Syntheses and herbicidal activity of new triazolopyrimidine-2-sulfonamides as acetohydroxyacid synthase inhibitor

Article abstract of DOI:10.1016/j.bmc.2010.06.015

The triazolopyrimidine-2-sulfonanilide, discovered from preparing bioisosteres of the sulfonylurea herbicides, is an important class of acetohydroxyacid synthase (AHAS, EC 4.1.3.18) inhibitors. At least over ten triazolopyrimidine sulfonanilides have been commercialized as herbicides for the control of broadleaf weeds and grass with cereal crop selectivity. Herein, a series of triazolopyrimidine-2-sulfonanilides were designed and synthesized with the aim of discovery of new herbicides with higher activity. The assay results of the inhibition activity of the synthesized compounds against Arabidopsis thatiana AHAS indicated that some compounds showed a little higher activity against flumetsulam (FS), the first commercial triazolopyrimidine-2- sulfonanilide-type herbicide. The k_i values of two promising compounds 3d and 8h are respectively, 1.61 and 1.29 μM, while that of FS is 1.85 μM. Computational simulation results indicated the ester group of compound 3d formed hydrogen bonds with the surrounding residues Arg'198 and Ser653, which accounts for its 11.5-folds higher AHAS inhibition activity than Y6610. Further green house assay showed that compound 3d has comparable herbicidal activity as FS. Even at the concentration of 37.5 g.ai/ha, 3d showed excellent herbicidal activity against Galium aparine, Cerastium arvense, Chenopodium album, Amaranthus retroflexus, and Rμmex acetasa, moderate herbicidal activity against Polygonum humifusum, Cyperus iria, and Eclipta prostrate. The combination of in vitro and in vivo assay indicated that 3d could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study.

Full text of DOI:10.1016/j.bmc.2010.06.015

Bioorganic & Medicinal Chemistry 18 (2010) 4897–4904
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Syntheses and herbicidal activity of new triazolopyrimidine-2-sulfonamides as
acetohydroxyacid synthase inhibitor
a,
Chao-Nan Chen a, Qiong Chen a, Yu-Chao Liu a, Xiao-Lei Zhu a, Cong-Wei Niu b, Zhen Xi b, , Guang-Fu Yang
*
*
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The triazolopyrimidine-2-sulfonanilide, discovered from preparing bioisosteres of the sulfonylurea herbi-
cides, is an important class of acetohydroxyacid synthase (AHAS, EC 4.1.3.18) inhibitors. At least over ten
triazolopyrimidine sulfonanilides have been commercialized as herbicides for the control of broadleaf
weeds and grass with cereal crop selectivity. Herein, a series of triazolopyrimidine-2-sulfonanilides were
designed and synthesized with the aim of discovery of new herbicides with higher activity. The assay
results of the inhibition activity of the synthesized compounds against Arabidopsis thatiana AHAS indi-
cated that some compounds showed a little higher activity against flumetsulam (FS), the first commercial
triazolopyrimidine-2-sulfonanilide-type herbicide. The ki values of two promising compounds 3d and 8h
Received 10 May 2010
Revised 3 June 2010
Accepted 4 June 2010
Available online 11 June 2010
Keywords:
1,2,4-Triazolopyrimidine-2-sulfonamide
Acetohydroxyacid synthase inhibitor
Herbicide
are respectively, 1.61 and 1.29 lM, while that of FS is 1.85 lM. Computational simulation results indi-
cated the ester group of compound 3d formed hydrogen bonds with the surrounding residues Arg’198
and Ser653, which accounts for its 11.5-folds higher AHAS inhibition activity than Y6610. Further green
house assay showed that compound 3d has comparable herbicidal activity as FS. Even at the concentra-
tion of 37.5 g.ai/ha, 3d showed excellent herbicidal activity against Galium aparine, Cerastium arvense,
Chenopodium album, Amaranthus retroflexus, and Rlmex acetasa, moderate herbicidal activity against
Polygonum humifusum, Cyperus iria, and Eclipta prostrate. The combination of in vitro and in vivo assay
indicated that 3d could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide
candidate for further study.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the trace residues of FS in soil will have adverse effect on the qual-
ity and yield of following crops.12,13
Triazolopyrimidine-2-sulfonamide is one of the most important
herbicidal groups targeting acetohydroxyacid synthase (AHAS, also
known as acetolactate synthase; EC 2.2.1.6, formerly EC 4.1.3.18),
which is known to catalyze the biosynthesis of branched-chain
amino acids including valine, leucine, and isoleucine.1–10 It has
been demonstrated that triazolopyrimidine-2-sulfonamides com-
peted with the amino acid leucine for binding to AHAS isolated
from cotton (Gossypium hirsutum).11 Up to now, at least seven
1,2,4-triazolopyrimidine-2-sulfonamide herbicides (Scheme 1)
are commercially available, including flumetsulam (FS),4 penoxsu-
lam,5 cloransulam,6 metosulam,7 florasulam,8 diclosulam,9 and
pyroxsulam,10 among which FS, N-2,6-difluorophenyl-5-methyl-
1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide, is the first product
extensively adopted in the control of broad-leaf weeds and grasses
in soya beans, peas and maize field. However, because of its high
herbicidal activity on broad-leaf plants and slow degradation rate,
Previously, with the aim to discover new triazolopyrimidine-2-
sulfonamide compounds with high herbicidal activity and faster
degradation rate in soil, we designed and synthesized a new herbi-
cidal compound, N-2,6-difluorophenyl-5-methoxy-1,2,4-triazol-
o[1,5-a]pyrimidine-2-sulfonamide (experimental code: Y6610,
Scheme 1).14 Because of the introduction of methoxy group rather
than the methyl group in FS, compound Y6610 had shorter half-life
in soil than FS. However, the enzymatic kinetic results indicated
that compound Y6610 has about 10-fold lower enzyme-inhibiting
activity (ki = 3.31 ꢀ 10ꢁ6 M, against Arabidopsis thaliana AHAS)
than FS, whose ki values against A. thaliana AHAS is 3.60 ꢀ 10ꢁ7 M.
