Synthesis and biological evaluation of new 3,5-di(trifluoromethyl)-1,2,4- triazolesulfonylurea and thiourea derivatives as antidiabetic and antimicrobial agents

Article abstract of DOI:10.1016/j.jfluchem.2011.06.014

Fluorinated 1,2,4-triazoles 3 and benzenesulfonyl urea and thiourea derivatives as well as their cyclic sulfonylthioureas 4-10 were prepared as antimicrobial agents. The chemistry involves the condensation of sulfanilamide derivatives 1 with trifluoroacet

Full text of DOI:10.1016/j.jfluchem.2011.06.014

Journal of Fluorine Chemistry 132 (2011) 870–877
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and biological evaluation of new
3,5-di(trifluoromethyl)-1,2,4-triazolesulfonylurea 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 1,2,4-triazoles 3 and benzenesulfonyl urea and thiourea derivatives as well as their cyclic
sulfonylthioureas 4–10 were prepared as antimicrobial agents. The chemistry involves the condensation
of sulfanilamide derivatives 1 with trifluoroacetic anhydride to give N-di(trifluoroacetyl)sulfonamides 2
which upon reaction with hydrazine hydrate afforded the corresponding triazole derivatives 3. Reaction
of triazole derivative 3a with isocyanates and isothiocyanates gave the corresponding ureas 4 and
thioureas 5. Cyclization of thiourea derivatives with ethyl bromoacetate, 1,2-diiodoethane, diethyl
Received 19 March 2011
Received in revised form 10 June 2011
Accepted 16 June 2011
Available online 23 June 2011
Keywords:
oxalate and
a-bromoacetophenone derivatives yielded the corresponding 4-oxothiazolidines 7,
Fluorinated 1,2,4-triazole
Benzenesulfonylureas
Thioureas
thiazolidines 8, 4,5-dioxothiazolidines 9 and thiazolines 10. Preliminary biological screening of the
prepared compounds revealed significant antimicrobial and mild antidiabetic activities.
ß 2011 Elsevier B.V. All rights reserved.
Thiazolidines
Antidiabetic and antimicrobial activity
1. Introduction
useful way of making a molecule more easily delivered to the
active site in the body. Some of the best known drugs have
The introduction of fluorine or appropriate fluorinated func-
tions into a molecule has become an invaluable tool for medicinal
chemists [1,2]. Replacing hydrogen and other functional groups
with fluorine can have a dramatic effect on the modulation of
electronic, lipophilic and steric parameters, all of which can
critically influence both the pharmacodynamic and pharmacoki-
netic properties of drugs [3,4]. Substitution of fluorine into a
potential drug molecule not only alters the electronic environ-
ment, but it also influences the properties of neighboring
functional groups. It exerts a substantial effect on the molecule’s
dipole moment, the acidity or basicity of other groups nearby, not
to mention the overall reactivity and stability of the molecule [5,6].
Trifluoromethyl group is recognized in medicinal chemistry as a
substituent of distinctive qualities and it is one of the most
lipophilic functional groups known. It provides an extremely
trifluoromethyl substitution. These include the SSRI anti-depres-
sant fluoxetine and fluvoxamine [7,8], the COX-2 inhibitor
celecoxib [9], the antimalarial drug mefloquine [10], HIV protease
inhibitor tipranavir [11], anticancer drug bicalutamide [12], and
antiemetic drug aprepitant [13].
Substituted 1,2,4-triazoles constitute an important class of
organic compounds with wide-ranging pharmacological activi-
ties such as antibacterial [14], antifungal [15], antimycobacterial
[16], anti-inflammatory [17], and anticancer [18,19] activities.
Some of the fluoro substituted and trifluoromethyl substituted
1,2,4-triazoles, Fluconazole [20] and Fluotrimazole [21] respec-
tively, are well known drugs in use. However, none of them have a
trifluoromethyl group in the triazole ring. Furthermore, fluoro-
and trifluoromethyl pyrazoles, benzenesulfonyl urea and thiourea
derivatives as well as their cyclic sulfonylthioureas were reported
by our group to possess hypoglycemic and antimicrobial activities
[22–24]. Therefore, it was considered worthwhile to introduce
trifluoromethyl groups in triazole ring. The current study involves
the preparation of fluorinated 1,2,4-triazoles and benzenesulfonyl
urea and thiourea derivatives as well as their cyclic sulfonylthiour-
eas as possible antimicrobial and antidiabetic agents.
* Corresponding author at: Department of Chemistry, Faculty of Science, King
Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia.
Tel.: +966 567743180.
