Design, syntheses and 3D-QSAR studies of novel N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2010.09.036

The characteristics of low application rates, good crop selectivity, low residue and environmental safety exhibited by Protoporphyrinogen oxidase (PPO, EC 1.3.3.4)-inhibiting herbicides have attracted a world-wide research interests. As continuation of ou

Full text of DOI:10.1016/j.bmc.2010.09.036

Bioorganic & Medicinal Chemistry 18 (2010) 7948–7956
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Bioorganic & Medicinal Chemistry
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Design, syntheses and 3D-QSAR studies of novel N-phenyl pyrrolidin-2-ones
and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase inhibitors
Li Zhang a, Yin Tan a, Neng-Xue Wang a, Qiong-You Wu a, Zhen Xi b, , Guang-Fu Yang a,
⇑
⇑
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 characteristics of low application rates, good crop selectivity, low residue and environmental safety
exhibited by Protoporphyrinogen oxidase (PPO, EC 1.3.3.4)-inhibiting herbicides have attracted a world-
wide research interests. As continuation of our research work on the development of new PPO inhibitors,
a series of mono-carbonyl analogues of cyclic imides, N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyr-
rol-2-ones, were designed and synthesized based on previously established DFT-QSAR results. The PPO
inhibition activities of 29 newly synthesized compounds were tested and a predictive comparative
molecular field analysis (CoMFA) model was established with the conventional correlation coefficient
Received 3 August 2010
Revised 14 September 2010
Accepted 15 September 2010
Available online 19 September 2010
Keywords:
Protoporphyrinogen oxidase
Herbicide
N-Phenyl pyrrolidin-2-one
N-Phenyl-1H-pyrrol-2-one
CoMFA
r
2 = 0.980 and the cross-validated coefficient q2 = 0.518. According to the CoMFA model, the substituent
effects on the PPO inhibition activity were explained reasonably. Further greenhouse assay showed that
2-(4-chloro-2-fluoro-5-propoxy-phenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C6, ki = 0.095 M) and
2-(5-allyloxy-4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C7, ki = 0.12 M) displayed
l
l
excellent post-emergency herbicidal activity at the concentration of 150 g.ai/ha against seven tested
weeds. Due to their high PPO inhibition effect and broad spectrum herbicidal activity, these two com-
pounds have the potential for further study on crop selectivity and field trial. These results confirmed
once again that only one of the carbonyl groups of cyclic imides is essential to the PPO inhibition activity.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
mides family (such as chlorphthalim) has led to discovery of some
commercialized products, such as oxadiargyl, oxadiazon, sulfent-
Protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4), the last com-
mon enzyme in the biosynthetic pathway leading to heme and
chlorophyll, has been identified as one of the most important
action targets for chemically diverse herbicides such as diphenyle-
thers,1 phenylpyrazoles,2 oxadiazoles,3 triazolinones,4 thiadiaz-
oles,5 pyrimidineones,6 oxazolidinediones,7 isoxazoles,8 and
N-phenyl phthalimides9 that have been introduced into market
for many years. The attributes of low application rates, good crop
selectivity, low residue and environmental safety exhibited by
these compounds are important characteristics for green agro-
chemicals. Therefore, PPO-inhibiting herbicides have achieved
great success in agriculture market and attracted a world-wide re-
search commitment.
razone, and pentoxazone as shown Figure 1. As well known, N-
phenyl phthalimides herbicides have a common structural feature
of N-2,4,5-trisubstituted phenylnitrogen. The substituents patterns
of phenyl group have been extensively investigated, but the role of
two carboxyl group in the PPO-inhibiting activity attracted little
attention.
Previously, we studied the quantitative structure–activity rela-
tionships of a series of cyclic imides (e.g., N-phenyl-1H-isoindole-
1,3(2H)-dione, A) with various heterocyclic rings and substituents
using the quantum chemical descriptors calculated at the B3LYP/6-
31G(d,p) level.13 Our DFT-QSAR results indicated that the approx-
imate nucleophilic superdelocalizability of the carbon atom of one
of the carbonyl group played an important role in determining the
activity of PPO inhibitors. The stronger the ability of the carbonyl
group to accept electrons from receptor, the higher the activity of
PPO inhibitor. These results indicated that only one of the carbonyl
groups is essential for the activity. Therefore, as a continuation of
our research work on the development of new PPO inhibitors,14,15
we are very interested in design and syntheses of N-phenyl pyrroli-
din-2-ones (B) and N-phenyl-1H-pyrrol-2-ones (C and D) and as
shown in Figure 2. As a control, three N-phenyl-1H-isoindole-
1,3(2H)-diones (A) were also synthesized. In the present work,
Since 1990s, research on PPO inhibitors has been actively pur-
sued, leading to two classes of commercial products, diphenyl
ethers and N-phenyl phthalimides, especially the latter which
has become a very interesting and hot research area.9–12 Structural
optimization of the pioneering compounds of N-phenyl phthali-
⇑
Corresponding authors. Tel.: +86 27 67867800; fax: +86 27 67867141 (G.-F.Y.).
E-mail addresses: gfyang@mail.ccnu.edu.cn, gfyang2010@yahoo.cn (G.-F. Yang).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.09.036

L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
7949
O
O
Cl
Cl
O
O
Cl
N
Cl
N
N
N
O
O
O
Cl
N
Oxadiargyl
F
Oxadiazon
O
F
O
O
Cl
Chlorphthalim
N
F
Cl
N
Cl
N
O
N
O
O
NH
CH3SO2
Sulfentrazone
Pentoxazone
Figure 1. Structures of some commercial PPO inhibitors derived from chlorphthalim.
R1
R1
R1
R1
O
O
O
O
R2
N
R2
N
R2
N
R2
N
R4
OR5
R4
R4
R4
O
OR5
B
A
D
C
Figure 2. Structures of the designed compounds (B–D) and the control (A).
we report the detailed synthetic route, PPO-inhibiting activity and
herbicidal activities of series A–D. The obtained result indicated
that these compounds displayed good or excellent PPO inhibition
activity and promising herbicidal activity. In addition, the three-
dimensional quantitative structure–activity relationships of 29
newly synthesized compounds were also performed by using the
method of Comparative Molecular Field Analysis (CoMFA).
with ethyl acetate. The ethyl acetate phase was dried with MgSO4
and evaporated at reduced pressure to obtain crude product, which
was purified by column chromatography eluting with acetone/
petroleum.
