Synthesis, fungicidal activity, and structure-activity relationship of 2-oxo-and 2-hydroxycycloalkylsulfonamides

Article abstract of DOI:10.1021/jf102348x

To explore new potential fungicides, a series of novel compounds, including 11 2-oxocycloalkylsulfonamide (3) and 21 2-hydroxycycloalkylsulfonamide (4) derivatives, were synthesized and their structures were confirmed by ¹H nuclear magnetic res

Full text of DOI:10.1021/jf102348x

11384 J. Agric. Food Chem. 2010, 58, 11384–11389
DOI:10.1021/jf102348x
Synthesis, Fungicidal Activity, and Structure-Activity
Relationship of 2-Oxo- and 2-Hydroxycycloalkylsulfonamides
X
ING-HAI
L
I
, DE
-CAI
W
U
, ZHI-QIU
Q
I
, XIU-WEI
L
I
, Z
U
-MIN
GU
, SONG-HONG
WEI,
Y
ANG
Z
HANG, YING-Z
I
WANG
,
AND
M
ING-SHAN
JI*
Department of Pesticide Science, Plant Protection College, Shenyang Agricultural University,
Shenyang 110161, Liaoning, People’s Republic of China
To explore new potential fungicides, a series of novel compounds, including 11 2-oxocycloalkyl-
sulfonamide (3) and 21 2-hydroxycycloalkylsulfonamide (4) derivatives, were synthesized and their
structures were confirmed by 1H nuclear magnetic resonance (NMR), infrared (IR), and elemental
analysis. The results of the bioassay showed that the compounds 3 and 4 possessed excellent
fungicidal activity against Botrytis cinerea Pers. both in vitro and in vivo. The fungicidal activity of the
compounds with 7- or 8-membered rings is better than those with 5-, 6-, or 12-membered rings.
According to the results of the mycelium growth rate test, the EC50 values of the compounds 3C,
4C, 3D, and 4D were 0.80, 0.85, 1.22, and 1.09 μg/mL, respectively, and similar to or better than
commercial fungicide procymidone. The bioassay results of spore germination indicated that most of
the compounds exhibited obvious inhibitory effects against B. cinerea and the inhibition rates of
2-oxocycloalkylsulfonamides were higher than 2-hydroxycycloalkylsulfonamides, among them. The
EC50 values of compounds 3A, 3B17, 3E, and 4A were 4.21, 4.21 3.24, and 5.29 μg/mL, respectively.
Those compounds containing 5- or 6-membered rings showed better activity than those containing
7-, 8-, or 12-membered rings. Furthermore, the results of the pot culture test showed that almost all
of the compounds had effective control activity in vivo and 2-hydroxycycloalkylsulfonamides were
obviously superior to 2-oxocycloalkylsulfonamides. The compounds 3E, 4C and 4D presented
higher control efficacy than procymidone and pyrimethanil against gray mold disease on cucumber
plants.
KEYWORDS: 2-Hydroxycycloalkylsulfonamides; synthesis; Botrytis cinerea; fungicidal activity; structure-
activity relationship
INTRODUCTION
research showed that 2-oxocycloalkylsulfonamides (J, Figure 2)
have excellent activity against B. cinerea Pers. (11). In our present
work, the 2-position carbonyl wasconverted to the corresponding
hydroxyl (K, Figure 2) and the size of the rings changed simulta-
neously. Many new derivatives were designed and synthesized for
the purpose of novel and effective pesticide discovery. The
fungicidal activities of those new compounds against B. cinerea
were evaluated using the mycelium growth rate tests, spore
germination tests, and pot culture tests. The relationships were
obtained between the size of the ring and the difference of the
substituent on benzene to the fungicidal activity, by comparing of
the influence of the 2-position carbonyl and the 2-position
hydroxyl on the fungicidal effect.
Sulfanilamide, the first synthetic antibacterial agent active
against a wide range of infections, is also used as an agricultural
fungicide,andtherepresentativeproductsincludeflusulfamide(1)
(A, Figure 1), tolnifanide (2) (B, Figure 1), cyazofamid (3, 4) (C,
Figure 1), and amisulbrom (5) (D, Figure 1). They all have an
excellent control effect toward the diseases caused by oomycetes.
Beucheta and co-workers found that the compounds of sulfon-
amide, which encompass the structure of thiazolidine (E, Figure 1),
had good fungicidal activity (6). The fungicidal activity of 1,2,4-
triazole sulfonamide (F, Figure 1) and coumarin sulfonamide
(G, Figure 1) had been reported in the literature (7, 8). Besides,
the structure-activity relationship between N-aryl benzene sulfon-
amide (H, Figure 1) and Botrytis cinerea Pers. was studied by
The synthetic route of compounds 4 is shown in Scheme 1.