E-mail address: hfaidallahm@hotmail.com (H.M. Faidallah).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.014

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
871
2. Results and discussion
using UV–vis light, most of the tested compounds showed
an additional activity especially towards E. coli and C. albicans
(Table 5). All test data in Tables 3 and 4 were of average values
from triplicate runs and the test compounds showed reduced
antimicrobial activities when compared with their respective
standards. In a related study of the non-fluorinated analogs
(11a–c and 12a–c; Scheme 2) when compared with their
fluorinated counterparts, the former could not exhibit the same
degree of zone inhibition thereby suggesting the trifluoromethyl
substitution in the triazole ring to be an activity enhancer in the
present study (Table 3).
2.1. Synthesis and spectral characterizations
Bi-nucleophlic attack on the 1,3-bicarbonyl compounds
under mild conditions is an important process in synthetic
organic chemistry, especially primary bi-nitrogen reagent led to
formation of functionalized 1,2,4-triazoles which easily form a
type of complexes with transition metals as antifungal agents
[25].
Thus, condensation of sulfanilamide derivatives 1a–d with
trifluoroacetic anhydride afforded N-di(trifluoroacetyl)sulfanila-
mides 2a–d which in turn react with hydrazine hydrate to give 3,5-
di(trifluoromethyl)-4-p-sulfonamidophenyl-1,2,4-triazoles 3a–d
(Scheme 1). The IR spectra of 2a–d displayed carbonyl band at
1700–1710 cmꢀ1, two absorption bands at 3265–3272 cmꢀ1 and
3368–3384 cmꢀ1 indicative of the NH2 group, in addition to the
strong bands at 1330–1352 cmꢀ1 and 1145–1156 cmꢀ1 for the
SO2N moiety. On the other hand The IR spectra of the triazole
derivatives 3a–d lacked the CO band and showed the NH2
absorption bands at 3258–3268 and 3365–3376 cmꢀ1 as well as
the two SO2 bands at 1148 cmꢀ1 and 1362 cmꢀ1. The 13C NMR
2.3. Antidiabetic activity
From the data presented in Table 5, it is implied that
tested compounds possess mild hypoglycemic activity. The
potency of these compounds is less than that of phenformine.
Introduction of bromine atom into the phenyl ring of com-
pounds 10 slightly increases the hypoglycemic activity of these
derivatives.
3. Conclusions
spectra of 2 exhibited a carbonyl carbon signal at
d 166.5 which is
in agreement with the suggested structures. The same peak was
absent in the 13C NMR spectra of compounds 3 (Table 2).
Condensation of triazole derivative 3a with the appropriate
isocyanate and isothiocyanate in dry acetone yielded the
In this paper, several new 3,5-di(trifluoromethyl)-4-p-sulfona-
midophenyl-1,2,4-triazole derivatives were synthesized by the
condensation of 4-hydrazino benzenesulfonamide hydrochloride
with N-di(trifluoroacetyl)sulfonamides. Moreover, many new
urea and thiourea derivatives were prepared from the reaction
of the above triazoles with the appropriate isocyanate and
isothiocyanate. Cyclization of the thiourea derivatives with the
appropriate reagent afforded the corresponding cyclic com-
pounds. The structures of the prepared compound were con-
firmed by elemental analysis, IR 1H and 13C NMR spectral analysis.
Preliminary biological testing of some of these compounds
revealed that some triazole derivatives exhibited significant
antimicrobial activities but weak antidiabetic activity. Further,
the incorporation of trifluoromethyl group is justified by a
comparative study with the non-fluorinated analogs. The
fluorinated analogs were found to be more active than their
non-fluorinated counterparts.
corresponding benzene urea
4 and thiourea 5 derivatives
respectively. Furthermore, condensation of 2 with appropriate
isothiocyanate afforded the thiourea derivative 6. Compound 5 can
alternatively be prepared from 6 by refluxing the latter with
equimolar amount of hydrazine hydrate in ethanol. The IR spectra
of these compounds exhibited two bands at 1330–1362 cmꢀ1 and
1144–1156 cmꢀ1 due to SO2N group as well as a urea carbonyl
band at 1654–1660 cmꢀ1 in case of compounds 4 and a thiourea
carbonyl absorption at 1133–1148 cmꢀ1 for compounds 5. The
structures of the above compounds 4 and 5, were further
supported by their elemental analyses (Table 1), 1H NMR and
13C NMR spectra (Table 2).
