Synthesis and biological activities of some fluorine- and piperazine-containing 1,2,4-triazole thione derivatives

Article abstract of DOI:10.1016/j.cclet.2015.09.015

A series of fluorine- and piperazine-containing 1,2,4-triazole thione derivatives were synthesized by the Mannich reaction of triazole intermediates with various substituted piperazines and formaldehyde in high yields. Structures of title compounds were confirmed by melting points, IR, ¹H NMR, ¹³C NMR and elemental analysis. The preliminary bioassays for 17 novel title compounds showed that several compounds have significant fungicidal activity against Cercospora arachidicola, Physalospora piricola and Rhizoctonia cerealis at 50 μg/mL.

Full text of DOI:10.1016/j.cclet.2015.09.015

G Model
CCLET 3439 1–5
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Synthesis and biological activities of some fluorine- and
piperazine-containing 1,2,4-triazole thione derivatives
*
*
5
Q1 Li-Yuan Zhang, Bao-Lei Wang , Yi-Zhou Zhan, Yan Zhang, Xiao Zhang, Zheng-Ming Li
6
7
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University,
Tianjin 300071, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of fluorine- and piperazine-containing 1,2,4-triazole thione derivatives were synthesized by the
Mannich reaction of triazole intermediates with various substituted piperazines and formaldehyde in
high yields. Structures of title compounds were confirmed by melting points, IR, 1H NMR, 13C NMR and
elemental analysis. The preliminary bioassays for 17 novel title compounds showed that several
compounds have significant fungicidal activity against Cercospora arachidicola, Physalospora piricola and
Received 22 April 2015
Received in revised form 10 July 2015
Accepted 16 September 2015
Available online xxx
Rhizoctonia cerealis at 50
mg/mL.
Keywords:
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Triazole thione derivatives
Fluorine
Published by Elsevier B.V. All rights reserved.
Piperazine
Mannich base
Biological activity
8
9
1. Introduction
antifungal activity [11,12], and some piperazine-containing 4,5- 30
disubstituted-1,2,4-triazole Mannich bases were found to have 31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Due to the excellent selectivity, low toxicity and versatile
biological activities, the chemistry of nitrogen containing hetero-
cyclic compounds has been a hot topic in pharmaceutical and
pesticidal research areas [1]. As one of the five-membered
nitrogen-containing heterocycles, 1,2,4-triazole introduced into
compounds will contribute to a wide-range spectrum of biological
activities including anti-inflammatory [2], anticancer [3,4], anti-
fungal [5], insecticidal [6], and plant growth regulating activities
[7]. Furthermore, piperazine ring is one of the important
heterocycles and has various properties such as low toxicity, easy
forming multiple hydrogen bonds or ionic bonds, and functional
effect that modulating drug lipid water partition coefficient and
acid-base equilibrium constant. Therefore it is often introduced
into some parent structures to enhance the biological properties
during the drug design. It has been found that N-substituted
piperazine compounds have a wide range of biological activities,
such as antimicrobial [8], anticancer [9], herbicidal and insecticidal
activities [10], especially they were often used as antimicrobial
agent. Mannich bases of 1,2,4-triazole derivatives containing
N-substituted piperazine moiety have been reported to possess
tuberculostatic activity [13]. However, there are comparatively 32
few literatures about the piperazine-containing compounds for the 33
design and development of agrochemicals.
34
In our early work, some 1,2,4-triazole Mannich bases contain- 35
ing piperazine and trifluoromethyl groups were synthesized 36
through Mannich reaction, and found to possess significant 37
fungicidal and herbicidal activities [14,15], which encourage us 38
to carry out further study on this topic. Therefore a series of novel 39
fluorine- and piperazine-containing 1,2,4-triazole thione deriva- 40
tives were herein designed and synthesized. According to the 41
structure of the lead compound, 1-(4-substitutedpyrimidylpiper- 42
azin-1-yl)methyl-4-(substituted)benzylideneamino-3-trifluoro-
43
methyl-1,2,4-triazole-5-thione [14] we reported previously and in 44
view of the importance of fluorine in enhancing bioactivities of 45
various compounds, our intentions were to retain the main 46
structural feature of triazole thione and piperazine moieties of lead 47
compound, change trifluoromethyl group on triazole ring to 48
fluorine-containing aryl group or methyl group, (substituted)ben- 49
zylideneamino group to phenyl or arylamide group, and study the 50
synthesis and the pesticidal activities of new triazole thione 51
Mannich bases with diverse structures. There are many literatures 52
reported the syntheses of triazole Mannich bases [16–18], while 53
there is no literature about such kind of compounds bearing an 54
o-fluorophenyl and a phenyl at 3- and 4-position respectively of 55
1,2,4-triazole ring, and various substituted piperazine moiety 56
*
Corresponding authors.
