Synthesis and biological evaluation of new 3- trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives as antidiabetic and antimicrobial agents

Article abstract of DOI:10.1016/j.jfluchem.2010.12.009

Fluorinated pyrazoles, and benzenesulfonylurea and thiourea derivatives as well as their cyclic sulfonylthioureas 2-18 were prepared as hypoglycemic and antibacterial agents. The chemistry involves the condensation of 4-hydrazino benzenesulfonamide hydroc

Full text of DOI:10.1016/j.jfluchem.2010.12.009

Journal of Fluorine Chemistry 132 (2011) 131–137
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and biological evaluationof new 3-trifluoromethylpyrazolesulfonyl-urea
and thiourea derivatives as antidiabetic and antimicrobial agents
a
a,b
Hassan M. Faidallah a, , Khalid A. Khan , Abdullah M. Asiri
*
a Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
b Center of Excellence for Advanced Materials Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluorinated pyrazoles, and benzenesulfonylurea and thiourea derivatives as well as their cyclic
sulfonylthioureas 2–18 were prepared as hypoglycemic and antibacterial agents. The chemistry involves
the condensation of 4-hydrazino benzenesulfonamide hydrochloride with 1-trifluoromethyl diketones 1
to give pyrazole derivatives 2 which upon bromination gave the bromopyrazole 3. Reaction of 2 or 3 with
isocyanates and isothiocyanates gave the corresponding ureas 4 and 5 and thioureas 6 and 7. Cyclization
Received 10 October 2010
Received in revised form 11 December 2010
Accepted 14 December 2010
Available online 21 December 2010
of thiourea derivatives with ethyl bromoacetate, ethyl b-bromopropionate, 1,3-dichloroacetone and a-
Keywords:
bromoacetophenone yielded the corresponding 4-oxothiazolidines 8 and 9, 4-oxo-5,6-dihydrothiazine
10, 5-oxo-4,5-dihydrothiazines 11 and 12 and thiazolines 13 and 14. Preliminary biological screening of
the prepared compounds revealed significant antidiabetic and antibacterial activities.
ß 2010 Elsevier B.V. All rights reserved.
Fluorinated pyrazoles
Benzenesulfonylureas
Thioureas
Thiazolidines
Thiazines
Antidiabetic and antimicrobial activities
1. Introduction
at N-1 and C-4 were reported to be selective inhibitors of
cyclooxygenase [10–12] and have antidiabetic [13], herbicidal [14]
The presence of fluorine and trifluoromethyl group in particu-
lar, is recognized in medicinal chemistry as a substituent of
distinctive qualities [1,2]. Insertion of fluorine in a strategic
position of a molecule has emerged as a very powerful and
versatile tool for the development of compounds endowed with
biological activities. In heterocyclic compounds trifluoromethyl
group plays a significant role to alter the physico-chemical and
biological characteristics of these molecules [3,4]. The incorpo-
ration of fluorine into a drug modulates the steric and electronic
parameters thereby influencing both the pharmacodynamic and
pharmacokinetic properties of drugs. In terms of bioisosterism,
trifluoromethyl group is smaller than the isopropyl, larger than the
methyl, and rather similar to the ethyl group [5]. The presence of
fluorine often leads to increased lipid solubility, thereby enhancing
rates of absorption and transport of drugs in vivo [6]. Therefore,
there has been greater effort towards the synthesis of biologically
active pyrazoles having trifluoromethyl group as one of the
substituents on either C-3 or C-5 [7–9]. Furthermore, 5-aminopyr-
azoles and 3-trifluoromethylpyrazoles with a wide array of groups
and antibacterial properties [15]. However, since several 3,5-
dimethylpyrazoles possess hypoglycemic activities as much as 100
times that of tolbutamide in glucose-primed intact rats [16–19],
studies have been conducted in our group on the synthesis of new
3,5-disubstituted pyrazoles [20–25]. In continuation of our
previous work in the preparation of 3,5-disubstituted pyrazole
[21–29] and fluorinated pyrazole [30,31] benzenesulfonylurea and
thiourea derivatives as well as their cyclic sulfonylthioureas, many
new trifluoromethyl pyrazole derivatives of these classes were
synthesized and were tested for hypoglycemic and antimicrobial
activities. Preliminary biological testing revealed that some
compounds showed significant antibacterial and antidiabetic
activities.