Herein, we reported the further structural optimization of
Y6610 and the synthesis of 22 new triazolopyrimidine-2-sulfona-
mides. The in vitro enzyme inhibition and in vivo herbicidal activ-
ities assay indicated that some compounds displayed higher
enzyme inhibition activity than Y6610 and FS. Most interestingly,
these compounds with high enzyme inhibition activity also dis-
played excellent broad spectrum herbicidal activities at the dosage
of 37.5–150 g/ha.
* Corresponding author. Tel.: +86 27 67867800; fax: +86 27 67867141.
E-mail address: gfyang@mail.ccnu.edu.cn (G.-F. Yang).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.06.015

4898
C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
OCH3
Cl
OCH2CH3
F
Cl
Cl
N
N
N
N
N
N
N
N
N
SO2NH
SO2NH
MeOOC
SO2NH
N
N
H3C
N
F
F
F
Flumetsulam
SO2NH
Cloransulam
OCH3
diclosulam
OCH3
N
OCH3
N
F3C
F
Cl
Cl
CH3
N
N
N
N
N
N
N
N
SO2NH
SO2NH
N
H3CO
N
F2HCH2CO
F
OCH3
F
Florasulam
Metosulam
Penoxsulam
F
OCH3
H3CO
NHSO2
N
N
N
N
N
N
N
N
SO2NH
H3C
N
H3CO
F
F3C
Pyroxsulam
Y6610
Scheme 1. Chemical structure of commercial triazolopyrimidine herbicides and Y6610.
2.1.1. Date for 3a
2. Materials and methods
Yield: 30.2%; mp 211–213 °C; 1H NMR (600 MHz, DMSO-d6): d
4.04 (s, 3H, OCH3), 7.05 (d, 1H, J = 7.8 Hz, Het-H), 7.26–7.32 (m,
2H, Ar-H), 9.23 (d, 1H, J = 7.2 Hz, Het-H), 11.16 (s, 1H, NH); EI
MS: m/z (%) 360 ([M+1], 100), 359 (M+, 38.2), 358 ([Mꢁ1], 56.2),
276 (35.3), 120 (37.8), 100 (65.5), 91 (6.2). Anal. Calcd for
Unless otherwise noted, reagents were purchased from com-
mercial suppliers and used without further purification, as all sol-
vents were redistilled before use. 1H NMR spectra were recorded
on a Mercury-Plus 400 spectrometer in CDCl3 or DMSO with TMS
as the internal reference. MS spectra were determined using a
TraceMS 2000 organic mass spectrometer. Elemental analyses
were performed on a Vario EL III elemental analysis instrument.
Melting points were measured on a Buchi B-545 melting point
apparatus and are uncorrected. Intermediates 1 and 4 were synthe-
sized according to the existing methods.14–16
C12H8F3N5O3S: C, 40.12; H, 2.24; N, 19.49. Found: C, 40.39; H,
2.49; N, 19.74.
2.1.2. Date for 3b
Yeild: 40%; mp 206–207 °C; 1H NMR (600 MHz, DMSO-d6): d
4.04 (s, 3H, OCH3), 7.05 (d, 1H, J = 7.2 Hz, Het-H), 7.09–7.34 (m,
3H, Ar-H), 9.25 (d, 1H, J = 7.8 Hz, Het-H), 11.16 (s, 1H, NH); EI
MS: m/z (%) 342 ([M+1], 100), 341 (M+, 24.3), 340 ([Mꢁ1], 76.0),
276 (28.6), 257 (49.7), 149 (38.8), 126 (33.7), 120 (50.8), 100
(43.5), 91 (6.2). Anal. Calcd for C12H9F2N5O3S: C, 42.23; H, 2.66;
N, 20.52. Found: C, 42.24; H, 2.70; N, 20.35.
2.1. General procedure for the synthesis of compound 3
Chlorine was bubbled into a suspension of 1 (40 mmol) in
100 mL of methylene chloride and 50 mL of water cooled to
ꢁ1 °C. During the course of the addition the temperature of the
reaction mixture was maintained below 5 °C. After the reaction
finished by TLC detection, the organic layer was separated and
the aqueous layer was extracted twice with methylene chloride.
The combined organic phases were dried with MgSO4 and
evaporated at reduced pressure to obtain crude product, which
was used directly for the next step reaction without further
purification.
The starting substituted aniline (60 mmol) was dissolved in
100 mL of pyridine. Then, the above-obtained crude product in
100 mL of dichloromethane was added. The resulted reaction mix-
ture was stirred at room temperature and monitored by TLC. After
the reaction finished, the pyridine was removed by evaporation at
reduced pressure and the residue was treated with 200 mL of
NaOH (0.5 M) and 100 mL of dichloromethane. After filteration,
the aqueous layer was separated and acidified with HCl (3 M).
The precipitate which separated upon acidification was collected
by filtration and dried to give 5.2 g (25–40% overall yield from 1)
of the desired product as a yellow solid.
2.1.3. Date for 3c
Yeild: 30.8%; mp 217–218 °C; 1H NMR (600 MHz, DMSO-d6): d
4.03 (s, 3H, OCH3), 7.04 (d, 1H, J = 7.8 Hz, Het-H), 7.14 (t, 1H,
J = 7.8 Hz, Ar-H), 7.09–7.34 (m, 2H, Ar-H), 7.40 (t, 1H, J = 7.8 Hz,
Ar-H), 9.23 (d, 1H, J = 7.8 Hz, Het-H), 10.86 (s, 1H, NH); EI MS: m/
z (%) 323 (M, 100), 322 (95.9), 258 (45.9), 239 (64.2), 150 (53.7),
121 (14.6), 110 (67.4), 108 (80.1), 91 (6.3), 77 (6.3). Anal. Calcd
for C12H10FN5O3S: C, 44.58; H, 3.12; N, 21.66. Found: C, 44.93; H,
3.14; N, 21.20.
