Design, synthesis, and SAR of novel 2-glycinamide cyclohexyl sulfonamide derivatives against botrytis cinerea

Article abstract of DOI:10.3390/molecules23040740

N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by ¹H-NMR, ¹³C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 μg mL^?1, and 7 compounds showed lower EC₅₀ values than boscalid (EC₅₀ = 4.46 μg mL^?1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 μg mL^?1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides.

Full text of DOI:10.3390/molecules23040740

molecules
Article
Design, Synthesis, and SAR of Novel 2-Glycinamide
Cyclohexyl Sulfonamide Derivatives against
Botrytis cinerea
Nan Cai 1 ID , Caixiu Liu 1, Zhihui Feng 1, Xinghai Li 1,*, Zhiqiu Qi 1, Mingshan Ji 1, Peiwen Qin 1,
Wasim Ahmed 2 and Zining Cui 2,
*
1
Department of Pesticide Science, Plant Protection College, Shenyang Agricultural University,
Shenyang 110866, Liaoning, China; ladycainan@126.com (N.C.); LCX14714027@163.com (C.L.);
zhihuige950820@163.com (Z.F.); syqizhiqiu@sina.com (Z.Q.); jimingshan@163.com (M.J.);
qinpeiwen08@sina.com (P.Q.)
State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources,
Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and
Disease Control, South China Agricultural University, Guangzhou 510642, Guangdong, China;
wasimahmed1485@gmail.com
2
*
Correspondence: xinghai30@163.com (X.L.); ziningcui@scau.edu.cn (Z.C.);
Tel.: +86-24-8834-2018 (X.L.); +86-20-8528-8229 (Z.C.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 6 February 2018; Accepted: 19 March 2018; Published: 23 March 2018
Abstract: N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in
the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring
more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine
coupling reactions with chesulfamide as the core moiety, and their structures were characterized
1
and established by H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-
2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl)
acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal
activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated
that most compounds exhibited excellent inhibitory activity against B. cinerea at 50
and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46
g mL−1) against B. cinerea
(CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4 II-5 II-12,
µ ,
g mL−1
µ
,
,
and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil
(88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two
analogs (II-8 and II-15) were 87.98 and 87.97% at 200 µ
g mL−1, which were significantly higher than
boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as
a lead compound for developing new pesticides.
Keywords: β-aminosulfonamide; glycinamide; N-alkylation reaction; fungicidal activity; Botrytis
cinerea
1. Introduction
Plant-pathogenic fungi, with the characteristics of diversity and wide distribution, are causing a
destructive economic and humanitarian problem, which threatens food security and biodiversity [1–5].
B. cinerea, one of the important representative fungi, has a necrotic lifestyle, and attacks over 200 major
dicotyledonous plants in temperate and subtropical regions, causing soft rotting of all aerial plant
parts, as well as decaying vegetables, fruits, and flowers after harvesting [
6,
7]. Despite the availability
of many fungicides to control it, many of them have failed due to the genetic plasticity [
6
]. The reality
Molecules 2018, 23, 740; doi:10.3390/molecules23040740
www.mdpi.com/journal/molecules

Molecules 2018, 23, 740
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is that the resistance in various parts of the world is not adequate [
8–
11]. The rapid development of
the resistance of Botrytis cinerea and the ongoing emergence of resistant strains attracted our attention
for the development of new fungicides.
In current research and development of fungicides, amide and sulfonamide compounds are
the center of attraction. Compounds with amide structures have been reported to have broad
pharmaceutical activities against bacteria [12], virus [13], inflammation [14], tumors [15] diabetes [16],
and also showed excellent fungicidal activity in agrochemicals. The molecular size and charge
distribution characteristics of sulfonamide are similar to amide. Additionally, reasonable introduction
of sulfonyl can increase metabolic stability of the functional molecule and prolong the duration of action
by blocking the metabolic instability site and improve the bioavailability [17]. Compounds with active
sulfonamide and amide substructure may have a new mechanism of action. Therefore, while designing
the new molecular structures, we introduced both sulfonamide and amide groups to examine the
fungicidal activity.
In our previous work, we found that chesulfamide (L-1) [18–21] can effectively control B. cinerea
and Corynespora cassiicola with strong preventive, therapeutic and osmotic activity [18]. It is worth
mentioning that chesulfamide has a unique mechanism of action, which includes (1) acting on
mycelium cell membrane, (2) reducing the content of DNA and polysaccharide in mycelium and having
certain binding effects with DNA, and (3) inducing disease resistance of plants [18]. Using chesulfamide
as the lead compound, we reduced the oxo group to the hydroxyl group [22,23] to make related
esters [23 24], and replaced the hydroxyl group by the amino group [25], which enabled the
,
introduction of aromatic and heterocyclic rings [26]. After analyzing the structure–activity relationship
(SAR), we found that converting carbonyl to amino group (L-2) improved the reactivity, made the
structure more variable, and enhanced the anticipation of introducing diversified active structures into
the main structure. Afterwards, the amino group was transformed to aminoacetate (L-3), a glycine
derivative structure, and we attempted to exploit the high affinity of glycine for organisms to increase
biological activity, but unfortunately we did not achieve the desired bioassay results [25]. In order
to get improved activity, aminoacetate was converted into aminoacetamide with alkyl, phenethyl,
benzyl, and substituted benzene ring (Figure 1). Aminoacetamide structure was found in the
listed fungicides, such as iprovalicarb, valifenalate and benthiavalicarb-isopropyl (Figure 2) [27],
and previous reports also showed that compounds containing this structure have outstanding
pharmacological activity [26,28–31]. Therefore, among the structures, nitrogen was functionalized
as alkyl, sulfonyl, benzene, piperidine, and acylated tetrazole, in order to get more diverse products
(Figure 3), but the cyclohexylsulfonamide structure that we linked in target compounds had not
yet been done before. Here, we designed and synthesized a series of 2-glycinamide cyclohexyl
sulfonamide derivatives. Their comprehensive fungicidal activity against B. cinerea were evaluated,
and the structure–activity relationship was analyzed. The synthetic routes of intermediates and target
compounds were shown in Schemes 1 and 2, respectively.

Molecules 2018, 23, 740
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Figure 1. The designed strategy for title compounds II.
Figure 2. Chemical structures of some fungicides.
Figure 3. Chemical structures of several N-substituted glycinamide compounds.
Scheme 1. Synthesis of substituted chloroacetamides I.

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Scheme 2. Synthesis of N-substituted glycinamide derivatives of 2-amino-cyclohexylsulfonamides II
.
2. Result and Discussion
2.1. Chemistry
The synthetic routes for the target compounds are shown in Scheme 2.
Substituted chloroacetamide (Intermediate I) was synthesized by the reaction of amines and
chloroacetyl chloride in dichloromethane (CH2Cl2) as solvent in the presence of triethylamine
(Et3N). The target compounds II-1 to II-28 were obtained by the nitrogen alkylation reaction of
N-(2-trifluoromethyl-4-chlorophenyl)-2-amino cyclohexyl sulfonamide (the key intermediate L-2
)
with intermediate I in the presence of cesium hydroxide (CsOH) in N,N-dimethylformamide
(DMF). N-(2-Trifluoromethyl-4-chlorophenyl)-2-ethoxyacylmethyl amino cyclohexyl sulfonamide
L-4 was transformed to N-(2-trifluoromethyl-4-chlorophenyl)-2-carboxymethyl amino cyclohexyl
sulfonamide L-5 by consecutive hydrolysis and acidification reaction. Then, the free acid of
L-5 was coupled with different amines in presence of 1-hydroxybenzotriazole (HOBt) and
◦
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide (EDCI) at 0 C to obtain the target compounds
II-29 to II-33.
By comparing the two methods used to synthesize the target compounds, we found the later
method resulted in higher yields and easier purification. Prior to this, we also tried to use potassium
tert-butoxide [32], magnesium methoxide, and calcium chloride [33] as catalysts, trying to promote the
amidation reaction of L-4 with amines, but we abandoned this method finally, because of its low yield.
1
The structures of the target compounds were characterized by H-NMR, 13C-NMR, MS and
1
elemental analysis. Twenty two of them were published in a Chinese patent [34]. The H-NMR
and 13C-NMR spectra are available in Supplementary Data. Additionally, the structure of II-19 was
confirmed by X-ray single crystal diffraction (Figure 4a). The molecular structure of II-19 existed as
a chair conformation, the sulfonamide moiety on the equatorial bond position and the glycinamide
moiety was linked to cyclohexane by an axial bond. The first chiral carbon atom (C11) had the
S configuration and the second chiral carbon atom (C10) had the R configuration. Based on the
structural similarities of all the target compounds, it was supposed that all the compounds had the
same configuration, the same as II-19. Interestingly, a reported compound (Figure 4b) with similar
structure showed proton transfer [25], which was not observed in this study. We found that the H atom
on SO2–NH (N2) was trapped by the N atom (N1) attached to the cyclohexane, whereas compound
II-19 did not present this behavior. Since the amino group (N2) linked to the acetamido structure
(which probably exerts an electron withdrawing effect) may acquire a weaker basicity, the lack of
proton migration phenomenon appears to be justified.