2.1.1. Data for A1
Yield, 75%; white solid; mp 118–120 °C. 1H NMR (400 MHz,
CDCl3): d = 1.52–1.54 (m, 4H, 2 Â CHCH2CH2–), 1.81–1.94 (m, 4H,
2 Â CHCH2–), 3.07–3.09 (m, 2H, 2 Â COCH–), 3.88 (s, 3H, OCH3),
6.73 (d, J = 6.0 Hz, 1H, –C(F) = CH), 7.28 (d, J = 8.8 Hz, 1H, NC@CH);
EI-MS: m/z (%) 313 ([M+1]+, 19), 312 (M+, 17), 311 ([MÀ1]+, 100),
201 (80), 81 (46), 67 (51). Anal. Calcd for C15H15ClFNO3: C, 57.79;
H, 4.85; N, 4.49. Found: C, 57.81; H, 4.45; N, 4.39.
2. Materials and methods
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 (Variant Co., America) and
samples were dissolved in CDCl3 or DMSO with TMS as the internal
reference. MS spectra were determined using a TraceMS 2000 or-
ganic mass spectrometer (Finnigan Co., America) and signals were
recorded in m/z. Elemental analyses were performed on a Vario EL
III elemental analysis instrument (Elementar Co., Germany). Melt-
ing points were measured on a Buchi B-545 melting point appara-
tus and are uncorrected. The starting material M1 and M2 were
prepared according to the existing methods,16,17 the intermediate
M3 was prepared by applying the same procedure as the synthesis
of compound A. The inhibition activity (ki) of all target compounds
against human PPO was tested as described previously,14 4-chlor-
ophthalimide and sulfentrazone were selected as control. In
Table 1, pki is the negative logarithm of ki value.
2.1.2. Data for A2
Yield, 85%; yellow oil; 1H NMR (400 MHz, CDCl3): d = 1.31–1.32
(m, 3H, –CH2CH3), 1.45–1.58 (m, 4H, 2 Â CHCH2CH2–), 1.82–1.95
(m, 4H, 2 Â CHCH2–), 3.07–3.09 (m, 2H, 2 Â COCH–), 4.28–4.32
(m, 2H, –CH2CH3), 4.68 (s, 2H, –OCH2–), 6.76 (d, J = 6.4 Hz, 1H, –
C(F)@CH), 7.30 (d, J = 8.8 Hz, 1H, NC@CH); EI-MS: m/z (%) 385
([M+1]+, 28), 384 (M+, 25), 383 ([MÀ1]+, 60), 301 (62), 116 (97),
115 (61), 88 (52), 81 (71), 66(100), 60 (54), 57 (55), 54 (68), 45
(58), 41 (80). Anal. Calcd for C18H19ClFNO5: C, 56.33; H, 4.99; N,
3.65; Found: C, 56.07; H, 4.78; N, 3.19.
2.1.3. Data for A3
Yield, 88%; yellow oil; 1H NMR (400 MHz, CDCl3): d = 1.27–
1.28 (m, 3H, –CH2CH3), 1.51–1.52 (m, 4H, 2 Â CHCH2CH2–),
1.67 (d, J = 6.4 Hz, 3H, CHCH3), 1.85–1.95 (m, 4H, 2 Â CHCH2–),
3.06–3.08 (m, 2H, 2 Â COCH–), 4.19–4.24 (m, 2H, –CH2CH3),
4.70 (q, J = 6.8 Hz, 1H, CH), 6.77 (d, J = 6.4 Hz, 1H, –C (F)@CH),
7.30 (d, J = 9.2 Hz, 1H, NC@CH); EI-MS: m/z (%) 399 ([M+1]+,
28), 398 (M+, 0), 397 ([MÀ1]+, 98), 324 (97), 297 (88), 187
(55), 104 (90), 77 (72), 72 (100), 43 (91). Anal. Calcd for
2.1. General procedure for the synthesis of compound A1–3
A mixture of intermediate M1 (5 mmol), anhydrous K2CO3
(7.5 mmol) in anhydrous N,N-dimethylformamide (DMF) was stir-
red for 0.5 h at room temperature and R3X (10 mmol) was added.
The resulted solution was stirred at room temperature until the
reaction was completed according to the TLC detection. The reac-
tion solution was poured into water. The product was extracted
C19H21ClFNO5: C, 57.36; H, 5.32; N, 3.52. Found: C, 57.07; H,
5.22; N, 3.37.

7950
L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
Table 1
Structures and PPO-inhibiting activities of the title compounds
R1
R1
R1
R1
O
O
O
O
R2
N
R2
N
R2
N
R2
N
R4
OR5
R4
R4
R4
O
OR5
B
A
D
C
Training set
No.
R1
R2
R4
R5
ki (
lM)
pki(exp)
pki(cal)
A1
A2
A3
F
F
F
Cl
Cl
Cl
OCH3
OCH2CO2C2H5
OCH(CH3)CO2C2H5
/
/
/
8.22
15.24
3.30
5.09
4.82
5.48
4.87
5.07
5.29
B1
F
Cl
O
H
24.64
4.61
4.58
B3
B4
B5
B6
B7
C1
C2
C4
C5
C6
C7
D1
D2
D4
D5
D6
D7
D8
D9
D10
F
F
F
F
F
F
H
F
Cl
F
F
F
F
Cl
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
OCH3
H
H
H
H
H
—
—
—
—
—
—
H
H
H
H
H
130.97
123.78
48.07
63.63
44.83
0.69
27.64
0.20
0.30
0.095
0.12
19.35
0.78
7.45
1.03
3.88
3.91
4.32
4.20
4.34
6.16
4.56
6.70
6.52
7.02
6.92
4.71
6.11
5.13
5.99
3.45
4.38
5.99
5.35
4.18
4.07
4.07
4.31
4.16
4.37
6.04
4.51
6.80
6.60
7.01
6.85
4.67
6.19
5.41
6.04
3.42
4.21
5.63
5.42
4.24
OCH2CO2C2H5
OCH(CH3)CO2C2H5
OCH2CCH
OCH2CHCH2
OCH(CH3)2
NH2
OCH2CH3
OCH2CH2CH3
OCH2CH2CH3
OCH2CHCH2
OH
3-F–C6H4CH2O
OCH2CHCH2
OCH2CHCH2
NO2
OCH2CH3
358.6
41.35
1.03
4.49
66.58
F
F
F
F
OH
CH2CHCH2
CH3
CH3
3-Cl–C6H4CH2O
OCH3
3-Cl–C6H4CH2O
CH2CHCH2
Test set
B2
C3
D3
D11
D12
F
Cl
F
F
F
Cl
Cl
Cl
Cl
Cl
OCH(CH3)2
OCH2CH3
3-Cl–C6H4CH2O
OCH2CHCH2
OCH2CH3
H
—
H
47.35
0.67
0.53
33.13
7.02
87.87
0.72
4.32
6.17
6.28
4.48
5.15
4.06
6.14
4.09
6.21
6.21
4.11
5.89
/
CH2CHCH2
CH2CHCH2
4-Chloro-phthalimide
Sulfentrazone
/
2.2. General procedure for the synthesis of compound B1–7
2.2.2. Data for B2
Yield, 88%; white solid; mp 151–153 °C. 1H NMR (400 MHz,
CDCl3): d = 1.24–1.26 (m, 4H, 2 Â CHCH2–), 1.36–1.37 (m, 6H,
2 Â CHCH3), 1.37–1.39 (m, 4H, 2 Â CHCH2–), 2.62–2.68 (m, 1H,
COCH), 2.98–3.00 (m, 1H, C(OH)CH), 4.46–4.50 (m, 1H, OCH),
5.12 (s, 1H, –(OH) CH), 7.05 (d, J = 6.8 Hz, 1H, –C(F)@CH), 7.22 (d,
J = 10.0 Hz, 1H, NC@CH); EI-MS: m/z (%) 343 ([M+1]+, 21), 342
(M+, 39), 341 ([MÀ1]+, 100), 323 (44), 299 (59), 161 (31). Anal.
