A quantitative structure-activity relationship study of herbicidal analogues of α-hydroxy-substituted 3-benzylidenepyrrolidene-2,4-diones

Article abstract of DOI:10.1021/jf061573j

A series of pyrrolidine-2,4-dione and piperidine-2,4-dione derivatives were prepared and evaluated for their herbicidal activities where some of these compounds exhibited good bioactivity against Echinochloa crus-galli in comparison with sulcotrione. Quan

Full text of DOI:10.1021/jf061573j

7200 J. Agric. Food Chem. 2006, 54, 7200−7205
A Quantitative Structure
−Activity Relationship Study of
Herbicidal Analogues of
r
-Hydroxy-Substituted
3-Benzylidenepyrrolidene-2,4-diones
YOU-QUAN ZHU, PEI LIU, XUE-KAI SI, XIAO-MAO ZOU, BIN LIU,
HAI-BIN SONG, AND HUA-ZHENG YANG*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
A series of pyrrolidine-2,4-dione and piperidine-2,4-dione derivatives were prepared and evaluated
for their herbicidal activities where some of these compounds exhibited good bioactivity against
Echinochloa crus-galli in comparison with sulcotrione. Quantitative structure-activity relationship
studies were performed on these compounds using physicochemical parameters (hydrophobic,
electronic, and Taft) as independent parameters and herbicidal activity as a dependent parameter,
where herbicidal activity correlated best (r > 0.8) with hydrophobic (πo + πp), steric (Es), STERIMOL
(B4), indicator (HM), van der Waals volume (V), and electronic parameter (σm + σp) in this set of
molecules; the optimum van der Waals volume for R2 is about 41.8 Å3; when B4 is equal to 3, the
target molecule possessed the lowest herbicidal activity.
KEYWORDS: Herbicide; triketone; pyrrolidine-2,4-dione; quantitative structure-activity relationship
(QSAR)
INTRODUCTION
ing groups such as chlorine, trifluoromethyl, nitro, or methane-
sulfonyl functional groups at ortho- and/or para-positions of the
benzene rings (1, 2). Interestingly, a different substitution effect
was observed in the series of R-hydroxy-substituted 3-ben-
zylidenepyrrolidene-2,4-diones (B) 4-HPPD inhibitors in our
previous work (3-5). 3-Benzoyl pyrrolidine-2,4-diones were
discovered as 4-HPPD inhibitors in our group through modifica-
tion of the natural product A, which was inhibitory toward
4-HPPD with an IC50 ) 18 µM (6), by the replacement of an
acetyl group with substituted benzoyl groups. The 4-HPPD
bioassay results showed that when R1 was electron-donating,
B (Table 1) exhibited better herbicidal activities. In contrast to
most of the known 4-HPPD inhibitors, the electron-donating
groups were preferred both at 2- and/or 4-positions of the
benzene ring. In the meantime, the herbicidal activity of B
against Echinochloa crus-galli and Digitaria sanguinalis varied
obviously with R1 and R2. In particular, when R1, R2, and R3
were 2,4-dimethoxy, iso-propyl, and hydrogen, respectively
(B30), it provided 93% control of E. crus-galli with crop
selectivity on corn and soybeans at pre-emergence at 187.5 g/ha.
As compared with sulcotrione, some of these compounds were
much more effective.
4-Hydoxyphenylpyruvate dioxygenase (4-HPPD) catalyzes
the conversion of the 4-hydroxyphenylpyruvate to homogentisate
in the biosynthesis pathway of plastoquinone and R-tocopherol.
Inhibition of the production of homogentisate by 4-HPPD
inhibitors down-regulates the production of plastoquinone, which
is thought to be an acceptor of hydrogen from phytoene.
Therefore, the absence of plastoquinone leads to an accumulation
of the phytoene, which results in the impairment of carotenoid
biosynthesis that is essential for the growth and survival of herbs.
Thus, the inhibitors of 4-HPPD, classified as bleaching herbi-
cides, have been intensively studied since the 1990s. Their
herbicidal activities have proven to be comparable to acetolactate
synthase and protoporphyrinogen-IX oxidase inhibitors, exhibit-
ing excellent herbicidal activities even at low dosages.