2. Results and discussion
2.1. Synthesis and spectral characterizations
Condensation of the key intermediates, p-sulfonylphenylhyr-
azine hydrochloride with fluorodiketones 1 afforded 5-substitut-
ed-3-trifluoromethyl-1-(p-sulfonylphenyl)pyrazoles 2 (Scheme 1
and Table 1). Bromination of 2 with bromine in chloroform
afforded the corresponding 4-bromo-pyrazole 3. The IR spectra of
these pyrazoles displayed two absorption bands at 3225–
3238 cmꢀ1 and 3352–3368 cmꢀ1 indicative of the NH2 group, in
* Corresponding author at: Department of Chemistry, P.O. Box 80203, Faculty of
Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Tel.: +966 567743180.
E-mail address: hfaidallahm@hotmail.com (H.M. Faidallah).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.12.009

[
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
Scheme 1.

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
133
Table 1
Physical and analytical data of pyrazole derivatives.
Compd.
R
R0
Yield (%)
mp (8C)
Mol. formula
Found %
C
Calc.
C
H
N
S
H
N
S
2a
2b
3a
CH3
86
82
80
88
70
75
72
78
72
76
73
75
77
70
70
76
72
68
72
63
65
69
62
66
72
74
76
70
76
65
68
71
72
75
62
76
77
70
68
73
69
70
66
69
62
58
56
54
144a
Furyl
CH3
194
164–166
207
C14H10F3N3O3S
C11H9BrF3N3O2S
C14H9BrF3N3O3S
C18H21F3N4O3S
47.18
34.28
38.75
50.36
2.91
2.45
2.11
4.71
11.66
11.02
9.48
8.75
8.21
7.42
7.51
47.07
34.39
38.55
50.26
2.82
2.36
2.08
4.88
11.76
10.94
9.63
8.97
8.34
7.35
7.44
3b
4a
Furyl
CH3
Cyclohexyl
Ph
166–168
143–145b
139–140
244–245
200–202
180–182
124–125
181–183
248–251
163–164
141–143
186–188
133–135
144c
13.15
13.02
4b
4c
CH3
CH3
Naphthyl
p-Cl C6H4
Cyclohexyl
Ph
C22H17F3N4O3S
55.92
47.34
52.39
53.05
57.15
43.06
40.35
44.79
45.45
42.75
49.22
3.76
3.12
4.47
4.62
3.38
2.91
2.56
4.01
2.61
2.25
3.35
11.91
12.21
11.55
11.88
10.77
11.24
10.56
9.78
6.81
7.05
6.72
6.89
6.21
6.51
6.01
5.71
5.88
5.48
55.71
47.12
52.28
52.95
57.04
42.96
40.21
44.93
45.42
42.77
49.12
3.61
3.07
4.38
4.44
3.25
2.81
2.44
3.59
2.54
2.22
3.41
11.81
12.21
11.61
11.76
10.64
11.13
10.42
9.98
6.76
6.99
6.64
6.73
6.09
6.37
5.96
5.71
5.77
5.43
4d
4e
CH3
C18H14ClF3N4O3S
Furyl
Furyl
Furyl
CH3
C
C
C
21H21F3N4O4S
21H15F3N4O4S
15H17F3N4O4S
4f
4g
Naphthyl
Ph
5a
C18H14BrF3N4O3S
5b
5c
CH3
p-Cl C6H4
Cyclohexyl
Ph
C18H13BrClF3N4O3S
Furyl
Furyl
Furyl
CH3
C
C
21H20BrF3N4O4S
21H14BrF3N4O4S
5d
5e
10.12
9.61
10.09
9.51
p-Cl C6H4
Ph
C21H13BrClF3N4O4S
C18H15F3N4O2S2
6a
12.81
14.52
12.72
14.54
6b
6c
CH3
Benzyl
Ph
Furyl
Furyl
Furyl
CH3
147–148
134–136
179–180
131–132
151–153
174–176
152–154
140–142
212–215
205d
C21H15F3N4O3S2
51.25
52.21
50.85
41.77
42.82
43.71
44.25
41.75
50.21
3.15
3.35
3.01
2.84
3.14
3.52
2.61
2.27
3.26
11.52
11.15
10.91
10.85
10.65
9.82
13.01
12.78
12.42
12.41
12.15
11.21
11.25
10.52
13.48
51.23
52.18
50.78
41.63
42.79
43.68
44.15
41.64
50.01
3.07
3.38
2.91
2.72
3.02
3.49
2.47
2.16
3.15
11.38
11.06
10.77
10.79
10.51
9.71
13.02
12.66
12.32
12.35
12.02