E-mail addresses: nkwbl@nankai.edu.cn (B.-L. Wang),
nkzml@vip.163.com (Z.-M. Li).
http://dx.doi.org/10.1016/j.cclet.2015.09.015
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: L.-Y. Zhang, et al., Synthesis and biological activities of some fluorine- and piperazine-containing
1,2,4-triazole thione derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.015

G Model
CCLET 3439 1–5
2
L.-Y. Zhang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
57
58
59
60
61
62
63
64
(substituted benzyl piperazine, phenyl piperazine, (pyridin-2-
yl)piperazine, 4,6-disubstituted pyrimidyl piperazine) as amine
part of Mannich base, also the symmetric bis(triazole) Mannich
bases containing these structural factors. In particular, the
Mannich reaction of 1,2,4-triazole thiol containing arylamide
group has not been studied so far. In this paper these novel
structures designed were successfully synthesized and their
herbicidal and fungicidal activities were evaluated.
2.3. Herbicidal and fungicidal activity test
117
Herbicidal activity in vivo of compounds were determined by
rape root test (Brassica campestris) and barnyardgrass cup test
(Echinochloa crusgalli) according to the reported method [24].
Fungicidal activity in vitro of the compounds against Fusarium
omysporum, Cercospora arachidicola, Physalospora piricola, Rhizoc-
tonia cerealis, Alternaria solani Sorauer and Gibberella sanbinetti
were evaluated via the mycelium growth rate test according to the
literature [15].
118
119
120
121
122
123
124
125
65
2. Experimental
66
67
68
69
70
71
72
73
74
75
76
Melting points were determined using an X-4 binocular
microscope apparatus and uncorrected. Infrared spectra (IR)
(potassium bromide) were recorded on a Bruker Tensor 27 spec-
trophotometer. 1H NMR and 13C NMR spectra were measured on a
Bruker AV-400 instrument (400 MHz) using TMS as an internal
standard. Elemental analyses were performed on an elementar
Vario EL CUBE elemental analyzer.
Intermediates 4-(4,6-disubstituted pyrimidin-2-yl) piperazine,
4-(substituted)benzylpiperazines, 4-phenyl-5-(2-fluorophenyl)-
4H-1,2,4-trizole-3-thiol, 4-Amino-5-methyl-4H-1,2,4-trizole-3-
thiol were prepared according to the literature [19–22].
3. Results and discussion
126
127
3.1. Synthesis and spectra characterization
The synthetic procedures for target compounds 2, 4 and 5 were
shown in Schemes 1 and 2. The Mannich reaction of 1 or 3 with
formaldehyde and substituted piperazine in ethanol at room
temperature led to novel Mannich bases with high yields in short
time. Using 1,2,4-triazole thiol 1, to react with formaldehyde and
various piperazine intermediates which bearing substituted benzyl,
or phenyl, or 2-pyridyl, or 4,6-disubstituted pyrimdin-2-yl at 4-
position of piperazine, the corresponding 1,2,4-triazole thione
derivatives containing various piperazine moieties 2a–i were
successfully synthesized. It is worthy to note that Foks et al.
prepared the similar compounds from the Mannich reaction of
triazole-thiol intermediate with methanol or dioxane as solvent
under condition of refluxing (1 h) [13], by contrast, our synthetic
procedure during this step for compounds 2a–i was to carry out the
reaction in ethanol at room temperature. Using this method, the
target compounds can also be obtained in moderate to excellent
yields within 1–2 h, which indicates our synthetic reaction has
advantage in some extent and this may be a favorable factor during
its possible industrial application. In a 2:1 molar ratio of 1,2,4-
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
77
78
2.1. General synthetic procedures for N-(3-mercapto-5-methyl-4H-
1,2,4-triazol-4-yl)-2/3-fluorobenzamide (3)
79
80
81
82
83
84
85
86
87
88
89
90
91
92
The procedures are similar to that described previously [23]. To
the o-fluorobenzoyl chloride (7.9 g, 0.5 mol) was added a solution
of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol (6.5 g, 0.5 mol) in
anhydrous acetonitrile (30 mL) under stirring at 80 8C. The mixture
was refluxed and stirred for 4 h, the solid precipitated was filtered
and washed with acetonitrile to give compound 3.