At present, quantitative structure-activity relationships
(QSARs), an important area of chemometrics, have been widely
utilized to study the relationship between chemical structures
and biological or other functional activities. QSAR has become
increasingly helpful in understanding many aspects of chemi-
cal-biological interactions in drug and pesticide research as
A survey of the known 4-HPPD inhibitors revealed that most
of them have very similar structural characteristics, i.e., their
benzoyl groups are substituted with various electron-withdraw-
* To whom correspondence should be addressed. Tel: +86-22-23503799.
Fax: +86-22-23503627. E-mail: nk_yanghz@126.com.
10.1021/jf061573j CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/25/2006

R
-Hydroxy-Substituted 3-Benzylidenepyrrolidene-2,4-diones
J. Agric. Food Chem., Vol. 54, No. 19, 2006 7201
Table 1. Compounds B−E
compd
R1
R2
R3
compd
R1
R2
R3
B1
B2
B3
B4
B5
B6
B7
B8
4-i-C3H7O
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
sec-C4H9
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
H
H
H
H
H
H
H
H
H
H
H
H
B38b
B39b
B40b
B41b
B42a
B43a
B44b
B45a
B46a
B47a
B48a
B49a
B50b
B51b
B52a
B53b
B54b
B55b
B56b
B57c
B58c
B59c
B60c
B61c
B62c
B63b
B64b
B65b
E1
4-Cl
3-CH3
4-CH3O
4-CH3
3,5-(CH3)2
3-C6H5O
2-CH3O
2,4-(CH3O)2
3-C6H5O
4-C2H5O
4-n-C5H11
4-CH3O
3-CH3
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
cyclo-C3H5
cyclo-C3H5
cyclo-C3H5
cyclo-C3H5
cyclo-C3H5
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-CH3O-4-C2H5O
2-CH3O-4-i-C3H7O
2,4-(CH3O)2
4-C2H5O
4-n-C3H7
3-n-C4H9O
4-n-C4H9O
4-CH3O
3,5-(CH3)2
3-C6H5O
2,4,5-(CH3O)3
3,4-(CH3O)2
4-CH3O
2-CH3O-4-i-C3H7O
2-methoxy-4-allyloxy
2-CH3O-4-OC2H5
2,4-(CH3O)2
4-i-C3H7O
2-CH3O-4-C2H5O
2-CH3O-4-i-C3H7O
3-n-C4H9O
4-n-C4H9O
4-n-C3H7O
2,4-(C2H5O)2
4-C6H5CH2O
3-i-C3H7O
2-methoxy-4-allyloxy
4-allyloxy
2,4-(CH3O)2
4-C2H5O
4-C3H7
4-C5H11
2-CH3
4-C(CH3)3
2,4-(CH3)2
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30a
B31a
B32a
B33a
B34b
B35a
B36a
B37b
H
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CH3
4-i-C3H7
4-CH3O
2-CH3O
2-CH3
4-C(CH3)3
H
4-CH3
2-OCH3
3-CH3
2-CH3
4-OCH3
3-CH3
4-n-C5H11
3-C6H5O
4-CH3O
4-C2H5O
2,4-(CH3O)2
CH3
CH3
E2
E3
H
H
H
H
H
H
R1
M
n
1
2
2
C1
C2
C3
2,4-(CH3O)2
4-C2H5O
2,4-(CH3O)2
Na
Zn
Zn
2-Cl
a From ref 5. b From ref 4. c From ref 3.
Table 2. Herbicidal Activity Against E. crus-galli at 10
µ
g/mL (% I)
compd
I (%)
B1
−
29
D
E1
E2
15
E3
see Table 6
5
±
1
0
±
1
6 ± 1
and Tween 20 was used as a negative control. The inhibition rate I
(%) is summarized in Tables 2, 3, and 6. Each value is the mean for
three independent reproducible repetitions.
Molecular Docking. The A chain of the dimeric crystal structure
(PDB 1T47) (9) was used as the core structure for our docking study.