11.11
11.22
10.58
13.34
6d
6e
Benzyl
Benzoyl
Ph
C
C
22H17F3N4O3S2
22H15F3N4O5S2
7a
C18H14BrF3N4O2S2
C19H16BrF3N4O2S2
7b
7c
CH3
Benzyl
Cyclohexyl
Ph
Furyl
Furyl
Furyl
CH3
C
C
21H20BrF3N4O3S2
21H14BrF3N4O3S2
7d
7e
9.92
9.81
p-Cl C6H4
Ph
C21H13BrClF3N4O3S2
C20H15F3N4O3S2
9.41
9.25
8a
11.71
11.66
8b
8c
CH3
Benzyl
Ph
Furyl
Furyl
Furyl
CH3
184–186
137–138
182
C23H15F3N4O4S2
51.92
52.88
51.52
43.01
45.21
42.84
52.82
51.12
52.88
53.67
44.01
57.88
2.95
3.24
2.81
2.64
2.41
2.13
3.21
3.56
3.22
3.32
3.43
3.62
10.66
10.36
10.11
10.15
9.31
12.15
11.85
11.61
11.41
10.55
9.84
51.88
52.75
51.43
42.95
45.19
42.78
52.75
51.01
52.75
53.57
43.99
57.77
2.84
3.13
2.71
2.52
2.31
2.03
3.13
3.46
3.13
3.41
3.34
3.54
10.52
10.25
9.99
12.04
11.73
11.44
11.46
10.49
9.93
8d
8e
Benzyl
Benzoyl
Ph
C
C
24H17F3N4O4S2
24H15F3N4O5S2
9a
248–250
254
C20H14BrF3N4O3S2
23H14BrF3N4O4S2
C23H13BrClF3N4O4S2
24H17F3N4O4S2
C21H17F3N4O3S2
10.02
9.16
9b
9c
Furyl
Furyl
Furyl
CH3
Ph
C
p-Cl C6H4
Ph
225
8.76
8.67
10a
11a
11b
11c
12a
13a
13b
13c
13d
14a
15
16
17
18
147–148
140–142
210
C
10.31
11.42
10.38
9.88
11.82
13.01
11.82
11.43
11.21
11.92
10.25
11.33
10.25
9.99
11.73
12.97
11.73
11.44
11.18
11.86
Ph
Furyl
Furyl
CH3
Ph
C
C
24H17F3N4O4S2
25H19F3N4O4S2
Benzyl
Ph
125–128
187–188
149–150
134e
C21H16BrF3N4O3S2
C26H19F3N4O2S2
9.86
9.77
CH3
Ph
10.41
10.36
CH3
Benzyl
Ph
Furyl
Furyl
CH3
156–158
121–122
159–161
188
C29H19F3N4O3S2
58.87
59.35
50.55
51.92
52.75
56.82
49.12
2.24
3.51
2.81
3.02
2.98
3.43
3.18
9.61
9.35
10.93
10.62
10.51
11.62
11.31
10.21
9.71
58.78
59.41
50.41
51.81
52.63
56.78
49.02
3.23
3.49
2.93
2.91
3.01
3.33
3.05
9.45
9.24
10.82
10.57
10.35
11.52
11.24
10.11
9.69
Benzyl
Ph
C
30H21F3N4O3S2
C26H18BrF3N4O2S2
9.12
9.04
Furyl
Furyl
Furyl
CH3
C
C
C
24H15F3N6O3S2
25H17F3N6O3S2
30H21F3N6O3S2
15.21
14.82
13.35
12.82
15.11
14.73
13.24
12.71
192
132–134
155–156
C27H20BrF3N6O2S2
Lit. [31].
a
mp 142 8C.
mp 144 8C.
mp 145 8C.
mp 204 8C.
mp 132 8C.
b
c
d
e
addition to the strong bands at 1330–1352 cmꢀ1 and 1145–
1156 cmꢀ1 for the SO2N moiety. Their 1H NMR spectra exhibited
It has been reported that condensation of N,N-disubstituted
thiourea with chloroacetic acid, its chloride or bromide esters
afforded 2-imino-4-oxothiazolidines, and the reaction proceeds
through the intermediate formation of the cyclic pseudothiohy-
dantoic acid [32–34]. In the present study, cyclization of the
the aromatic and NH2 protons as multiplets at
2). Condensation of pyrazole derivatives
d
2
6.53–8.20 (Table
or with the
3
appropriate isocyanate and isothiocyanate in dry acetone yielded
the corresponding benzene urea 4 and 5 and thiourea 6 and 7
derivatives respectively. The IR spectra of these compounds
exhibited two bands at 1330–1362 cmꢀ1 and 1148–1158 cmꢀ1
due to SO2N group as well as a urea carbonyl band at 1652–
1658 cmꢀ1 in case of compounds 4 and 5 and a thiourea carbonyl
absorption at 1134–1145 cmꢀ1 in the case of compounds 6 and 7.
