3HOJ and 3PGQ, the same
results were gotten. In order to minimize false positive,
docking experiments were done with different grid
spacing. After re-dock training, best results could be
gotten with grid spacing 0.600 Å, which meant that with
grid spacing 0.600 Å, all crystal ligands were docked to
their own binding sites with docking conformation in
first cluster (cluster was sorted by binding energy) and
these docking conformations were very similar with
their crystal conformations (the rmsd between docking
conformation and crystal conformation was less than
one: diclofop: rmsd＝0.414, ∆G＝−9.07 kcal/mol, same
site as haloxyfop; pinoxaden: rmsd＝0.509, ∆G＝−8.83
Since 2-(but-3-yn-2-yl)isoindoline-1,3-dione had
similar solubility in petroleum ether or ethyl ether with
triphenylphosphine oxide, it was not easy to be sepa-
rated from the reaction mixture. Crude 2-(but-3-yn-2-
yl)isoindoline-1,3-dione with little triphenylphosphine
oxide was firstly extracted with petroleum ether (30－
60 ℃) by Soxhlet extractor and then it was purified by
flash column chromatography on silica gel, using ethyl
acetate-petroleum ether as the eluent.
Because but-3-yn-2-amine shared lower boiling
point, it was transformed to crude but-3-yn-2-amine
hydrochloride used for next step without further purifi-
cation. The crude product was transformed into D1－D4
by reacting with aroyl chloride at the presence of
triethylamine (Scheme 1).[29,30]
When the ratios of Pd(PPh3)2Cl2 and CuI to D were
decreased from 5% and 2%[31] to 0.5% and 0.2% respec-
tively, Sonogashira coupling of C and D was proceeded
smoothly and the B’s yields were not influenced sig-
nificantly.
Structure-activity relationships
As shown in Table 1, many compounds presented
moderate fungicidal activities at 50 µg/mL (Table 1),
but the result was not satisfying. In order to explore the
reason, B26’s crystal structure was determined[32] (Fig-
ure 3d) and it was docked into the binding pocket of the
crystal structures of the CT domain of yeast ACC’s
complex with diclofop (pdb ID: 1UYR). The docking
result indicated B26 had similar interaction with the CT
domain of 1UYR as A1, haloxyfop and tepraloxydim,
Chin. J. Chem. 2013, 31, 173—181
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179

Zhu et al.
FULL PAPER
Figure 3 (a) The binding position of B26 close to the binding position of inhibitor diclofop; (b) docking model of B26 with the CT do-
main of yeast ACC; (c) the binding position of B26 close to the binding position of inhibitor CP-640186; (d) the crystal structure of com-
pound B26; (e) three binding position of B26, the orange one is the ideal binding position, the blue and yellow represent other two possi-
ble binding positions, the grids show the binding positions of two co-crystal inhibitors.
but it could not explain the reason why compound B did
not show excellent fungicidal activities. However, when
compound B26 was docked into 1UYR with grid spac-
ing 0.600 Å and box size 75.6 Å×75.6 Å×75.6 Å
which covers most part of protein to detect binding po-
sition, it was observed that B26 adopted three clusters
positive docking conformations (Figure 3e) and only
part of B26 was located in the binding pocket. Further
analysis demonstrated that two aryl groups for each
positive docking conformation bound with two hydro-
phobic areas (constructed by VAL2001 and ILE1735,
ILE2033 and ILE1593 in Figure 3a; constructed by
LEU1756 and ILE1762, ILE1782 and ILE1903 and a
hydrogen bond with PHE1956 in Figure 3c). From this,
it suggested that molecules of B26 may be trapped by
the two hydrophobic areas mentioned above before they
got to the binding site of the CT domain. In further, this
improper interaction with the CT domain leads to the
lower fungicidal activities of B1－B30 and may be the
reason why B1－B30 did not possess good herbicidal
activities against B. campestris and E. crus-galli (Table
2).
observed bioactivity by molecular docking analysis.
This would provide a possible way for further structure
optimization. Further investigation on lead optimization
and fungicidal activities for the compounds is underway
in our group.
Acknowledgement
We are grateful for financial support by the National
Basic Research Program of China (973 Program) (No.
2010CB126103), the National Natural Science Founda-
tion of China (Nos. 20772066, 21072108) and the Na-
tional Key Technologies R&D Program (No.
2011BAE06B05-3).
References
[1] Burton, J. D.; Gronwald, J. W.; Keith, R. A.; Somers, D. A.; Gen-
genbach, B. G.; Wyse, D. L. Pestic. Biochem. Physiol. 1991, 39,
100.
[2] Rendina, A. R.; Felts, J. M. Plant Physiol. 1998, 86, 983.
[3] Egli, M. A.; Gengenbach, B. G.; Gronwald, J. W.; Somers, D. A.;
Wyse, D. L. Plant Physiol. 1993, 101, 499.
[4] Wakil, S. J.; Stoops, J. K.; Joshi, V. C. Annu. Rev. Biochem. 1983,
52, 537.
Conclusions
[5] Tong, L. Cell Mol. Life Sci. 2005, 62, 1784.
In this paper, we provide a new chemical scaffold as
ACCase inhibitor and reasonable explanation for the
[6] Wakil, S. J.; Abu-Elheiga, L. A. J. Lipid Res. 2009, 50, S138.