3a: White solid, yield 85%, mp 251–252 8C; 1H NMR (400 MHz,
DMSO-d6):
d 13.79 (s, 1H, SH), 12.02 (s, 1H, NH), 7.88 (d, 1H,
J = 7.7 Hz, Ph-H), 7.81 (dd, 1H, J = 9.5, 1.7 Hz, Ph-H), 7.67 (m, 1H,
Ph-H), 7.56 (m, 1H, Ph-H), 2.22 (s, 3H, CH3).
triazole thiol 1 and piperazine, novel piperazine-containing
bis(1,2,4-triazole thione) 2j was prepared conveniently in 89%
yield using the same procedure. It was also found that the easy
synthetic procedure and satisfactory yield for 2j were similar with
those of compounds we reported previously [14], although the
substituents at 3- and 4-positions of 1,2,4-triazole were obviously
different between two kinds of compounds (3-position: o-
fluorophenyl vs. trifluoromethyl; 4-position: phenyl vs. (substitu-
ted)benzylideneamino). When arylamide-containing 1,2,4-triazole
thiol 3 was used, the Mannich reaction also can occur smoothly to
give corresponding thione derivatives 4 and 5. Comparing with the
usual cases that the (substituted)benzylideneamino or aryl at 4-
position of 1,2,4-triazole [16,17,25,26], such novel arylamide case
expands the application range for the heterocyclic Mannich
reaction. It is known that the intermediates 1 and 3 can exist
either as a thiol or the thione tautomeric forms or as an equilibrium
mixture of both forms owing to the thioamide structure (–NH–
C(55S)). In some cases the mercapto group (–SH) took part in
nucleophilic reaction and the sulfoether products obtained
[27,28]. These results in our experiments indicate the thione
3b: White solid, yield 86%, mp 255–256 8C; 1H NMR (400 MHz,
DMSO-d6): d 13.73 (s, 1H, SH), 11.56 (s, 1H, NH), 7.84 (m, 1H, Ph-H),
7.69 (m, 1H, Ph-H), 7.42 (dd, 2H, J = 15.3, 8.1 Hz, Ph-H), 2.22 (s, 3H,
CH3).
93
2.2. General synthetic procedures for 1,2,4-triazole thione derivatives
94
95
96
97
98
99
General synthetic procedure for 1-((4-substituted piperazin-1-
yl)methyl)-3-(2-fluorophenyl)-4-phenyl-1H-1,2,4-triazole-5(4H)-
thione (2a–i): to a solution of 5-(2-fluorophenyl)-4-phenyl-4H-
1,2,4-trizole-3-thiol 1 (0.27 g, 1 mmol) in anhydrous ethanol
(10 mL), 4-substituted piperazine (1 mmol) and 37% formaldehyde
(3 mmol) was added, then the resulting solution was stirred at
room temperature for 1–2 h. The resulting precipitate was filtered
and recrystallized from ethanol and water to give compounds 2a–i.
General synthetic procedure for 1,10-(piperazine-1,4-diylbis(-
methylene))bis(3-(2-fluorophenyl)-4-phenyl-1H-1,2,4-triazole-
5(4H)-thione) (2j): to a solution of 5-(2-fluorophenyl)-4-phenyl-
4H-1,2,4-trizole-3-thiol 1 (0.4 g, 1.48 mmol) in anhydrous ethanol
(15 mL), anhydrous piperazine (0.06 g, 0.74 mmol) and 37%
formaldehyde (4.5 mmol) was added, then the reaction solution
was stirred at room temperature for 20 min. The resulting
precipitate was filtered and recrystallized from ethanol to give
compound 2j.