Molecules 2018, 23, 740
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(a) Target compound II-19
(b) Structure in our previous study
Figure 4. X-ray crystal structures (red represents oxygen, green is fluorin, light blue stands for hydrogen,
deep blue symbolizes nitrogen).
2.2. Biological Activity and Structure–Activity Relationship Study
The mycelium inhibition of all target compounds against B. cinerea was initially tested at
50 µg mL−1, and most of them exhibited significant fungicidal activity similar or superior to control
(Tables 1 and 2). The inhibitory rate of II-4, II-12, and II-13 (90.66%, 90.41%, and 90.90%) was higher
than boscalid (89.18%) against CY-09. Next, we further carried out a concentration gradient test
on CY-09 and calculated the EC50 values (Table 1). The result showed that the EC50 values of
14 compounds were less than procymidone (EC50 = 10.31
had higher fungicidal activity than all positive control, with the EC50 values of 3.38, 3.38, 3.26, 3.40,
and 3.57 µg mL−1
II-4 II-11 II-18 II-30 II-31, and II-33 also showed outstanding fungicidal activity,
µg/mL). II-5, II-6, II-19, II-26, and II-28
.
,
,
,
,
which were significantly better than carbendazim, and substantially the same or better than the other
four. Based on the results, 9 compounds were tested on HLD-15 and DL-11 in the same manner,
and further confirmed the high fungicidal activity again (Table 2).

Molecules 2018, 23, 740
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Table 1. In vitro fungicidal activities of target compounds against Botrytis cinerea (CY-09).
Compd.
R
Inhibition Rate (%)
EC50 Values
II-1
II-2
II-3
II-4
II-5
II-6
II-7
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
II-21
II-22
II-23
II-24
II-25
II-26
II-27
II-28
II-29
II-30
C6H5–
3-F–C6H4–
4-F–C6H4–
12.49
51.08
76.89
90.66
85.74
89.18
81.32
84.76
84.51
69.27
72.71
90.41
90.90
88.94
85.25
53.05
73.45
33.87
82.79
6.59
31.91
14.70
33.38
51.57
56.00
88.20
66.81
75.42
55.75
75.42
>100
>100
16.23
4.01
3.38
3.38
2,4-2F–C6H3–
2,5-2F–C6H3–
2-F–4-Cl–C6H3–
2-F–4-Br–C6H3–
3-F–4-Br–C6H3–
2-CF3–4-F–C6H3–
2-F–5-CF3–C6H3–
3-Br–4F–C6H3–
3-CN–4-F–C6H3–
2,3,4-3F–C6H2–
2,4,5-3F–C6H2–
2-Br–C6H4–
9.44
7.23
23.57
13.66
12.68
16.27
14.67
8.9
4.99
3-Br–C6H4–
>100
16.48
>100
3.26
>100
>100
>100
>100
>100
8.02
3.4
15.13
3.57
34.18
5.9
2,4-2Br–C6H3–
2-CH3–C6H4–
2-CF3–C6H4–
3-CF3–C6H4–
3,5-2CF3–C6H3–
3-CH3O–C6H4–
4-CH3O–C6H4–
2-CF3O–C6H4–
2-Cl-C6H4-CH2–
2-Br–C6H4–CH2–
2-CH3–C6H4–CH2–
2-Br–C6H4–CH2CH2–
CH3CH2–
CH3(CH2)2–
II-31
69.52
3.77
II-32
81.32
14.07
II-33
CH3(CH2)3–
83.78
33.87
69.27
89.18
6.5
867.82
10.31
4.46
Carbendazim
Procymidone
Boscalid
/
/
/
Table 2. In vitro fungicidal activities of specific target compounds against B. cinerea (HLD-15 and DL-11).
HLD-15
Inhibition
DL-11
Inhibition
Rate (%)
Compd.
R
EC50
EC50
Values
Rate (%)
Values
II-4
II-5
II-6
II-26
II-27
II-28
II-30
2,4-2F–C6H3–
2,5-2F–C6H3–
83.41
83.93
71.75
70.19
79.52
96.89
84.19
1.88
2.3
89.47
87.63
91.57
94.47
78.94
95.00
86.05
2.07
2.55
3.94
2.92
5.55
2.47
5.79
2-F–4-Cl–C6H3–
2-Br–C6H4–CH2–
2-CH3–C6H4–CH2–
2-Br–C6H4–CH2CH2–
CH3(CH2)2–
2.13
2.96
7.25
2.26
7.12
II-31
75.12
5.31
65.24
4.36
II-33
CH3(CH2)3–
76.67
10.32
79.00
87.82
6.34
427.78
10.13
2.44
95.26
10.48
75.25
86.57
2.97
673.38
8.61
Carbendazim
Procymidone
Boscalid
/
/
/
2.27

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The compounds with outstanding fungicidal activity in vitro tests also demonstrated excellent
control effect and stable performance in cucumber and tomato pot experiments (Tables 3 and 4).
Meanwhile, there was no phytotoxicity occurred during the tests. II-4, II-5, II-12 and II-13,
which showed superb activity in vitro tests, had higher inhibition rates (90.48%, 93.45%, 92.86%,
and 91.07%) in cucumber pot test than carbendazim (59.52%), procymidone (83.33%), boscalid (88.10%),
pyrimethanil (82.14%), and cyprodinil (88.69%). In tomato pot test, the control efficacy of II-4
II-8 II-15, and II-33 were 67.19%, 68.43%, 73.83%, 80.14%, 76.96%, and 72.02% at the concentration
of 500
g mL−1, which were similar to boscalid (77.05%), the best performing amongst the controls.
Subsequently, we selected 9 compounds to test, and reduced the concentration to 200
g mL−1
The results showed that the test compounds basically maintained high control effect, and the control
efficacy of II-4 II-5, II-8, and II-15 (78.51%, 78.91%, 87.98%, and 87.97%) were better than all control
, II-5, II-7,
,
µ
µ
.
,
agents. Due to the growth status of tomato seedlings and the pathogenicity of spores at different
stages, the two batches of results did not show a directly proportional to the concentration, but overall,
results showed the same trend, that specific compounds showed higher effect than control.
−1
Table 3. Fungicidal activities of specific compounds in cucumber pot test at 500 µg mL
.
Compd.
Inhibition Rate (%)
Compd.
Inhibition Rate (%)
II-2
II-3
II-4
II-5
II-6
II-7
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
33.33
79.76
90.48
93.45
86.31
80.36
79.17
73.81
72.62
62.50
92.86
91.07
75.60
88.69
30.95
59.52
83.33
II-17
II-18
II-20
II-23
II-24
II-25
II-26
II-27
II-28
II-29
II-30
II-31
II-32
59.52
20.83
64.88
27.38
71.43
35.71
53.57
37.50
51.19
66.07
42.86
63.09
71.43
75.00
82.14
88.10
88.69
II-33
Pyrimethanil
Boscalid
Cyprodinil
Carbendazim
Procymidone
Table 4. Control efficiency of specific compounds against B. cinerea in tomato pot tests.
−1
−1
200 µg mL
500 µg mL
Compd.
Disease Index
Control Efficacy (%)
Disease Index
Control Efficacy (%)
II-2
II-4
II-5
II-6
II-7
5.82
7.47
7.19
18.66
5.96
4.52
12.69
11.28
21.39
9.73
74.43
67.19
68.43
18.04
73.83
80.14
44.27
50.46
6.04
57.27
76.96
13.43
36.25
35.33
24.40
4.66
11.37
8.42
8.26
/
12.10
4.71
/
/
/
/
4.71
/
70.98
78.51
78.91
/
69.11
87.98
/
/
/
/
87.97
/
/
/
II-8
II-10
II-11
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
5.25
19.71
14.52
14.72
17.21
21.71
/
/
/
/
/
/