Saız-Urra et al. (9). Accordingly, we can conclude that they all
´
containing the structure of arylsulfonamide.
MATERIALS AND METHODS
General. Infrared (IR) spectra were recorded in potassium bromide
disks on a Bruker IFS 55 spectrophotometer. Nuclear magnetic resonance
(NMR) spectra were recorded in CDCl3 unless indicated otherwise with a
Bruker 300 MHz spectrometer, using tetramethylsilane (TMS) as the
internal standard. Elemental analysis was performed by the analytical
center at the Institute of Chemistry, Chinese Academy of Sciences, Beijing,
China. Melting points were measured on a X-5 melting-point apparatus,
Furthermore, the compounds 2-oxocyclododecylsulfonamides
(I, Figure 2) had been proven to have excellent fungicidal activity
against Gibberella zeae and Venturia nashicola (10). Further
*To whom correspondence should be addressed. Telephone: 86-24-
88492673. E-mail: jimingshan@syau.edu.cn.
pubs.acs.org/JAFC
Published on Web 10/07/2010
© 2010 American Chemical Society

Article
J. Agric. Food Chem., Vol. 58, No. 21, 2010 11385
Figure 1. Structures of compounds A-H.
Scheme 1. Synthetic Route of Compounds 4
and the thermometer was uncorrected. The solvents and reagents were
used as received or were dried prior to use as needed.
Chemical Synthesis. Synthesis of compounds followed the outline in
Scheme 1.
Synthesis of Compounds 2. Compounds 2 were synthesized from
cyclanones according to the method given in ref 12. Potassium 2-oxocyclo-
pentylsulfonate (2A) and potassium 2-oxocyclooctylsulfonate (2D) are new
compounds. Their physical data were shown as follows. 2A: white solid, with
Figure 2. Structures of compounds I-K.
1
a yield of 73%. mp 214-216 °C. H NMR (D2O) δ: 1.76-1.85 (m, 1H),
1.99-2.08 (m, 1H), 2.16-2.42 (m, 4H), 3.65 (t, 1H, J = 8.41 Hz). IR (ν,
cm-1): 3450, 2920, 2850, 1700. 2D: white solid, with a yield of 82%. mp
Bioassay of Fungicidal Activities. Effect of the New Compounds
on the Mycelial Growth of B. cinerea in Solid Media. The compounds 3A,
3B17, 3C, 3D, 3E, 4A, 4B1-4B17, 4C, 4D, and 4E were dissolved in acetone
and mixed with sterile molten potato dextrose agar (PDA) to obtain final
concentrations of 50, 25, 12.5, 6.25, 3.13, 1.56, and 0.78 μg/mL. The
commercial fungicide procymidone (with a percentage composition of
96%) was used as the positive control. Fungicidal activities of the
compounds against B. cinerea were evaluated in vitro using the method
given in ref 12. The inhibition rate was calculated according to eq 1
1
235-238 °C. H NMR (D2O) δ: 1.01-1.10 (m, 1H), 1.30-1.44 (m, 3H),
1.69-1.84 (m, 4H), 2.10-2.18 (m, 2H), 2.33-2.40 (m, 1H), 2.64-2.74 (m,
1H), 3.86 (dd, 1H, J = 8.72, 6.41 Hz). IR (ν, cm-1): 3450, 2920, 2850, 1700.
Synthesis of Compounds 3. Compounds 3 were synthesized from
compounds 2 as previously described (11). Foregone compounds, N-(4-
methylphenyl)-2-oxocyclohexylsulfonamide (3B2), N-(2,4-dimethylphenyl)-
2-oxocyclohexylsulfonamide (3B3), N-(2-methyl-4-fluorophenyl)-2-oxo-
cyclohexylsulfonamide (3B6), N-(2-chlorophenyl)-2-oxocyclohexylsulfon-
amide (3B8), N-(2-bromophenyl)-2-oxocyclohexylsulfonamide (3B9), N-(4-
chlorophenyl)-2-oxocyclohexylsulfonamide (3B10), N-(3,4-dichlorophenyl)-
2-oxocyclohexylsulfonamide (3B14), N-[2,5-di(trifluoromethyl)phenyl]-2-
oxocyclohexylsulfonamide (3B15), N-[3,5-di(trifluoromethyl)phenyl]-2-oxo-
cyclohexylsulfonamide (3B16), and N-(2-trifluoromethyl-4-chlorophenyl)-2-
oxocyclohexylsulfonamide (3B17), were synthesized in ref 11.
I1 ¼ ðD1 - D0Þ=D1 ꢀ 100%
ð1Þ
where I1 is the inhibition rate, D1 is the average diameter of mycelia in the
blank test, and D0 is the average diameter of mycelia in the presence of
compounds. The EC50 and EC80 values were estimated using logit
analysis (13), and the results are given in Table 3.