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
isomer undertake the Mannich reaction via the N–H at a-position of
thiocarbonyl (C55S). Overall these Mannich reactions for such kind
of structures (including bis(triazole thione) derivative) exhibit
noticeable advantages, such as mild reaction condition, high yield
and short reaction time, which may be useful factors for possible
application during the development of novel agrochemicals.
General synthetic procedure for N-(1-((4-substituted piper-
azin-1-yl)methyl)-3-methyl-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)-
2/3-fluorobenzamide (4a-c, 5a-d): the procedure was similar to
those of 2a–i. Using N-(3-mercapto-5-methyl-4H-1,2,4-triazol-4-
yl)-2/3-fluorobenzamide (3) as trizole material, compounds 4a-c,
5a-d were obtained.
The target compounds were identified by melting point, IR, 1
H
NMR and 13C NMR spectra. The measured elemental analyses were
also consistent with the corresponding calculated ones (see
Supporting Information). In 1H NMR, the resonance signals of
CH2 protons neighboring to the triazole ring were observed at
5.30–5.40 in Mannich bases 2, while at 5.10–5.15 in Mannich
d
d
Please cite this article in press as: L.-Y. Zhang, et al., Synthesis and biological activities of some fluorine- and piperazine-containing
1,2,4-triazole thione derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.015

G Model
CCLET 3439 1–5
L.-Y. Zhang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Scheme 1. General synthetic route for title compounds 2. Reagents and conditions: (a) SOCl2, EtOH, refluxing, 3 h; (b) 85% hydrazine hydrate, EtOH, 6 h; (c) PhNCS, EtOH,
refluxing, 3 h; (d) NaOH solution, HCl, refluxing, 4 h; (e) 37% CH2O, 4-substitutied piperazine, EtOH, r.t., 1–2 h; (f) 37% CH2O, anhydrous piperazine, EtOH, r.t., 20 min.
Scheme 2. General synthetic route for title compounds 4 and 5. Reagents and conditions: (a) water, 90–95 8C, 1 h; (b) HOAc, refluxing, 4 h; (c) SOCl2, toluene, refluxing, 3 h; (d)
dry acetonitrile, 80 8C, 4 h; (e) 37% CH2O, 4-substitutied piperazine, EtOH, r.t., 1–2 h.
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
bases 4 and 5 as a singlet, and the substituted benzyl CH2 proton
appeared at 3.49–3.61 as a singlet in Mannich bases 2 and 5. The
chemical shifts at 2.81–3.96 and 2.40–3.20 can be ascribed to
piperazine ring protons, which were appeared as two broad
signals, respectively. Comparing the situation of two active N–H
protons in Mannich bases 4 and 5, it was found that the –NH–C55O
concentration of 100 mg/mL, however compound 5a exhibited 199
72.0% of inhibitory activity and was comparable with the control. 200
For the barnyardgrass (E. crusgalli) cup tests, compounds did not 201
d
d
d
show potent herbicidal activity at 100
m
g/mL.
202
The in vitro fungicidal results of compounds against six fungi 203
were listed in Table 1. It was found that most compounds showed 204
obvious growth inhibitory activity against all test fungi at 50 mg/ 205
proton of 4 appeared at
d
9.62–10.05, while it appeared at upfield
d
8.97–9.16 in 5, which indicates that meta-fluorinated phenyl has
better deshielding effect than that of orth-fluorinated. In 13C NMR,
almost all carbons of the benzene rings were split by the adjacent
fluorine, even the C55O groups in Mannich bases 4 and 5, although
very few of them could not be seen clearly. In IR spectra, the
mL. For C. arachidicola, several compounds were more effective 206
than the control Triadimefon, e.g. 2c and 2d showed 70.0% of 207
inhibitory activity, which data were higher than that of Triadi- 208
mefon (40.0%) against C. arachidicola. For P. piricola, compounds 2a, 209
2c, 2d, 2g and 2j exhibited 63.6%, 68.2%, 65.9%, 63.6%, and 63.6% 210
activity, respectively, and had similar inhibitory level with that of 211
the control Chlorothalonil (63.6%). For R. cerealis, compounds 212
2b–2d, 2g and 2i possessed 63.3–77.6% inhibitory activity. 213
Although these compounds were less effective than the control, 214
they showed favorable and significant fungicidal activity against 215
the two fungi, which will provide important structural information 216
for designing novel fungicides. As we see in Table 1, compounds 2 217
seemed to be more active against test fungi than compounds 4 and 218
5 broadly. It was worthy to note that 2c and 2d exhibited more 219
favorable fungicidal activity and broad fungicidal spectrum than 220
characteristic stretching vibrations n(C–F) and n(C55S) appears at
1311–1359 per cm and 1155–1171 per cm, respectively. The
spectra of Mannich bases 4 and 5 showed bands at 3213–3287 per
cm for N–H stretching and 1678–1689 per cm for C55O stretching.