The structures of the above compounds (4–7) were further
supported by their elemental analyses (Table 1), 1H NMR (Table
2) and 13C NMR spectra (Table 3).
thiourea derivatives 6 and 7 with ethyl bromoacetate, ethyl
b-
bromopropionate, 1,3-dichloroacetone and -bromoacetophe-
a
none afforded the corresponding 4-oxothiazolidine 8 and 9, 4-
oxo-5,6-dihydrothiazine 10, 5-oxo-4,5-dihydrothiazine 11 and 12,
and thiazoline 13 and 14 derivatives respectively. IR spectra of
compounds 8–12 showed cyclic carbonyl absorption at 1720–
1740 cmꢀ1 and two other absorption bands at 1335–1344 cmꢀ1
and 1150–1164 cmꢀ1 for the SO2N group. The structures of the
above compounds 8–14 were further supported by their 1H NMR

134
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
Table 2
1H NMRa spectral data (
d) of pyrazole derivatives.
Compd.
R
R0
ArH and NH (m)
Others
2a
2b
3a
6.70–8.12 (7H)
6.64–8.02 (10H)
6.62–8.20 (6H)
6.53–8.14 (9H)
7.12–8.38 (6H)
7.00–8.10 (11H)
6.98–7.99 (10H)
6.78–8.17 (9H)
7.02–8.04 (13H)
7.11–8.12 (15H)
6.85–7.97 (9H)
7.02–8.03 (8H)
6.92–8.12 (7H)
6.87–8.02 (12H)
6.92–7.89 (10H)
6.89–8.01 (10H)
6.99–8.01 (13H)
7.00–8.14 (13H)
7.12–8.05 (13H)
7.02–7.98 (9H)
7.01–8.08 (7H)
7.00–7.98 (12H)
7.10–8.05 (10H)
7.05–8.11 (10H)
6.82–8.02 (13H)
6.79–8.13 (13H)
6.88–8.02 (12H)
6.92–8.10 (12H)
6.89–8.00 (13H)
6.92–8.01 (10H)
6.82–8.12 (13H)
6.80–8.09 (13H)
6.89–8.05 (9H)
6.90–8.12 (16H)
7.09–8.19 (16H)
7.00–8.01 (19H)
6.82–8.12 (15H)
6.92–8.07 (13H)
6.84–8.11 (14H)
6.62–8.13 (19H)
6.67–8.09 (18H)
3.35 (s, 3H, CH3)
Furyl
CH3
3.38 (s, 3H, CH3)
3b
4a
Furyl
CH3
Cyclohexyl
Ph
3.32 (s, 3H, CH3); 8.65 (s, 1H, NH)
4b
4d
4e
CH3
3.40 (s, 3H, CH3); 8.56 (s, 1H, NH)
CH3
p-Cl C6H4
Cyclohexyl
Ph
3.29 (s, 3H, CH3); 8.75 (s, 1H, NH)
Furyl
Furyl
Furyl
CH3
0.92–1.85 (m, 11H, cyclohexyl); 8.55 (s, 1H, NH)
8.60 (s, 1H, NH); 8.75 (s, 1H, NH)
4f
4g
Naphthyl
Ph
8.78 (s, 1H, NH); 9.01 (s, 1H, NH)
5a
3.32 (s, 3H, CH3); 8.56 (s, 1H, NH); 8.78 (s, 1H, NH)
3.28 (s, 3H, CH3); 8.62 (s, 1H, NH); 8.81 (s, 1H, NH)
0.88–1.76 (m, 11H, cyclohexyl); 8.58 & 8.82 (2s, 1H, NH)
8.59 (s, 1H, NH); 8.80 (s, 1H, NH)
5b
5c
CH3
p-Cl C6H4
Cyclohexyl
Ph
Furyl
Furyl
CH3
5d
6a
Ph
3.35 (s, 3H, CH3); 8.45 (s, 1H, NH); 8.70 (s, 1H, NH)
3.29 (s, 3H, CH3); 8.56 (s, 1H, NH); 8.78 (s, 1H, NH)
8.55 (s, 1H, NH); 8.80 (s, 1H, NH)
6b
6c
CH3
Benzyl
Ph
Furyl
Furyl
Furyl
CH3
6d
6e
Benzyl
Benzoyl
Ph
4.52 (d, 2H, CH2); 8.62 (s, 1H, NH); 8.85 (s, 1H, NH)
8.49 (s, 1H, NH); 8.72 (s, 1H, NH)
7a
3.30 (s, 3H, CH3); 8.52 (s, 1H, NH); 8.68 (s, 1H, NH)
0.95–1.82 (m, 11H, cyclohexyl); 8.60 & 8.75 (2s, 1H, NH)