The physical and elemental data of new compounds 3A, 3B1, 3B4, 3B5,
3B7, 3B11, 3B12, 3B13, 3C, 3D, and 3E are listed in Table 1, and the 1H
NMR and IR data are listed in Table 2.
Effect on the Germination of B. cinerea. The spore germination method
was given in ref 14. Conidial germination assays were carried out on
microscope slides. The conidial suspensions were prepared by seeding
about 2ꢀ105 spores/mL conidia in a 0.05% Tween 80 solution, and the
acetone solution of compounds (5000 μg/mL) was diluted with conidial
suspension to obtain five different final concentrations of 200, 50, 12.5,
3.12, and 0.78 μg/mL. Then, 30 μL of these cultures was taken to
inoculate in a concave slide and incubated in a humid chamber with 23 (
1 °C and 100%relative humidity. Three replicates were performed, and the
commercial fungicide procymidone was used as the positive control. After
8 h, conidial germination was determined directly on the slides by counting
the number of germinatedconidia in fivemicroscopefields eachcontaining
Synthesis of Compounds 4. To the solution of compound 3 (0.01 mol) in
methanol (30 mL) at 0-5 °C, sodium borohydride solution (0.016 mol of
NaBH4 þ 8 mL of 1% NaOH þ 8 mL of CH3OH) was added dropwise,
and the mixture was stirred at 5-15 °C for 1 h. After the methanol was
evaporated in vacuum, the residue was dissolved in ethyl acetate (80 mL),
washed with 5% HCl (30 mL) and water (20 mL), and dried over sodium
sulfate. Afterthe solvent was evaporatedinvacuum, the crude product was
recrystallized from the acetone/petroleum ether to give pure compound 4.
The physical and elemental data of the title compounds are listed in
Table 1, and the 1H NMR and IR data are listed in Table 2.

11386 J. Agric. Food Chem., Vol. 58, No. 21, 2010
Li et al.
Table 1. Physical and Elemental Data of Compounds 3 and 4
compound
elemental analysis (%)
H (calcd)
number
n
R
mp (°C)
yield (%)
C (calcd)
N (calcd)
3A
1
2
2
2
2
2
2
2
3
4
8
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
4
8
2-CF3-4-ClC6H3
C6H5
89-91
105-106
83-85
76-78
143-144
81-82
89-90
103-104
64-66
79-80
96-98
93-95
87-88
82-83
100-102
103-105
104-105
115-117
102-104
94-95
80-82
95-97
96-97
127-128
104-105
125-127
90-91
112-113
109-110
74-75
61
86
81
68
83
80
77
85
78
76
73
78
88
80
86
83
76
90
89
85
88
91
82
78
87
86
89
86
87
71
59
55
42.34 (42.18)
56.71 (56.90)
61.33 (60.99)
53.96 (53.66)
53.45 (53.12)
43.14 (43.38)
48.69 (48.59)
44.98 (44.73)
45.76 (45.47)
46.67 (46.94)
51.49 (51.87)
42.12 (41.93)
56.67 (56.45)
58.05 (57.97)
59.08 (59.34)
60.52 (60.58)
53.61 (53.32)
49.54 (49.26)
52.64 (52.73)
49.61 (49.74)
43.46 (43.12)
50.02 (49.74)
43.04 (43.12)
48.56 (48.29)
44.67 (44.45)
44.60 (44.45)
42.78 (42.97)
43.15 (42.97)
43.90 (43.64)
45.51 (45.23)
46.43 (46.69)
51.76 (51.64)
3.15 (3.24)
6.12 (5.97)
7.16 (7.17)
6.02 (6.11)
5.12 (5.20)
4.36 (4.25)
4.50 (4.39)
4.01 (4.07)
3.93 (4.09)
4.59 (4.46)
5.56 (5.73)
3.56 (3.81)
6.78 (6.71)
7.31 (7.11)
7.40 (7.47)
7.86 (7.79)
6.53 (6.71)
5.01 (5.13)
5.98 (5.90)
5.76 (5.57)
4.69 (4.83)
5.48 (5.57)
4.76 (4.83)
4.78 (4.99)
4.54 (4.66)
4.48 (4.66)
4.02 (3.86)
3.80 (3.86)
4.12 (4.23)
4.43 (4.61)
5.17 (4.96)
6.23 (6.16)
4.26 (4.10)
5.47 (5.53)
4.58 (4.74)
4.28 (4.47)
5.19 (5.16)
4.40 (4.22)
4.23 (4.36)
4.30 (4.35)
3.91 (3.79)
3.70 (3.65)
3.23 (3.18)
4.15 (4.07)
5.31 (5.49)
5.08 (5.20)
4.99 (4.94)
4.58 (4.71)
4.65 (4.44)
4.79 (4.60)
5.22 (5.12)
4.80 (4.83)
4.33 (4.19)
4.87 (4.83)
4.23 (4.19)
4.50 (4.33)
4.26 (4.32)
4.48 (4.32)
3.67 (3.58)
3.67 (3.58)
3.86 (3.91)
3.69 (3.77)
3.48 (3.63)
3.02 (3.17)
3B1
3B4
3B5
3B7
3B11
3B12
3B13
3C
2-Me-6-EtC6H3
2,5-(OMe)2C6H3
2-FC6H4
4-BrC6H4
4-CF3C6H4
