Design of novel CSA analogues as potential safeners and fungicides

Article abstract of DOI:10.1016/j.bmcl.2014.12.085

Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues.

Full text of DOI:10.1016/j.bmcl.2014.12.085

Bioorganic & Medicinal Chemistry Letters 25 (2015) 791–794
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design of novel CSA analogues as potential safeners and fungicides
Yang Zheng a, , Bin Liu b, , Zhaopin Gou , Yao Li , Xiao Zhang , Yanqing Wang , Shujing Yu ,
Yonghong Li , Dequn Sun
a
a
a
b
a
b
b,
⇑
a,
⇑
Marine College, Shandong University at Weihai, No. 180, Wenhua West Road, Weihai 264209, PR China
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin 300071, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylb-
enzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA)
as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on
maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight
of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably,
two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further
antifungal assay showed their excellent activity against Physollospora piricola. The structure–activity rela-
tionships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further
molecular modification of new CSA analogues.
Received 10 November 2014
Revised 14 December 2014
Accepted 26 December 2014
Available online 6 January 2015
Keywords:
Herbicide safeners
CSA analogues
Synthesis
Ó 2015 Elsevier Ltd. All rights reserved.
SAR
Antifungal activity
Herbicides are not always sufficiently compatible with some
important crops such as corn, rice or cereals, and their use is
strictly limited. In some crops, they cannot be used or only be
In particular, the continued requirements of environmental
friendly crop protection and the resistance of herbicides are depen-
dent on fundamental knowledge of herbicide metabolism between
target and non-target plants. Safeners, with their unique modes of
action, are vital tools in the acquisition of such knowledge. There-
fore, finding new safeners is always meaningful to agriculture.
Recently, some new herbicides have been developed, however,
few safeners were provided to meet the needs of the herbicide
1
used at so low application rates that the desired broad herbicidal
activity against harmful weeds is not ensured. Specifically, many
herbicides cannot be used entirely selectively against harmful
weeds in corn, rice, cereal, sugarcane and other crops.2 To over-
come these disadvantages, it is considerably necessary to employ
safeners in combination with herbicides. As it is well known that
safeners can improve selectivity of herbicide between crop and
weed species, also it can be applied either as a mixture with the
,3
1
0
market until a novel type and important safener cyprosulfamide
1
,11–13
(CSA, Fig. 1)
was invented by Bayer Crop Science in 2005.
This safener has been co-developed with herbicides benzoylpyraz-
4
,5
11
14
herbicide or as a seed-treatment to the crop seed before sowing.
ole and thiencarbazone-methyl (TCM, Fig. 1) and was demon-
Since last century, several compounds have been developed as
safeners and have been used in agricultural field including classes
of dichloroacetanilides, carboxylic acid analogues, oxime esters
and so on. The first commercial synthetic herbicide safener Naph-
thalic anhydride (NA) was discovered by Hoffman in 1969. It was
versatile and could protect various crops from a great variety of
strated to have excellent activity as a safener combined with
1
5
TCM in 2007. Since TCM is a very important herbicide for the
selective control of grasses and broadleaf weeds primarily in corn
and has now been registered in some important corn producing
countries of Europe and other parts of the world. Many new herbi-
cide compositions, such as Corvus and Adengo 465 SC16 comprised
of TCM and CSA have been registered in different countries since
2007.
6
,7
8
herbicides. After Dichlormid (R-25788) was developed as a saf-
9
ener and Eradicane composed of the herbicide and Dichlormid
was on sale, safeners have played an important role in protecting
crops from the damage of herbicides.
CSA belongs to the chemical class of aromatic sulfonamides. It
can reliably protect corns from the damage of TCM through
enhancing herbicide metabolism via gene activation. Using herbi-
cides composed of TCM and CSA is a successful path for weed con-
trol in conventional and herbicide-tolerant corn production
systems and the herbicidal activity is maintained in the presence
⇑
Corresponding authors.
E-mail addresses: bioassay@nankai.edu.cn (Y. Li), dequn.sun@sdu.edu.cn
(
D. Sun).
These authors contribute equally.