195
3.2. The biological activity
196
197
198
As shown in Table 1, most of the title compounds showed
rather weak herbicidal activity based on the rape (B. campestris)
root test compared with commercial herbicide chlorsulfuron at a
Please cite this article in press as: L.-Y. Zhang, et al., Synthesis and biological activities of some fluorine- and piperazine-containing
1,2,4-triazole thione derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.015

G Model
CCLET 3439 1–5
4
L.-Y. Zhang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Table 1
The biological activities of title compounds.
Compd.
Herbicidal activity (%
Fungicidal activity (% inhibition) 50 mg/mL
inhibition) 100
mg/mL
Brassica
Echinochloa
crusgalli
Fusarium
Cercospora
Physalospora
piricola
Rhizoctonia
cerealis
Alternaria solani
Sorauer
Gibberella
sanbinetti
campestris
omysporum
arachidicola
2a
18.2
41.3
30.7
13.0
0.0
5.9
55.3
0
30.0
15.0
10.0
25.0
10.0
5.0
29.0
19.4
58.1
58.1
16.1
9.7
35.0
45.0
70.0
70.0
20.0
15.0
55.0
25.0
35.0
25.0
15.0
20.0
45.0
15.0
15.0
15.0
10.0
NT
63.6
54.5
68.2
65.9
45.5
47.7
63.6
50.0
56.8
63.6
40.9
43.2
38.6
34.1
38.6
36.4
43.2
NT
61.2
63.3
77.6
77.6
38.8
44.9
67.3
36.7
67.3
57.1
28.6
30.6
46.9
30.6
8.2
33.3
33.3
33.3
27.8
27.8
27.8
22.2
38.9
33.3
27.8
16.7
38.9
27.8
16.7
22.2
16.7
22.2
NT
35.5
35.5
22.6
19.4
19.4
12.9
19.4
16.1
12.9
35.5
12.9
29.0
16.1
12.9
16.1
19.4
22.6
NT
2b
2c
2d
2e
2f
2g
20.0
5.0
25.8
16.1
22.6
16.1
16.1
12.9
16.1
6.5
2h
2i
0
25.0
10.0
5.0
2j
0
4a
0
4b
0
25.0
10.0
2.0
4c
0
5a
72.0
0
5b
10.0
0
6.5
5c
0
9.7
14.3
18.4
NT
5d
0
15.0
29.9
NT
19.4
NT
Chlorsulfuron
Triadimefon
Chlorothalonil
Carbendazim
80.4
NT
NT
NT
71.0
84.0
100
40.0
88.5
8.3
75.0
63.6
97.4
100
NT
50.0
58.8
43.5
22.6
73.1
100
NT
NT
NT
NT = not tested.
[3] Q.H. Li, G. Zhang, Y. Ding, et al., Synthesis and anti-tumor activities of novel
triazole Schiff-base derivatives, J. Southwest Univ. Natl: Natl. Sci. Ed. 40 (2014)
826–832.
[4] Y.G. Zheng, W. Xue, Q.Q. Guo, et al., Synthesis and antitumor activity of 5,6-2H-
[1,2,4]-triazolo[3,4-b][1,3,4] thiadiazine derivatives, Chin. J. Org. Chem. 31 (2011)
912–916.
[5] Z.X. Feng, W.N. Zhang, Y.J. Zhou, et al., Synthesis and antifungal activities of 1-[2-
(N-methyl-N-substituted-benzyl)amino-2-(4-tert-butylphenyl)ethyl]-1H-1,2,4-
triazoles, Chem. J. Chin. Univ. 21 (2000) 1221–1226.
[6] K. Yin, L.H. Jiang, H.X. Zhou, Y. Huang, J.N. Xiang, Synthesis and insecticidal activity
of 2-perfluoroalkyl-substituted or glucopyranosyl-substituted 2,4-dihydro-1,2,4-
triazole-3-thione Schiff base, Chin. J. Org. Chem. 28 (2008) 1016–1023.