Preparation of the ligand input files was carried out using SYBYL6.9
(Tripos Inc.). The receptor description file was used to describe the
HPPD. The ligand (NTBC) from PDB 1T47 was used as the reference
compound of the coordinate, and the test ligand was produced by
extracting it from PDB 1T47, atom typing the test compound and B30,
and then adding hydrogens, followed by energy minimization. In this
study, all carboxylic acid and phosphoric acid groups were ionized,
and all amino, amidino, and guanidine groups (but no amide groups)
were protonated. Assignments of hydrogen positions for the receptor
were made on the basis of default rules, except for the definition of
the torsion angles at the hydroxyl groups of the amino acids serine,
threonine, and tyrosine and the hydrogen position inside the histidine
side chain. Suitable torsion angles and the optimal tautomeric histidine
state, respectively, were selected by visual inspection of the protein.
The residues of lysine and arginine were protonated, and the acid
groups of aspartic and glutamic acid were ionized. The ferric ion was
set as Fe2+. To define the active site of the protein, 16 residues were
selected that are located no farther than 6.5 Å apart from the ligand
atom at its crystalline position. All water molecules of the PDB file
were removed.
Figure 1. Chemical structures of B−E.
well as many other areas (7). The objectives of this study were
to (i) prepare the analogues B-E (Figure 1 and Table 1) to
further explore pharmacophoric characters of 3-benzoyl pyrro-
lidine-2,4-diones and (ii) understand the QSAR for R1 and R2.
MATERIALS AND METHODS
Compounds. The compounds used in this study were substituted
3-benzoyl pyrrolidine-2,4-dione as listed in Table 1. B1-29 and C-E
(Figure 1 and Table 1) were prepared according to the references
described (3, 4, 5, 8), and their structures were confirmed by elementary
and 1H NMR analyses (see the Supporting Information). B30-65
(Figure 1 and Table 1) were reported in our previous papers (3-5).
Herbicidal Activity Tests. Herbicidal activities of B-E and the
triketone, sulcotrione [2-(2-chloro-4-mesylbenzoyl)cyclohexane-1,3-
dione], were evaluated by a procedure described in our previous paper
(5). A mixture of the same amount of water, N-dimethylformamide,

7202 J. Agric. Food Chem., Vol. 54, No. 19, 2006
Table 3. Herbicidal Activity of Compounds (% Inhibition)a
Zhu et al.
pre-emergence treatment
E. crus-galli D. sanguinalis
compd
B4
rate (g/ha)
750
375
187.5
93.75
750
100
76
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
0
1
1
2
1
1
1
1
2
1
1
2
0
0
1
2
0
1
1
2
0
0
0
2
0
0
1
2
0
0
1
1
0
0
2
1
80
63
4
±
±
±
1
1
1
14
13
0
B5
93
82
28
7
99
94
56
10
100
100
95
36
100
95
96
59
41
18
95
95
84
20
93
77
66
5
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
1
1
1
1
1
1
2
1
1
1
2
1
2
1
2
375
187.5
93.75
750
B30
B31
B29
C1
375
187.5
93.75
750
375
187.5
93.75
750
79
74
36
375
187.5
93.75
750
55
30
0
100
100
100
73
100
100
96
100
100
90
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
0
0
1
1
0
0
1
1
0
0
1
1
0
0
0
0
375
Figure 2. Docking model of B30 with HPPD from Streptomyces avermitilis
and the scheme for planes A and B.
187.5
93.75
750
10
C2
100
100
64
Table 4. Herbicidal Activity (% Inhibition) and the Dihedral Angle (°)
between Planes A and B
375
187.5
93.75
750
57
8
E. crus-galli
cup test
pre-emergence treatment
for E. crus-galli (g/ha)
C3
100
100
85
100
100
82
375
187.5
93.75
750
375
187.5
93.75
dihedral
angle for
72
15
sulcotrione
100
100
93
100
100
100
100
compd
A and B (
°
)
10
µ
g/mL
750
100
375
100
187.5
93.75
B30
B44
B53
B57
62
53
21
10
78
±
±
±
±
1
1
2
1
±
0
±
0
94
0
±
1
34
0
± 2
77
10
2
73
14
0
±
±
1
2
28
0
± 1
70
0
0
0
0
0
a B30 and B31 were reported in ref 5, and their herbicidal activities were
determined under the same conditions as B4,5, B29, C1 3, and sulcotrione.
−
Table 5. Value of the Van Der Waals Volume (V) for R2
After the extracted NTBC (the ligand in PDB 1T47) was redocked
into the active pocket successfully, B18 was docked. The docking results
were sorted by FlexX score and Cscore, and rational binding conforma-
tions were selected.