2.1.4. Date for 3d
Yeild: 33.8%; mp 224–225 °C; 1H NMR (600 MHz, DMSO-d6): d
3.67 (s, 3H, COOCH3), 4.03 (s, 3H, OCH3), 7.03 (d, 1H, J = 7.8 Hz,
Het-H), 7.46 (t, 1H, J = 7.8 Hz, Ar-H), 7.68–7.71 (m, 2H, Ar-H),
9.22 (d, 1H, J = 7.8 Hz, Het-H), 10.82 (s, 1H, NH); EI MS: m/z (%)
341 (100), 340 (95.7), 257 (63.9), 148 (51.5), 127 (42.6), 120
(30.6), 100 (79.8), 91 (11.3). Anal. Calcd for C12H10FN5O3S: C,
42.27; H, 3.04; N, 17.61. Found: C, 42.07; H, 3.12; N, 17.26.

C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
4899
2.1.5. Date for 3e
2.3.1. Date for 6a
Yeild: 47.0%; mp 280–281 °C; 1H NMR (600 MHz, DMSO-d6): d
4.01 (s, 3H, OCH3), 7.03 (d, 1H, J = 7.8 Hz, Het-H), 7.20 (d, 2H,
J = 8.4 Hz, Ar-H), 7.48 (d, 2H, J = 8.4 Hz, Ar-H), 9.22 (d, 1H,
J = 7.8 Hz, Het-H), 11.22 (s, 1H, NH); EI MS: m/z (%) 385 ([M+1],
90.4), 384 (M+, 100), 383 ([Mꢁ1], 99.3), 382 (81.7), 319 (30.5),
240 (26.0), 171 (64.5), 91 (31.3). Anal. Calcd for C12H10BrN5O3S:
C, 37.51; H, 2.62; N, 18.23. Found: C, 37.44; H, 2.76; N, 18.45.
1H NMR (400 MHz, CDCl3): d 2.30 (s, 3H), 2.63 (s, 3H), 4.55 (s,
2H), 6.89 (s, 1H), 7.22 (m, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.44 (d,
J = 7.8 Hz, 2H).
2.3.2. Date for 6b
1H NMR (400 MHz, CDCl3): d 2.68 (s, 3H), 4.55 (s, 2H), 6.93 (s,
1H), 7.22 (m, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H).
2.1.6. Date for 3f
2.3.3. Date for 6c
Yeild: 30.7%; mp 187–188 °C; 1H NMR (600 MHz, DMSO-d6): d
4.04 (s, 3H, OCH3), 7.06 (d, 1H, J = 7.8 Hz, Het-H), 7.35 (t, 1H,
J = 8.4 Hz, Ar-H), 7.45 (d, 1H, J = 7.8 Hz, Ar-H), 7.56 (d, 1H,
J = 8.4 Hz, Ar-H), 9.25 (d, 1H, J = 7.2 Hz, Het-H), 10.99 (s, 1H, NH);
EI MS: m/z (%) 374 (M+, 7.88), 373 (61.2), 372 (51.7), 323 (72.6),
322 (100), 259 (27.3), 258 (44.2), 149 (30.4), 109 (46.3), 91 (12),
77 (8.3). Anal. Calcd for C12H9Cl2N5O3S: C, 38.52; H, 2.42; N,
18.72. Found: C, 38.41; H, 2.04; N, 18.20.
1H NMR (400 MHz, CDCl3): d 2.35 (s, 3H), 2.63 (s, 3H), 4.55 (s,
2H), 7.24 (m, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H).
2.4. General procedure for the synthesis of compound 8
Chlorine was bubbled into a suspension of 6 (40 mmol) in
100 mL of methylene chloride, 50 mL of water cooled to ꢁ1 °C.
During the course of the addition the temperature of the reaction
mixture was kept under 5 °C. After the reaction finished by TLC
detection, the organic layer was separated and the aqueous layer
was extracted twice with methylene chloride. The combined or-
ganic phases were dried (MgSO4) and evaporated at reduced pres-
sure to obtain crude product 7, which was used for he next reaction
without further purification.
The starting substituted alinine (60 mmol) was dissolved in
100 mL of pyridine and the above suspension in 100 mL dichloro-
methane was added. The reaction mixture was stirred at room
temperature and monitored by TLC. The pyridine was removed by
evaporation at reduced pressure after the reaction finished, and
the residue was treated with 200 mL of NaOH (0.5 M) and dichloro-
methane (100 mL). The aqueous layer was separated by filtration
and acidified with 3 M HCl. The precipitate which separated upon
acidification was collected by filtration and dried to give 5.2 g
(25–40% overall yield from 6) of the desired product as a yellow
solid.
2.1.7. Date for 3g
Yeild: 34.0%; mp 177–178 °C; 1H NMR (600 MHz, DMSO-d6): d
4.04 (s, 3H, OCH3), 7.05 (d, 1H, J = 7.8 Hz, Het-H), 7.22 (t, 1H,
J = 7.8 Hz, Ar-H), 7.35 (t, 1H, J = 7.8 Hz, Ar-H), 7.41 (d, 1H, J = 7.2 Hz,
Ar-H), 7.65 (d, 1H, J = 7.2 Hz, Ar-H), 9.24 (d, 1H, J = 7.8 Hz, Het-H),
10.67 (s, 1H, NH); EI MS: m/z (%) 385 ([M+1], 10.9), 384 (M+, 19.3),
383 ([Mꢁ1], 16.3), 304 (88.7), 303 (100), 239 (9.3), 197 (15.9), 169
(18.8), 108 (12.3), 91 (20.8). Anal. Calcd for C12H10BrN5O3S: C,
37.51; H, 2.62; N, 18.23. Found: C, 37.81; H, 2.75; N, 18.49.
2.1.8. Date for 3h
Yeild: 28.5%; mp 222–223 °C; 1H NMR (600 MHz, DMSO-d6): d
4.01 (s, 3H, OCH3), 7.03 (d, 1H, J = 7.2 Hz, Het-H), 7.32–7.33 (m,
4H, Ar-H), 9.22 (d, 1H, J = 7.2 Hz, Het-H), 11.28 (s, 1H, NH); EI
MS: m/z (%) 390 ([M+1], 26.0), 389 (M+, 76.4), 388 ([Mꢁ1], 100),
324 (49.2), 255 (29.2), 175 (48.3), 148 (40.9), 91 (4.3), 77 (7.3).