It has been reported that condensation of N,N0-disubstituted
thiourea with chloroacetic acid, its chloride or
a-bromo esters
afforded 2-imino-4-oxothiazolidines, and the reaction proceeds
through the intermediate formation of the cyclic pseudothiohy-
dantoic acid [26–28]. In the present study, cyclization of the
4. Experimental
4.1. Chemicals and methods
thiourea derivatives
iodoethane, diethyl oxalate and
5
with ethyl bromoacetate, 1,2-di-
-bromoacetophenone deriva-
a
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
tives afforded the corresponding 4-oxothiazolidine 7, thiazolidine
8, 4,5-di-oxothiazolidine 9 and 4-subistituted thiazoline 10
derivatives respectively. IR spectra of compounds 7 and 9 showed
cyclic carbonyl absorptions 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 fluorinated
compounds 7–10 and the non-fluorinated analogs 11 and
12 were further supported by their 1H NMR and 13C NMR data
(Table 2).
spectrophotometer using the plate technique. The 1H NMR and 13
C
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
2.2. Anti-microbial activity
detected by exposure to UV lamp at l 254. Biological testing was
performed in the Faculty of Medicine University of Alexandria,
Egypt. Reagents were of analytical grade and were used without
further purification.
Compounds 2–12 were screened in vitro for their anti-
microbial and antifungal activity against Escherichia coli,
Staphylococcus aureus, Aspergillus niger and Candida albicans.
The zones of inhibition formed for the compounds against
bacteria and fungi are summarized in Table 3. All compounds
were found to possess mild to moderate activity. Compounds
3c,d, 4c, 5c–f, 6d, 7d,e, 8c and 10f,g were however, significantly
active when compared with rest of the series. Moreover, after
4.1.1. N-Di(trifluoroacetyl)sulfonamides (2a–d)
A mixture of the appropriate sulfonamide 1 (10 mmol) in THF
(30 mL) and trifluroacetic anhydride (10 mmol) was refluxed for
2 h. The solid which separated on cooling was recrystallized from
ethanol as needles.

872
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
4.1.2. 3,5-Di(trifluoromethyl)-4-p-sulfonamidophenyl-1,2,4-triazoles
(3a–d)
4.1.9. 3,4-Disubstituted-2-[p-(3,5-di(trifluoromethyl)-1,2,4-triazol-
4-yl)benzenesulfonylimino]-1,3-thiazolines (10a–g)
A solution of the appropriate N-di(trifluoroacetyl)sulfonamide
A solution of the corresponding thiourea derivative 5 (10 mmol)
in absolute ethanol (25 mL) was refluxed with the appropriate
derivative
2 (10 mmol) in THF (25 mL) was refluxed with
hydrazine hydrate (12 mmol) for 2 h. The reaction mixture was
then, cooled poured onto ice and the obtained solid was
recrystallized from ethanol as needles.
a-bromoacetophenone (10 mmol) and sodium acetate (20 mmol)
for 2 h. The reaction mixture was then cooled and poured into
water; the precipitated thiazoline was recrystallized from ethanol
as needles.
4.1.3. p-(3,5-Di(trifluoromethyl)-1,2,4-triazol-4-
yl)benzenesulfonylureas (4a–c)
4.1.10. N-Disubstituted sulfonamides (11a–c)
A mixture of the 1,2,4-triazole derivative 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.
A mixture of the appropriate sulfonamide 1 (10 mmol) and the
proper anhydride (5 mL) was refluxed for 4 h. The reaction mixture
was then, cooled poured onto ice and the obtained solid was
recrystallized from ethanol as needles.
4.1.11. 3,5-Disubstituted-4-p-sulfonamidophenyl-1,2,4-triazoles
(12a–c)
A solution of the appropriate N-disubstituted sulfonamide
derivative 11a–c (10 mmol) in THF (25 mL) was refluxed with
hydrazine hydrate (12 mmol) for 2 h. The reaction mixture was
then, cooled poured onto ice and the obtained solid was
recrystallized from ethanol as needles.
4.1.4. p-(3,5-Di(trifluoromethyl)-1,2,4-triazol-4-
yl)benzenesulfonylthioureas (5a–f)
A mixture of 3 (10 mmol) and anhydrous K2CO3 (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. Alternatively, compounds 5 has been prepared by
refluxing the appropriate thiourea derivative 6 (10 mmol) with
equimolar amount of hydrazine hydrate in ethanol (20 mL)
for 2 h.
4.2. Procedure for biological activity
4.2.1. Procedure for anti-microbial activity
The preliminary anti-microbial activities of new fluorinated
1,2,4-triazole and pyrimidine derivatives were measured in a
concentration of 50 mg/L by disc diffusion method [29,30]. The
prepared compounds were tested for their antimicrobial activity
against two types of bacterium, S. aureus (ATCC 25923) as Gram
positive bacteria, E. coli (ATCC 25922) as an example of Gram
negative bacteria, and the antifungal activity was tested using
the 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.