8.60 (s, 1H, NH); 8.90 (s, 1H, NH)
7c
Furyl
Furyl
CH3
Cyclohexyl
Ph
7d
8a
Ph
3.32 (s, 3H, CH3); 3.85 (s, 2H, CH2); 4.42 (s, 2H, CH2)
3.30 (s, 3H, CH3); 3.80 (s, 2H, CH2); 4.51 (s, 2H, CH2)
3.90 (s, 2H, CH2); 4.52 (s, 2H, CH2)
8b
8c
CH3
Benzyl
Ph
Furyl
Furyl
CH3
8e
Benzoyl
Ph
3.84 (s, 2H, CH2); 4.46 (s, 2H, CH2)
9a
3.29 (s, 3H, CH3); 3.87 (s, 2H, CH2); 4.50 (s, 2H, CH2)
3.79 (s, 2H, CH2); 4.48 (s, 2H, CH2)
9b
10a
11a
11b
11c
12a
13a
13b
13d
14a
15
Furyl
Furyl
CH3
Ph
Ph
3.52–4.12 (m, 4H, 2CH2)
Ph
3.30 (s, 3H, CH3); 3.72 (s, 2H, CH2); 4.02 (s, 2H, CH2)
3.84 (s, 2H, CH2); 4.15 (s, 2H, CH2)
Furyl
Furyl
CH3
Ph
Benzyl
Ph
3.75 (s, 2H, CH2); 4.09 (s, 2H, CH2)
3.32 (s, 3H, CH3); 3.78 (s, 2H, CH2); 4.08 (s, 2H, CH2)
3.30 (s, 3H, CH3); 4.35 (s, 2H, CH2)
CH3
Ph
CH3
Benzyl
Benzyl
Ph
3.29 (s, 3H, CH3); 4.38 (s, 2H, CH2)
Furyl
CH3
4.42 (s, 2H, CH2)
3.35 (s, 3H, CH3)
Furyl
Furyl
Furyl
CH3
3.75 (s, 2H, CH2)
16
3.62 (s, 3H, CH3)
17
4.50 (d, 1H, CH); 5.20 (m, 1H, CH)
18
4.42 (d, 1H, CH); 3.80 (m, 1H, CH)
a
Solutions in a mixture of CDCl3 and DMSO-d6,
d in ppm.
Table 3
13C NMRa spectral data (
d
) of pyrazole derivative.
Compd.
R
R0
Ar and pyrazole C
CH3
Other C
2a
2b
CH3
148.9, 141.2, 138.7, 126.2, 124.1, 122.4, 114.5
147.8, 140.9, 142.6, 139.5, 128.1, 127.2, 124.2,
123.2, 121.1, 112.5, 109.3
14.6
Furyl
3a
4a
CH3
CH3
146.7, 140.4, 136.5, 127.8, 125.5, 121.4, 110.3
145.0, 142.3, 137.8, 128.2, 125.3, 120.2, 112.6
14.8
14.5
Cyclohexyl
176.2 (CO); 23.0, 29.1,
34.5, 49.6 (cyclohexyl)
175.0 (CO)
4b
4f
CH3
Ph
Ph
146.0, 141.2, 138.6, 129.3, 128.4, 127.9, 126.4,
14.3
125.1, 123.5, 122.1, 110.3
Furyl
146.3, 144.5, 142.6, 140.3, 138.2, 129.5, 128.4,
178.0 (CO)
128.2, 127.4, 125.1, 123.0, 122.6, 120.1, 113.5, 108.6
149.0, 143.4, 140.6, 137.2, 129.0, 128.3, 128.1, 127.5, 126.3, 120.6, 109.2
147.0, 145.6, 143.2, 141.3, 139.6, 129.4, 128.2,
5a
5d
CH3
Ph
Ph
14.2
14.6
14.6
177.4 (CO)
176.5 (CO)
Furyl
128.0, 127.3, 126.2, 122.6, 121.0, 112.6, 110.4
6b
7c
CH3
Benzyl
146.4, 142.3, 140.0, 136.9, 129.2, 128.4, 128.0, 127.6, 125.6, 122.4, 110.3
147.7, 143.2, 141.0, 138.9, 128.6, 127.6, 124.2, 123.0, 122.6, 112.5, 108.6
204 (CS); 63.2 (CH2)
201 (CS); 22.9, 28.8,
34.2, 48.6 (cyclohexyl)
192 (CO); 38.6 (CH2)
Furyl
Cyclohexyl
8a
8c
CH3
Ph
Ph
146.2, 142.8, 140.4, 137.6, 134.2, 129.5, 128.3, 128.2, 127.8, 125.3,
121.8, 109.2
Furyl
147.6, 142.9, 140.5, 139.2, 134.0, 133.2, 129.4,
194 (CO); 39.2 (CH2)
128.6, 128.3, 127.5, 126.4, 123.6, 122.6, 121.4, 113.5, 106.5
146.8, 143.6, 141.2, 138.6, 135.4, 133.3, 129.8, 128.2, 128.0, 127.6, 125.0, 116.5
149.2, 147.6, 146.4, 142.2, 140.6, 139.8, 138.7, 136.5, 134.2, 133.6, 129.8, 128.3,