17
of CSA.
http://dx.doi.org/10.1016/j.bmcl.2014.12.085
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
0

7
92
Y. Zheng et al. / Bioorg. Med. Chem. Lett. 25 (2015) 791–794
O
O
O
screening.19,20 Maize seedlings of Zhengdan 958 (from Henan Agri-
cultural Science without treatments) were used to evaluated the
O
O
O
S
O
O
O
S
O
N
2
1
N
H
N
N
N
H
H
N
protective effect of CSA analogues
(20 g per unit area,
2
S
666.7 m ). Results of repeated experiments (five seedlings for each
group, twice) were summarized in Table 1 and Table 2.
O
O
Thiencarbazone-methyl (TCM)
Cyprosulfamide (CSA)
When exposed to thiencarbazone-methyl (2.5 g per unit area,
66.7 m ), growth of maize seedlings was strongly arrested, its
2
6
O
O
main performance was a loss of fresh and dry weight of aerial
O
S
parts. This effect was largely reversed in the presence of CSA
N
H
2
(
20 g per unit area, 666.7 m ). All title compounds except 6IIa,
CONHR1
R2
6
IIe, 6IId exhibited better activity to plant height of maize than
CSA (À7.3%). The inhibition rate of TCM to the fresh weight of aer-
ial parts of maize was 12.9% (Table 1, entry 2), which was reduced
to 8.0% after the addition of CSA (Table 1, entry 3). It was found
that for the inhibition of fresh weight of aerial parts, ten com-
pounds (6Ia, 6Ib, 6Ic, 6Id, 6Ie, 6If, 6Ih, 6Ii, 6IId, 7II) could protect
maize from the damage of TCM at a certain extent (À11.6%,
À6.7%, À2.8%, À11.2%, À8.5%, À10.3%, À14.9%, À3.4%, À5.8%,
À18.6%, respectively). The inhibition rate of TCM to the dry weight
of aerial parts of maize was 14.7% (Table 1, entry 2), which was
reduced to 13.4% after the addition of CSA (entry 3), obvious pro-
tective effect was displayed by five compounds (6Ia, 6Id, 6If, 6Ih,
Figure 1. Structures of TCM, CSA and title compounds.
However, structure–activity relationships (SAR) study of CSA
and its analogues beneficial to new safener development have been
1
8
rarely reported. Owing to the excellent bioactivity of CSA as one
of the best sellers and its unclear mechanism, a series of novel acy-
lsulfamoylbenzamide analogues (Fig. 1, Scheme 1) was designed
and synthesized for the first time with CSA as the leading com-
pound based on molecular similarity. Their activity assay as safen-
ers on protecting the maize from the damage of TCM was
evaluated.
7
II) at a certain extent (À0.7%, À6.4%, À10.1%, À13.5%, À7.1%).
For the dry weight of underground parts, most of title com-
The preparation of target compounds contains four steps
pounds exhibited obvious inhibition (Table 2). While three com-
pounds (6Ie, 6Ih, 7II) could protect the root of maize seedling at
a certain extent (À0.6%, À3.9%, À6.7%, respectively).
(
Scheme 1), the carboxyl group in starting material 1 was firstly
activated to the mixed anhydride group, following amination by
three different amines to give intermediates 2. Oxidation of methyl
group of 2 by KMnO in water afforded acids 3, which was acti-
4
For all compounds tested, 6Ih and 7II showed protective effect
to all the four aspects of maize growth.
vated to give mixed anhydrides similar with the first step.
However, amination of anhydrides with sulfanilamides were
unsuccessful, therefore, the final condensation of anhydrous 3 with
sulfanilamides (4 and 5) was fulfilled by EDCI and DMAP to give
title compounds 6 and 7, respectively.