4.1.5. N1-Subistituted N3-[p-
di(trifluoroacetylamino)benzenesulfonylthioureas (6a–d)
A mixture of 2 (10 mmol) and anhydrous K2CO3 (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.
4.2.2. Procedure for anti-microbial activity using UV (366 nm) light
This test was performed as mentioned before but the Petri-discs
containing microorganisms and the testing compounds were
subjected to UV light (366) for 3 h before transferred to the
incubation periods.
4.1.6. 3-Substituted-2-[p-(3,5-di(trifluoromethyl)-1,2,4-triazol-4-
yl)benzenesulfonylimino]-4-oxothiazolidines (7a–e)
A mixture of 5 (10 mmol), ethyl bromoacetate (10 mmol) and
sodium acetate (20 mmol) in absolute ethanol (30 mL) was
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.
4.2.3. Procedure for antidiabetic activity
Compounds 2a,b, 3a,c,d, 4a–c, 5b,c, 6b, 7a,b, 8a,b, 10a,c,f,g
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.
4.1.7. 3-Substituted-2-[p-(3,5-di(trifluoromethyl)-1,2,4-triazol-4-
yl)benzenesulfonylimino]thiazolidines (8a–c)
A solution of 5 (10 mmol) in absolute ethanol (20 mL) was
refluxed with 1,2-di-iodoethane (10 mmol) and sodium 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.
4.1.8. 3-Substituted-2-[p-(3,5-di(trifluoromethyl)-1,2,4-triazol-4-
yl)benzenesulfonylimino]-4,5-dioxothiazolidines (9a–c)
A mixture of the appropriate thiourea, 5 (10 mmol), diethyl
oxalate (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.
Glucose was determined by the micro-colorimetric copper
reduction technique of Haslewood and Strookman [31]. 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 calculated t-value exceeded the tabulated t-value at the
p = 0.05 level.

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
873
Acknowledgement
Appendix A
The authors wish to thank Department of Pharmacology,
Faculty of Pharmacy, University of Alexandria.
See Schemes 1 and 2.
Scheme 1.

874
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
Scheme 2.
Appendix B
See Tables 1–5.
Table 1
Characterization data of compounds 2–13.
Compd.
R1, R2 or R3
X
Yield (%)
m.p. (8C)
Mol. formula
Calc. %
C
Found %
C
H
N
H
N
a
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
5a
5b
5c
5d
5e
5f
–
80
70
74
78
94
82
84
87
76
78
80
68
70
74
72
78
76
70
72
78
80
66
76
70
78
75
62
66
68
64
67
69
211–213
229–230
178–180
150–152
194–196
162–164
150–152
124–126
184–186
180–181
220–222
182–184
128–130
150–152
120–122
172–174
126–128
172–173
180–182
202–204
125–127
167–169
230–232
130–132
222–224
170–172
202–204
228–230
218–220
160–162
180–182
148–150
C10H6F6N2O4S
32.98
35.48
34.99
45.07
33.34
35.83
35.30
45.42
42.06
42.60
39.74
33.26
40.72
41.21
42.44
38.53
39.77
32.96
40.40
42.11
39.46
42.14
42.62
43.72
40.04
41.23
43.26
43.76
41.05
41.08
41.53
39.08
1.66
1.98
1.81
2.39