Molecules 2018, 23, 740
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Table 4. Cont.
−1
−1
200 µg mL
500 µg mL
Compd.
Disease Index
Control Efficacy (%)
Disease Index
Control Efficacy (%)
II-24
II-26
II-28
II-29
II-30
II-31
II-32
II-33
20.99
13.30
8.21
9.17
11.56
8.58
16.02
6.37
15.25
5.91
5.23
22.77
7.81
41.57
63.93
59.74
49.21
62.33
29.63
72.02
33.00
74.05
77.05
/
/
/
12.61
/
/
15.08
/
9.74
19.62
13.45
8.58
39.18
/
/
67.83
/
/
61.51
/
75.15
49.93
65.67
78.10
/
Pyrimethanil
Procymidone
Boscalid
CK
Accordingly, by analyzing the experimental results, we determined the relationship between
chemical structures and fungicidal activity as (1) the compounds with substituents on benzene ring
were better than that without substituents (II-1), and fluorine and bromine atoms on benzene ring
showed better activity, while fluorine was the best; (2) Substituents on phenyl ring were more active
at para- and ortho-position than at meta-position. Activity was generally low with substituents only
at meta-position (II-2
,
II-16
,
II-20, II-22) and with little activity at both 3- and 5-position (II-21);
(3) Compared II-3 II-4
,
,
II-5
,
II-13 and II-14, we found that there was no significant difference
between di- and multi-substituted compounds, but it was obviously better than the mono-substituted;
(4) The halogen atoms on the benzene ring were superior to the electron-donating groups (CH3O-);
(5) Comparison of II-18 and II-27 or comparison among II-15, II-26, and II-28 showed that extension
of the carbon chain between the amine group and benzene ring increased in vitro fungicidal activity;
(6) By comparing II-29 to II-33, it can be concluded that increasing the length of the alkyl carbon
chain enhanced fungicidal activity, and the cyclic structure (II-31) had a higher activity than the chain
structure (II-30) of the same carbon number. In total, compounds with substituted benzene ring
showed more stable and highly fungicidal activity than compounds with alkyl substituents.
Based on overall bioassay results, the compounds had a stronger fungicidal effect on in vitro
assays and cucumber pot experiments (infected with mycelium) compared to tomato pot experiments
(infected with spraying spores), that is to say, the compounds had slightly better inhibitory effects on
mycelium than spores.
3. Materials and Method
3.1. Materials and Instrumentation
All solvents and reagents were commercially available for analytical reagent (AR) grade and dried
prior to use. Column chromatography (Silica gel: 200–300 mesh) was used to purify target compounds.
The melting points were determined by the X-5 binocular microscope melting point apparatus
1
(Beijing Tech Instrument Co. Ltd., Beijing, China). H-NMR and 13C-NMR spectra were recorded
on a Bruker 600 MHz and 101 MHz spectrometer (Bruker, Karlsruhe, Germany), using dimethyl
sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as the internal standard. MS data were
obtained on the 7000C Triple Quad GC/MS and 6460 Triple Quad LC/MS Mass Spectrometers
(Agilent Technologies, Santa Clara, CA, USA).

Molecules 2018, 23, 740
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3.2. Synthesis
3.2.1. Synthesis of N-(2-Trifluoromethyl-4-chlorophenyl)-2-aminocyclohexyl Sulfonamide L-2
The synthesis of intermediate L-2 was done according to the reported method [35].
3.2.2. Synthesis of Substituted Chloroacetamide I
Under nitrogen atmosphere, dry CH2Cl2 (30 mL), amine (0.02 mol), and Et3N (0.05 mol) were
added to a three-necked round bottom flask and stirred for 0.5 h, then chloroacetyl chloride dropped
slowly and reacted for 3 h at room temperature. Then, the solution was washed with 2 mol L−1
hydrochloric acid (30 mL), saturated aq NaHCO3 solution (30 mL), and brine (40 mL), successively,
then dried over anhydrous Na2SO4 and filtered. After evaporating CH2Cl2 in vacuum, the obtained
crude product was refined by recrystallization using ethyl acetate/petroleum ether.
3.2.3. Synthesis of 2-Glycinamide Cyclohexyl Sulfonamide Derivatives II-1 to II-28
Under nitrogen atmosphere, DMF (10 mL), 4 Å molecular sieves (0.5 g), and CsOH (2 mmol) were
placed in a three-necked round bottom flask and stirred for 10 min, then compound L-2 (1.5 mmol)
was added to the flask and reacted for 0.5 h. Hereafter, intermediate I (1.8 mmol) was slowly added
at room temperature, and reaction was terminated according to TLC monitoring results [25
The solution was filtered in vacuum and 100 mL distilled water added. Organic compounds were
extracted with ether (3 120 mL), organic solvent was dried over anhydrous Na2SO4 and filtered.
,36].
×
Solvent was evaporated in vacuum, and the residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate as eluents). Finally, the samples were recrystallized to give target
compounds with higher purity.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethy◦lphenyl)sulfamoyl)-cyclohexylamino)-N-phenylacetamide II-1
.
1
White solid, yield: 57.2%. mp 190–192 C. H-NMR (600 MHz, DMSO-d6):
δ
(ppm) 10.13 (s, 1H,
NH–C=O), 7.63–7.06 (m, 10H, NH + NH + C6H3 + C6H5), 3.65 (d, J = 16.0 Hz, 1H, CH–SO2),
3.50–3.39 (m, 2H, CH2), 3.29–3.23 (m, 1H, CH–N), 1.97–1.29 (m, 8H, 4CH2). 13C-NMR (101 MHz,
DMSO-d6): δ(ppm) 168.46, 138.81, 133.14, 129.19, 128.02, 126.67, 126.28, 124.46, 123.87, 122.65, 120.84,
119.33 (2), 62.67, 54.56, 49.95, 27.79, 23.93, 22.01, 19.24. EIMS, m/z 490.2 [M]+. Elemental analysis for
C21H23ClF3N3O3S: found C 51.66, H 4.58, N 8.39; calcd C 51.48, H 4.73, N 8.58.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-fluorophenyl)acetamide
II-2. White solid, yield: 62.4%. mp 179–180 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm) 10.29 (s, 1H,
NH–C=O), 7.67–6.89 (m, 9H, NH + NH + C6H3 + C6H4), 3.61 (d, J = 16.7 Hz, 1H, CH–SO2), 3.45–3.35
(m, 2H, CH2), 3.29–3.19 (m, 1H, CH–N), 2.00–1.29 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
δ
(ppm) 169.50, 163.33, 161.73, 140.56, 133.26, 130.89, 128.87, 126.83, 124.31, 122.50, 115.09, 110.22, 106.16,
105.99, 63.21, 54.28, 50.09, 27.98, 24.05, 21.90, 19.11. EIMS, m/z 508.4 [M]+. Elemental analysis for
C21H22ClF4N3O3S: found C 49.82, H 4.15, N 8.37; calcd C 49.66, H 4.37, N 8.27.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)s◦ulfamoyl)-cyclohexylamino)-N-(4-fluorophenyl)acetamide
1
II-3. White solid, yield: 56.5%. mp 157–158 C. H-NMR (600 MHz, DMSO-d6):
δ(ppm) 10.18
(s, 1H, NH–C=O), 7.66–7.15 (m, 9H, NH + NH + C6H3 + C6H4), 3.63 (d, J = 15.3 Hz, 1H, CH–SO2),
3.48–3.36 (m, 2H, CH2), 3.29–3.20 (m, 1H, CH–N), 1.95–1.30 (m, 8H, 4CH2). 13C-NMR (101 MHz,
DMSO-d6): δ(ppm) 168.55, 159.27, 157.68, 135.25, 133.18, 128.28, 126.71, 124.41, 122.60, 121.01, 115.85 (2),
115.70 (2), 62.84, 54.46, 49.91, 27.84, 23.96, 21.97, 19.20. EIMS, m/z 508.4 [M]+. Elemental analysis for
C21H22ClF4N3O3S: found C 49.38, H 4.61, N 8.52; calcd C 49.66, H 4.37, N 8.27.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2,4-difluorophenyl)acetamide
II-4. White solid, yield: 30.3%. mp 145–146 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm) 9.95 (s, 1H,
NH–C=O), 7.88–7.07 (m, 6H, C6H3 + C6H3), 6.59–6.38 (m, 2H, NH + NH), 3.76 (s, 1H, CH–SO2),
3.58–3.41 (m, 2H, CH2), 3.29–3.21 (m, 1H, CH–N), 1.94–1.30 (m, 8H, 4CH2). 13C-NMR (101 MHz,