Anal. Calcd for C13H10F3N5O4S: C, 40.11; H, 2.59; N, 17.99. Found:
C, 40.39; H, 2.82; N, 18.02.
2.4.1. Date for 8a
Yeild: 44.7%; mp 140–141 °C; 1H NMR (400 MHz, DMSO-d6): d
2.61 (s, 3H, CH3), 2.84 (s, 3H, CH3), 7.21–7.30 (m, 2H, Ar-H)),
11.25 (s, 1H, NH); EI MS: m/z (%) 393 ([M+2], 31), 391 (M+,
95), 367 (48), 145 (100), 119 (40). Anal. Calcd for
2.2. General procedure for the synthesis of intermediates 5
Compound 4 (0.086 mol), 15.5 mL of carbon disulfide (0.258 mol),
48 mL of triethylamine (0.344 mol), and 400 mL of ethanol were
mixed and heated to reflux with stirring for 2.5 h. After the resulted
mixture wascooled toambienttemperature, 16.4 g ofbenzyl chloride
(0.129 mol)wasthen added withstirring. The mixture was allowedto
react for additional 3 h. The volatiles were removed by evaporation
under reduced pressure and the residue was dissolved in methylene
chloride. The resulted solution was washed with water, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was triturated with hexane and filtered to obtain the crude
product 5 (mixed with trace 6). The obtained product was used for
next reaction without further purification.
C13H9ClF3N5O2S: C, 39.86; H, 2.32; N, 17.88. Found: C, 39.54; H,
2.55; N, 17.42.
2.4.2. Date for 8b
Yeild: 30.5%; mp 148–149 °C; 1H NMR (400 MHz, DMSO-d6): d
3.12 (s, 3H, CH3), 6.90–7.55 (m, 3H, Ar-H), 7.56 (s, 1H, Het-H),
8.05 (s, 1H, NH); EI MS: m/z (%) 393 (M+, 44), 265 (28), 161
(81), 152 (23), 149 (33), 128 (37), 101 (88), 64 (40), 54 (60), 51
(100). Anal. Calcd for C13H8F5N5O2S: C, 39.70; H, 2.05; N, 17.81.
Found: C, 40.13; H, 2.36; N, 17.39.
2.4.3. Date for 8c
2.3. General procedure for the synthesis of intermediates 6
Yeild: 29.5%; mp 185–186 °C; 1H NMR (400 MHz, CDCl3): d 2.66
(s, 3H, CH3), 2.92 (s, 3H, CH3), 7.03–7.54 (m, 4H, Ar-H)), 7.71 (s, 1H,
NH); EI MS: m/z (%) 357 ([M+2], 28), 355 (M+, 100), 291 (22), 110
(49), 83 (28). Anal. Calcd for C13H11ClFN5O2S: C, 43.89; H, 3.12;
N, 19.68. Found: C, 44.16; H, 3.59; N, 19.28.
A
solution of sodium methoxide in methanol (7.4 mL,
0.033 mol) was added to a solution of 19.9 g of 5 (ꢂ0.065 mol,
containing trace of 6) in 200 mL methanol at ambient temperature
with stirring and allowed to react for about 30 min. Then, acetic
acid (10 mL) was added and the volatiles were removed by evapo-
ration under reduced pressure. The residue was dissolved in meth-
ylene chloride and the resulting solution was washed with water,
dried over magnesium sulfate, and concentrated in vacuo. The res-
idue was triturated with hexane, filtered, and dried to obtain the
desired compounds 6.
2.4.4. Date for 8d
Yeild: 27.2%; mp 212–213 °C; 1H NMR (400 MHz, DMSO-d6): d
2.51 (s, 3H, CH3), 2.84 (s, 3H, CH3), 7.22–7.30 (m, 2H, Ar-H), 7.75
(s, 1H, Het-H), 11.13 (s, 1H, NH); EI MS: m/z (%) 357 (M+, 100),
274 (27), 146 (51). Anal. Calcd for C13H10F3N5O2S: C, 43.70; H,
2.82; N, 19.60. Found: C, 43.37; H, 2.99; N, 19.32.

4900
C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
2.4.5. Date for 8e
(m, 2H, Ar-H), 7.36 (s, 1H, Ar-H), 7.76 (s, 1H, Het-H), 10.69 (s, 1H,
NH); EI MS: m/z (%) 351 (M+, 5.0), 307 (9.4), 237 (9.3), 148
(48.7), 141 (61.5), 140 (100), 139 (67.3), 117 (42.2), 105 (89.5),
91 (25.3), 77 (71.0). Anal. Calcd for C14H14ClN5O2S: C, 47.80; H,
4.01; N, 19.91. Found: C, 48.09; H, 4.31; N, 19.80.
Yeild: 25.0%; mp 163–164 °C; 1H NMR (400 MHz, CDCl3): d 3.09
(s, 3H, CH3), 6.96–7.47 (m, 2H, Ar-H), 7.60 (s, 1H, Het-H), 8.06 (s,
1H, NH); EI MS: m/z (%) 411 (M+, 91), 391 (69), 390 (53), 318
(44), 290 (24), 261 (24), 209 (100), 161 (22), 146 (99), 101 (96),
91 (36), 72 (36), 70 (21), 45 (24), 42 (43). Anal. Calcd for
C
13H7F6N5O2S: C, 37.96; H, 1.72; N, 17.03. Found: C, 38.06; H,
2.4.14. Date for 8n
Yeild: 27.4%; mp 177–178 °C; 1H NMR (600 MHz, DMSO-d6): d
2.61 (s, 3H, CH3), 2.86 (s, 3H, CH3), 7.11–7.33 (m, 3H, Ar-H), 7.75
(s, 1H, Het-H), 11.28 (s, 1H, NH); EI MS: m/z (%) 340 ([M+1],
23.6), 339 (M+, 98.7), 338 ([Mꢁ1], 70.5), 274 (41.8), 255 (51.2),
181 (27.7), 148 (67.3), 127 (100), 100 (31.3), 69 (21.2), 57 (31.9).