Calcd for C17H21ClFNO3: C, 59.74; H, 6.19; N, 4.10. Found: C,
59.88; H, 6.08; N, 3.93.
A mixture of compound A (1 mmol) in anhydrous methanol was
stirred at room temperature. NaBH4 (1 mmol) was added portion
wise and the mixture was stirred for about 2 h. The reaction solu-
tion was poured into ice water (30 mL). Precipitated solids were fil-
tered and recrystallized from acetone or ethanol to give the pure
title compounds.
2.2.1. Data for B1
Yield, 95%; white solid; mp 157–158 °C. 1H NMR (400 MHz,
CDCl3): d = 1.21–1.64 (m, 8H, –OCHCH2CH2CH2–; COCHCH2-
CH2CH2–), 1.81–1.96 (m, 8H, 2 Â CHCH2–; 2 Â OCHCH2–),
2.14–2.19 (m, 1H, COCH), 2.34–2.38 (m, 1H, C (OH) CH), 4.72–
4.76 (m, 1H, OCH), 5.10 (s, 1H, –(OH)CH), 7.02 (d, J = 7.2 Hz, 1H,
–C(F)@CH), 7.18 (d, J = 6.0 Hz, 1H, NC@CH); EI-MS: m/z (%) 369
([M+1]+, 22), 368 (M+, 12), 367 ([MÀ1]+, 61), 301 (62), 299 (95),
281 (55), 189 (88), 187 (87), 161 (100), 93 (62), 41 (70). Anal. Calcd
for C19H23ClFNO3: C, 62.04; H, 6.30; N, 3.81. Found: C, 62.02; H,
6.01; N, 3.70.
2.2.3. Data for B3
Yield, 68%; white solid; mp 139–140 °C. 1H NMR (400 MHz,
CDCl3): d = 1.23–2.18 (m, 8H, –CH2CH2CH2CH2–), 2.38–2.39 (m,
1H, COCH), 2.99–3.00 (m, 1H, –CH(OH)CH–), 3.88 (s, 3H, OCH3),
5.11 (s, 1H, CH(OH), 7.01 (d, J = 6.8 Hz, 1H, –C(F)@CH), 7.43 (d,
J = 6.4 Hz, 1H, NC@CH); EI-MS: m/z (%) 315 ([M+1]+, 12), 314 (M+,
21), 313 ([MÀ1]+, 49), 176 (36), 175 (99), 174 (100), 81 (37). Anal.
Calcd for C15H17ClFNO3: C, 57.42; H, 5.46; N, 4.46. Found: C, 57.36;
H, 5.23; N, 4.25.

L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
7951
2.2.4. Data for B4
2.3.2. Data for C2
Yield, 70%; white solid; mp 154–156 °C. 1H NMR (400 MHz,
CDCl3): d = 1.24–1.28 (m, 3H, CH2CH3), 1.57–2.12 (m, 8H, –
CH2CH2CH2CH2–), 2.34–2.39 (m, 1H, COCH), 2.96–2.98 (m, 1H, –
CH(OH)CH–), 3.81 (s, 2H, OCH2), 4.67–4.69 (m, 2H, CH2CH3), 5.09
(s, 1H, CH(OH), 7.01 (d, J = 4.4 Hz, 1H, –C(F)@CH), 7.43 (d,
J = 10.4 Hz, 1H, NC@CH); EI-MS: m/z (%) 386 ([M+1]+, 11), 385
(M+, 17), 384 ([MÀ1]+, 9), 370 (44), 261 (44), 259 (47), 233 (93),
231 (58), 93 (90), 90 (45), 81 (100), 67 (83), 66 (59), 57 (63), 54
(77), 41 (69). Anal. Calcd for C18H21ClFNO5: C, 56.04; H, 5.49; N,
3.63. Found: C, 55.93; H, 5.12; N, 3.57.
Yield, 85%; white solid; mp 102–104 °C. 1H NMR (400 MHz,
CDCl3): d = 1.75–1.80 (m, 4H, 5-CH2, 6-CH2), 2.28–2.34 (m, 4H, 4-
CH2, 7-CH2), 4.19 (s, 2H, 3-CH2), 6.75–6.98 (m, 3H, Ph). Anal. Calcd
for C14H15ClN2O: C, 64.00; H, 5.75; N, 10.66. Found: C, 64.50; H,
5.95; N, 10.65 .