2,4-Cl2C6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
C6H5
3D
3E
4A
4B1
4B2
4B3
4B4
4B5
4B6
4B7
4B8
4B9
4B10
4B11
4B12
4B13
4B14
4B15
4B16
4B17
4C
4-MeC6H4
2,4-Me2C6H3
2-Me-6-EtC6H3
2,5-(OMe)2C6H3
2-Me-4-FC6H3
2-FC6H4
2-ClC6H4
2-BrC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
2,5-(CF3)2C6H3
3,5-(CF3)2C6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
2-CF3-4-ClC6H3
4D
4E
117-118
142-143
approximately 60 conidia, respectively. The germination inhibition rate
was calculated according to eq 2
were somewhat increased, accompanying the decrease of the
yields. The yields of compounds 4 from 3 are fair too good
(55-91%), as shown in Table 1. The structures of compounds 4
were confirmed by elemental analysis (Table 1), 1H NMR, and IR
(Table 2).
Fungicidal Activity and Structure-Activity Relationship (My-
celial Growth Rate Method). As shown in Table 3, the compounds
4 exhibited good fungicidal activity against B. cinerea. Among
them, compounds 4B15, 4B16, 4B17, 4C, and 4D, with EC50 values
of 2.53, 4.44, 3.37, 0.85, and 1.09 μg/mL, repectively, exhibited
excellent fungicidal activity against B. cinerea.
Structure-Activity Relationship 1. The substituent of the
benzene ring might exert a greater influence on the activity. The
activity was significantly decreased with the benzene ring contain-
ing electron-donating groups (Me, Et, and MeO). The com-
pounds with a halogen atom in the para postiton of the
benzene ring showed higher activities than in the adjacent posi-
tion. For example, the compounds 4B8, 4B9, and 4B13 (with EC50
values of 75.65, 10.98, and 53.24 μg/mL, respectively) had lower
fungicidal activity than the compounds 4B10, 4B11, and 4B14 (with
EC50 values of 7.38, 8.79, and 7.80 μg/mL, respectively). Besides,
all of the compounds with a trifluoromethyl group on the benzene
ring presented higher fungicidal activity, particularly the one with
bis-(trifluoromethyl).
Structure-Activity Relationship 2. The fungicidal activity
was affected obviously by the size of cycloalkane and was
consistent with the structure-activity relationship of 2-hydroxy-
cycloalkylsulfonamides 4 and 2-oxocycloalkylsulfonamides 3
(Figure 3). The contribution of a 7-membered ring for fungicidal
activity was the biggest according to the EC50 values. The EC50
I2 ¼ ðG1 - G0Þ=G1 ꢀ 100%
ð2Þ
where I2 is the adjusted germination inhibition rate, G1 is the average
germination rate of spores in the blank test, and G0 is the average
germination rate of spores in the presence of compounds. The EC50 and
EC80 values were estimated using logit analysis (13), and the results are
given in Table 4.
Effect on the Ability of B. cinerea To Colonize Cucumber Leaves (15).
The cucumber (Cucumis sarivus L.) seedlings at 2-3 leaf stages were used
to assay the fungicidal activity against B. cinerea. The compounds were
confected to 2.5% EC formulations, in which pesticide emulsifier 500
(0.375%) and pesticide emulsifier 600 (2.125%) were the additives,
methanol (5%) was the co-solvent, and xylene was the solvent. The
formulation was diluted to a series of concentrations at 500, 125, and
31.25 μg/mL with water to obtain the solutions that were spread on the
surface of the cucumber leaves. After air drying, the upper sides of the
leaves were inoculated with 6 mm plugs of B. cinerea Pers., which was
maintained on PDA. This procedure was repeated 3 times, and 9 replicates
were performed. The commercial fungicides procymidone and pyrimetha-
nil (with a percentage composition of 95%) were used as the positive
control. The inhibition rate was calculated according to eq 1, and the
results were shown in Table 5.