1.68
2.00
1.82
2.41
3.53
2.31
1.96
2.09
3.42
2.24
2.57
1.90
1.96
2.07
3.39
2.55
1.95
3.16
2.07
2.38
1.77
1.82
3.63
2.51
2.18
2.72
1.65
1.38
7.69
33.01
35.51
34.04
45.13
33.19
35.91
35.42
45.52
42.12
42.45
39.88
33.17
40.81
41.25
42.48
38.56
39.82
33.11
40.51
42.21
39.55
42.01
42.73
43.82
40.15
41.25
43.28
43.67
41.21
41.11
41.64
39.12
1.59
2.03
1.92
2.41
1.72
1.98
1.76
2.38
3.64
2.29
2.02
2.11
3.35
2.19
2.62
2.02
2.11
2.14
3.40
2.71
2.13
3.18
2.20
2.41
1.82
1.79
3.71
2.62
2.20
2.83
1.74
1.42
7.62
a
–
C12H8F6N2O5S
6.90
12.55
11.06
15.55
13.93
19.00
16.73
14.43
14.61
13.63
16.16
13.97
14.14
13.75
13.22
13.64
9.61
6.81
12.58
11.17
15.60
13.89
18.97
16.72
14.42
14.60
13.75
16.17
14.03
14.21
13.82
13.35
13.70
9.66
a
–
C13H8F6N4O5S
a
–
C19H12F6N4O4S
C10H6F6N4O2S
a
–
a
–
C12H8F6N4O3S
a
–
C13H8F6N6O3S
a
–
C19H12F6N6O2S
C17H17F6N5O3S
C17H11F6N5O3S
C17H10ClF6N5O3S
C12H9F6N5O2S2
C17H17F6N5O2S2
C17H11F6N5O2S2
C18H13F6N5O2S2
C17H10ClF6N5O2S2
C17H10F7N5O2S2
C12H9F6N3O4S2
C17H17F6N3O4S2
C18H13F6N3O4S2
C17H10F7N3O4S2
C19H17F6N5O3S2
C19H11F6N5O3S2
C20H13F6N5O3S2
C19H10ClF6N5O3S2
C19H10F7N5O3S2
C19H19F6N5O2S2
C19H13F6N5O2S2
C19H12ClF6N5O2S2
C19H15F6N5O4S2
C19H9F6N5O4S2
C19H8ClF6N5O4S2
Cyclohexyl
C6H5
4-ClC6H4
CH3
Cyclohexyl
C6H5
4-CH3C6H4
4-ClC6H4
4-FC6H4
CH3
6a
6b
6c
6d
7a
7b
7c
7d
7e
8a
8b
8c
9a
9b
9c
Cyclohexyl
4-CH3C6H4
4-FC6H4
Cyclohexyl
C6H5
8.31
8.45
8.18
8.21
8.12
8.17
12.93
13.08
12.75
12.29
12.65
13.28
13.43
12.60
12.61
12.75
11.99
13.04
12.99
12.72
12.31
12.74
13.33
13.48
12.73
12.56
12.84
12.06
4-CH3C6H4
4-ClC6H4
4-FC6Hv
Cyclohexyl
C6H5
4-ClC6H4
Cyclohexyl
C6H5
4-ClC6H4

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
875
Table 1 (Continued )
Compd.
R1, R2 or R3
X
Yield (%)
m.p. (8C)
Mol. formula
Calc. %
C
Found %
C
H
N
H
N
10a
10b
10c
10d
10e
10f
C6H5
72
68
74
73
64
74
72
68
70
59
70
74
65
232–234
248–250
186–187
136–138
130–132
120–122
125–127
262–264
178–179
186–188
216–218
226–228
198–200
C25H15F6N5O2S2
C26H17F6N5O2S2
C25H14ClF6N5O2S2
C25H14F7N5O2S2
C25H20BrF6N5O2S2
C25H14BrF6N5O2S2
C25H13BrClF6N5O2S2
C10H12N2O4S
50.42
51.23
47.66
48.94
44.13
44.52
42.36
46.87
53.83
51.76
47.61
54.52
52.29
2.54
2.81
2.24
2.30
2.96
2.09
1.85
4.72
6.45
5.62
4.79
6.54
5.68
11.76
11.49
11.12
11.41
10.29
10.38
9.88
50.41
51.31
47.81
49.12
44.18
44.64
42.45
46.92
53.77
51.82
47.72
54.55
52.30
2.63
2.67
2.31
2.38
3.12
2.11
1.92
4.80
6.56
5.54
4.81
6.61
5.78
11.84
11.60
11.24
11.52
10.33
10.44
9.78
4-CH3C6H4
4-ClC6H4
4-FC6H4
Cyclohexyl
C6H5
Br
Br
Br
10g
11a
11b
11c
12a
12b
12c
4-ClC6H4
b
–
10.93
8.97
11.10
9.02
b
–
C14H20N2O4S
b
–
C17H22N4O5S
14.20
22.21
18.71
21.52
14.17
22.24
18.85
21.63
b
–
C10H12N4O2S
b
–
C14H20N4O2S
b
–
C17H22N6O3S
a
For R1 see Scheme 1.
For R2 see Scheme 2.
b
Table 2
1H and 13C NMR spectral data ( /ppm)c of compounds 2–13.