2.3.3. Data for C3
Yield, 75%; white solid; mp 89–90 °C. 1H NMR (400 MHz,
CDCl3): d = 1.45 (t, 3H, J = 6.8 Hz, OCH2CH3), 1.75–1.81 (m, 4H, 5-
CH2, 6-CH2), 2.29–2.35 (m, 4H, 4-CH2, 7-CH2), 4.06 (q, 2H,
J = 10.4 Hz, OCH2CH3), 4.22 (s, 2H, 3-CH2), 6.92 (s, 1H, Ph), 7.45
(s, 1H, Ph). Anal. Calcd for C16H17Cl2NO2: C, 58.91; H, 5.25; N,
4.29. Found: C, 58.84; H, 5.14; N, 4.23.
2.2.5. Data for B5
Yield, 68%; white solid; mp 105–107 °C. 1H NMR (400 MHz,
CDCl3): d = 1.19–1.29 (m, 6H, CH2CH3 and CHCH3), 1.59–2.16
(m, 8H, –CH2CH2CH2CH2–), 2.35–2.37 (m, 1H, COCH), 2.96–2.98
(m, 1H, –CH(OH)CH–), 4.20–4.25 (m, 2H, –CH2CH3), 4.70–4.72
(m, 1H, OCHCH3), 5.05 (s,1H, CH (OH), 7.02 (d, J = 6.8 Hz, 1H,
–C(F)@CH), 7.43 (d, J = 10.0 Hz, 1H, NC@CH); EI-MS: m/z (%) 401
([M+1]+, 16), 399 ([MÀ1]+, 52), 161 (89), 95 (48), 93 (100), 91
(48), 81 (78), 79 (50), 55 (50). Anal. Calcd for C19H23ClFNO5: C,
57.07; H, 5.80; N, 3.50. Found: C, 56.90; H, 5.61; N, 3.24.
2.3.4. Data for C4
Yield, 74%; white solid; mp 90–92 °C. 1H NMR (400 MHz,
CDCl3): d = 1.45 (t, J = 6.8 Hz, 3H, OCH2CH3), 1.78–1.81 (m, 4H, 5-
CH2, 6-CH2), 2.28–2.35 (m, 4H, 4-CH2, 7-CH2), 4.08 (q, J = 10.4 Hz,
2H, OCH2CH3), 4.30 (s, 2H, 3-CH2), 7.16–7.43 (m, 2H, Ph). Anal.
Calcd for C16H17ClFNO2: C, 62.04; H, 5.53; N, 4.25. Found: C,
62.51; H, 5.64; N, 4.62.
2.3.5. Data for C5
2.2.6. Data for B6
Yield, 72%; white solid; mp 76–78 °C. 1H NMR (400 MHz,
CDCl3): d = 1.04 (t, J = 7.4 Hz, 3H, OCH2CH2CH3), 1.78–1.86 (m,
6H, OCH2CH2CH3, 5-CH2, 6-CH2), 2.30–2.35 (m, 4H, 4-CH2, 7-
CH2), 3.95 (t, J = 6.6 Hz, 2H, OCH2CH2CH3), 4.23 (s, 2H, 3-CH2),
6.91 (s, 1H, Ph) 7.45 (s, 1H, Ph). Anal. Calcd for C17H19Cl2NO2: C,
60.01; H, 5.63; N, 4.12. Found: C, 60.49; H, 5.25; N, 4.18.
Yield, 88%; white solid; mp 156–158 °C. 1H NMR (400 MHz,
CDCl3): d = 1.22–2.39 (m, 8H, –CH2CH2CH2CH2–), 2.58 (s, 1H,
„CH), 2.69–2.72 (m, 1H, COCH), 2.98–3.00 (m, 1H, –CH(OH)CH–
), 4.76 (s, 2H, –OCH2–), 5.11 (s, 1H, CH(OH), 7.20–7.24 (m, 2H,
ArH); EI-MS: m/z (%) 339 ([M+1]+, 17), 338 (M+, 27), 337
([MÀ1]+, 65), 94 (99), 79 (99), 66 (100), 60 (54), 53 (99). Anal. Calcd
for C17H17ClFNO3: C, 60.45; H, 5.07; N, 4.15. Found: C, 60.62; H,
4.89; N, 4.02.
2.3.6. Data for C6
Yield, 76%; white solid; mp 80–81 °C. 1H NMR (400 MHz,
CDCl3): d = 1.04 (t, J = 7.6 Hz, 3H, OCH2CH2CH3), 1.77–1.86 (m,
6H, OCH2CH2CH3, 5-CH2, 6-CH2), 2.29–2.35 (m, 4H, 4-CH2, 7-
CH2), 3.96 (t, J = 6.4 Hz, 2H, OCH2CH2CH3), 4.30 (s, 2H, 3-CH2),
7.15–7.41 (m, 2H, Ph). Anal. Calcd for C17H19ClFNO2: C, 63.06; H,
5.91; N, 4.33. Found: C, 62.82; H, 5.61; N, 4.29.
2.2.7. Data for B7
Yield, 90%; grey solid; mp 132–134 °C. 1H NMR (400 MHz,
CDCl3): d = 1.21–2.39 (m, 8H, –CH2CH2CH2CH2–), 2.68–2.71 (m,
1H, COCH), 2.98–3.00 (m, 1H, –CH(OH)CH–), 4.57 (d, J = 5.2 Hz,
2H, –OCH2–), 5.11 (s, 1H, CH(OH), 5.31 (d, J = 10.8 Hz, 1H,
CH@CHH), 5.44 (d, J = 10.8 Hz, 1H, CH@CHH), 6.01–6.05 (m, 1H, –
CH@CH2), 7.04–7.24 (m, 2H, ArH); EI-MS: m/z (%) 341 ([M+1]+,
49), 340 (M+, 46), 339 ([MÀ1]+, 100), 95 (61), 93 (97), 81 (87), 67
(90), 55 (65). Anal. Calcd for C17H19ClFNO3: C, 60.09; H, 5.64; N,
4.12. Found: C, 59.36; H, 5.29; N, 3.92.
2.3.7. Data for C7
Yield, 71%; white solid; mp 112–114 °C. 1H NMR (400 MHz,
CDCl3): d = 1.75–1.80 (m, 4H, 5-CH2, 6-CH2), 2.29–2.35 (m, 4H, 4-
CH2, 7-CH2), 4.31 (s, 2H, 3-CH2), 4.58 (d, J = 2.4 Hz, 2H,
OCH2CHCH2), 5.30–5.33 (m, 1H, OCH2CHCH2), 5.44–5.49 (m, 1H,
OCH2CHCH2), 6.02–6.06 (m, 1H, OCH2CHCH2), 7.16–7.46 (m, 2H,
Ph). Anal. Calcd for C17H17ClFNO2: C, 63.46; H, 5.33; N, 4.35. Found:
C, 63.54; H, 5.52; N, 4.34.