Safener activity: In the bioassay of Oryzeae, Echinochloa, wheat
and maize are always used to evaluate the toxicity of potential
compounds because of low compounds usage and rapid
Structure–activity relationship: For the plant height of maize
seedlings, difference among compounds with cyclopropyl (6Ia,
6
6
Id, 6Ie), methyl (6IIa ,6IId, 6IIe) and isopropyl group (6IIIa, 6IIId,
IIIe) showed that compounds with the cyclopropyl group exhib-
ited stronger protective effect (À25.4%, À22%, À24.2% for 6Ia,
6
Id, 6Ie, respectively) than compounds with methyl group
(À1.6%, À18.9%, 6.1% for 6IIa ,6IId, 6IIe, respectively) and
O
O
O
SO2NH2
R
S
2
N
H
R2
CONHR1
COOH
ClCOOMe
COOCOOMe
CONHR1
KMnO4
73-78%
CONHR1
COOH
6Ia~i
6
IIa,d,e
R1 NH2
4.8-95%
6IIIa,d,e
9
5
:
H3CO
SO2NH2
1
2I~III
O
3I~III
O
O
S
N
H
CONHR1
H3CO
R1
=
I
,
II
CH3
,
III
7I~III
i
O
R2=
a
O
b
,
,
c
OCH3 ,
d
CH3 ,
e
H
,
f
CF
3 ,
g
Cl ,
h
NO
2 ,
CF3
O
O
O
O
O
4
c 90.7%
SO2Cl
SO NH2
2
NH3gas
O
O
O
ClSO2OH
5
87%
SO2Cl
SO2NH2
Scheme 1. General synthetic routes for title compounds.

Y. Zheng et al. / Bioorg. Med. Chem. Lett. 25 (2015) 791–794
793
Table 1
Protective effect of CSA analogues to aerial parts of TCM treated maize seedling
Entry Compd no
Plant height
Fresh weight of aerial parts
Dry weight of aerial parts
ꢀ
x
Significance Inhibition rate
of difference (%)
Five plants
(g)
Significance Inhibition rate
of difference (%)
Five plants
(g)
Significance Inhibition rate
of difference (%)
(cm)
5
%
1%
BC
5%
1%
5%
1%
*
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
Control
TCM
49.2
50.4
52.8
61.7
59.5
53.2
60
61.1
62
53.8
55.3
54.5
50
de
bcde
0
30.04
26.17
27.64
33.53
32.04
30.89
33.39
32.59
33.12
29.97
34.53
31.05
25.65
31.79
19.08
27.95
25.89
27.98
29.98
35.62
29.48
ab
ab
ab
a
ab
ab
a
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
0
12.9
8
À11.6
À6.7
À2.8
À11.2
À8.5
À10.3
0.2
À14.9
À3.4
14.6
À5.8
36.5
7
7.03
6
ab
ab
ab
ab
ab
ab
a
ab
a
ab
a
ab
ab
ab
b
ab
ab
ab
ab
a
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
0
14.7
13.4
À0.7
3.8
ABC À2.4
TCM+CSA
TCM+6Ia
TCM+6Ib
TCM+6Ic
TCM+6Id
TCM+6Ie
TCM+6If
TCM+6Ig
TCM+6Ih
TCM+6Ii
TCM+6IIa
TCM+6IId
TCM+6IIe
TCM+6IIIa 56.1
TCM+6IIId 52.2
TCM+6IIIe 55.1
TCM+7I
TCM+7II
TCM+7III
abcde ABC À7.3
6.09
7.08
6.76
6.69
7.48
6.36
7.74
6.65
7.98
6.87
5.64
6.76
3.61
5.74
5.47
5.42
6.22
7.53
6.06
a
abc
AB
À25.4
ABC À20.9
abcde ABC À8.1
4.8
ab
a
a
AB
AB
A
À22
À6.4
À24.2
À26
a
a
9.5
À10.1
5.4
0
1
2
3
4
5
6
7
8
9
0
1
abcde ABC À9.3
abcde ABC À12.4
abcde ABC À10.8
ab
a
ab
ab
ab
b
ab
ab
ab
ab
a
À13.5
2.3
cde
abcd
e
ABC À1.6
19.8
3.8
58.5
46.2
ABC À18.9
C
6.1
48.6
18.3
22.2
22.9
11.5
À7.1
13.8
abcd
ABC À14
abcde ABC À6.1
abcde ABC À12
13.8
6.9
0.2
58.5
61.1
57.2
abcd
a
abcd
ABC À18.9
AB
À24.2
À18.6
ABC À16.3
ab
1.9
ab
ABCDE, abcde: no significant difference (P >0.05) between groups have at least one same letter.
*
Treated with no compounds.