128.2, 127.6, 126.4, 124.2, 122.3, 116.6
11a
14a
CH3
CH3
Ph
Ph
14.2
14.2
189 (CO); 38.8, 36.4 (CH2)
15
Furyl
148.9, 147.2, 145.4, 142.3, 140.6, 138.8, 136.4,
39.5 (CH2)
134.0, 130.5, 129.8, 128.4, 128.3, 126.9, 125.4, 123.8, 122.4, 120.5, 108.2
a
Solutions in a mixture of CDCl3 and DMSO-d6,
d in ppm.

[
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
135
Scheme 2.
(Table 2) and 13C NMR data (Table 3). Moreover, some new
condensed ring systems namely 3-phenyl-7H-thiazolo [3,4-
c][1,2,4]triazoles 15 and 16 (Scheme 2), starting from the
appropriate 3-benzoyl-2-(substituted benzenesulfonylimino)thia-
zolidin-4-one 8e were prepared by reacting such compounds with
the suitable hydrazine refluxing in ethanol. On the other hand, the
targeted pyrazolo [3,4-d]thiazole fused ring system 17 and 18 was
achieved by condensing the thiazolidinones 8c and 9a with
benzaldehyde followed by reaction with hydrazine hydrate. The IR
spectra of the above compounds 15–18 were characterized by the
absence of the carbonyl absorption band of thiazolidinones. The 1H
NMR and 13C NMR spectra of the above compound are listed in
Tables 2 and 3 respectively.
calculated t-value exceeded the tabulated t-value at the P = 0.05
level.
From the data presented in Table 4, it is obvious that the 3,5-
disubstituted-benzenesulfonylurea derivatives 4 and 5 possess
marked hypoglycemic activity. The potency of these compounds is
more than that of phenformine, and they are much more active
than the parent compound 3,5-dimethylpyrazole. Introduction of
bromine at position
4 of the pyrazole ring increases the
Table 4
Antidiabetic activity of pyrazole derivatives.
Compd.
Reduction in plasma glucose level (%)
P
Phenformin
10
4
<0.01a
<0.05
0.05
3,5-Dimethylpyrazole
2.2. Antidiabetic activity
2a
<1
<1
17
14
13
20
16
18
3a
0.05
4a
<0.01a
<0.01a
<0.01a
<0.01a
<0.01a
<0.01a
0.05
Compounds 2a, 3a, 4a,b,c, 5a,c,d, 6a,c, 7a,c, 8a,c, 9a, 11a, 12a,
13a,d and 15 were tested for hypoglycemic activity using alloxan-
treated female albino mice weighing 20 g. Alloxan 100 mg/kg was
injected into the tail vein in a 10 mg/mL saline solution. Three days
later the mice were given the test compounds orally in suspension
in 1% carboxymethylcellulose solution at the rate of 0.2 mmol/kg of
the body weight. Each day a group of four mice was used as a
control group and one group of five mice was given the standard
100 mg of phenformine/kg. Up to six groups of four mice received
the test compounds. Blood samples were collected into 0.04% NaF
solution at 0, 1 and 3 h.