2.3. General procedure for the synthesis of compound C1–7
Compound B (1 mmol) was dissolved in anhydrous methanol
(20 mL). The solution was acidified with concentrated hydrochloric
acid until the pH of the mixture was set to be pH 1. The reaction
mixture was stirred at room temperature for 14 h and concen-
trated in vacuo. Then, water (100 mL) was added and the product
was extracted with dichloromethane. The dichloromethane phase
was dried with magnesium sulfate and concentrated in vacuo.
The obtained crude product was purified by column chromatogra-
phy eluting with acetone/petroleum.
2.4. General procedure for the synthesis of compound D1–12
A mixture of compound M3 (1 mmol) in anhydrous methanol
was stirred at room temperature. NaBH4 (1 mmol) was added por-
tion wise and the mixture was stirred for about 2 h. The reaction
solution was poured into ice water (30 mL). Precipitated solids
were filtered and recrystallized from acetone or ethanol to give
the pure compounds D with free hydroxyl group. Then, by applying
the similar procedure as described for the synthesis of compound
A, the alkylation of hydroxyl group afforded the corresponding hy-
droxyl-protected products D.
2.3.1. Data for C1
Yield, 70%; white solid; mp 92–94 °C. 1H NMR (400 MHz,
CDCl3): d = 1.37 (d, J = 6.4 Hz, 6H, 2 Â CHCH3), 1.78–1.85 (m, 4H,
–CH2CH2CH2CH2–), 2.28–2.35 (m, 4H, –CH2C@CCH2–), 4.30 (s, 2H,
–CH2–), 4.48–4.50 (m, 1H, OCH), 7.15 (d, J = 11.2 Hz, 1H, –
C(F)@CH), 7.43 (d, J = 7.4 Hz, 1H, NC@CH); EI-MS: m/z (%) 324
(M+, 2), 323 ([MÀ1]+, 7), 90 (66), 77 (50), 42 (82), 41 (100). Anal.
Calcd for C17H19ClFNO2: C, 63.06; H, 5.91; N, 4.33. Found: C,
63.12; H, 5.80; N, 4.02.
2.4.1. Data for D1
Yield, 80%; white solid; mp 110–112 °C. 1H NMR (400 MHz,
CDCl3): d = 1.74–1.78 (m, 4H, 5-CH2, 6-CH2), 2.28–2.46 (m, 4H, 4-
CH2, 7-CH2), 5.73 (s, 1H, CH), 7.35–7.40 (m, 3H, Ph). Anal. Calcd
for C14H13BrFNO2: C, 51.55; H, 4.02; N, 4.29. Found: C, 52.00; H,
4.19; N, 4.27.

7952
L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
2.4.2. Data for D2
7.45 (m,6H, Ph). Anal. Calcd for C24H22Cl2FNO3: C, 62.35; H, 4.80;
N, 3.03. Found: C, 62.33; H, 5.67; N, 18.17.
Yield, 72%; white solid; mp 102–103 °C. 1H NMR (400 MHz,
CDCl3): d = 1.73–1.82 (m, 4H, 5-CH2, 6-CH2), 2.27–2.50 (m, 4H, 4-
CH2, 7-CH2), 5.08 (q, J = 9 Hz, 2H, OCH2), 5.78 (s, 1H, CH), 7.03–
7.37 (m, 6H, Ph). Anal. Calcd for C21H18ClF2NO3: C, 62.15; H,
4.47; N, 3.45. Found: C, 61.48; H, 5.03; N, 3.03.
2.4.11. Data for D11
Yield, 75%; yellow oil; 1H NMR (400 MHz, CDCl3): d = 1.73–1.85
(m, 4H), 2.30–2.35 (m, 4H), 3.79–3.96 (m, 2H), 4.57–4.59 (m, 2H),
5.17–5.47 (m, 4H), 5.73 (s, 2H), 5.74–5.81 (m, 1H), 5.99–6.07 (m,
1H), 6.85 (s, 1H), 7.49 (m, 2H). Anal. Calcd for C20H21ClFNO3: C,
63.58; H, 5.60; N, 3.71. Found: C, 63.42; H, 5.58; N, 3.59.
2.4.3. Data for D3
Yield, 78%; white solid; mp 115–116 °C. 1H NMR (400 MHz,
CDCl3): d = 1.72–1.78 (m, 4H, 5-CH2, 6-CH2), 2.27–2.53 (m, 4H, 4-
CH2, 7-CH2), 5.06 (q, J = 8.2 Hz, 2H, OCH2), 5.79 (s, 1H, CH), 7.23–
7.46 (m, 6H, Ph). Anal. Calcd for C21H18Cl2FNO3: C, 59.73; H,
4.30; N, 3.32. Found: C, 59.80; H, 4.66; N, 3.17.
2.4.12. Data for D12
Yield, 76%; yellow oil. 1H NMR (400 MHz, CDCl3): d = 1.21–1.46
(m, 3H, OCH2CH3), 1.73–1.83 (m, 4H, 5-CH2, 6-CH2), 2.31–2.34 (m,
4H, 4-CH2, 7-CH2), 3.78–3.86 (m, 2H, OCH2CH3), 4.02–4.11 (m, 2H,
OCH2CHCH2), 5.10–5.19 (m, 2H, OCH2CHCH2), 5.75–5.80 (m, 2H,
OCH2CHCH2, CH), 7.01–7.22 (m, 2H, Ph). Anal. Calcd for
C19H21ClFNO3: C, 62.38; H, 5.79; N, 3.83. Found: C, 62.20; H,
5.73; N, 3.61.
2.4.4. Data for D4
Yield, 67%; white solid; mp 98–99 °C. 1H NMR (400 MHz,
CDCl3): d = 1.74–1.79 (m, 4H, 5-CH2, 6-CH2), 2.30–2.47 (m, 4H, 4-
CH2, 7-CH2), 4.57–4.58 (m, 2H, OCH2CHCH2), 5.32–5.48 (m, 2H,
OCH2CHCH2), 5.68 (s, 1H, CH), 6.01–6.08 (m, 1H, OCH2CHCH2),
6.89 (s, 1H, Ph), 7.50 (s, 1H, Ph). Anal. Calcd for C17H17Cl2NO3: C,
57.64; H, 4.84; N, 3.95. Found: C, 56.98; H, 5.13; N, 3.87.