Table 2
For the fresh weight and dry weight of aerial parts, similar pro-
Protective effect of CSA analogues to underground parts of TCM treated maize
seedling
tective effect could be included from compounds with cyclopropyl,
methyl and isopropyl group. Cyclopropyl group was further proved
to be an important pharmacophore, because compounds with
cyclopropyl group exhibited better protective activity (À11.6%,
À11.2%, À8.5% for 6Ia, 6Id, 6Ie, respectively) than compounds with
methyl (14.6%, À5.8%, 36.5% for 6IIa ,6IId, 6IIe, respectively) and
compounds with isopropyl group (5.74%, 5.47%, 5.42% for 6IIIa,
IIId, 6IIIe, respectively). The substitution of methyl groups on
6Ic and 6Id with trifluoromethyl groups on 6Ii and 6If reduced
the inhibition (enhance the protective effect) to maize root growth
Entry Compd no
Dry weight of underground parts
Five plants (g)
Significance of
difference
Inhibition rate (%)
5
%
1%
*
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
Control
TCM
3.58
3.86
4.21
3.3
2.82
2.97
3.06
3.6
3.12
2.81
3.72
3.04
2.21
2.51
2.03
abcd
ab
a
AB
AB
A
0
À7.8
À17.6
7.8
6
TCM+CSA
TCM+6Ia
TCM+6Ib
TCM+6Ic
TCM+6Id
TCM+6Ie
TCM+6If
TCM+6Ig
TCM+6Ih
TCM+6Ii
TCM+6IIa
TCM+6IId
TCM+6IIe
TCM+6IIIa 2.54
TCM+6IIId 2.14
TCM+6IIIe 2.95
TCM+7I
TCM+7II
TCM+7III
abcd
abcd
abcd
abcd
abcd
abcd
abcd
abc
abcd
cd
bcd
d
bcd
cd
abcd
abcd
ab
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
AB
B
AB
AB
AB
AB
AB
AB
21.2
17.0
14.5
À0.6
12.8
21.5
À3.9
15.1
38.3
29.9
43.3
29.1
40.2
17.6
23.5
À6.7
32.7
(
4.8–2.3%, À6.4% to À10.1%). This result indicated further that the
introduction of fluorine atom would contribute to the increase of
the activity.
For the dry weight of underground parts, compounds with
cyclopropyl group (6Ia, 6Id, 6Ie) showed better activity (7.8%,
0
1
2
3
4
5
6
7
8
9
0
1
1
6
4.5%, À0.6%) than those with methyl (38.3%, 29.9%, 43.3% for
IIa, 6IId, 6IIe, respectively) or isopropyl (29.1%, 40.2%, 17.6% for
6IIIa, 6IIId, 6IIIe, respectively). Replace of methyl groups on 6Ic
and 6Id with trifluoromethyl groups on 6Ii and 6If reduced the
inhibition to root growth of maize seedling (17–15.1%, 14.5–
2.8%). This result revealed again that cyclopropyl group and fluo-
rine atom were very necessary pharmacophores for the design of
potential safeners.
For all the compounds, the activity were not be affected signif-
icantly by the introduction of an electron-withdrawing or an elec-
tron-donating group at ortho position of sulfonamide group on the
benzene ring.
1
2.74
3.82
2.41
bcd
ABCDE, abcde: no significant difference between groups have at least one same
letter.
*
Treated with no compounds.
Antifungal activity: Phytopathogenic fungi that easily infect
many crops are hard to control and risking resistance to the widely
2
2
compounds isopropyl group (À14%, À6.1%, À12% for 6IIIa, 6IIId,
used commercial fungicides. Sulfonamides which were exten-
sively employed as effective antimicrobial antifolic agents for the
prevention and cure of bacterial infections in human biological sys-
tems as early as 70 years ago, have aroused considerable interest in
biology and medicine for their diversified pharmacological activi-
6
IIIe, respectively) on the height of maize seedling, which revealed
the cyclopropyl group might be an important pharmacophore. The
substitution of methyl groups on 6Ic and 6Id with trifluoromethyl
groups on 6Ii and 6If reduced the inhibition to maize root growth
2
3a,b
24
(
from À8.1% to À10.8%, and from À22% to À26%, respectively). This
ties including carbonic anhydrase inhibitors,
viral, antitumor, and anti-inflammatory ones in recent years.