RESULTS AND DISCUSSION
Synthesis of Compounds 4. There are advantages of high yields,
short reaction times, easy preparation, and mild reaction condi-
tions when the compounds 3 are being reduced. In general, the
compounds with a small ring were easy to reduce, but with the
increase of the rine size, both the reaction time and temperature

Article
J. Agric. Food Chem., Vol. 58, No. 21, 2010 11387
Table 2. 1H NMR and IR Data of Compounds 3 and 4
compound
number
1H NMR (CDCl3, δ)
IR (ν, cm-1
)
3A
1.87-2.57 (m, 6H, 3CH2), 3.84 (t, 1H, CH, J = 8.85 Hz), 7.24 (br, 1H, NH), 7.52 (dd, 1H, J = 8.85, 2.25 Hz),
7.63 (d, 1H, J = 2.25 Hz), 7.71 (d, 1H, J = 8.85 Hz)
3299, 2977, 2919, 1753
3B1
3B4
1.62-2.66 (m, 8H, 4CH2), 3.72 (dd, 1H, CH, J = 10.80, 6.00 Hz), 6.87 (br, 1H, NH), 7.19-7.34 (m, 5H, C6H5)
1.23 (t, 3H, CH3), 1.71-2.81 (m, 8H, 4CH2), 2.39 (s, 3H, CH3), 4.02 (dd, 1H, CH, J = 11.70, 5.70 Hz),
6.54 (br, 1H, NH), 7.07-7.19 (m, 3H, C6H3)
3248, 2951, 2861, 1705
3298, 2952, 2860, 1708
3B5
1.63-2.59 (m, 8H, 4CH2), 3.82 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.69 (dd, 1H, CH, J = 11.70, 5.70 Hz), 6.96 (br, 1H, NH),
6.25 (dd, 1H, Ph-H, J = 9.00, 3.00 Hz), 7.84 (d, 1H, Ph-H, J = 9.00 Hz), 7.12 (d, 1H, Ph-H, J = 3.00 Hz)
1.69-2.68 (m, 8H, 4CH2), 3.86 (dd, 1H, CH, J = 11.20, 5.60 Hz), 7.06-7.60 (m, 5H, C6H4 þ NH)
1.61-2.67 (m, 8H, 4CH2), 3.72 (dd, 1H, CH, J = 10.52, 5.92 Hz), 6.95 (s, 1H, NH), 7.12-7.17 (m, 2H, Ph-H),
7.23-7.29 (m, 2H, Ph-H)
3308, 2954, 2859, 1708
3B7
3B11
3238, 2948, 2865, 1705
3267, 2943, 2865, 1724
3B12
3B13
3C
1.66-2.67 (m, 8H, 4CH2), 3.76 (dd, 1H, J = 10.52, 5.96 Hz), 7.12 (s, 1H, NH), 7.21-7.50 (m, 4H, C6H4)
1.64-2.67 (m, 8H, 4CH2), 3.85 (dd, 1H, CH, J = 11.20, 5.70 Hz), 7.12 (br, 1H, NH), 7.26-7.83 (m, 3H, C6H3)
1.40-2.73 (m, 10H, 5CH2), 4.11 (dd, 1H, CH-SO2, J = 10.5, 4.2 Hz), 7.24 (br, 1H, NH),
7.51 (dd, 1H, J = 8.70, 2.10 Hz, Ph-H), 7.61 (d, 1H, J = 2.10 Hz, Ph-H), 7.74 (d, 1H, J = 8.70 Hz, Ph-H)
1.19-2.67 (m, 12H, 6CH2), 4.24 (dd, 1H, CH-SO2, J = 11.40, 3.30 Hz), 7.17 (br, 1H, NH),
7.51 (dd, 1H, J = 9.00, 2.10 Hz, Ph-H), 7.61 (d, 1H, J = 2.10 Hz, Ph-H), 7.77 (d, 1H, J = 9.00 Hz, Ph-H)
1.28-1.42 (m, 14H), 1.61-1.67 (m, 1H), 1.82-1.92 (m, 2H), 2.29-2.37 (s, 1H), 2.73-2.91 (m, 2H), 4.18 (dd, 1H,
J = 11.70, 3.00 Hz), 6.74 (br, 1H, NH), 7.53 (dd, 1H, J = 8.82, 2.28 Hz, Ph-H), 7.62 (d, 1H, J = 2.28 Hz, Ph-H),
7.78 (d, 1H, J = 8.82 Hz, Ph-H)
3262, 2957, 2870, 1724
3340, 2950, 2869, 1714
3359, 2928, 2858, 1708
3D
3E
3198, 2929, 2870, 1675
3267, 2924, 2870, 1708
4A
1.63-2.37 (m, 6H, 3CH2), 2.39 (br, 1H, OH), 3.55 (m, 1H, CH-O), 4.58 (dd, 1H, J = 9.30, 4.80 Hz, CH-SO2), 7.14