Anal. Calcd for C13H11F2N5O2S: C, 46.02; H, 3.27; N, 20.64. Found:
C, 46.25; H, 3.49; N, 20.37.
1.65; N, 17.50.
2.4.6. Date for 8f
Yeild: 46.6%; mp 233–234 °C; 1H NMR (400 MHz, DMSO-d6): d
2.61 (s, 3H, CH3), 2.84 (s, 3H, CH3), 7.32–7.67 (m, 2H, Ar-H), 7.68
(m, 2H, Ar-H), 11.79 (s, 1H, NH); EI MS: m/z (%) 407 ([M+2], 4),
405 (M+, 9), 214 (10), 182 (13), 141 (12), 125 (11), 91 (100). Anal.
Calcd for C14H11ClF3N5O2S: C, 41.44; H, 2.73; N, 17.26. Found: C,
41.63; H, 2.46; N, 17.62.
2.4.15. X-ray diffraction analysis of 8e
Colorless blocks of 8e (0.20 ꢀ 0.10 ꢀ 0.10 mm) were counted
on a quartz fiber with protection oil. Cell dimensions and intensi-
ties were measured at 298 2 K on a Bruker SMART CCD area
2.4.7. Date for 8g
Yeild: 37.1%; mp 176–177 °C; 1H NMR (400 MHz, DMSO-d6): d
2.53 (s, 3H, CH3), 2.84 (s, 3H, CH3), 7.12–7.40 (m, 4H, Ar-H), 7.75
(s, 1H, Het-H), 10.96 (s, 1H, NH); EI MS: m/z (%) 321 (M+, 100),
257 (14), 109 (13). Anal. Calcd for C13H12FN5O2S: C, 48.59; H,
3.76; N, 21.79. Found: C, 48.81; H, 3.94; N, 21.96.
detector diffractometer with graphite monochromated Mo K
a
radiation (k = 0.71073 Å); hmax = 25.99; 12085 measured reflec-
tions; 3112 independent reflections (Rint = 0.0700) of which
2508 had I >2r(I). Data were corrected for Lorentz and polariza-
2.4.8. Date for 8h
tion effects and for absorption (Tmin = 0.8959; Tmax = 0.9944).
The structure was solved by direct methods using SHELXS-
2001,17 all other calculations were performed with Bruker SAINT
System and Bruker SMART programs.18 Full-matrix least-squares
Yeild: 39.6%; Mp 209–210 °C; 1H NMR (400 MHz, DMSO-d6): d
2.65 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.64 (s, 3H, CH3), 7.46–7.72
(m, 3H, Ar-H), 11.09 (s, 1H, NH); EI MS: m/z (%) 431 ([M+2]+, 23),
430 ([M+1]+, 35), 405 (M+, 69), 394 (100), 362 (36), 333 (33), 308
(29), 153 (29). Anal. Calcd for C15H13Cl2N5O4S: C, 41.87; H, 3.05;
N, 16.28. Found: C, 42.20; H, 2.92; N, 16.26.
refinement based on F2 using the weight of 1/[
r
2(Fo2) +
R =
0.1697, and GOF(F) = 0.583. Hydrogen atoms were observed and
(0.0849P)2 + 0.0555P] gave final values of R = 0.0654,
x
refined with
parameter.
a fixed value of their isotropic displacement
2.4.9. Date for 8i
Yeild: 43.5%; mp 151–152 °C; 1H NMR (400 MHz, DMSO-d6): d
2.96 (s, 3H, CH3), 7.13–7.36 (m, 4H, Ar-H), 8.64 (s, 1H, Het-H),
11.12 (s, 1H, NH); EI MS: m/z (%) 376 ([M+1]+, 11), 375 (M+, 100),
110 (70), 82 (30). Anal. Calcd for C13H9F4N5O2S: C, 41.60; H, 2.42;
N, 18.66. Found: C, 41.99; H, 2.35; N, 18.97.
2.5. Determination of ki value against A. thaliana AHAS
he expression and purification of wild-type A. thaliana AHAS was
performed as described in existing method.19,20 During purification
of AHAS, the inhibitory activities of the synthesized compounds
against wild-type A. thaliana AHAS activity was assayed using the
colorimetric method of Singh et al. exactly as described previously.20
The optimized assay contained pyruvate (100 mM), ThDP (1 mM),
2.4.10. Date for 8j
Yeild: 26.4%; mp 241–242 °C; 1H NMR (400 MHz, DMSO-d6): d
2.97 (s, 3H, CH3), 7.36–7.53 (m, 3H, Ar-H), 8.65 (s, 1H, Het-H),
11.20 (s, 1H, NH); EI MS: m/z (%) 426 ([M+1]+, 11), 425 (M+, 33),
392 (84), 390 (96), 389 (100), 162 (40), 160 (82). Anal. Calcd for
MgCl2 (10 mM), and FAD (10 lM) in 50 mM of potassium phosphate
buffer at pH 7.5. The DMSO solutions of different concentrations of
compounds were used for the assay. The final amount of DMSO in
the assay mixture was kept under four percent so that the effect of
DMSO on the reaction can be ignored. After pre-incubation at room
temperature for 5 min, the reaction was initiated by the addition of
AHAS enzyme. Then, after incubation at 37 °C for 1 h, the reaction
was stopped by the addition of sufficient H2SO4 (3 M). Upon incuba-
tion at 60 °C for 15 min, the enzymatic product of AHAS activity, 2-
acetolactate, is converted to acetoin. Acetoin was then quantified by
further incubation at 60 °C for 15 min in the presence of 0.5% crea-
C
13H8Cl2F3N5O2S: C, 36.64; H, 1.89; N, 16.43. Found: C, 36.99; H,
1.53; N, 16.78.