The sulfanilamide group in title compounds encouraged us to
antifungal, anti-
2
5
26
27
result indicated that the introduction of fluorine atom was favor-
able to the activity improvement of safener.

7
94
Y. Zheng et al. / Bioorg. Med. Chem. Lett. 25 (2015) 791–794
Table 3
for maize seedling from the damage of TCM, twelve compounds
6Ia, 6Ib, 6Ic, 6Id, 6Ie, 6If, 6Ig, 6Ih, 6Ii, 6IId, 7I, 7II) exhibited better
Antifungal activity of CSA analogues
(
Entry
Compound (50
lg/mL)
Inhibition rate (%)
activity than CSA on the dry weight of aerial parts. Most important
of all, two compounds (6Ih, 7II) had protective effect on the four
aspects of TCM treated maize, which could be leading compounds
for developing potential safeners. The antifungal activity of title
compounds showed five compounds (6If, 6Ih, 6IIa, 6IId, 6IIIa)
had excellent antifungal activity against PP. The given structure–
activity relationship of them was useful for design of more novel
potential molecules. Furthermore, the further study of them
regarding test on other crops as well as using other herbicides as
synergistic composition are ongoing, more extensive details will
be reported in future.
FO
MA
PP
AS
FG
1
2
3
4
5
6
7
8
9
CSA
6Ia
6Ib
6Ic
6Id
6Ie
10.5
0
13.3
13.3
6.7
6.7
6.7
26.7
26.7
6.7
6.7
0
46.7
26.7
20
20
33.3
60
13.3
20
6.7
51.9
55.6
51.9
70.4
48.1
55.6
96.3
77.8
92.6
74.1
96.3
92.6
51.9
92.6
74.1
48.1
74.1
66.7
88.9
26.3
36.8
31.6
36.8
31.6
36.8
36.8
36.8
31.6
36.8
36.8
36.8
52.6
21.1
42.1
52.6
31.6
26.3
26.3
27.8
44.4
50
15.8
10.5
10.5
15.8
10.5
5.3
10.5
0
31.6
36.8
0
15.8
5.3
26.3
15.8
10.5
15.8
50
44.4
38.9
55.6
50
55.6
61.1
61.1
66.7
22.2
27.8
50
6If
6Ig
6Ih
6Ii
6IIa
6IId
6IIe
6IIIa
6IIId
6IIIe
7I
10
11
12
13
14
15
16
17
18
19
Acknowledgment
This work was financially supported by the National High-Tech
Program of China (863 Project No. 2012AA020306).
38.9
44.4
55.6
61.1
7II
7III
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.12.
conjecture whether the title compounds in our work had some
antifungal activity or not. It would be meaningful if safeners have
antifungal activity as well. Therefore, five typical fungi included
Fusarium oxysporum (FO), Mycosphaerella arachidicola (MA), Physol-
lospora piricola (PP), Alternaria sonali (AS), Fusarium graminearum
0
85.
References and notes
1.
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D. E. U.S. Pat. 20070010399 A1, 2007.
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to evaluated the antifungal activity of CSA analogues (Table 3).
All the new CSA analogues exhibited certain growth inhibition
effects against most of the tested fungi. Low inhibition was showed
for FO (0–36.8%) and MA (0–60.0%) with the exception of 60.0%
showed by 6IIIe to MA. Moderate inhibition was exhibited for AS
2. Fischer, R. S.; Jensen, R. A. U.S. Pat. 1993005187071 A, 1993.
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4
5
.
.
.
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(
6
21.1–52.6%) and FG (22.2–61.1%). While to PP, the activities of
If, 6Ih, 6IIa, 6IId, 6IIIa (96.3%, 92.6%, 96.3%, 92.6%, 92.6%, respec-
2
3, 15.
9. Chang, T. S.; Merkle, M. G. Weed Sci. 1982, 30, 70.
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new CSA analogues might represent a novel chemical skeleton
with good activity for inhibiting PP.
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The inhibition activities against the two fungi PP and FG were
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better protective effect than CSA on the fresh weight of aerial parts