CH3CH-
CH2CH3
R2
CH3
25
CH(CH2)2
47
CH(CH3)2
59
C(CH3)3
76
C6H5CH2
97
V (Å3)a
76
RESULTS AND DISCUSSION
a The volumes are calculated according to ref 14.
Bioassay. In our previous reports (3-5), it was found that
when R1 was 4-methoxy, 4-ethoxy, or 2,4-dimethoxy, the target
molecule always displayed a better herbicidal activity. As shown
in Table 2, when the substituted benzoyl group was replaced
by a phenylacetyl group (D), the herbicidal activity decreased
dramatically, which indicates that the benzoyl moiety at the
3-position is very important for their bioactivity. While R2 was
iso-propyl, R1 was fixed such as 2,4-dimethoxy (B30), 4-ethoxy
(B31), or 4-methoxy(B40), and the five-member ring was
modified into a piperidine ring (E1-3); the target molecules
showed very low or even no herbicidal activity against E. crus-
galli at 10 µg/mL, which differentiates this class of compounds
in SARs from other kinds of 4-HPPD inhibitors as herbicides
(such as 1,3-cyclohexane-diones). When R3 was a methyl group,
their inhibition rate to E. crus-galli (B14-18) at 10 µg/mL was
decreased significantly in comparison with the parent molecules
(R3 ) H) (B20, B21, B28, B30, and B40). In order to explain
this phenomenon and obtain information regarding the steric
requirements, B30 was docked into the HPPD from Strepto-
myces aVermitilis (Figure 2). It was found that the docking
configuration was the trans-form not the cis-form, which
compound B30 adopted in the crystal state (Figure 2) (10).
According to this result, it may be deduced that the area formed
by the pyrrole ring, Fe2+ and HPPD, may be more narrow and
the introduction of a methyl group was not in favor for binding.
In this docking model, the dihedral angle between plane A and
plane B for the inhibitor was about 60°. It was also noticed
that the closer the dihedral angles for B30, B44, B53, or B57
(10-13) were to 60°, the higher the herbicidal activity was
(Table 4). This may indicate that the configuration for planes
A and B was the optimal for compound B.
When B30 and B31 were transformed into their sodium (or
zinc) salts (C1-3), respectively, their herbicidal activities were
improved significantly: They exhibited better herbicidal activi-
ties against E. crus-galli in comparison with sulcotrione at the
rate of 93.75 g/ha (Table 3). It can be rationalized that the
transformation is helpful to improve the test compounds’ uptake
and distribution and/or strengthen the target molecule’s com-
bination with Fe2+sthe reaction center of the HPPD enzyme.
It was also noticed that C1’s herbicidal activity against D.
sanguinalis dropped from 90 to 10 with only a 2-fold loss in

R
-Hydroxy-Substituted 3-Benzylidenepyrrolidene-2,4-diones
J. Agric. Food Chem., Vol. 54, No. 19, 2006 7203
Table 6. Topological and Physicochemical Parameters of Compounds B1
−B65*
compd
Es
Σ
(
σm + σp
)
B4
(B4)2
HM
Σ
(
πo + πp
)
VN
(VN)2
I (%)