d
Compd. R1, R2 or R3
X
1H NMR
13C NMR
Ar-H (m)
NH2 or NH Other H
Ar-C
CO or CS
Other C
a
2a
2b
2c
–
–
–
6.85–7.71 (4H)
7.05–7.82 (4H)
6.99–7.92 (4H)
8.12
120.1, 125.7, 134.9, 144.0
120.7, 126.1, 135.3, 145.6
166.3
167.7
166.2,
173.8
165.9
122.2 (CF3)
16.8 (CH3), 123 (CF3)
a
a
8.03
2.02 (s, CH3)
8.00, 8.13
2.24 (s, CH3)
120.8, 126.1, 133.9, 143.2, 163.8
53.4 (CH2), 114.8 (CF3)
a
2d
–
7.12–7.84 (10H) 8.17, 11.24
120.5, 122.1, 123.5, 125.6, 127.0,
128.5, 129.0, 134.9, 136.4, 136.9,
144.0
122.6 (CF3)
a
a
a
3a
3b
3c
–
–
–
6.98–7.46 (4H)
7.24–7.92 (4H)
7.68–7.91 (4H)
8.07
126.3, 129.1, 132.4, 139.3, 161.6
126.1, 128.9, 131.8, 138.9, 161.3
114.3 (CF3)
8.24
2.15 (s, CH3)
2.36 (s,CH2)
173.3
16.6 (CH3), 114.9 (CF3)
53.1 (CH2), 115.2 (CF3)
8.14, 8.34
1321.3, 125.9, 135.0, 144.6, 161.0, 174.1
163.2
a
3d
4a
–
7.08–7.91 (10H) 8.10, 12.02
121.3, 122.2, 122.9, 125.1, 127.2,
128.9, 129.2, 135.1, 136.7, 137.0,
143.8
Cyclohexyl
7.46–7.76 (4H)
8.03, 8.32
[1.44–1.65 (m, 10H), 126.1, 129.3, 132.2,139.4, 160.1
3.54 (m, 1H);
161.3
21.6, 27.1, 32.7, 47.0
(cyclohexyl C), 114.1 (CF3)
cyclohexyl]
4b
4c
C6H5
7.00–7.90 (9H)
7.25–7.88 (9H)
8.16, 8.24
8.25, 8.40
120.4, 124.1, 126.3, 128.6, 129.4,
132.0, 138.2, 139.5, 161.1
121.8, 126.0, 129.1, 129.4, 130.3,
132.2, 136.4, 139.2, 161.4
159.9
160.2
114.6 (CF3)
114.9 (CF3)
4-ClC6H4
5a
5b
CH3
7.61–7.91 (4H)
7.68–7.90 (4H)
8.12, 8.64
8.18, 8.34
2.47 (s, CH3)
126.2, 129.2, 132.4, 139.4, 161.5
125.8, 129.1, 133.3, 140.1, 161.3
186.3
186.1
33.7 (CH3), 113.9 (CF3)
27.6, 27.3, 33.4, 52.0
Cyclohexyl
[1.36–1.52 (m,10H),
2.56 (m, 1H);
cyclohexyl]
(cyclohexyl C), 114.2 (CF3)
5c
5d
5e
5f
C6H5
6.62–7.71 (9H)
6.58–7.77 (8H)
6.64–7.82 (8H)
6.68–7.87 (4H)
7.82–7.90 (4H)
8.14, 8.20
8.11, 8.42
8.30, 8.56
8.23, 8.51
8.01, 8.18
124.5, 125.3, 126.1, 128.7, 129.4,
132.3, 139.3, 140.2, 162.3
187.4
185.9
188.2
187.4
167.3
115.1 (CF3)
4-CH3C6H4
4-ClC6H4
4-Fv
2.35 (s, CH3)
125.2, 126.3, 128.9, 129.5, 132.4,
133.7, 136.4, 139.6, 161.2
20.9 (CH3), 114.5 (CF3)
114.9 (CF3)
123.9, 125.2, 126.7, 128.5, 129.2,
129.8, 137.6, 161.9
115.8, 126.0, 126.9, 129.2, 132.8,
135.6, 139.5, 158.1, 161.7
114.1 (CF3)
6b
Cyclohexyl
[1.38–1.59 (m, 10H), 120.6, 124.9, 135.0, 143.8
22.6, 27.4, 33.2, 53.1
2.43 (m, 1H);
cyclohexyl]
(cyclohexyl C), 123.2 (CF3)
6c
4-CH3C6H4
6.64–7.89 (8H)
8.13, 8.19
8.04, 8.19
2.36 (s, CH3)
120.8, 125.6, 125.2, 129.3, 134.4,
135.7, 136.2, 143.8
168.6
20.9 (CH3), 124.3 (CF3)
32.8 (CH2), 114.7 (CF3)
6d
7b
4-FC6H4
C6H5
6.70–7.91 (8H)
7.00–7.86 (9H)
3.81 (s,CH2)
120.4, 124.3, 126.4, 128.7, 129.1,
132.5, 138.8, 140.6
168.9
169.3
7c
4-CH3C6H4
7.04–7.91 (9H)
2.40 (s, CH3),
3.62 (s,CH2)
3.80 (s,CH2)
3.79 (s,CH2)
120.2, 126.8, 129.3, 129.4, 132.4,
133.3, 137.8, 139.7, 161.7
21.5 (CH3), 33.1 (CH2),
113.8 (CF3)