(br, 1H, NH), 7.50 (dd, 1H, J = 8.70, 2.10 Hz, Ph-H), 7.61 (d, 1H, J = 2.10 Hz, Ph-H), 7.81 (d, 1H, J = 8.70 Hz, Ph-H)
1.20-2.06 (m, 8H, 4CH2), 2.86 (s, 1H, OH), 3.08 (ddd, 1H, J = 12.00, 3.90, 2.10 Hz, CH-O), 4.53 (s, 1H, CH-SO2),
6.83 (s, 1H, NH), 7.14-7.33 (m, 5H, C6H5)
1.22-2.06 (m, 8H, 4CH2), 2.32 (s, 3H, CH3), 2.62 (br, 1H, OH), 3.02-3.08 (dd, 1H, J = 12.15, 4.12, 1.89 Hz, CH-O),
4.52 (s, 1H, CH-SO2), 6.79 (s, 1H, NH), 7.08-7.13 (m, 4H, C6H4)
1.23-2.06 (m, 8H, 4CH2), 2.29 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.41 (br, 1H, OH), 3.01-3.08 (ddd, 1H, J = 12.09, 4.32,
1.89 Hz, CH-O), 4.53 (s, 1H, CH-SO2), 6.59 (s, 1H, NH), 6.90-7.01 (m, 2H, Ph-H), 7.21-7.24 (m, 1H, Ph-H)
1.25 (t, 3H, CH3), 1.69-2.76 (m, 9H, 4CH2 þ OH), 2.36 (s, 3H, CH3), 3.01-309 (m, 1H, J = 12.18, 4.47, 1.82 Hz,
CH-O), 4.50 (s, 1H, CH-SO2), 6.97 (br, 1H, NH), 7.06-7.13 (m, 3H, C6H3)
3504, 3141, 2962, 2856
3453, 3168, 2945, 2859
3504, 3244, 2938, 2856
3465, 3228, 2943, 2856
3493, 3242, 2934, 2850
3426, 3325, 2952, 2850
3504, 3262, 2943, 2861
3458, 3121, 2978, 2859
3516, 3251, 2939, 2853
3508, 3253, 2939, 2859
3429, 3136, 2939, 2859
3428, 3138, 2939, 2859
3454, 3150, 2946, 2902
3479, 3281, 2936, 2866
3442, 3158, 2944, 2854
3483, 3278, 2939, 2869
3466, 3263, 2940, 2859
3477, 3235, 2957, 2855
3527, 3233, 2934, 2855
3498, 3228, 2930, 2864
3508, 3183, 2934, 2865
4B1
4B2
4B3
4B4
4B5
4B6
4B7
4B8
4B9
4B10
4B11
4B12
4B13
4B14
4B15
4B16
4B17
4C
1.23-2.09 (m, 9H, 4CH2 þ OH), 2.99 (m, 1H, CH-O), 3.77 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.46 (br, 1H, CH-SO2),
6.91 (br, 1H, NH), 6.23 (dd, 1H, J = 9.00, 3.00 Hz, Ph-H), 7.83 (d, 1H, J = 9.00 Hz, Ph-H), 7.18 (d, 1H, J = 3.00 Hz, Ph-H)
1.23-2.12 (m, 8H, 4CH2), 2.25 (s, 3H, CH3), 3.01-3.07 (ddd, 1H, J = 11.41, 4.42, 1.86 Hz, CH-O), 4.52 (s, 1H, CH-SO2),
6.73-6.79 (m, 2H, NH þ Ph-H), 7.08-7.13 (m, 1H, Ph-H), 7.23-7.28 (m, 1H, Ph-H)
1.26-2.05 (m, 8H, 4CH2), 2.90 (br, 1H, OH), 3.03-3.09 (ddd, 1H, J = 12.11, 4.04, 1.89 Hz, CH-O), 4.55 (br, 1H, CH-SO2),
7.05 (br, 1H, NH), 7.07-7.63 (m, 4H, C6H4)
1.23-2.12 (m, 8H, 4CH2), 2.98 (br, 1H, OH), 3.09-3.15 (ddd, 1H, J = 11.52, 4.40, 1.92 Hz, CH-O), 4.55 (br, 1H, CH-SO2),
7.08-7.13 (m, 1H, Ph-H), 7.23-7.28 (m, 1H, Ph-H), 7.35 (s, 1H, NH), 7.37 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H)
1.25-2.08 (m, 8H, 4CH2), 2.94 (br, 1H, OH), 3.05-3.11 (ddd, 1H, J = 11.62, 4.34, 1.82 Hz, CH-O), 4.50 (br, 1H, CH-SO2),
6.96-7.02 (m, 1H, Ph-H), 7.24-7.30 (m, 1H, Ph-H), 7.33 (s, 1H, NH), 7.52 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H)