2.4.11. Date for 8k
Yeild: 26.1%; mp 148–149 °C; 1H NMR (400 MHz, CDCl3): d 3.11
(s, 3H, CH3), 6.80–8.03 (m, 3H, Ar-H), 7.58 (s, 1H, Het-H), 8.04 (s,
1H, NH); EI MS: m/z (%) 393 (M+, 100), 308 (22), 161 (22), 128
(61), 101 (28). Anal. Calcd for C13H8F5N5O2S: C, 39.70; H, 2.05; N,
17.81. Found: C, 40.12; H, 1.97; N, 18.25.
tine and 0.5%
the data to equation:
a
-naphthol. The kai pp values were determined by fitting
2.4.12. Date for 8l
Yeild: 25.5%; mp 165–166 °C; 1H NMR (600 MHz, DMSO-d6): d
2.60 (s, 3H, CH3), 2.97 (s, 3H, CH3), 7.41 (s, 1H, Het-H), 7.51 (d,
1H, J = 8.4 Hz, Ar-H), 7.62 (s, 1H, Ar-H), 7.51 (d, 1H, J = 9.0 Hz, Ar-
H), 10.04 (s, 1H, NH); EI MS: m/z (%) 406 ([M+1], 12.5), 405 (M+,
25.4), 404 ([Mꢁ1], 22.5), 370 (100), 369 (87.0), 305 (14.9), 195
(24.3), 148 (23.0), 106 (29.6), 91 (5.85). Anal. Calcd for
mi
¼
m1 þ ðm0
ꢁ
m1Þ=ð1 þ ½Iꢃ=kapp
Þ
i
In this equation, mi and m0 represent the rates in the presence or
absence of the test compound, respectively, and [I] is the concen-
tration of the compound. The kai pp is apparent inhibition constant,
that is, the concentration of inhibitor giving 50% inhibition. If the
initial analysis indicated that the residual activity (m1) at a saturat-
ing inhibitor concentration is not significantly greater than zero,
C14H11ClF3N5O2S: C, 41.44; H, 2.73; N, 17.26. Found: C, 41.12; H,
2.67; N, 17.05.
the data reanalyzed with the m1 = 0. kapp was calculated by non-
2.4.13. Date for 8m
i
Yeild: 29.2%; mp 178–179 °C; 1H NMR (600 MHz, DMSO-d6): d
2.19 (s, 3H, CH3), 2.54 (s, 3H, CH3), 3.35 (s, 3H, CH3), 7.21–7.25
linear least-squares and the Simplex method for error
minimization.

C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
4901
2.6. Herbicidal activities assay
was evaluated visually 15 days post treatment. The results of her-
bicidal activities were shown in Tables 1 and 2.
The herbicidal activities of all target compounds against Echino-
chloa crusgalli, Digiatria sanguinalis, Poa annua, Brassica juncea, Ama-
ranthus retroflexus, Eclipta prostrate, Galium aparine, Cerastium
arvense, Polygonum humifusum, Cyperus iria, Chenopodium album,
3. Results and discussion
3.1. Synthetic chemistry of the title compounds
and Rlmex acetasa were evaluated according to a previously re-
ported procedure,14,21–23 Y6610 and FS were selected as a control.
All test compounds were formulated as a 100 g/L emulsified con-
centrates by using DMF as solvent and TW-80 as emulsification re-
agent. The concentrates were diluted with water to the required
concentration and applied to pot-grown plants in a greenhouse.
The soil used was a clay soil, pH 6.5, 1.6% organic matter, 37.3% clay
particles, and CEC 12.1 mol/kg. The rate of application (g.ai/ha) was
calculated by the total amount of active ingredient in the formula-
tion divided by the surface area of the pot. Plastic pots with a diam-
All the title compounds were synthesized according to two dif-
ferent routes showed in Scheme 2. In route A, the starting mate-
rial 1, prepared readily from 3-amino-5-benzylthio-1,2,4-triazole
according to the method as described previously,14 was chloro-
sulfonylated by chlorine to afford 5-methoxy-1,2,4-triazolo[1,5-
a]pyrimidine-2-sulfonyl chloride 2. Without purification, com-
pound 2 reacted with various aniline to afford the desired com-
pounds 3a–h in overall yields of 25–40% from compound 1. In
route B, cyclization of 4 with carbon disulfide afforded 3-benzyl-
thio-5,7,8-trisubstituted-1,2,4-triazolo[4,3-c]pyrimidines 5, which
was rearranged in the presence of sodium methoxide to the cor-
responding 2-benzylthio-1,2,4-triazolo[1,5-c]pyrimidines 6. Then,
6 reacted with chlorine gas under ice bath to afford the key inter-
mediate 7, which reacted subsequently with substituted anilines
using pyridine as base to yield the target compounds 8a–n
smoothly in overall yields of 25–45%. The structures of all inter-
mediates and target compounds were characterized by 1H NMR,
EI-MS spectral data and elemental analyses. In addition, the crys-
tal structure of 8e was determined by X-ray diffraction analysis.
As shown in Figure 1, the fused triazolopyrimidine system
eter of 9.5 cm were filled with soil to
a depth of 8 cm.
Approximately 20 seeds of E. crusgalli, D. sanguinalis, P. annua, B.
juncea, A. retroflexus, E. prostrate, G. aparine, C. arvense, P. humifusum,
C. iria, C. album and R. acetasa were sown in the soil at the depth of
1–3 cm and grown at 15–30 °C in a greenhouse. The diluted formu-
lation solutions were applied for post-emergence treatment, dicot-
yledon weeds were treated at the 2-leaf stage and monocotyledon
weeds were treated at the 1-leaf stage, respectively. The post-
emergence application rate was 150 g.ai/ha. Untreated seedlings
were used as the control group and the solvent (DMF) treated seed-
lings were used as the solvent control group. Herbicidal activity
Table 1
AHAS inhibition activities and herbicidal activities of compounds 3a–h and 8a–n
CH3
N
N
R
N
N
R
N
N
SO2NH
N
SO2NH
MeO
N
R1
R2
8
a~n
3
a~h
No.