2.5. Herbicidal activities
The herbicidal activities of 29 newly synthesized compounds
against Echinochloa crusgalli (EC), Digiatra sanguinalis (DS), Setaria
viridis (SV), Brassica juncea (BJ), Amaranthus retroflexus (AR), Cheno-
podium album (CA) and Eclipta Prostrata (EP) were evaluated
according to the standard protocol as described previously.14 All
test compounds were formulated as a 150 g/L emulsified concen-
trates 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-
2.4.5. Data for D5
Yield, 72%; white solid; mp 102–103 °C. 1H NMR (400 MHz,
CDCl3): d = 1.70–1.85 (m, 4H, 5-CH2, 6-CH2), 2.26–2.45 (m, 4H, 4-
CH2, 7-CH2), 4.56–4.58 (m, 2H, OCH2CHCH2), 5.31–5.48 (m, 2H,
OCH2CHCH2), 5.78 (s, 1H), 6.01–6.08 (m, 1H, OCH2CHCH2), 7.16–
7.23 (m, 2H, Ph); EI-Ms (m/z) 337 (M+). Anal. Calcd for
C17H17ClFNO3: C, 60.45; H, 5.07; N, 4.15. Found: C, 60.38; H,
5.09; N, 3.77 .
2.4.6. Data for D6
Yield, 78%; white solid; mp 114–115 °C. 1H NMR (400 MHz,
CDCl3): d = 1.45 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.74–1.74 (m, 4H, 5-
CH2, 6-CH2), 2.18–2.29 (m, 4H, 4-CH2, 7-CH2), 4.17 (q, J = 7.2 Hz,
2H, OCH2CH3), 5.78 (s, 1H, CH), 7.05 (s, 1H, Ph), 8.08 (s, 1H, Ph).
Anal. Calcd for C16H17ClN2O5: C, 54.47; H, 4.86; N, 7.94. Found: C,
54.88; H, 4.56; N, 7.76.
eter of 9.5 cm were filled with soil to
a depth of 8 cm.
Approximately 20 seeds of E. crusgalli, D. sanguinalis, S. viridis, B.
juncea, A. retroflexus, C. album and E. Prostrata were sown in the soil
at the depth of 1–3 cm and grown at 15–30 °C in a greenhouse. The
diluted formulation solutions were applied for post-emergence
treatment, dicotyledon weeds were treated at the 2-leaf stage
and monocotyledon weeds were treated at the 1-leaf stage, respec-
tively. The post-emergence application rates were 150 g.ai/ha. Un-
treated seedlings were used as the control group and the solvent
(DMF) treated seedlings were used as the solvent control group.
Herbicidal activity was evaluated visually after 15 days post treat-
ment. The results of herbicidal activities were summarized in
Table 2.
2.4.7. Data for D7
Yield, 73%; white solid; mp 112–113 °C. 1H NMR (400 MHz,
CDCl3): d = 1.73–1.83 (m, 4H, 5-CH2, 6-CH2), 2.31–2.34 (m, 4H, 4-
CH2, 7-CH2), 3.71–3.85 (m, 2H, OCH2CHCH2), 5.10–5.19 (m, 2H,
OCH2CHCH2), 5.70–5.77 (m, 1H, OCH2CHCH2), 5.80 (s, 1H, CH),
7.29–7.36 (m, 3H, Ph). Anal. Calcd for C17H17BrFNO2: C, 55.75; H,
4.68; N, 3.82. Found: C, 55.47; H, 4.66; N, 3.75.
2.4.8. Data for D8
Yield, 74%; white solid; mp 65–67 °C. 1H NMR (400 MHz,
CDCl3): d = 1.74–1.84 (m, 4H, 5-CH2, 6-CH2), 2.32 (s, 4H, 4-CH2,
7-CH2), 3.02 (s, 3H, OCH3), 5.08 (q, J = 22.0 Hz, 2H, OCH2), 5.78 (s,
1H, CH), 7.13–7.46 (m, 6H, Ph). Anal. Calcd for C22H20Cl2FNO3: C,
60.56; H, 4.62; N, 3.21. Found: C, 61.03; H, 4.84; N, 3.16.
2.6. CoMFA anlysis
The 3D structures of all the compounds were built by SYBYL 7.3/
Sketch,18 and then optimized using MMFF94 force field,19 by Pow-
ell method with energy termination of 0.005 kcal/mol, and a max-
imum of 1000 iterations. Then, the Gasteiger–Hückel charges were
added. Pharmacophore-based molecule alignment method was ap-
plied to superimpose all the compounds by using GALAHAD in
SYBYL 7.3. The steric and electrostatic field energies for CoMFA
were calculated using the SYBYL default parameters: 2.0Å grid
points spacing, a sp3 carbon probe atom with +1 charge and a
van der Waals radius of 1.52Å, and column filtering of 2.0 kcal/
mol. The CoMFA descriptors were used as independent variables,
and pki values were used as dependent variables in partial least-
squares (PLS) regression analyses to derive 3D-QSAR models.
Leave-one-out (LOO) cross-validated PLS analyses were performed
to determine the optimal number of components to be used in
the final QSAR models and to check the predictive ability of the
2.4.9. Data for D9
Yield, 84%; white solid; mp 124–125 °C. 1H NMR (400 MHz,
CDCl3): d = 1.74–1.86 (m, 4H, 5-CH2, 6-CH2), 2.31–2.32 (m, 4H, 4-
CH2, 7-CH2), 3.10 (s, 3H, 3-OCH3), 3.88 (s, 3H, Ph-OCH3), 5.80 (s,
1H, CH), 7. 08–7.23 (m, 2H, Ph). Anal. Calcd for C16H17ClFNO3: C,
58.99; H, 5.26; N, 4.30. Found: C, 58.72; H, 5.50; N, 3.98.
2.4.10. Data for D10
Yield, 78%; yellow oil. 1H NMR (400 MHz, CDCl3): d = 1.73–1.85
(m, 4H, 5-CH2, 6-CH2), 2.31–2.32 (m, 4H, 4-CH2, 7-CH2), 3.74 (q,
J = 6.4 Hz, 2H, OCH2CHCH2), 5.02–5.16 (m, 4H, OCH2CHCH2,
OCH2Ph), 5.66–5.73 (m, 1H, OCH2CHCH2), 5.81 (s, 1H, CH), 7.08–

L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
7953
Table 2
Table 3
Post-emergency herbicidal activity of compounds A–D (150 gÁai/ha)
Crystal data and structural refinement parameters for B1 and C4
a
No.