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DMSO-d6): δ(ppm) 170.05, 160.24, 158.62, 133.23, 131.71, 130.72, 128.66, 126.73, 124.30, 123.95, 122.49,
120.57, 114.17, 63.04, 54.09, 49.81, 27.97, 24.00, 22.03, 19.31. EIMS, m/z 526.4 [M]+. Elemental analysis
for C21H21ClF5N3O3S: found C 47.72, H 3.89, N 8.16; calcd C 47.96, H 4.02, N 7.99.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2,5-difluorophenyl)acetamide
◦
1
II-5. White solid, yield: 57.9%. mp 95–97 C. H-NMR (600 MHz, DMSO-d6): δ(ppm) 9.89 (s, 1H,
NH–C=O), 8.01–7.13 (m, 6H, C6H3 + C6H3), 4.02 (m, 2H, NH + NH), 3.67 (s, 1H, CH–SO2), 3.53–3.43
(m, 2H, CH2), 3.35–3.27 (m, 1H, CH–N), 1.98–1.32 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
δ
(ppm) 169.12, 159.74, 157.09, 139.96, 133.65, 134.41, 128.96, 127.07, 123.95, 122.51, 116.66, 107.28,
101.23, 63.45, 54.09, 50.13, 28.09, 24.03, 22.01, 19.09. EIMS, m/z 526.3 [M]+. Elemental analysis for
C21H21ClF5N3O3S: found C 48.17, H 4.28, N 7.75; calcd C 47.96, H 4.02, N 7.99.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoy◦l)-cyclohexylamino)-N-(2-fluoro-4-chloro phenyl)
1
acetamide II-6. White solid, yield: 49.9%. mp 116–118 C. H-NMR (600 MHz, DMSO-d6):
δ
(ppm)
10.27 (s, 1H, NH–C=O), 8.32–7.57 (m, 6H, C6H3 + C6H3), 6.92 (s, 2H, NH + NH), 3.68 (d, J = 15.4 Hz
,
1H, CH–SO2), 3.52–3.40 (m, 2H, CH2), 3.27 (s, 1H, CH–N), 1.96–1.25 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 170.70, 152.66, 151.02, 133.26, 131.34, 129.94, 126.76, 122.44, 119.84,
119.69, 118.23, 106.45, 63.30, 60.12, 54.04, 50.48, 24.10, 21.89, 21.12, 19.22, 14.45. EIMS, m/z 542.3 [M]+.
Elemental analysis for C21H21Cl2F4N3O3S: found C 46.72, H 4.11 N 7.52; calcd C 46.51, H 3.90, N 7.75.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-fluoro-4-bromo phenyl)
◦
1
acetamide II-7. White solid, yield: 52.1%. mp 88–90 C. H-NMR (600 MHz, DMSO-d6):
10.03 (s, 1H, NH–C=O), 7.96–7.38 (m, 6H, C6H3 + C6H3), 7.12 (s, 2H, NH + NH), 3.68 (d, J = 15.3 Hz
1H, CH–SO2), 3.53–3.41 (m, 2H, CH2), 3.27 (s, 1H, CH–N), 1.99–1.21 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): (ppm) 169.35, 154.12, 152.46, 133.16, 128.22, 127.90, 126.68, 125.79, 124.59,
δ(ppm)
,
δ
124.48, 122.57, 119.29, 119.14, 115.90, 62.88, 54.29, 50.10, 28.01, 24.00, 21.97, 19.32. EIMS, m/z 588.2
[M]+. Elemental analysis for C21H22BrClF4N3O3S: found C 42.76, H 3.39, N 7.31; calcd C 42.98, H 3.61,
N 7.16.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-fluoro-4-bromo phenyl)
◦
1
acetamide II-8. White solid, yield: 64.8%. mp 149–151 C. H-NMR (600 MHz, DMSO-d6) :δ(ppm)
10.39 (s, 1H, NH–C=O), 7.72–7.31 (m, 6H, C6H3 + C6H3), 6.92 (s, 2H, NH + NH), 3.59 (d, J = 16.7 Hz,
1H, CH–SO2), 3.38 (d, J = 23.7 Hz, 2H, CH2), 3.32 (s, 1H, CH–N), 1.97–1.29 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 170.02, 159.24, 157.64, 140.03, 133.82, 133.31, 129.16, 126.87, 124.25,
122.43, 116.64, 107.31, 107.13, 101.37, 63.46, 54.13, 50.20, 28.10, 24.12, 21.83, 19.03. EIMS, m/z 588.1
[M]+. Elemental analysis for C21H21BrClF4N3O3S: found C 42.72, H 3.78, N 6.99; calcd C 42.98, H 3.61,
N 7.16.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethyl-4-
fluorophenyl)acetamide II-9. White solid, yield: 61.4%. mp 153–155 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ
(ppm) 9.86 (s, 1H, NH–C=O), 7.74–7.55 (m, 6H, C6H3 + C6H3), 7.01 (s, 2H, NH + NH), 3.61
d, J = 16.4 Hz, 1H, CH–SO2), 3.53–3.42 (m, 2H, CH2), 3.31 (s, 1H, CH–N), 1.97–1.31 (m, 8H, 4CH2).
13C-NMR (101 MHz, DMSO-d6):
(ppm) 170.00, 160.24, 158.62, 133.23, 131.71, 130.72, 128.63, 126.73,
(
δ
124.30, 123.95, 122.49, 122.14, 120.58, 120.50, 114.20, 63.08, 54.05, 49.82, 28.11, 23.99, 21.93, 19.38. EIMS,
m/z 576.4 [M]+. Elemental analysis for C22H21ClF7N3O3S: found C45.62, H 3.41, N 7.49; calcd C 45.88,
H 3.68, N 7.30.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-fluoro-5-
trifluoromethylphenyl)acetamide II-10. White solid, yield: 65.3%. mp 163–165 ◦C. 1H-NMR (600 MHz,
DMSO-d6):
d, J = 16.8 Hz, 1H, CH–SO2), 3.45 (m, 2H, CH2), 3.33 (s, 1H, CH–N), 2.01–1.26 (m, 8H, 4CH2).
13C-NMR (101 MHz, DMSO-d6):
(ppm) 170.30, 155.83, 154.16, 133.25, 127.22, 127.14, 126.77, 125.75,
124.27, 123.19, 122.46, 119.65, 117.17, 117.04, 63.24, 54.02, 50.11, 49.35, 28.09, 24.06, 21.89, 19.24. EIMS,
δ(ppm) 10.23 (s, 1H, NH–C=O), 8.48–7.51 (m, 8H, NH + NH + C6H3 + C6H3), 3.70
(
δ