Glucose was determined by the micro-colorimetric copper
reduction technique of Haslewood and Strookman. Results are
expressed as a percentage reduction of the plasma glucose levels
compared to the control value. Statistical significance was assessed
by a Student t-test. Statistical significance was accepted where the
4b
4e
5a
5c
5d
6a
1.5
6c
2
0.05
7a
3
0.05
7c
2.5
8
0.05
8a
0.01a
0.01a
0.01a
0.01a
0.01a
0.01a
0.01a
0.05
8c
5
9a
10
11a
12a
13a
13d
15
7.5
9
7
8.5
<1
a
Statistically significant.

136
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
Table 5
NMR spectral analysis. Preliminary biological testing of some of
these compounds revealed that 3a, 3b, 6e and 7e exhibited
significant antimicrobial activities and compounds 4 and 5 showed
marked hypoglycemic activities.
Anti-bacterial and anti-fungal data of trifluoromethylpyrazole derivatives.
Compd.
Zone of inhibition in mm
Anti-bacterial activity
Zone of inhibition in
mm
Anti-fungal activity
Escherichia
coli
Staphylococcus
Aspergillus
niger
Candida
4. Experimental
aureus
albicans
4.1. Chemicals and methods
2a
14
15
16
19
9
12
13
18
20
10
7
11
14
19
18
8
12
13
16
21
6
2b
3a
Melting points were determined in open glass capillaries on a
Gallenkamp melting point apparatus and were uncorrected. The
infrared (IR) spectra were recorded on Perkin-Elmer 297 infrared
spectrophotometer using the plate technique. The 1H NMR and 13
NMR spectra were recorded in CDCl3 and DMSO-d6 as a solvent on
Bruker DPX-400-FT spectrometer using tetramethylsilane as the
internal standard. Elemental analyses were performed at the
Microanalytical Unit, Faculty of Science, Cairo University, Cairo,
Egypt. Follow-up of the reactions and checking the homogeneity of
the compounds were made by TLC on silica gel-protected
aluminum sheets (Type 60 F254, E. Merck) and the spots were
3b
4a
4b
8
10
11
10
9
11
12
7
4d
12
6
13
8
C
4e
4f
8
10
8
10
9
5a
10
11
10
14
15
12
16
17
15
14
20
10
6
11
12
10
13
14
14
12
20
12
13
21
11
7
5b
10
11
15
17
13
14
18
16
15
18
9
13
8
5c
6a
16
15
13
11
19
11
12
19
10
6
6b
6c
6d
detected by exposure to UV lamp at
l 254. Biological testing was
6e
7a
performed in the Faculty of Medicine University of Alexandria,
Egypt. Reagents were of analytical grade and were used without
further purification.
7c
7e
8a
8b
7
4.1.1. 3-Trifluoromethyl-5-substituted-1-(p-
9c
8
10
7
9
11
8
10a
11a
11b
12a
13a
13b
14a
15
8
6
sulfamylphenyl)pyrazoles (2)
9
8
9
10
12
12
15
12
13
8
A solution of the appropriate diketone 1 (10 mmol) in ethanol
(50 mL) was refluxed with 4-hydrazinobenzenesulfonamide hy-
drochloride (10 mmol) for 4 h, cooled and diluted with water. The
precipitated crude product was filtered and recrystallized from
ethanol as needles.
11
12
14
13
15
10
8
10
13
12
14
16
11
10
9
11
14
16
15
14
10
7
16
6
4.1.2. 4-Bromo-3-trifluoromethyl-5-substituted-1-(p-
17
11
13
33
–
11
10
–
8
sulfamylphenyl)pyrazoles (3)
18
12
29
–
11
–
Ampicillin
Griseofulvin
A
solution of the appropriate pyrazole 2 (10 mmol) in
30
28
chloroform (30 mL) was refluxed and stirred with bromine
(10 mmol) for 1 h. The crude product that separated during
heating was filtered and recrystallized from ethanol as needles.
hypoglycemic activity of the urea derivative. On the other hand
although the hypoglycemic activity of the thioureas is low, their
cyclic thio-analogs showed potent antidiabetic activity (Table 4).
4.1.3. p-(3-Trifluoromethyl-5-substituted-pyrazole-1-
yl)benzenesulfonylureas (4 and 5)
2.3. Anti-microbial activity
A mixture of the appropriate pyrazole 2 or 3 (10 mmol) and
anhydrous K2CO3 (20 mmol) in dry acetone (25 mL) was stirred and
refluxed for 1 h. At this temperature, a solution of the appropriate
isocyanate (15 mmol) in dry acetone (5 mL) was added dropwise.