[7] X.Y. Zhao, Y.X. Gong, Z.W. Zhang, et al., Synthesis and plant growth regulating
activity of N-5-(3-carboxy-1,2,4-triazolyl)-N0-aroyl urea, Chin. J. Appl. Chem. 20
(2003) 594–596.
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
221
222
others, and could be novel lead structures for further optimization
during our fungicides innovation program.
223
4. Conclusion
224
225
226
227
228
229
230
231
232
233
234
235
236
In conclusion, series of fluorine- and piperazine-containing
1,2,4-triazole thione derivatives have been synthesized by the
Mannich reaction of triazole intermediates with formaldehyde and
various substituted piperazines under mild conditions in short
time and high yields. The preliminary bioassays for 17 novel
compounds showed that most of the compounds exhibit weak
[8] Q. Wu, Z.C. Wang, X. Wei, W. Xue, Synthesis and antibacterial activities of
1-substituted-4-[5-(4-substitutedphenyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine
derivatives, Chin. J. Synth. Chem. 22 (2014) 429–434.
herbicidal activity against B. campestris and E. crusgalli at 100
mL, while several compounds have significant fungicidal activities
against C. arachidicola, P. piricola and R. cerealis at 50 g/mL.
mg/
m
[9] D.H. Jiang, M. Huang, Design and synthesis of thieno[3,2-d]pyrimidine derivatives
containing
797–799.
a piperazine unit as anticancer agents, Chem. Reag. 34 (2012)
Among which, compounds 2 are broadly more active than
compounds 4 and 5, especially 2c and 2d showed broad activities
and could be used as novel fungicidal lead structures for further
optimization.
[10] G.Y. Li, S.G. Yan, S. Jiang, et al., Synthesis of piperazine derivatives containing
pyridinemethyl/thiazolemethyl and their biological activities, Chin. J. Org. Chem.
28 (2008) 2001–2006.
[11] S. Liang, C.M. Liu, Y.S. Jin, et al., Synthesis and the antifungal activity of 1-(1H-
1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted)-piperazine-1-yl]-
2-propanols, Chin. J. Med. Chem. 14 (2004) 71–75.
[12] G.M. Ye, Q.Y. Sun, Y.Y. Jiang, et al., Synthesis and antifungal activity of 1-(1H-1,2,4-
triazole-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted-piperazine)-1-yl]-2-pro-
panols, Acad. J. Sec. Mil. Med. Univ. 26 (2005) 1161–1164.
237
Acknowledgments
238
239
240
241
242
This work was supported by the National Natural Science
Foundation of China (No. 21372133) and ‘‘111’’ Project of Ministry
of Education of China (No. B06005). We thank Dr. Yong-Hong Li of
the Biological Assay Center, Nankai University, for herbicidal tests
of compounds.
´
[13] H. Foks, M. Janowiec, Z. Zwolska, E. Augustynowicz-Kopec, Synthesis and tuber-
culostatic activity of some 2-piperazinmethylene derivatives 1,2,4-triazole-3-
thiones, Phosphorus Sulfur Silicon Relat. Elem. 180 (2005) 537–543.
[14] B.L. Wang, Y.X. Shi, Y. Ma, et al., Synthesis and biological activity of some novel
trifluoromethyl-substituted 1,2,4-triazole and bis(1,2,4-triazole) Mannich bases
containing piperazine rings, J. Agric. Food Chem. 58 (2010) 5515–5522.
[15] B.L. Wang, X.H. Liu, X.L. Zhang, et al., Synthesis, structure and biological activity of
novel 1,2,4-triazole Mannich bases containing a substituted benzylpiperazine
moiety, Chem. Biol. Drug Des. 78 (2011) 42–49.
[16] A. Demirbas, D. Sahin, N. Demirbas, S.A. Karaoglu, Synthesis of some new 1,3,4-
thiadiazol-2-ylmethyl-1,2,4-triazole derivatives and investigation of their anti-
microbial activities, Eur. J. Med. Chem. 44 (2009) 2896–2903.