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m/z 574.93 [M]+. Elemental analysis for C22H21ClF3N3O3S: found C 45.99, H 3.45, N 7.11; calcd C
45.88, H 3.68, N 7.30.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-bromo-4-fluorophenyl)
acetamide II-11. White solid, yield: 63.2%. mp 180–182 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm)
10.29 (s, 1H, NH–C=O), 8.04–7.33 (m, 8H, NH + NH + C6H3 + C6H3), 3.59 (d, J = 16.7 Hz, 1H, CH–SO2),
3.39 (d, J = 29.7 Hz, 2H, CH2), 3.33 (d, J = 10.8 Hz, 1H, CH–N), 2.01–1.27 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 169.56, 155.43, 153.83, 136.35, 133.30, 126.83, 123.43, 122.45, 120.20,
120.16, 117.27, 117.12, 108.11, 107.97, 63.38, 54.16, 50.04, 28.04, 24.10, 21.84, 19.06. EIMS, m/z 586.72
[M]+. Elemental analysis for C21H21BrClF4N3O3S: found C 43.18, H 3.88, N 6.98; calcd C 42.98, H 3.61,
N 7.16.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-cyano-4-fluorophenyl)
acetamide II-12. White solid, yield: 57.1%. mp 114–116 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm)
10.43 (s, 1H, NH–C=O), 8.07–7.52 (m, 6H, C6H3 + C6H3), 6.86 (s, 2H, NH + NH), 3.59 (d, J = 16.9 Hz,
1H, CH–SO2), 3.40 (s, 1H, CH–N), 3.31 (s, 2H, CH2), 1.98–1.30 (m, 8H, 4CH2). 13C-NMR (101 MHz,
DMSO-d6): δ(ppm) 169.89, 135.30, 133.57, 133.24, 128.11, 126.69, 126.25, 124.96, 124.31, 123.15, 122.49,
121.34, 63.10, 54.06, 50.05, 28.27, 24.03, 21.89, 19.41. EIMS, m/z 533.2 [M]+. Elemental analysis for
C22H21ClF4N4O3S: found C 49.72 H 3.81, N 10.69; calcd C 49.58, H 3.97, N 10.51.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2,3,4-trifluorophenyl)
acetamide II-13. White solid, yield: 58.2%. mp 159–161 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm)
10.09 (s, 1H, NH–C=O), 7.65–7.30 (m, 5H, C6H2 + C6H3), 7.05 (s, 2H, NH + NH), 3.67 (d, J = 16.4 Hz,
1H, CH–SO2), 3.51–3.41 (m, 2H, CH2), 3.29–3.23 (m, 1H, CH–N), 1.95–1.25 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 169.56, 148.01, 146.38, 144.13, 142.46, 140.44, 138.79, 133.20, 128.45,
126.75, 124.33, 122.51, 118.38, 112.30, 63.03, 54.21, 49.91, 27.97, 24.01, 21.94, 19.26. EIMS, m/z 544.3 [M]+.
Elemental analysis for C21H20ClF6N3O3S: found C 46.60, H 3.92, N 7.55; calcd C 46.37, H 3.71, N 7.73.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2,3,4-trifluorophenyl)
acetamide II-14. White solid, yield: 67.5%. mp 156–158 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ
(ppm)
10.08 (s, 1H, NH–C=O), 8.05–7.56 (m, 5H, C6H2 + C6H3), 6.99 (s, 2H, NH + NH), 3.66 (d, J = 16.5 Hz
1H, CH–SO2), 3.50–3.40 (m, 2H, CH2), 3.28 (s, 1H, CH–N), 1.95–1.25 (m, 8H, 4CH2). 13C-NMR
,
(101 MHz, DMSO-d6): δ(ppm) 169.75, 164.12, 137.38, 133.22, 128.62, 126.76, 126.12, 124.30, 122.93,
122.49, 117.37, 111.12, 106.98, 106.32, 54.11, 52.37, 50.03, 28.05, 24.03, 21.92, 19.25. EIMS, m/z 544.2 [M]+.
Elemental analysis for C21H20ClF6N3O3S: found C 46.17, H 3.95, N 7.58; calcd C 46.37, H 3.71, N 7.73.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-bromophenyl)acetamide
II-15. White solid, yield: 68.7%. mp 173–175 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm) 9.91 (s, 1H,
NH–C=O), 7.96–7.10 (s, 1H m, 7H, C6H4 + C6H3), 7.05–6.79 (m, 2H, NH + NH), 3.54 (s, 2H, CH2), 3.46
(s, 1H, CH–SO2), 3.30–3.21 (m, 1H, CH–N), 1.97–1.33 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
δ
(ppm) 169.52, 136.06, 133.30, 133.05, 129.11, 128.62, 126.84, 126.80, 126.60, 126.08, 124.26, 122.45, 120.63,
115.56, 63.25, 54.11, 50.46, 28.50, 24.05, 21.91, 19.53. EIMS, m/z 570.1 [M]+. Elemental analysis for
C21H22BrClF4N3O3S: found C 44.55, H 4.13, N 7.19; calcd C 44.34, H 3.90, N 7.39.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-bromophenyl)acetamide
II-16. White solid, yield: 60.3%. mp 166–168 ◦C. 1H-NMR (600 MHz, DMSO-d6): δ(ppm) 10.25 (s, 1H,
NH–C=O), 7.93–7.23 (m, 7H, C6H4 + C6H3), 7.00 (s, 2H, NH + NH), 3.59 (d, J = 16.2 Hz, 1H, CH–SO2),
3.46–3.33 (m, 2H, CH2), 3.30–3.19 (m, 1H, CH–N), 2.01–1.29 (m, 8H, 4CH2). 13C-NMR (101 MHz,
DMSO-d6): δ(ppm) 169.60, 140.39, 137.17, 133.28, 131.20, 128.94, 128.29, 126.81, 126.44, 124.29, 122.47,
121.99, 121.63, 118.06, 63.28, 54.23, 50.11, 28.02, 24.06, 21.88, 19.08. EIMS, m/z 490.2 [M]+. Elemental
analysis for C21H22BrClF3N3O3S: found C 44.73, H 4.11, N 7.14; calcd C 44.34, H 3.90, N 7.39.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2,4-dibromophenyl)acetamide
II-17. White solid, yield: 57.8%. mp 178–180 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm) 9.97 (s, 1H,