After the mixture was stirred and refluxed overnight, acetone was
removed under pressure, and the solid residue was dissolved in
water. The crude product was isolated by acidification with 2 N HCl
and purified by recrystallization from ethanol as needles.
Compounds 2–18 were screened in vitro for their anti-microbial
and antifungal activity against Escherichia coli, Staphylococcus
aureus, against Aspergillus niger and Candida albicans. The zones of
inhibition formed for the compounds against bacteria and fungi are
summarized in Table 5. Compounds 3a, 3b, 6e and 7e exhibited
significant activities against various strains of micro-organisms. All
test data in Table 5 were of average values from triplicate runs and
the test compounds showed reduced antimicrobial activities when
compared with their respective standards.
4.1.4. p-(3-Trifluoromethyl-5-substituted-pyrazol-1-
yl)benzenesulfonylthioureas (6 and 7)
A mixtureof2 or3 (10 mmol) and anhydrousK2CO3 (20 mmol)in
dry acetone (25 mL) was stirred and treated with the appropriate
isothiocyanate (12 mmol). After the mixture was stirred and
refluxed for 10 h, acetone was removed under pressure, and the
solid mass dissolved in water and acidified with 2 N HCl. The crude
product was purified by recrystallization from ethanol as needles.
3. Conclusions
In this paper, several new 3-trifluoropyrazole derivatives were
synthesized by the condensation of 4-hydrazino benzenesulfona-
mide hydrochloride with 1-trifluoromethyl diketones. 4-Bromo-
pyrazoles were prepared by the bromination of the corresponding
pyrazole derivative. Furthermore, many new urea and thiourea
derivatives were prepared from the reaction of the above pyrazoles
with the appropriate isocyanate and isothiocyanate. Cyclization of
the thiourea derivatives with the appropriate reagent afforded the
corresponding cyclic compounds. The structures of the prepared
compound were confirmed by elemental analysis, IR 1H and 13C
4.1.5. 3-Substituted-2-[p-(3-trifluoro-5-substituted-pyrazol-1-
yl)benzenesulfonylimino]- and 3-subsituted-2-[p-(4-bromo-3-
trifluoro-5-substituted-pyrazol-1-yl)benzenesulfonylimino]-4-
oxothiazolidines (8 and 9)
A mixture of 6 or 7 (10 mmol), ethyl bromoacetate (10 mmol)
and sodium acetate (20 mmol) in absolute ethanol (30 mL) was

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 131–137
137
refluxed for 2 h. The reaction mixture was then filtered while hot,
concentrated and allowed to cool. The product obtained was
recrystallized from ethanol as needles.
pathogenic yeast strain C. albicans and A. niger. DMSO was used as a
solvent control and the standard drugs used were Ampicillin and
Griseofulvin. The disc diffusion method was performed using
Muller-Hinton agar (Hi-Media) medium. The inhibition zones were
measured in mm at the end of an incubation period of 24 h at 37 8C
for bacteria and 72 h at 24 8C for fungi.
4.1.6. 3-Substituted-2-[p-(3-trifluoro-5-substituted-pyrazol-1-
yl)benzenesulfonylimino]-4-oxo-5,6-dihydro-1,2-thiazines (10)
A solution of 6 (10 mmol) in absolute ethanol (20 mL) was
refluxed with ethyl
b-bromopropionate (10 mmol) and sodium
Acknowledgement
acetate (20 mmol) for 2 h. The reaction mixture was then cooled
and poured into water; the precipitated thiazine was recrystallized
from ethanol as needles.
The authors wish to thank Department of Pharmacology,
Faculty of Pharmacy, University of Alexandria for their helpful
contribution and for facilities.
4.1.7. 3-Substituted-2-[p-(3-trifluoro-5-substituted-pyrazol-1-
yl)benzenesulfonylimino]- and 3-substituted-2-[p-(4-bromo-3-
trifluoro-5-substitued-pyrazol-1-yl)benzenesulfonylimino]-5-oxo-
4,6-dihydrothiazines (11 and 12)
A mixture of the appropriate thiourea, 4 or 10 (10 mmol), 1,3-
dichloroacetone (10 mmol) and sodium acetate (20 mmol) in
absolute ethanol (25 mL) was refluxed for 2 h. The thiazine which
separated on cooling was recrystallized from ethanol as needles.
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