R1
R2
R
kia
(l
M)
Post-emergenceb (150 g.ai/ha)
ECc
DS
PA
BJ
AR
EP
3a
3b
3c
3d
3e
3f
3g
3h
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Cl
H
Cl
H
H
Cl
H
Cl
H
H
H
H
H
H
/
3,4,5-F3
2,5-F2
2-F
2-Cl-6-COOMe
4-Br
2,3-Cl2
2-Br
4-OCF3
2,3,4-F3
2,6-F2
2-F
2,3,4-F3
2,3,4-F3
4-CF3
>1000
53.3
25.9
1.61
>1000
14.8
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ND
+
ꢁ
ꢁ
+
+
+++
ꢁ
+
ꢁ
+
+
+
++
+++
ꢁ
+++
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
++
++
ꢁ
++
++
ꢁ
22.6
+
>1000
>1000
70.6
ꢁ
ꢁ
+
CH3
CF3
CH3
CH3
CF3
CH3
CH3
CH3
CF3
CF3
CF3
CH3
CH3
CH3
/
ꢁ
ꢁ
++
+
++
+
25.8
+
>1000
>1000
>1000
27.7
1.29
569
ꢁ
ꢁ
ꢁ
+
+
+
+
+
+
+
++
+
ꢁ
ꢁ
2-F
+
2-Cl-6-COOMe
2-F
+++
+
+
+
2,6-Cl2
2,5-F2
2-Cl-4-CF3
2-CH3-5-Cl
2,5-F2
/
5.02
+++
ꢁ
+++
ꢁ
NDd
ꢁ
ꢁ
ꢁ
ꢁ
+++
+++
178
7.75
28.1
18.5
ꢁ
ꢁ
8m
8n
Y6610
FS
ꢁ
+
ꢁ
ꢁ
+++
+++
+++
+++
/
/
/
1.85
a
b
c
The ki values were determined against wild-type A. thaliana AHAS (EC 4.1.3.18).
EC for E. crusgalli, DS for D. sanguinalis, PA for P. annua, BJ for B. juncea, AR for A. retroflexus, and EP for E. prostrate.
Rating system for the growth inhibition percentage: +++ P 90%; ++ P 80%; +, 50–80%; ꢁ, <50%.
Not determined.
d

4902
C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
Table 2
Herbicidal spectrum of selected compounds (post-emergence)
No.
Dosageb (g.ai/ha)
GAa
PH
CAR
CI
CA
AR
RA
EP
3d
37.5
75
150
++
+++
+++
+
+
+
++
++
+++
+
+
+
++
+++
+++
++
++
++
++
++
++
+
++
+++
3f
37.5
75
150
+
+
+
+
+
+
ꢁ
ꢁ
ꢁ
+
+
+
ꢁ
ꢁ
ꢁ
+
+
++
+
+
+
+
+
+
3j
37.5
75
150
++
++
++
+
+
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
+
+
+
+
+
++
+
+
+
ꢁ
ꢁ
ꢁ
8b
8h
8j
37.5
75
150
+
++
++
ꢁ
ꢁ
+
+
+
+
ꢁ
ꢁ
ꢁ
+
+
+
++
++
+++
ꢁ
ꢁ
ꢁ
+
+
+
+
+
+
+
++
++
37.5
75
150
++
++
++
+
+
+
ꢁ
+
+
++
++
++
+
+
+
+
+
+
37.5
75
150
+
++
++
+
++
++
ꢁ
+
+
+
+
+
++
++
+++
ꢁ
ꢁ
ꢁ
++
++
++
+
+
+++
FS
37.5
75
150
+
+
++
++
+++
+++
+++
+++
+++
+
+
+
+
+++
+++
+++
+++
+++
+
+
++
+++
+++
+++
a
GA for G. aparine, PH for P. humifusum, CAR for C. arvense, CI for C. iria, CA for C. album, AR for A. retroflexus, RA for R. acetasa, and EP for E. prostrate.
Rating system for the growth inhibition percentage: +++ ꢄ 90%;++ ꢄ 80%; +, 50–80%; ꢁ, <50%.
b
Route A
R
N
N
3
N
N
N
N
N
N
N
b
a
SO2NH
SCH2Ph
SO2Cl
CH3O
N
CH3O
N
CH3O
N
1
2
Route B
CH3
N
CH3
CH3
SCH2Ph
N
N
N
N
N
N
c, d
N
N
SCH2Ph
e
R1
R1
N
R1
NHNH2
R2
R2
R2
4
6a: R1 = CH3, R2 = H;
6b: R1 = CF3, R2 = H;
6c: R1 = CH3, R2 = Cl.
5
f
CH3
CH3
N
R
N
N
g
N
N
N
N
SO2NH
SO2Cl
R1
N
R1
R2
R2
8
7a: R1 = CH3, R2 = H;
7b: R1 = CF3, R2 = H;
7c: R1 = CH3, R2 = Cl.
a: Cl2, CH2Cl2/H2O, 0-5ºC; b: RNH2, Py, CH2Cl2, rt; c: CS2 , NEt3, EtOH, reflux; d: PhCH2Br, rt; e:
CH3ONa, CH3OH, rt; f: Cl2, CH2Cl2/H2O, 0-5ºC; g: RNH2, Py, CH2Cl2, rt.
Scheme 2.

C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
4903
hydrogen bonds with residue Arg377 and one hydrogen bond with
residue Lys’256, but compound 3d formed two hydrogen bonds
with residue Arg377, one hydrogen bond with residue Lys’256,
and two additional hydrogen bonds with residues Arg’198 and
Ser653 due to the existence of ester group. Therefore, two addi-
tional hydrogen bonds should be the accounts for its 11.5-folds
higher binding affinity of compound 3d.
Besides, the series of 1,2,4-triazolo[1,5-c]pyrimidine 8a–n
showed very similar structure–activity relationships to 3a–h.
However, it should be pointed out that bulky and electron-with-
drawing substituents at position-2 and position-6 are more favor-
able for the enzyme inhibition activity. As for the substituent R1 of
compound 8a–n, CH3 rather than CF3 seems to be favorable. For
example, compound 8g (R1 = CH3, R2 = H, R = 2-F) showed higher
activity than 8i (R1 = CF3, R2 = H, R = 2-F). Besides, the effects of
R2 substituents on the enzyme inhibition activity seem not very
clear. Therefore, more derivatives bearing diverse substituents of
R2 need to be synthesized in the future to understand the struc-
ture–activity relationships.