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NH–C=O), 8.02–7.53 (m, 8H, NH + NH + C6H3 + C6H3), 3.54 (m, J = 16.7 Hz, 2H, CH2), 3.45 (s, 1H,
CH–SO2), 3.33 (s, 1H, CH–N), 2.06–1.25 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
(ppm)
δ
169.90, 135.66, 134.84, 133.35, 131.57, 130.02, 126.88, 126.85, 125.23, 124.20, 122.39, 117 .12, 116.15,
63.46, 54.00, 50.60, 48.98, 28.66, 24.10, 21.87, 19.48. EIMS, m/z 648.10 [M]+. Elemental analysis for
C21H21Br2ClF3N3O3S: found C 39.11, H 3.43, N 6.68; calcd C 38.94, H 3.27, N 6.49.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-methylphenyl)acetamide
II-18. White solid, yield: 43.8%. mp 184–185 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ
(ppm) 9.58 (s, 1H,
NH–C=O), 7.61–7.06 (m, 9H, NH + NH + C6H3 + C6H4), 3.71 (d, J = 16.2 Hz, 1H, CH–SO2), 3.52
d, J = 16.0 Hz, 2H, CH2), 3.26 (s, 1H, CH–N), 2.21 (s, 3H, CH3), 2.05–1.30 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): (ppm) 168.12, 136.10, 133.07, 131.16, 130.91, 130.73, 127.41, 126.64, 126.60,
(
δ
126.42, 125.36, 124.52, 124.02, 122.71, 62.44, 54.62, 49.84, 27.74, 23.89, 22.07, 19.36, 18.00. EIMS, m/z
504.3 [M]+. Elemental analysis for C22H25ClF3N3O3S: found C 52.26, H 5.21, N 8.16; calcd C 52.43,
H5.00, N 8.34.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl)
◦
acetamide II-19. White solid, yield: 40.3%. mp 151–152 C. 1H-NMR (600 MHz, DMSO-d6) :
δ
(ppm) 9.89
(s, 1H, NH–C=O), 7.79–7.41 (m, 6H, C6H3 + C6H3), 6.99 (s, 2H, NH + NH), 3.59 (s, 1H, CH–SO2), 3.52
(m, 2H, CH2), 3.44 (s, 1H, CH–N), 1.96–1.32 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
(ppm)
δ
169.89, 135.30, 133.57, 133.24, 128.11, 126.69, 126.25, 124.96, 124.31, 123.15, 122.49, 121.34, 63.10, 54.06,
50.05, 28.27, 24.03, 21.89, 19.41. EIMS, m/z 558.3 [M]+. Elemental analysis for C22H22ClF6N3O3S:
found C 47.21, H 4.11, N 7.72; calcd C 47.36, H 3.97, N 7.53.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-trifluoromethylphenyl)
acetamide II-20. White solid, yield: 71.5%. mp 175–177 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm)
10.41 (s, 1H, NH–C=O), 8.07–7.41 (m, 7H, C6H4 + C6H3), 6.94 (s, 2H, NH + NH), 3.61 (d, J = 16.2 Hz,
1H, CH–SO2), 3.39 (d, J = 21.9 Hz, 2H, CH2), 3.32 (s, 1H, CH–N), 1.99–1.30 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 170.08, 164.71, 139.57, 133.28, 130.44, 129.83, 126.82, 125.33, 124.23,
123.53, 122.80, 122.41, 120.15, 115.36, 63.50, 54.10, 52.73, 50.10, 28.04, 24.12, 21.83, 19.04. EIMS, m/z 558.2
[M]+. Elemental analysis for C22H22ClF6N3O3S: found C 47.58, H 3.75, N 7.68; calcd C 47.36, H 3.97,
N 7.53.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3,5-ditrifluoromethylphenyl)
acetamide II-21. White solid, yield: 53.0%. mp 213–215 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm)
10.69 (s, 1H, NH–C=O), 8.28–7.58 (m, 6H, C6H3 + C6H3), 6.65 (s, 2H, NH + NH), 3.59 (d, J = 17.0 Hz,
1H, CH–SO2), 3.37 (d, J = 14.8 Hz, 2H, CH2), 3.31 (s, 1H, CH–N), 2.03–1.31 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 171.48, 140.66, 133.37, 131.35, 131.13, 130.92, 130.24, 126.94, 126.25,
124.45, 124.03, 122.64, 122.22, 120.83, 118.89, 116.57, 64.18, 53.74, 50.21, 28.24, 24.29, 21.66, 18.84. EIMS,
m/z 626.3 [M]+. Elemental analysis for C23H21ClF9N3O3S: found C 44.39, H 3.19, N 6.57; calcd C 44.13,
H 3.38, N 6.71.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(3-methoxyphenyl)acetamide
II-22. White solid, yield: 62.4%. mp 185–187 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm) 10.12 (s, 1H,
NH–C=O), 7.60–6.64 (m, 9H, NH + NH + C6H3 + C6H4), 3.71 (s, 3H, CH3), 3.62 (d, J = 15.3 Hz, 1H,
CH–SO2), 3.48–3.35 (m, 2H, CH2), 3.30–3.21 (m, 1H, CH–N), 1.97–1.29 (m, 8H, 4CH2). 13C-NMR
(101 MHz, DMSO-d6): δ(ppm) 168.68, 159.92, 139.96, 133.17, 130.01, 128.25, 127.35, 126.73, 126.23,
124.42, 122.60, 111.63, 109.30, 105.17, 62.82, 55.30, 54.47, 53.69, 50.00, 27.83, 23.97, 21.97, 19.19. EIMS,
m/z 520.2 [M]+. Elemental analysis for C22H25ClF3N3O4S: found C 51.03, H 5.09, N 7.84; calcd C 50.82,
H 4.85, N 8.08.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(4-methoxyphenyl)acetamide
II-23. White solid, yield: 59.1%. mp 158–160 ◦C. 1H-NMR (600 MHz, DMSO-d6): δ(ppm) 10.02 (s, 1H,
NH–C=O), 7.60–6.88 (m, 9H, NH + NH + C6H3 + C6H4), 3.71 (s, 3H, CH3), 3.64 (d, J = 16.6 Hz, 1H,
CH–SO2), 3.51–3.37 (m, 2H, CH2), 3.26 (s, 1H, CH–N), 2.02–1.29 (m, 8H, 4CH2). 13C-NMR (101 MHz,

Molecules 2018, 23, 740
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DMSO-d6): δ(ppm) 167.59, 155.76, 133.07, 131.97, 127.64, 126.65, 126.61, 126.35, 124.53, 122.72, 120.84
(2), 114.32 (2), 62.42, 55.54, 54.66, 49.74, 27.67, 23.87, 22.04, 19.29. EIMS, m/z 520.1 [M]+. Elemental
analysis for C21H25ClF3N3O4S: found C 51.01, H 4.65, N 7.90; calcd C 50.82, H 4.85, N 8.08.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethoxyphenyl)
acetamide II-24. White solid, yield: 75.3%. mp 147–148 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm)
9.96 (s, 1H, NH–C=O), 8.07–7.24 (m, 7H, C6H4 + C6H3), 7.12 (s, 2H, NH + NH), 3.65 (s, 1H, CH–SO2),
3.57–3.45 (s, 2H, CH2), 3.29–3.21 (m, 1H, CH–N), 1.96–1.26 (m, 8H, 4CH2). 13C-NMR (101 MHz,
DMSO-d6): δ(ppm) 169.28, 139.40, 133.18, 130.62, 128.08, 126.73, 125.59, 124.35, 123.82, 123.08, 122.54,
121.50, 121.37, 119.67, 117.96, 62.90, 54.19, 50.28, 28.25, 23.99, 21.87, 19.43. EIMS, m/z 574.3 [M]+.
Elemental analysis for C22H22ClF6N3O4S: found C 45.91, H 4.02, N 7.51; calcd C 46.04, H 3.86, N 7.32.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-chlorobenzyl)acetamide
II-25. White solid, yield: 50.8%. mp 130–131 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ(ppm) 8.70 (s, 1H,
NH–C=O), 7.77 (s, 2H, NH + NH), 7.54–7.30 (m, 7H, C6H4 + C6H3), 4.38 (qd, J = 15.6, 5.9 Hz, 2H,CH2),
3.67 (d, J = 15.8 Hz, 1H, CH–SO2), 3.51 (d, J = 14.7 Hz, 2H, CH2), 3.25 (s, 1H, CH–N), 2.00–1.27 (m, 8H,
4CH2). 13C-NMR (101 MHz, DMSO-d6):
δ(ppm) 168.59, 136.09, 132.82, 132.55, 129.91, 129.47 (2), 129.23,
127.82, 127.51, 126.39, 124.76, 122.95, 61.46, 54.94, 48.77, 27.22, 23.62, 22.18, 19.57. EIMS, m/z 538.4 [M]+.
Elemental analysis for C22H24Cl2F3N3O3S: found C 48.98, H 4.58, N 7.97; calcd C 49.08, H4.49, N 7.80.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-bromobenzyl)acetamide
◦
1
II-26. White solid, yield: 54.6%. mp 123–124 C. H-NMR (600 MHz, DMSO-d6) :
m, J = 5.7 Hz, 1H, NH–C=O), 7.88–7.20 (m, 9H, NH + NH + C6H3 + C6H4), 4.35 (m, J = 5.9 Hz, 2H,
CH2–Ph), 3.68 (d, J = 16.1 Hz, 1H, CH–SO2), 3.51 (m, 2H, CH2), 3.26 (s, 1H,CH–N), 2.04–1.26 (m, 8H,
4CH2). 13C-NMR (101 MHz, DMSO-d6):
(ppm) 168.62, 137.60, 132.86, 132.79, 130.03, 129.50, 129.49,
δ(ppm) 8.70
(
δ
128.08, 126.46, 126.42, 124.73, 121.11, 118.99, 61.46, 54.95, 48.98, 48.75, 43.10, 27.19, 23.59, 22.19, 19.59.
EIMS, m/z 582.0 [M]+. Elemental analysis for C22H24BrClF3N3O3S: found C 45.21, H 3.99, N 7.36;
calcd C 45.34, H 4.15, N 7.21.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-methylbenzyl)acetamide
II-27. White solid, yield: 52.1%. mp 135–137 ◦C. 1H-NMR (600 MHz, DMSO-d6) :
δ(ppm) 8.54 (s, 1H,
NH–C=O), 7.89 (s, 2H, NH + NH), 7.50–7.19 (m, 7H, C6H4 + C6H3), 4.54 (s, 3H,CH3), 4.28 (m, 2H,
CH2), 3.65 (d, J = 15.4 Hz, 1H, CH–SO2), 3.49 (m, 2H, CH2), 3.22 (m, 1H, CH–N), 2.03–1.30 (m, 8H,
4CH2). 13C-NMR (101 MHz, DMSO-d6):
δ(ppm) 167.86, 164.25, 136.66 (2), 136.14, 133.99, 132.74, 130.75,
130.34, 128.28, 127.87, 127.48, 126.32, 126.12, 61.15, 55.11, 49.45, 48.65, 46.48, 27.10, 22.22, 19.05. EIMS,
m/z 518.3 [M]+. Elemental analysis for C23H27ClF3N3O3S: found C 53.46, H 5.01, N 8.39; calcd C 53.33,
H 5.25, N 8.11.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-bromophenethyl)acetamide
II-28. White solid, yield: 45.2%. mp 113–115 ◦C. 1H-NMR (600 MHz, DMSO-d6): (ppm) 1H-NMR
δ
(600 MHz, DMSO)
3.54 (d, J = 15.9 Hz, 1H, CH–SO2), 3.42 (d, J = 33.4 Hz, 2H, CH2), 3.35 (m, 2H), 3.22 (s, 1H, CH–N),
2.84 (t, J = 7.3 Hz, 2H), 2.01–1.26 (m, 8H, 4CH2). 13C-NMR (101 MHz, DMSO-d6):
(ppm) 168.11,
δ 8.33 (m, J = 5.2 Hz, 1H, NH–C=O), 7.94–7.11 (m, 9H, NH + NH + C6H3 + C6H4),
δ
138.52, 132.92, 132.82, 132.41, 131.37, 128.91, 128.22, 126.38, 125.96, 124.24, 122.98, 113.15, 61.24, 54.96,
48.72, 38.93, 35.50, 27.07, 27.05, 23.50, 22.23, 19.54. EIMS, m/z 597.0 [M]+. Elemental analysis for
C23H26BrClF3N3O4S: found C 46.54, H 4.11, N 6.89; calcd C 46.28, H 4.39, N 7.04.
3.2.4. Synthesis of N-(2-Trifluoromethyl-4-chlorophenyl)-2-ethoxyacylmethyl Amino Cyclohexyl
Sulfonamide L-4 and N-(2-Trifluoromethyl-4-chlorophenyl)-2-carboxymethyl Amino Cyclohexyl
Sulfonamide L-5
L-4 was synthesized according to the method in Section 3.2.3. Subsequently, L-4 was dissolved in
CH3OH and transferred to a round bottom flask containing 1 mol L−1 NaOH solution and stirred for