Xobs
Xcalcd
B1
B2
B3
B4
B5
B6
B7
B8
0
−
−
−
−
−
−
0.45
0.24
0.45
0.27
0.24
0.13
0.1
0
0
0
0
0
0
4.79
0
0
2.04
5.89
2.87
2.87
0
0
0
0
0
0
0
0
4.79
0
0
0
0
3.61
0
0
0
0
0
0
0
0
0
0
0
2.04
0
0
2.04
5.89
0
0
5.89
0
0
0
2.04
0
0
0
0
0
0
0
0
0
2.04
0
0
2.04
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.36
0.38
0.36
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.59
0.47
0.47
0.47
0.47
0.47
0.76
0.76
0.76
0.76
0.76
0.76
0.76
0.97
0.97
0.97
0.97
0.97
0.97
0.25
0.25
0.25
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.22
0.22
0.22
0.22
0.22
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.94
0.94
0.94
0.94
0.94
0.94
0.06
0.06
0.06
46
68
33
79
78
18
32
28
64
9
58
18
9
4
9
44
32
25
79
69
57
47
21
73
26
39
9
77
78
78
79
27
6
77
28
74
51
25
49
80
77
22
57
77
78
58
78
5
−
2.57
2.20
2.85
1.93
1.93
3.14
2.85
2.93
2.21
3.46
2.41
3.20
3.51
3.84
3.55
2.64
2.85
2.98
1.91
2.16
2.40
2.55
3.08
2.05
2.98
2.74
3.49
2.00
1.93
1.94
1.89
2.89
3.69
1.89
2.89
1.98
2.43
2.92
2.43
1.84
1.89
2.99
2.41
1.92
1.94
2.39
1.91
3.74
2.22
3.72
2.69
3.43
1.89
1.98
2.19
3.88
3.07
3.53
3.29
3.35
3.24
3.30
2.84
3.18
2.44
−
2.55
2.41
2.40
2.18
2.56
3.20
3.14
2.91
2.34
3.24
2.68
3.20
3.36
3.15
3.19
3.32
3.20
2.99
2.20
2.06
2.03
2.79
2.56
2.57
2.43
2.90
3.02
2.17
2.33
1.83
2.21
2.84
3.59
1.96
3.08
2.27
2.12
2.39
2.89
1.99
2.31
2.89
2.33
1.84
1.71
2.21
2.09
3.48
1.87
3.24
2.66
3.18
2.34
2.19
2.32
3.43
3.09
3.39
2.93
3.98
3.05
3.08
2.87
3.57
2.31
−0.55
−0.55
−0.55
0
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
0.04
0.38
1.55
0
0
0
0
0
0
0
22.94
0
0
4.16
34.69
8.24
8.24
0
0
0
0
0
0
0
0
−
−
−
0.32
0.27
0.14
0.25
0.15
0.15
0.27
0.45
0.25
0.24
0.27
0.45
0.24
0.45
0.1
1.03
0.02
0
B9
−
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30
B31
B32
B33
B34
B35
B36
B37
B38
B39
B40
B41
B42
B43
B44
B45
B46
B47
B48
B49
B50
B51
B52
B53
B54
B55
B56
B57
B58
B59
B60
B61
B62
B63
B64
B65
0
−0.55
−
−
−
−
−
−
−
−
−
−
−
−
−
0.04
0.02
0.02
0.34
0.58
0.36
0.04
0.36
0.38
0.34
0
0
0
−0.55
−0.55
−0.55
−0.55
0
−
−
−
0.55
0.55
0
22.94
0
0
0
0
0
0.04
0
0
−0.32
−0.25
−0.24
−0.23
0.1
1.03
1.05
0.76
1.66
0
0
13.03
0
0
0
0
0
0
0
0
0
0
0
4.16
0
0
4.16
34.69
0
0
34.69
0
0
0
4.16
0
0
0
0
0
0
0
0
−0.55
0
−0.25
−0.25
−0.27
−0.24
−0.13
−0.15
0
0.58
0.6
−0.55
0
−
0.04
0.38
1.55
2.93
0.56
1.98
1.12
0.71
0.71
0
0
0
−1.24
0
−0.2
−
−
1.24
0.97
0
−0.17
0
0.23
0.07
0.27
0.17
0.14
0.25
0
0
0
0
0
−
−
−
−
−
0.02
0.56
0
0
0
−
−
0.55
0.55
0
−
−
0.02
0.04
0
−
0.27
0.25
0.24
0.15
0.27
0.07
0.17
0.15
0.27
0
0
0
0
0
0
0
0
−
−
−
−
−
−
−
0.38
2.93
0.02
0
−
62
5
0.56
1.53
0.02
0.02
0.56
1.98
0
36
10
79
75
64
4
−
−
−
−
0.55
1.24
0
0
−
−
−
0.2
0
0.17
0
0.07
0
0
0
20
8
0.56
0.02
0
0.56
0.02
0
−0.55
0
0
4.16
0
0
4.16
0
−
−
14
12
15
14
25
16
53
−1.24
0
−0.27
−0.07
−0.15
0.25
0
0
0
2.93
0
5.89
34.69
applied herbicide (Table 3), which may be a result from the
soil’s metabolism and D. sanguinalis’s sensitivity to C1 at a
lower dosage.