7d
7e
4-ClC6H4
4-FC6H4
7.25–7.88 (8H)
6.95–7.90 (8H)
115.9, 122.0, 126.2, 129.4, 132.2,
136.4, 140.1, 156.6, 161.6
167.3
32.8 (CH2), 114.6 (CF3)
8a
8b
Cyclohexyl
7.12–7.65 (4H)
6.63–7.76 (9H)
[1.43–1.52 (m, 10H),
2.55 (m, 1H);
cyclohexyl],
2.99 (s,CH2),
3.22 (s,CH2)
C6H5
2.80 (s,CH2),
3.14 (s,CH2)
112.3, 116.9, 126.0, 129.1, 129.3,
132.4, 138.9, 143.5, 163.2
31.6 (C-5), 54.6 (C-4),
114.6 (CF3)

876
H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
Table 2 (Continued )
Compd. R1, R2 or R3
X
1H NMR
13C NMR
Ar-H (m)
NH2 or NH Other H
2.90 (s,CH2),
Ar-C
CO or CS
Other C
8c
9a
4-ClC6H4
6.45–7.81 (8H)
113.7, 122.2, 126.3, 129.2, 129.6,
132.6, 139.9, 141.2, 162.9
30.7 (C-5), 56.6 (C-4),
114.2 (CF3)
3.26 (s,CH2)
Cyclohexyl
7.62–7.93 (4H)
[1.48–1.62 (m, 10H), 126.3, 129.4, 132.9, 139.2, 162.1
3.36 (m,1H);
164.2,
185.4
22.1, 26.9, 31.0,
40.2 (cyclohexyl C),
114.1 (CF3)
cyclohexyl]
9b
C6H5
7.01–7.79 (9H)
7.23–7.81 (8H)
6.68–7.90 (14H)
120.4, 124.1, 126.3, 128.7, 129.2,
132.1, 138.2, 139.3, 163.0
121.8, 126.1, 129.2, 129.3, 129.6,
132.7, 136.1, 139.4, 163.0
165.1, 186.3 114.2 (CF3)
164.9, 187.1 114.6 (CF3)
114.1 (CF3)
9c
4-ClC6H4
C6H5
10a
5.73 (s, H-5)
89.4, 115.1, 118.5, 125.9, 126.2,
127.6, 128.4, 129.2, 129.4, 132.6,
134.7, 139.1, 148.0, 151.2, 163.1
84.6, 115.0, 126.3, 126.7, 127.4,
127.7, 128.3, 130.5, 132.3, 134.2,
139.1, 142.8, 150.1, 162.8
10b
4-CH3C6H4
6.38–7.88 (13H)
2.33 (s, CH3),
5.80 (s, H-5)
20.9 (CH3),
114.5 (CF3)
10c
10d
4-ClC6H4
4-FC6H4
6.44–7.91 (13H)
6.58–7.82 (13H)
5.77 (s, H-5)
5.80 (s, H-5)
87.6, 116.3, 116.8, 126.0, 126.3,
127.7, 128.2, 129.4, 131.9, 134.0,
138.7, 141.8, 152.2, 153.1, 161.4
115.1 (CF3)
10e
Cyclohexyl
Br 6.63–7.90 (8H)
[1.40–1.68 (m, 10H), 88.1, 126.2, 126.8, 127.7, 128.5,
22.4, 27.1, 31.2,
2.62 (m, 1H);
cyclohexyl], 6.77
(s, H-5)
129.3, 132.6, 134.8, 139.1,
151.6, 160.2
42.9 (cyclohexyl C),
114.3 (CF3)
10f
C6H5
Br 6.54–7.90 (13H)
Br 7.19–7.82 (12H)
6.72 (s, H-5)
6.62 (s, H-5)
10g
4-ClC6H4
86.1, 116.3, 122.2, 123.8, 126.3,
128.1, 129.0, 129.7, 131.9,
132.0, 133.4, 139.1, 144.2,
157.0, 163.4
114.8 (CF3)
b
11a
11b
–
7.91–7.92 (4H)
7.82–7.95 (4H)
2.40 (s, 6H,2CH3)
1.19 (d, 12H, 4CH3),
2.78 (m, 2H, CH2)
1.16 (d, 12H, 4CH3),
2.23 (s, 2H, CH2),
2.70 (m, 2CH)
120.7, 125.8, 134.7, 144.1
121.2, 125.9, 135.3, 145.4
168.2
167.4
14.9 (CH3)
b
–
18.0 (CH3), 33.1 (CH)
b
11c
–
7.78–7.80 (4H)
120.9, 125.7, 134.2, 143.8
166.8, 173.2 18.2 (CH3), 33.4 (CH)
b
12a
12b
12c
–
7.75–7.92 (4H)
7.70–7.86 (4H)
7.87–7.91 (4H)
2.35 (s, 6H,2CH3)
126.1, 129.3, 133.4, 139.2
7.4 (CH3), 161.1
(C-3, triazole)
b
–
1.29 12H, 4CH3), (d,
3.12 (m, 2CH)
125.9, 128.9, 132.8, 138.9
–
24.4 (CH3), 25.6 CH),
160.7 (C-3, triazole)
b
–
1.29 12H, 4CH3),
2.28 (s, CH2),
–
–
3.16 (m, 2CH)
a
For R1 see Scheme 1.