1.24-2.00 (m, 8H, 4CH2), 2.96 (br, 1H, OH), 3.04-3.10 (ddd, 1H, J = 11.67, 4.37, 1.84 Hz, CH-O), 4.52 (br, 1H, CH-SO2),
7.34 (br, 1H, NH), 7.19-7.30 (m, 4H, C6H4)
1.23-2.02 (m, 8H, 4CH2), 2.97 (br, 1H, OH), 3.03-3.08 (ddd, 1H, J = 12.10, 4.12, 1.83 Hz, CH-O), 4.51 (br, 1H, CH-SO2),
7.31 (br, 1H, NH), 7.10-7.22 (m, 4H, C6H4)
1.22-2.18 (m, 8H, 4CH2), 2.79 (br, 1H, OH), 3.11-3.17 (ddd, 1H, J = 11.03, 5.06, 2.01 Hz, CH-O), 4.56 (br, 1H, CH-SO2),
7.39 (br, 1H, NH), 7.34 (d, 2H, J = 8.51 Hz, Ph-H), 7.57 (d, 2H, J = 8.51 Hz, Ph-H)
1.24-2.07 (m, 8H, 4CH2), 2.64 (br, 1H, OH), 3.02-3.07 (ddd, 1H, J = 12.19, 3.83, 2.03 Hz, CH-O), 4.55 (br, 1H, CH-SO2),
7.00 (br, 1H, NH), 7.24-7.70 (m, 3H, C6H3)
1.22-2.06 (m, 8H, 4CH2), 2.56 (br, 1H, OH), 3.04-3.10 (ddd, 1H, J = 12.08, 4.06, 2.01 Hz, CH-O), 4.54 (s, 1H, CH-SO2),
6.99 (br, 1H, NH), 7.09 (dd, 1H, J = 8.7, 2.52 Hz, Ph-H), 7.37 (d, 1H, J = 2.60 Hz, Ph-H), 7.38 (d, 1H, J = 8.60 Hz, Ph-H)
1.26-2.06 (m, 8H, 4CH2), 2.35 (br, 1H, OH), 3.10-3.17 (m, 1H, CH-O), 4.60 (br, 1H, CH-SO2), 7.29 (br, 1H, NH),
7.49 (d, 1H, J = 8.22 Hz, Ph-H), 7.76 (d, 1H, J = 8.22 Hz, Ph-H), 8.13 (s, 1H, Ph-H)
1.23-2.09 (m, 8H, 4CH2), 2.40 (br, 1H, OH), 3.14-3.20 (m, 1H, CH-O), 4.63 (br, 1H, CH-SO2), 7.31 (br, 1H, NH),
7.63 (s, 1H), 7.70 (s, 2H)
1.25-2.09 (m, 8H, 4CH2), 2.45 (br, 1H, OH), 3.07-3.13 (ddd, 1H, J = 12.08, 4.10, 1.99 Hz, CH-O), 4.52 (br, 1H, CH),
6.98 (br, 1H, NH), 7.48-7.80 (m, 3H, C6H3)
1.40-2.18 (m, 10H, 5CH2), 2.40 (br, 1H, OH), 3.15-3.20 (m, 1H, CH-O), 4.68-4.70 (m, 1H, CH-SO2), 7.05 (br, 1H, NH),
7.49-7.80 (m, 3H, C6H3)
1.40-2.14 (m, 10H, 5CH2), 2.41 (br, 1H, OH), 3.33-3.37 (m, 1H, CH-O), 4.52-4.55 (m, 1H, CH-SO2), 7.19 (br, 1H, NH),
7.48-7.80 (m, 3H, C6H3)
1.24-1.39 (m, 14H), 1.47-1.56 (m, 2H), 1.74 (br, 1H, OH), 1.83-2.76 (m, 4H), 3.29-3.31 (m, 1H, CH-OH), 4.19
(s, 1H, CH-SO2), 6.94 (br, 1H, NH), 7.52-7.77 (m, 3H, C6H3)
4D
4E
values of compounds 4C and 3C were 0.85 and 0.80 μg/mL, which
were better than procymidone (with an EC50 value of 0.99 μg/
mL), respectively. According to the EC80 values, the contribution
of a 8-membered ring for fungicidal activity became the biggest.
The EC80 values of compounds 4D and 3D were 2.50 and 2.88 μg/
mL, which were 1.18 and 1.03 times that of procymidone,
respectively. Therefore, regardless of the size of the ring reducing
or increasing, the fungicidal activity will significantly decrease.

11388 J. Agric. Food Chem., Vol. 58, No. 21, 2010
Li et al.
Figure 3. Relationshipbetween thesize of the ring andthe EC50 and EC80 values ofthecompounds 4 and 3. The ordinateisthe ratio of EC50 and EC80 values
of procymidone to the EC50 and EC80 values of the compounds.