EC
DS
SV
BJ
AR
CA
EP
B1
C4
b
A1
A2
A3
B1
B2
B3
B4
B5
B6
B7
C1
C2
C3
C4
C5
C6
C7
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
+
+
+
+
+++
À
À
+
Empirical formula
Formula weight
Crystal system
Space group
Unit cell dimensions
a (Å)
C19H22ClFNO3
366.83
Monoclinic
P21/c
C16H17ClFNO2
309.76
Triclinic
P-1
À
À
À
À
À
À
À
À
À
À
À
À
++
À
++
++
À
À
À
À
À
À
+
À
À
À
À
À
À
À
À
À
À
À
À
++
À
++
++
+
À
À
À
À
À
À
À
À
À
+
À
À
++
À
++
++
À
À
À
À
À
À
À
À
+
À
À
À
++
À
À
À
À
À
À
À
++
À
+
+
+++
À
+
À
À
À
À
À
À
À
++
À
À
+
À
++
++
À
+
À
À
À
À
À
12.1284(15)
11.1700(14)
13.7126(17)
90
95.752(2)
90
1848.4(4)
4
1.318
8.7953(10)
8.9495(11)
10.4144(12)
103.523(2)
103.998(2)
99.048(2)
753.23(15)
2
1.366
324
0.20 Â 0.20 Â 0.15
2.10–27.25
7207
3324
211
1.096
R1 = 0.0496,
wR2 = 0.1373
R1 = 0.0624,
wR2 = 0.1529
0.168, À0.246
À
À
b (Å)
c (Å)
À
À
À
À
a
(°)
À
À
b (°)
+++
À
++
À
c (°)
Volume (Å3)
+
+
Z
++
++
++
+++
+
++
+
+
+++
À
+
Calcd density (Mg/m3)
F(0 0 0)
À
+++
+++
+
+
+
+
+
+
+
+
+
+
++
+++
+++
772
+++
+++
+
Crystal size (mm)
h range (°)
Reflections collected
Independent reflections
Number of parameters
Goof
0.30 Â 0.20 Â 0.20
1.69–27.50
17,103
4219
227
+
+
+
+
++
+
À
À
À
À
+
+
+
+
À
À
+
1.045
++
++
+
Final R indices [I >2
r
(I)]
R1 = 0.0595,
wR2 = 0.1586
R1 = 0.0710,
wR2 = 0.1684
0.423, À0.326
+
+
R indices (all data)
+
+
À
+
+
+
++
++
+++
+++
+++
++
À
Max. diff. peak and hole
(eÅÀ3
À
+
++
+
À
À
++
+
À
+++
+
)
+
+
++
+++
+++
D12
Sulfentrazone
À
++
+++
A total number of 7207 reflections were measured of which 3324
reflections were independent with Rint = 0.0619. The data sets were
corrected for Lorentz and polarization effects and for absorption
(Tmin = 0.924; Tmax = 0.948). The structure was solved by direct
methods using SHELXS-9720 and refined on F2 by full-matrix
least-squares techniques with SHELXL package program.21 All the
non-hydrogen atoms were refined anisotropically and all the
hydrogen atoms were positioned at there ideal positions. In the
refinement, the C2–C5 atoms on the cyclohexyl group were disor-
dered over two sites. They are refined by using these commands
‘SADI’ and ‘ISOR’. The final occupancies were 0.74:0.26 for the ma-
jor and minor components, respectively. Similarly, data sets of col-
orless crystal of B1 were collected in the 1.69 6 hmax 6 27.50°
range. A total number of 17103 reflections were measured of
which 4219 reflections were independent with Rint = 0.0212. The
data sets were corrected for Lorentz and polarization effects and
for absorption (Tmin = 0.923; Tmax = 0.955). The refinement of B1
was in a similar way to that of complex C4. Relevant crystal data,
collection parameters and refinement results can be found in
Table 3.
a
EC for E. crusgalli, DS for D. sanguinalis, SV for S. viridis, BJ for B. juncea, AR for A.
retroflexus, CA for C. album and EP for E. Prostrata.
b
Rating system for the growth inhibition percentage: +++, 100%; ++, >80%; +, 50–
80%; À, <50%.
models. To visualize the 3D-QSAR results in term of field contri-
butions, isocontour maps were generated using the field type
‘stdev coeff’ and the contour levels were set to default values.
In CoMFA, compounds 24 and 5 were selected randomly as the
training set and the test set, respectively.
*
2.7. X-ray diffraction
Colorless crystal of C4 (0.30 Â 0.20 Â 0.20 mm) was mounted on
a thin quartz fiber for X-ray diffraction data collection. Initial cell
constants were indexed by three separated ‘matrix’ runs using
3151 reflections. Intensity data sets were collected on a Bruker
SMART APEX CCD diffractometer with graphite monochromated
Mo Ka radiation (k = 0.71073 Å) in the 2.10 6 hmax 6 27.25° range.
R1
O
R1
R1
O
O
R3-X
NaBH4
CH3OH
N
R2
N
R2
N
R2
K2CO3, DMF
R4
O
R4
OH
O
OH
M1
A1~3
B1~7
H+
EtOH
O
R1
N
R2
R4
C1~7
Scheme 1. Synthetic route for the target compounds A–C.

7954
L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
R1
O
O
R1
R1
O
R3-X
NaBH4
CH3OH
R2
OH
N
R2
N
R2
N
K2CO3, DMF
O
R4
OH
R4
O
D1~6
M2
M3
R5-X
K2CO3/DMF
O
R1
N
R2
OR5
D7~12
R4
Scheme 2. Synthetic route for the target compound D.
Figure 3. Crystal structures of B1 and C4.