Table 5, and the optimal V should exist. In order to validate
the hypothesis and to perform the QSAR study, some analogues
(B1-13) (R2 ) sec-butyl) were prepared. The bioassay results
(Tables 2 and 3) showed that they exhibited better herbicidal
activities but worse than corresponding N-iso-propyl analogues.
QSAR Analysis. In order to gain insight into SARs, B1-29
and B30-65 (3-5) were analyzed by a physicochemical-based
According to our previous works (3-5), when R1 was fixed,
the target molecule B’s herbicidal activity changed with R2 and
the rank of them is iso-propyl >cyclopropyl > tert-butyl, methyl
> benzyl. The van der Waals volume (V) for R2 is listed in

7204 J. Agric. Food Chem., Vol. 54, No. 19, 2006
Zhu et al.
Table 7. Correlation Matrix of the Parameters Used in QSAR Study
QSAR (Hansch) approach using physicochemical parameters
such as hydrophobic (π), Taft (Es), Verloop’s sterimol (B4),
indicator (HM), van der Waals volume (VN ) V/100), and
electronic parameters (Hammett’s constants) as independent
parameters, and the herbicidal activity data (% I) at 10 µg/mL
was converted to log {I/[(100 - I) × MW]} (15) as dependent
parameters. As listed in Table 6, when R3 was methyl group,
the target molecule showed very poor herbicidal activity in
comparison with when R3 was hydrogen. So, the indicator
variable HM was introduced and assigned to be zero for the
methyl group, while it was one for hydrogen. The values of the
physicochemical parameters in the study were taken from the
literature (16), and multiparameter linear regression analysis was
carried out using SYBYL 6.9 (Tripos Inc.). Variations in the
herbicidal activities of N-iso-propyl compounds, B19-44, which
constituted about half of these compounds, were first analyzed.
Preliminary QSAR analysis showed the substituent R1’s hy-
drophobic parameter [∑(πo + πp)] for the ortho- and para-
position (r ) 0.474), Taft (Es) parameter for the ortho-position
(r ) 0.407), electronic parameter [∑(σm + σp)] for the meta-
and para-position (r ) 0.263), and Verloop’s sterimol [B4 and
(B4)2] parameter for the meta-position (r ) 0.369); to a certain
extent, showing correlation, stepwise regression analysis of
different combinations of these parameters was studied, which
led to the derivation of eq 1, with the best correlation (r )
0.816).
Es
B4
(B4)2
HM
∑
(
πo + πp
)
VN
(VN)2
Es
1.000
0.265
0.230
0.170
0.109
0.101
0.083
B4
1.000
0.961
0.141
0.348
0.145
0.117
(B4)2
HM
1.000
0.117 1.000
0.287 0.109
0.179 0.115
0.152 0.141
∑
(
πo + πp
)
−
−
−
−
−
−
1.000
0.218
0.214
VN
−
−
−
−
1.000
0.982 1.000
(VN)2
Figure 3. Relationship between observed and calculated activity.
X ) log{I/[(100 - I) × MW]}
where MW is molecular weight and
In comparison with eq 1, the electronic parameter item [∑-
(σm + σp)] was not included in eq 2. The analysis result showed
that when the substitute R3 was introduced into B, its herbicidal
activity was mainly correlated with R1’s steric and hydrophobic
parameters and the steric effect on herbicidal activity was more
important than the electronic effect. The coefficient of the HM
term meant that the compounds with R3 ) H had a herbicidal
activity about 33 times that of those with R3 ) CH3 and also
suggested that hydrogen was preferred for R3. In order to gain
more information about R2, B1-13 and B45-65 were consid-
ered and gave eq 3.
X ) -2.111((0.194) - 0.279((0.196) Es -
0.581((0.527) (σm + σp) -0.597((0.181) B4 +
∑
0.098((0.033) (B4)2 - 0.529((0.114) (πo + πp) (1)
∑
where n ) 26, r ) 0.816, s ) 0.3508, and F ) 7.984.