For R2 see Scheme 2.
b
c
Solution in a mixture of CDCl3 and DMSO-d6.
Table 3
Anti-bacterial and anti-fungal data of trifluoromethyltriazole derivatives.
Table 3 (Continued )
Compd.
Zone of inhibition in mm
Anti-bacterial activity
Zone of inhibition in mm
Anti-fungal activity
Compd.
Zone of inhibition in mm
Anti-bacterial activity
Zone of inhibition in mm
Anti-fungal activity
Escherichia
coli
Staphylococcus
Aspergillus
niger
Candida
albicans
Escherichia
coli
Staphylococcus
Aspergillus
niger
Candida
albicans
aureus
aureus
7d
19
20
11
15
20
14
12
14
13
15
13
13
22
26
8
18
22
13
14
19
15
13
7
17
20
15
11
20
13
11
7
16
19
14
12
21
14
10
6
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
5a
5b
5c
5d
5e
5f
11
14
13
15
14
13
19
18
12
13
19
14
15
18
17
22
25
14
20
9
12
13
15
14
11
12
16
15
14
12
17
12
14
17
16
20
23
12
22
8
10
12
14
16
12
10
18
17
11
12
18
13
10
16
18
19
22
10
12
14
16
15
10
8
7e
8a
8b
8c
9a
10b
10a
10b
10c
16
15
10
11
16
12
12
19
18
17
21
8
11
13
10
11
23
22
7
10
11
12
11
20
21
6
13
10
13
12
21
22
9
10d
10e
10f
10g
11a
11b
11c
9
6
7
6
10
9
11
10
9
7
8
12a
12b
12c
8
6
6b
6d
7a
7b
7c
10
11
33
–
6
7
16
8
10
29
–
8
9
7
9
Ampicillin
Griseofulvin
–
–
11
15
10
13
8
30
28
12
11

H.M. Faidallah et al. / Journal of Fluorine Chemistry 132 (2011) 870–877
877
References
Table 4
Anti-bacterial and anti-fungal data of trifluoromethyltriazole derivatives using UV
(366) light.
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Compd.
Zone of inhibition in mm
Anti-bacterial activity
Zone of inhibition in mm
Anti-fungal activity
Escherichia
coli
Staphylococcus
Aspergillus
niger
Candida
albicans
aureus
2a
11
15
–
–
–
–
–
13
14
17
16
–
2b
2c
16
15
–
–
2d
3a
16
16
–
17
–
3b
3c
–
–
–
22
19
–
17
16
–
19
–
17
16
–
3d
4a
–
4b
4c
–
–
–
12
17
–
20
16
17
20
19
24
26
15
22
–
–
–
5a
13
–
14
12
–
5b
5c
12
–
18
18
21
–
5d
5e
–
19
18
22
–
–
5f
23
10
–
6b
6d
7a
–
23
8
–
–
–
7b
7c
–
–
–
9
16
20
21
12
18
–
–
–
12
18
21
15
16
22
–
7d
7e
19
24
–
18
22
–
8a
8b
8c
–
–
–
–
9a
–
–
–
10b
10a
10b
10c
10d
10e
10f
10g
–
–
12
–
–
15
–
–
–
–
–
14
11
15
13
22
–
16
15
–
15
11
–
–
12
–
23
–
24
–
–
–
–, no activity.
Table 5
Antidiabetic activity of triazole derivatives.
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Compd.
Reduction in plasma glucose level, %
P
Phenformin
2a
10
<1
<1
5
<0.01a
<0.05
0.05
2b
3a
<0.01a
<0.01a
<0.01a
<0.01a
<0.01a
<0.01a
<0.01a
<0.05
0.05
3c
7
3d
6
4a
9
4b
8
4c
7
5b
6
5c
4
6b
3
7a
1.5
2
0.05
7b
0.05
8a
1
0.05
8b
2
0.05
10a
10c
10f
10g
5
0.01a
0.05
4
8
0.01a
0.01a
9
a
Statistically significant.