Molecules 2018, 23, 740
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3 h. CH3OH was evaporated under vacuum on rotavapor, then 3 mol L−1 HCl solution was added to
adjust to pH 3, and the formed precipitate was collected by filtration to obtain L-5 as white solid.
3.2.5. Synthesis of 2-Glycinamide Cyclohexyl Sulfonamide Derivatives II-29 to II-33
Under nitrogen atmosphere, L-5 (1.5 mmol), HOBt (1.8 mmol), EDCI (1.8 mmol), and Et3N
(1.8 mmol) were placed in a three-necked flask with 30 mL CH2Cl2, and stirred for 3 h at 0 ◦C. Then,
amine was added slowly and allowed to react for 8 h. The reaction was monitored by TLC and after
completion of reaction, the solution was washed with saturated aq NaHCO3 solution and distilled
water successively. Then it was dried over anhydrous Na2SO4, filtered and evaporated on rotavapor
in vacuum. Finally, products were purified by silica gel column chromatography and recrystallized to
obtain pure products II-29 to II-33.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-ethylacetamide II-29
.
White solid, yield: 68.2%. mp 128–129 ◦C. 1H-NMR (600 MHz, DMSO-d6):
δ
(ppm) 8.18 (t, J = 5.1 Hz
,
1H, NH–C=O), 7.90 (s, 1H, NH–Ph), 7.49 (m, 3H, C6H3), 3.57 (d, J = 15.8 Hz, 1H, CH–SO2), 3.50
(s, 2H, CH2–C=O), 3.39 (d, J = 15.8 Hz, 1H, NH), 3.21 (d, J = 9.8 Hz, 1H, CH–N), 3.11 (m, 2H, CH2),
2.04–1.27(m, 8H, 4CH2), 1.02 (t, J = 7.2 Hz, 3H, CH3). 13C-NMR (101 MHz, DMSO-d6):
δ(ppm) 167.43,
132.75, 130.03, 126.69, 126.33, 124.82, 123.13, 61.05, 55.08, 48.61, 33.87, 27.00, 26.75, 23.54, 22.19, 19.56,
14.78. EIMS, m/z 442.1 [M]+. Elemental analysis for C17H23ClF3N3O3S: found C 46.17, H 5.04, N 9.76;
calcd C 46.21, H 5.25, N 9.51.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-propylacetamide II-30
White solid, yield: 73.2%. mp 139–141 ◦C. 1H-NMR (600 MHz, DMSO-d6):
(ppm) 8.19 (t, J = 5.5 Hz
1H, NH–C=O), 7.94 (s, 1H, NH–Ph), 7.48 (m, 3H, C6H3), 3.59 (d, J = 15.9 Hz, 1H, CH–SO2), 3.51
d, J = 3.0 Hz, 2H, CH2–C=O), 3.42 (d, J = 15.9 Hz, 1H, NH), 3.21 (d, J = 10.4 Hz, 1H, CH–N), 3.05
(m, 2H, CH2), 2.04–1.26 (m, 10H, 4CH2 + CH2), 0.84 (t, J = 7.4 Hz, 3H, CH3). 13C-NMR (101 MHz,
.
δ
,
(
DMSO-d6): δ(ppm) 167.57, 142.07, 132.73, 126.38, 125.63, 124.79, 123.06, 121.21, 61.03, 55.11, 48.59, 40.76,
26.99, 23.54, 22.62, 22.19, 19.55, 11.68. EIMS, m/z 456.0 [M]+. Elemental analysis for C18H25ClF3N3O3S:
found C 47.16, H 5.35, N 9.47; calcd C 47.42, H 5.53, N 9.22.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-cyclopropylacetamide II-31
White solid, yield: 65.7%. mp 99–101 ◦C. 1H-NMR (600 MHz, DMSO-d6):
(ppm) 8.23 (d, J = 3.9 Hz
1H, NH–C=O), 7.72 (m, 1H, NH–Ph), 7.50 (m, 3H,C6H3), 3.52 (d, J = 15.9 Hz, 1H, CH–SO2), 3.47
d, J = 3.0 Hz, 2H, CH2–C=O), 3.35 (s, 1H, NH), 3.20 (d, J = 10.6 Hz, 1H, CH–N), 2.65 (m, 1H,
CH–N–C=O), 1.99–1.27 (m, 8H, 4CH2), 0.44–0.66 (m, 4H, CH2 + CH2). 13C-NMR (101 MHz, DMSO-d6):
.
δ
,
(
δ
(ppm) 169.13, 132.84, 126.43, 124.72, 122.99, 61.26, 60.15, 54.99, 48.65, 27.12, 23.58, 22.55, 22.17, 21.13,
19.51, 14.46, 5.95, 5.81. EIMS, m/z 454.1 [M]+. Elemental analysis for C18H23ClF3N3O3S: found C 47.87,
H 4.96, N 9.54; calcd C 47.63, H 5.11, N 9.26.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-cyclopropylmethylacetamide
◦
1
II-32. White solid, yield: 66.5%. mp 147–149 C. H-NMR (600 MHz, DMSO-d6):
δ(ppm) 8.29
(m, J = 5.2 Hz, 1H, NH–C=O), 7.92 (s, 1H, NH–Ph), 7.49 (dd, J = 8.7 Hz, 3H, C6H3), 3.60 (d, J = 15.8 Hz,
1H, CH–SO2), 3.51 (s, 2H, CH2–C=O), 3.42 (d, J = 15.9 Hz, 1H, NH), 3.21 (d, J = 9.3 Hz, 1H, CH–N),
2.98 (m, 2H, CH2), 2.05–1.26 (m, 8H, 4CH2), 0.12–0.09 (m, 5H, C3H5). 13C-NMR (101 MHz, DMSO-d6):
δ
(ppm) 167.54, 132.85, 126.34, 126.31, 124.94, 124.87, 123.06, 60.98, 55.14, 48.64, 43.44, 26.99, 26.93, 23.55,
22.20, 21.11, 19.74, 11.09, 3.50. EIMS, m/z 468.1 [M]+. Elemental analysis for C19H25ClF3N3O3S: found
C 48.98, H 5.28, N 9.12; calcd C 48.77, H 5.39, N 8.98.
(1R,2S)-2-(2-(N-(4-Chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-butylacetamide II-33
White solid, yield: 68.9%. mp 122–124 ◦C. 1H-NMR (600 MHz, DMSO-d6):
(ppm) 8.17 (t, J = 5.4 Hz
1H, NH–C=O), 7.93 (s, 1H, NH–Ph), 7.49 (m, 3H,C6H3), 3.58 (d, J = 15.8 Hz, 1H, CH–SO2), 3.50
d, J = 2.7 Hz, 2H, CH2–C=O), 3.41 (d, J = 15.9 Hz, 1H, NH), 3.21 (d, J = 10.4 Hz, 1H, CH–N), 3.09
(m, 2H, CH2–N–C=O), 2.04–1.22 (m, 12H, 4CH2 + CH2 + CH2), 0.85 (t, J = 7.3 Hz, 3H, CH3). 13C-NMR
.
δ
,
(