The analysis result indicated that the presence of R1 at the
ortho-position with a negative value for Taft parameter Es
positively contributed to the activity, possibly due to intramo-
lecular steric interaction, and suggested that the ortho-substituent
in the benzene ring may be involved in the binding of these
molecules with the active center of HPPD. For the electronic
influence, the herbicidal activity mainly related to the substit-
uents at the meta- and para-positions of the benzene ring. The
presence of the electron-donating groups at the para-position
may increase the electron density at O6 or O7 (Figure 1) and
finally improve activity. The hydrophobicity impact of the
substituents at the ortho- and para-positions of benzene ring
was also important for herbicidal activity. B4 represented the
width of the substituent R1 at the meta-position. In the case of
dimeta-substituents, only one was under consideration. The
coefficients of the (B4)2 and B4 terms meant that when the B4
value for R1 was about 3, the compound showed the lowest
herbicidal activity. To further study the relationship between
R3 and their herbicidal activities, B14-18 were exploited and
gave eq 2.
X ) -3.732((0.513) - 0.275((0.126) Es -
0.639((0.096) B4 + 0.099((0.017) (B4)2 +
1.159((0.169) HM + 3.339((1.448) VN -
3.994((1.091) (V )2 - 0.544((0.067) (πo + πp) (3)
∑
N
where n ) 65, r ) 0.853, s ) 0.3416, and F ) 21.795.
VN was 1% of the van der Waals volume (V) for R2 at the
nitrogen atom and calculated according to ref 14. The coef-
ficients of the (VN)2 and VN terms meant that the van der Waals
volume (V) for R2 had an optimum value for B and was about
41.8 Å3. This result was consistant with our docking result. The
intercorrelation of variable was given in Table 7, and the
calculated activities for B1-65 by eq 3 were in good agreement
with the observed activity (Table 6 and Figure 3).
Conclusions. In summary, we further extended the study of
SAR of 3-benzoyl pyrrolidine-2,4-diones series 4-HPPD inhibi-
tors and gained insight of the pharmacophore through physi-
cochemical-based QSAR study. At first, it was further proven
that the pyrrolidine triketone compounds possessed different
SARs between R1 and their bioactivities from other kinds of
herbicides (such as 1,3-cyclohexane diones), in which electron-
donating groups were preferred for R1. Second, when a substitute
(R3) was introduced into the five-member ring, compound B’s
X ) -3.200((0.200) - 0.339((0.200) Es -
0.596((0.195) B4 + 0.091((0.037) (B4)2 -
0.495((0.121) (πo + πp) + 1.517((0.206) H (2)
∑
M
where n ) 31, r ) 0.803, s ) 0.3892, and F ) 9.088.

R
-Hydroxy-Substituted 3-Benzylidenepyrrolidene-2,4-diones
J. Agric. Food Chem., Vol. 54, No. 19, 2006 7205
herbicidal activity was mainly related to R1’s steric and
hydrophobic parameters. Third, the van der Waals volume for
R2, the hydrophobic (πo + πp), Taft (Es) for the ortho-position,
STERIMOL (B4) for the meta-position, and electronic parameter
[∑(σm + σp)] for the meta- and para-positions for R1 of the
benzoyl group were very important for herbicidal activity in
this class of compounds; hydrogen was preferred for R3, and
when the B4 was equal to 3, the target molecules possessed
the lowest herbicidal activity. Fourth, when the R1 was fixed
and R3 was hydrogen, the herbicidal activity against E. crus-
galli rank for R2 was iso-propyl > sec-butyl > cyclo-propyl >
tert-butyl, methyl > benzyl and its optimum volume was about
41.8 Å3. Fifth, the translation of B to its salt may strengthen its
combination with the Fe2+ of HPPD therefore exhibited better
herbicidal activity. Finally, the benzoyl group’s existence was
essential for their herbicidal activities.
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ACKNOWLEDGMENT
We thank Dr. Yin Zheng (Novartis Institute for Tropical
Diseases, Singapore) for helpful discussions.
Supporting Information Available: Chemical structures of
B-E; synthetic procedures; synthesis schemes; mps, yields, and
elemental analyses of compounds A-D; and 1H NMR of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Received for review June 5, 2006. Revised manuscript received July
23, 2006. Accepted July 24, 2006. We gratefully acknowledge the
support of this work by the National Key Project for Basic Research
(2003CB114400), the National Natural Science Foundation of China
(20572054), and the Research Foundation for the Doctoral Program of
Higher Education (20020055022).
JF061573J