L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
7955
values for all the compounds are given in Table 1, and the plots
of the predicted versus the actual activity values for all the com-
pounds are shown in Figure 4. In Figure 5, the isocontour diagrams
of the steric and electrostatic field contributions (‘‘stdev*coeff”) ob-
tained from the CoMFA analysis are illustrated together with
exemplary ligands. The steric field contour map is plotted in Fig-
ure 5A. The green region highlights positions where a bulky group
would be favorable for higher PPO inhibition activity. In contrast,
yellow indicates positions where a decrease in the bulk of the de-
sired compounds is favored. As shown in Figure 5A, the CoMFA ste-
ric contour plots indicated that a big yellow region is located
around the group of R5, while a big green region surrounded the
R4 group. This map means that the R4 and R5 substituents should
be bulky and small groups, respectively. This steric map explained
clearly why compound C except for C3 always displayed higher
activity (6.16 < pki < 7.02) than other compounds. The electrostatic
contour plot is shown in Figure 5B. The blue contour defines a re-
gion where an increase in the positive charge will result in an in-
crease in the activity, whereas the red contour defines a region of
space where increasing electron density is favorable. As shown in
Figure 5B, the target compounds bearing an electron-withdrawing
group at the position of R1 and R4 will display higher activity. For
example, compounds containing fluorine atom at position R1
always displayed higher activity than other compounds, such as
compound C2 (R1 = H), C5 (R1 = Cl), D4 (R1 = Cl), and D6
(R1 = OCH2CH3). In addition, the electrostatic contour plot showed
that a red region is around the carbonyl group, whereas a blue re-
gion is around the R5 group. This contour map indicated that the
more electronegative the oxygen atom of the carbonyl, the higher
the activity of inhibitors, which is accordance with our previous
DFT-QSAR result13 that the approximate nucleophilic superdeloc-
alizability of the carbon atom of one of the carbonyl group played
an important role in determining the activity of PPO inhibitors. The
stronger the ability of the carbonyl group to accept electrons from
receptor, the higher the activity of PPO inhibitor.
3. Results and discussion
3.1. Synthesis of the title compounds
As shown in Scheme 1, the target compounds A–C were pre-
pared by using 2-(5-hydroxy-2,4-disubstitutedphenyl)hexahydro-
isoindole-1,3-dione (M1) as starting material. At the presence of
potassium carbonate, alkylation of M1 with various alkyl halide
afforded the desired compounds A1–3 in yields of 75–88%. Then,
treatment of compound A with methanol solution of NaBH4 re-
sulted in compounds B1–7 in yields of 68–95%. In ethanol solution
of concentrated hydrochloric acid, compound B underwent dehy-
dration smoothly to afford the desired compounds C1–7 in yields
of 70–85%.
As shown in Scheme 2, the target compound D was synthesized
by using 2-(5-hydroxy-2,4-disubstitutedphenyl)-4,5,6,7-tetrahy-
dro-isoindole-1,3-dione (M2) as starting material. Firstly, M2 took
place alkylation reaction with various alkyl halide at the presence
of potassium carbonate to provide intermediate M3 in excellent
yields. Then, one of the carbonyl group was reduced to hydroxyl
group with sodium borohydride to afford compound D, some of
which reacted with various alkyl halide at the presence of potas-
sium carbonate to obtain the hydroxyl-protected compound D.
The structures of all intermediates and title compounds were
confirmed by elemental analyses, 1H NMR and MS spectral data.
In addition, the crystal structures of compounds B1 and C4 were
determined by X-ray diffraction analyses as shown in Figure 3.
The cyclohexane ring of compound B1 takes chair conformation, the
crystal packing is stabilized by three intermolecular hydrogen-
bonding [C(14)–H(14)Á Á ÁO(3), C(2)–H(2)Á Á ÁO(2), O(3)–H(3)Á Á ÁO(2)]
interactions. In addition, the dihedral angel between the benzene
ring and the isoindolone ring of compound C4 is 40.2°, while two
carbon atoms [C(3) and C(4)] of the cyclohexene moiety are
disordered.
3.2. PPO-inhibiting activity and CoMFA analysis
3.3. Greenhouse herbicidal activities
The ki values against human PPO of the newly synthesized 29
compounds were listed in Table 1. 4-Chlorophthalimide and sulf-
entrazone were used as positive control. As shown in Table 1, most
of the newly design and synthesized compounds showed higher
PPO-inhibiting activity than 4-chlorophthalimide. However, all of
compounds A, B and D (except for compounds D2 and D3) exhibited
lower activity than sulfentrazone. Most interestingly, all of com-
pound C (except for compound C2), the mono-carbonyl analogues
of cyclic imides, displayed higher in vitro PPO inhibition activity
The post-emergence herbicidal activity of series A–D
were tested in greenhouse at the concentration of 150 g.ai/ha, a
7
6
5
4
3
than sulfentrazone, among which compound C6 (ki = 0.095
lM) is
7.6-folds higher active than sulfentrazone (ki = 0.72 M). These re-
l
sults confirmed once again that only one of the carbonyl groups of
cyclic imides is essential to the PPO inhibition activity.
In order to understand the substituent effects on the PPO inhi-
bition of these compounds, the method of comparative molecular
field analysis (CoMFA) was applied to understand the quantitative
structure–activity relationships. As listed in Table 4, a predictive
CoMFA model was established with the conventional correlation
coefficient r2 = 0.980 and the cross-validated coefficient q2 =
0.518, the contribution of steric and electrostatic fields are 48.5%
and 51.5%, respectively. The observed and calculated activity
3
4
5
6
7
Experimental
K
i
p
Figure 4. Predicted pki (Y-axis) are versus experimental pki (X-axis) values. The
dots and the triangle represent training and test compounds, respectively.
Table 4
Statistical results of CoMFA
Method
CoMFA
Cross-validation
Conventional
Contribution
Electrostatic
0.515
q2
OCN
5
r2
F
SEE
Steric
0.485
0.518
0.980
175.441
0.168

7956
L. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 7948–7956
Figure 5. CoMFA contour maps with compound 16 as the reference structure. (A) Steric contours. Scattered green areas are regions where bulky substituents are favorable,
yellow areas are unfavorable. (B) Electrostatic contours. The red areas are the regions where negative potential is favorable for the activity, blue areas are unfavorable.
triazolinone-type commercial product, sulfentrazone, was selected
as a positive control. As shown in Table 3, some of compounds (C1,
C4, C6, C7, D11 and D12) were found to display promising and broad
spectrum herbicidal activities. Most interestingly, compounds C6
and C7 displayed over 80% inhibiting activities against all seven
tested weeds. However, sulfentrazone did not show significant
herbicidal activity against monocot weeds, such as E. crusgalli
and D. sanguinalis. These results showed that these compounds
have the potential for further test with crop selectivity and herbi-
cidal spectrum.
selectivity and field trial of these two compounds are under the
way.
Acknowledgments
We thank Dr. Jie Chen for the greenhouse test of biological
activities. We also thank the financial support from the National
Basic Research Program of China (No. 2010CB126103), the NSFC
(Nos. 20925206, 20932005 and 21002038) and the PCSIRT (No.
IRT0953).
References and notes
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