Molecules 2018, 23, 740
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(101 MHz, DMSO-d6):
δ
(ppm) 167.61, 132.66, 130.05, 126.34, 125.65, 124.86, 123.05, 121.22, 61.05, 55.08,
48.58, 38.61, 31.41, 26.99, 23.54, 22.26, 19.81, 19.55, 13.89. EIMS, m/z 469.6 [M]+. Elemental analysis for
C19H27ClF3N3O3S: found C 48.22, H 5.99, N 9.12; calcd C 48.56, H 5.79, N 8.94.
3.3. Fungal Bioassay
In vitro and in vivo fungicidal activities of all target compounds against B. cinerea were tested
by mycelium growth inhibition tests and greenhouse pot experiments. Three strains of B. cinerea
(CY-09, DL-11, HLD-15) were isolated from naturally infected tomato leaves in three different areas
(CY-09, DL-11, and HLD-15 came from Chaoyang, Dalian, and Huludao, respectively) in Liaoning
Province, China. Carbendazim, procymidone, boscalid, pyrimethamine, and cyprodinil were provided
by Shenyang Research Institute of the Chemical Industry, National Pesticides Engineering Research
Centre and used as positive control.
3.3.1. Evaluation of Target Compounds II on the Inhibition of B. cinerea
Preliminary tests verified the in vitro fungicidal effect of B. cinerea on plates by the mycelium
growth inhibition method. Commercial fungicides were used as positive control, while acetone was
the blank. Compounds to be tested were dissolved in acetone and diluted with sterilized molten
potato-dextrose agar (PDA) medium to obtain the drug-containing medium at the final concentration
of 50 µ
g mL−1, and poured it into sterile 90 mm Petri dishes (15 mL per dish). The medium solidified
and reduced to room temperature, and 5 mm plugs of B. cinerea culture were placed in the center
of the PDA plates. Then, the plates were sealed with parafilm and incubated under a regular 12:12
◦
h light/dark regimen at 26 C for 96 h. The radial growth diameters were measured, and relative
inhibition rate of treatment compared to blank assay was calculated by the following equation:
Relative inhibition rate (%) = (dc − dt/dc − dd) × 100%
where dd was the diameter of the original disk (5 mm), dc and dt represented the average diameter of
3 replicates of the control and treatment plates, respectively.
3.3.2. Evaluation of the Fungicidal Activity on B. cinerea by Concentration Gradient Test
Based on the result of multiple preliminary tests, the EC50 values of specific compounds were
evaluated to verify further fungicidal effect on B. cinerea by the method as previously described.
The four concentrations of the tested compounds in PDA were 50, 12.5, 3.125 and 0.78125
The EC50 values were calculated using log-probit analysis.
µ .
g mL−1
3.3.3. In Vivo Fungicidal Activity against B. cinerea (CY-09) by Greenhouse Pot Experiments
(1). Evaluation of Fungicidal Activity on Cucumber Leaves
The compounds to be tested were processed to 5% emulsifiable concentrate (EC) formulations and
diluted with water to 500 µ
g mL−1. The rest of the procedures were given in ref [17]. The seedlings
were maintained in a greenhouse pot at 24 ± 1 ◦C and relative humidity above 90%. When the blank
control was infected completely, the lesion diameters of all cotyledons were measured. The calculation
method was referred to the formula given in Section 3.3.1.
(2). Evaluation of Fungicidal Activity on Tomato Leaves
The conidia of B. cinerea were obtained from a 4-week-old PDA medium, which was cultured at
25 ◦C. The mixtures of 10 mL sterile distilled water and 0.05 mL Tween 80 were poured into culture
dishes to let the spores fall off. The spore-rich suspension was filtered through four layers of sterilized
gauze to remove mycelium. Finally, the conidia concentration was measured using a hemocytometer
and diluted to 106–107 spores per mL. The processing method of the compound-containing EC

Molecules 2018, 23, 740
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formulation at the concentration of 500
µ
g mL−1 and 200
µ
g mL−1 was identical to Section 3.3.3 (1).
When the number of tomato leaves was about 30, the solution of the compound to be tested were
sprayed evenly onto tomato leaves and dried naturally. Subsequently, the spore suspension was
sprayed on seedlings and plants kept in the same condition as test Section 3.3.3 (1). When the blank
assay was infected completely, the Disease Index of all leaves were investigated and the Control
Efficiency was calculated [37].
4. Conclusions
In summary, 33 novel 2-glycinamide cyclohexyl sulfonamide derivatives were designed and
synthesized. II-4, II-5, and II-15 were found as the best active compounds in inhibiting B. cinerea in this
series of compounds, which were superior to the commercial fungicides carbendazim, procymidone,
boscalid, pyrimethanil, and cyprodinil in both in vitro and in vivo tests. The structure–activity
relationship showed that docking glycinamide on the lead compound and introducing a benzene ring
structure with two fluorine atoms at 2,4- or 2,5-positions could greatly enhance activity. Studies on the
structural optimization and mechanism of action are in progress. We believe these compounds will
become promising candidates for pesticides.
Supplementary Materials: Supplementary materials are available online. The 1H-NMR and 13C-NMR spectra of
target compounds II and detailed description of the crystal structure of II-19.
Acknowledgments: This research was supported in part by the National Key Research and Development Plan
(No. 2017YFD0200504), the Natural Science Foundation of Liaoning Province (2015020766), the National Key
Project for Basic Research (973 Project, 2015CB150600) and the Scientific Research Project of Department of
Education of Liaoning Province (LSNYB201611).
Author Contributions: Xinghai Li, Zining Cui, Caixiu Liu and Nan Cai conceived and designed the route of the
experiments; Nan Cai and Caixiu Liu performed the experiments; Caixiu Liu, Nan Cai and Zhihui Feng analyzed
the data; Mingshan Ji, Zhiqiu Qi and Peiwen Qin contributed the materials, instruments and strains; Xinghai Li,
Wasim Ahmed and Zining Cui revised the paper. Nan Cai wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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