[17] B.S. Holla, B.S. Rao, K. Shridhara, P.M. Akberali, Studies on arylfuran derivatives:
Part XI. Synthesis, characterisation and biological studies on some Mannich bases
carrying 2,4-dichlorophenylfurfural moiety, Il Farmaco 55 (2000) 338–344.
[18] K.V. Sujith, J.N. Rao, P. Shetty, B. Kalluraya, Regioselective reaction: synthesis
and pharmacological study of Mannich bases containing ibuprofen moiety, Eur. J.
Med. Chem. 44 (2009) 3697–3702.
243
Appendix A. Supplementary data
244
245
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.09.015.
246
References
247
248
249
250
251
[1] J. Zhang, G.M. Xiao, Study progress in nitrogenous heterocyclic compounds,
Petrochem. Technol. 40 (2011) 579–584.
[2] J.Y. Xu, Y. Zeng, B. Jiang, et al., Synthesis, anti-inflammatory activities and SAR
studies of 1,5-diaryl substituted-1,2,4-triazoles, Chin. J. Med. Chem. 18 (2008)
321–328.
[19] P. Zlatoidsky´, T. Maliar, Synthesis of 1-(4-acyloxybenzoyloxyacetyl)-4-alkylpi-
perazines and 1-(4-acyloxybenzoyl)-4-alkylpiperazines as inhibitors of chymo-
trypsin, Eur. J. Med. Chem. 31 (1996) 669–674.
Please cite this article in press as: L.-Y. Zhang, et al., Synthesis and biological activities of some fluorine- and piperazine-containing
1,2,4-triazole thione derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.015

G Model
CCLET 3439 1–5
L.-Y. Zhang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
5
303
304
305
306
307
308
309
310
311
312
313
314
315
316
[20] R.R. Adams, F.C. Whitmore, Heterocyclic basic compounds. IV. 2-aminoalkyla-
mino-pyrimidines, J. Am. Chem. Soc. 67 (1945) 735–738.
[21] J.Y. Tong, Y.X. Shi, X.H. Liu, N.B. Sun, B.J. Li, Synthesis and fungicidal activity of
1,2,4-triazole derivatives containing 2-fluorophenyl moiety, Chin. J. Org. Chem.
32 (2012) 2373–2377.
[22] C.Y. Liu, Q.Q. Zhao, J. Li, Synthesis study of new Schiff base containing thiocaba-
mide group derivatives of 3-argl-4-amino-5-mercapto-1,2,4-triazoles, Chem.
Reag. 23 (2001) 344–345.
[23] S.J. Xue, C.S. Xiang, S.R. Yu, et al., Synthesis and crystal structure of 5-(p-tolyl)-4-
[2-(2,4-dichlorophenoxy)acetamido]-1,2,4-triazole-3-thione ethyl acetate sol-
vate, Chin. J. Struct. Chem. 27 (2008) 389–393.
[25] H. Bayrak, A. Demirbas, S.A. Karaoglu, N. Demirbas, Synthesis of some new 1,2,4- 317
triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial 318
activities, Eur. J. Med. Chem. 44 (2009) 1057–1066.
319
[26] S. Ceylan, H. Bektas, H. Bayrak, et al., Syntheses and biological activities of new 320
hybrid molecules containing different heterocyclic moieties, Arch. Pharm. 346 321
(2013) 743–756.
[27] F. Micheli, G. Bonanomi, F.E. Blaney, et al., 1,2,4-Triazol-3-yl-thiopropyl-tetra- 323
hydrobenzazepines: series of potent and selective dopamine D3 receptor 324
antagonists, J. Med. Chem. 50 (2007) 5076–5089.
322
a
325
[28] P. Polucci, P. Magnaghi, M. Angiolini, et al., Alkylsulfanyl-1,2,4-triazoles, a new 326
class of allosteric valosine containing protein inhibitors. Synthesis and structure- 327
[24] B.L. Wang, R.G. Duggleby, Z.M. Li, et al., Synthesis, crystal structure and herbicidal
activity of mimics of intermediates of the KARI reaction, Pest Manag. Sci. 61
(2005) 407–412.
activity relationships, J. Med. Chem. 56 (2013) 437–450.
328
Please cite this article in press as: L.-Y. Zhang, et al., Synthesis and biological activities of some fluorine- and piperazine-containing
1,2,4-triazole thione derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.015