Table 3. Fungicidal Activities of Compounds 4 and 3 against B. cinerea
(Mycelial Growth Rate Method)
Table 5. Control Efficiency of Compounds 3A-3E and 4A-4E against B.
cinerea Pers. (Leaf Method)
compound number
EC50 (μg/mL)
EC80 (μg/mL)
average
diameter
of the spot (cm)
compound
number
concentration
(μg/mL)
control
efficiency (%)
4B1
4B2
4B3
4B4
4B5
4B6
4B7
4B8
4B9
4B10
4B11
4B12
4B13
4B14
4B15
4B16
4A
22.90
18.01
21.49
104.68
22.30
34.06
23.99
75.65
10.98
7.38
443.24
65.37
332.24
>104
500
125
0.36
0.39
0.56
1.00
1.13
1.19
0.72
1.06
1.25
0.46
0.47
0.50
0.04
0.06
0.24
0.27
0.44
0.53
0.09
0.39
0.66
0.07
0.10
0.36
0.08
0.10
0.12
1.05
1.20
1.30
0.10
0.38
0.55
0.00
0.24
0.33
1.42
74.77 ( 11.02 def
72.42 ( 13.25 defg
60.68 ( 12.18 hi
28.99 ( 11.02 k
20.78 ( 9.56 klm
16.08 ( 12.90 lmn
49.53 ( 11.95 j
21.95 ( 15.15 klm
11.97 ( 16.85 mn
67.72 ( 18.86 efgh
67.14 ( 12.86 efgh
64.79 ( 9.50 fgh
97.07 ( 3.62 a
3A
181.29
310.15
84.16
>104
31.25
500
125
3B17
31.25
500
125
250.23
86.49
21.40
65.86
517.71
25.47
16.02
14.64
64.39
14.26
5.27
3C
7.07
8.79
31.25
500
125
53.24
7.80
3D
31.25
500
125
2.53
4.44
95.60 ( 6.90 a
3E
36.38
3.37
31.25
500
125
82.98 ( 8.20 bcd
81.12 ( 18.83 cd
68.90 ( 11.81 efgh
62.44 ( 8.67 ghi
93.54 ( 9.59 ab
72.42 ( 16.30 defg
53.05 ( 11.76 ij
95.01 ( 7.27 a
92.67 ( 7.72 ab
74.77 ( 11.81 def
94.42 ( 6.27 a
93.55 ( 7.63 ab
91.49 ( 6.96 abc
26.06 ( 18.39 kl
15.49 ( 18.51 lmn
8.45 ( 9.96 n
4B17
4C
0.85
1.09
4A
4D
4E
2.50
31.25
500
125
5.72
2.50
49.36
15.08
5.20
3A
4B17
3B17
3C
2.16
0.80
31.25
500
125
3.70
2.88
3D
3E
1.22
1.94
4C
39.83
2.96
31.25
500
125
procymidone
0.99
4D
31.25
500
125
Table 4. Fungicidal Activity of Compounds 3A-3E and 4A-4E against the
Spores of B. cinerea
4E
31.25
500
125
compound number
EC50 (μg/mL)
EC80 (μg/mL)
91.78 ( 8.93 abc
73.59 ( 14.75 def
61.27 ( 9.73 hi
100.00 ( 0 a
82.98 ( 10.17 bcd
76.53 ( 9.17 de
3A
3B17
4.21
4.21
226.64
124.27
387.82
549.44
114.57
43.03
260.18
>103
procymidone
31.25
500
125
3C
3D
18.07
18.96
3.24
pyrimethanil
CK
3E
4A
31.25
0
5.29
4B17
4C
40.09
76.96
23.62
419.99
0.98
Results of the Spore Germination Test. As shown in Table 4,
those two types of compounds restrained spore germination at
low concentrations, and they could inhibit the germ tube elonga-
tion of B. cinerea under certain concentrations. This result is
consistent with the mycelium growth rate method. Most of the
compounds (except the compounds 4C and 4E) had fair to good
inhibitory activity. Furthermore, the activitiy of 2-oxocyclo-
alkylsulfonamides 3 showed better than 2-hydroxycycloalkylsulfon-
amides 4, and there was no regularity relationship between the
4D
4E
693.34
>103
3.18
procymidone
Structure-Activity Relationship 3. The fungicidal activity of
2-hydroxycycloalkylsulfonamides 4 against B. cinerea was similar
to that of 2-oxocycloalkylsulfonamides 3. We can infer that the
two series of compounds have a similar mode of action.

Article
J. Agric. Food Chem., Vol. 58, No. 21, 2010 11389
size of the ring and their activity. Overall, the compounds
containing a 5-membered ring had a preferable activity compared
to other compounds.
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