[7] Gu, Y. G.; Weitzberg, M.; Clark, R. F.; Xu, X.; Li, Q.; Zhang, T.;
180
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 173—181

Synthesis and Bioactivities of Novel N-(4-(2-Aryloxythiazol-5-yl)but-3-yn-2-yl)benzamides
Hansen, T. M.; Liu, G.; Xin, Z.; Wang, X.; Wang, R.; McNally, T.;
Camp, H.; Beutel, B. A.; Sham, H. L. J. Med. Chem. 2006, 49, 3770.
[8] Clark, R. F.; Zhang, T.; Xin, Z.; Liu, G.; Wang, Y.; Hansen, T. M.;
Wang, X.; Wang, R.; Zhang, X.; Frevert, E. U.; Camp, H. S.; Beutel,
B. A.; Sham, H. L.; Gu, Y. G. Bioorg. Med. Chem. Lett. 2006, 16,
6078.
[Chem. Abstr. 1999, 131, 170272].
[20] Michelotti, E. L.; Young, D. H. US 5304572, 1994 [Chem. Abstr.
1994, 121, 76155].
[21] Gu, Y. G.; Weitzberg, M.; Xu, X.; Clark, R. F.; Zhang, T.; Li, Q.;
Hansen, T. M.; Sham, H.; Beutel, B. A.; Camp, H. S.; Wang, X. WO
2007095602, 2007 [Chem. Abstr. 2007, 147, 301162].
[22] Swithenbank, C.; McNulty, P. J.; Viste, K. L. J. Agric. Food Chem.
1971, 19, 417.
[9] Xiang, S.; Callaghan, M. M.; Watson, K. G.; Tong, L. Proc. Natl.
Acad. Sci. U. S. A. 2009, 106, 20723.
[10] Zhang, H.; Tweel, B.; Li, J.; Tong, L. Structure 2004, 12, 1683.
[11] Zhang, H.; Tweel, B.; Tong, L. Proc. Natl. Acad. Sci. U. S. A. 2004,
101, 5910.
[12] Harwood, H. J.; Petras, S. P.; Shelly, L. D.; Zaccaro, L. M.; Perry, D.
A.; Makowski, M. R.; Hargrove, D. M.; Martin, K. A.; Tracey, W.
R.; Chapman, J. G.; Magee, W. P.; Dalvie, D. K.; Soliman, V. F.;
Martin, W. H.; Mularski, C. J.; Eisenbeis, S. A. J. Biol. Chem. 2003,
278, 37099.
[13] Cheng, J.; Liu, G.; Zhang, J.; Xu, Z.; Tang, Y. J. Mol. Model. 2011,
17, 495.
[14] Zhu, X.-L.; Hao, G.-F.; Zhan, C.-G.; Yang, G.-F. J. Chem. Inf.
Model. 2009, 49, 1936.
[23] Tarun, K. C.; Prem, D. J. Agric. Food Chem. 2006, 54, 2129.
[24] Zhu, Y.-Q.; Zou, X.-M.; Hu, F.-Z.; Yao, C.-S.; Liu, B.; Li, Y.-H.;
Yang, H.-Z. J. Agric. Food Chem. 2005, 53, 9566.
[25] Zhu, Y.-Q.; Liu, C.; Zhu, R.; Zhang, J.; Yuan, Y.-W.; Zou, X.-M.;
Hu, F.-Z.; Yang, H.-Z. Chin. J. Org. Chem. 2010, 30, 1088 (in
Chinese).
[26] Zhu, Y.-Q.; Zhu, R.; Yuan, Y.-W.; Zhang, J.; Zou, X.-M.; Hu, F.-Z.;
Yang, H.-Z. Chin. J. Org. Chem. 2010, 30, 1207 (in Chinese).
[27] Zhu, Y.-Q.; Wang, D.-Y.; Yuan, Y.-W.; Ma, Y.; Zou, X.-M.; Yang,
H.-Z. Chin. J. Org. Chem. 2012, DOI: 10.6023/cjoc201207004 (in
Chinese).
[28] Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W.
E.; Belew, R. K.; Olson, A. J. J. Comput. Chem. 1998, 19, 1639.
[29] Ma, S.; Wu, B.; Jiang, X. J. Org. Chem. 2005, 70, 2588.
[30] Roush, W. R.; Straub, J. A.; Brown, R. J. J. Org. Chem. 1987, 52,
5127.
[15] Zhu, X.-L.; Yang, G.-F. Curr. Computer-Aided Drug Design 2012, 8,
2.
[16] Zhu, X.-L.; Yang, W.-C.; Yu, N.-X.; Yang, S.-G.; Yang, G.-F. J.
Mol. Model. 2011, 17, 495.
[17] Zhu, X.-L.; Zhang, L.; Chen, Q.; Wan, J.; Yang, G.-F. J. Chem. Inf.
Model. 2006, 46, 1819.
[31] Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
[18] Oda, M.; Sasaki, N.; Sakaki, T.; Nonaka, N.; Yamagishi, K.; Tomita,
H. J. Pest Sci. (International Edition) 1992, 17, 91.
[19] Moloney, B. A.; Hardy, D.; Saville-Stones, E. A. WO 9942447, 1999
[32] The crystal structure has been deposited at the Cambridge Crystallo-
graphic Data Centre and allocated the deposition number: CCDC
902011.
(Cheng, F.)
Chin. J. Chem. 2013, 31, 173—181
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