Figure 1. Molecular structure of 8e.
(N2–N5/C7–C9) is close to planarity with a maximum deviation of
0.010 Å for C7. The dihedral angle between the triazolopyrimidine
system and the benzene ring (C1–C6) is 52.68°.
3.3. Greenhouse herbicidal activities
3.2. Inhibition activity against At AHAS
The post-emergence herbicidal activity of series 3 and 8 were
tested in greenhouse at the concentration of 150 g.ai/ha, FS was se-
lected as a positive control. As shown in Table 1, all the compounds
did not show obvious herbicidal activities against monocotyledon
weeds such as E. crusgalli, D. sanguinalis, and P. annua. In addition,
seven compounds (3a, 3e, 3h, 8a, 8d, 8e, and 8f) with ki values of
The ki values against A. thaliana AHAS of the synthesized
compounds 3a–h and 8a–p were listed in Table 1. FS and Y6610
were used as a positive control. As shown in Table 1, compounds
3d, 3f, 8h, 8j, and 8m showed higher enzyme inhibitory activity
than Y6610, among which compounds 3d (ki = 1.61
(ki = 1.29 M) exhibited a little higher enzyme inhibitory activity
than FS (ki = 1.85 M). In addition, structure–activity relationships
lM) and 8h
l
over 1000 lM against At AHAS did not display obvious herbicidal
l
activities against the tested weeds. Overall, the compounds with
higher enzyme inhibition activity showed higher herbicidal activ-
ity against dicotyledon weeds such as B. juncea, A. retroflexus, and
E. prostrate. For example, compound 3d with the highest enzyme
inhibition activity within the series of 1,2,4-triazolo[1,5-a]-pyrim-
idine displayed over 90% inhibition activity against B. juncea, A.
retroflexus, and E. prostrate at the dosage of 150 g ai/ha. Compound
8h with the highest enzyme inhibition activity and compound 8j
with the second-highest enzyme inhibition activity within the ser-
ies of 1,2,4-triazolo[1,5-c]pyrimidine showed good or excellent
herbicidal activity against B. juncea and E. prostrate at the dosage
of 150 g ai/ha. Therefore, in order to evaluate the potential of these
newly synthesized compounds, six compounds (3d, 3f, 3j, 8b, 8h,
8j,) having over 80% inhibition activity against at least two kinds
of weeds were selected for further test against eight dicotyledon
weeds such as G. aparine, P. humifusum, C. arvense, C. iria,
C. album, A. retroflexus, R. acetasa, and E. prostrate. As shown in
Table 2, 3d seems to be the most promising candidate. Even at
analysis indicated that the substitution position at benzene ring of
compounds 3 and 8 has significant effect on the enzyme inhibition
activity. For example, compounds 3a, 3e, 3h, 8a, 8d, 8e, 8f, and 8l
who bearing substituents at position-4 always showed very low
activity. On the contrary, compounds bearing substituents both
at position-2 and position-6 always showed higher activity. For
example, 3d (2-Cl-6-COOMe) is the most potent compound within
the series of 1,2,4-triazolo[1,5-a]-pyrimidine. In order to under-
stand why compound 3d showed 11.5-folds higher enzyme-inhib-
iting activity, we carried out molecular simulations by using the
same computational protocol as described previously.14 As shown
in Figure 2, the simulated models indicated that compound 3d
binds with A. thaliana AHAS in a similar mode to Y6610. Their triaz-
olopyrimidinyl moiety formed p–p stacking interactions with res-
idue Trp574, which made a great contribution to the binding free
energies. However, compared with the structure of AHAS-Y6610
complex, compound 3d formed stronger hydrogen-bonding inter-
actions with the enzyme. For example, Y6610 formed only two
Figure 2. The simulated binding models of 3d and Y6610 with A. thaliana AHAS.

4904
C.-N. Chen et al. / Bioorg. Med. Chem. 18 (2010) 4897–4904
the concentration of 37.5 g.ai/ha, 3d showed excellent herbicidal
activity with broad spectrum. Its inhibition effects against
G. aparine, C. arvense, C. album, A. retroflexus, and R. acetasa are over
80%. At the same time, 3d also displayed moderate herbicidal activ-
ity against P. humifusum, C. iria and E. prostrate at the concentration
of 37.5 g.ai/ha. In addition, compound 3d showed better herbicidal
activities against G. aparine, C. arvense, and R. acetasa than FS at the
concentration of 37.5 g.ai/ha. However, FS displayed higher herbi-
cidal activities against G. aparine, P. humifusum, and C. arvense than
P. humifusum, C. arvense, A. retroflexus, and E. prostrate at the con-
centration of 37.5 g.ai/ha. As for the weed of C. iria, 3d showed
the same level of herbicidal activity as FS.
In summary, a series of 1,2,4-triazolo[1,5-a]pyrimidine-2-sul-
fonamides and 1,2,4-triazolo[1,5-c]pyrimidine-2-sulfonamides
were designed and synthesized as potential AHAS inhibitors. The
results of in vitro and greenhouse test indicated that some com-
pounds showed good AHAS inhibition activity and herbicidal activ-
ities at the concentration of 150 g.ai/ha. Most interestingly, 3d,
methyl 3-chloro-2-(5-methoxy-1,2,4-triazolo[1,5-a]pyrimidine-2-
sulfonamido)benzoate, was identified as the most promising can-
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Acknowledgments
23. Jiang, L. L.; Tan, Y.; Zhu, X. L.; Wang, Z. F.; Zuo, Y.; Chen, Q.; Xi, Z.; Yang, G. F. J.
Agric. Food Chem. 2010, 58, 2643.
The research was supported in part by the National Basic Re-
search Program of China (No. 2010CB126103), the NSFC (Nos.
20925206, 20932005, and 20702018).