Synthesis and antiproliferative evaluation of 3,5-disubstituted 1,2,4-triazoles containing flurophenyl and trifluoromethanephenyl moieties

Article abstract of DOI:10.1016/j.bmcl.2011.07.009

An efficient 1,3-dipolar cycloaddition method was performed for the synthesis of a series of monofluoro- and trifluoromethane-3,5-disubstituted 1,2,4-triazoles. This efficient cycloaddition method was to react hydrazonoyl hydrochlorides with a series of aldehydes in the presence of NEt₃ as catalytic basic agent to provide the corresponding product in 28-94%. Their growth inhibitory results against cancer cells indicated that some of the fluorine- and trifluoromethane-containing compounds could effectively inhibit the growth of NCI-H226 and T-cell leukemia (Jurkat) cells. Among the compounds, trifluoromethane-containing 1,2,4-triazoles possessed the five-membered ring groups on the C-5 position of the triazolic ring, including cyclopentyl, 3-furyl, 3-thienyl, and 2-pyrrolyl, possessed the significant inhibitory activity for NCI-H226 cancer cells.

Full text of DOI:10.1016/j.bmcl.2011.07.009

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5358–5362
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiproliferative evaluation of 3,5-disubstituted
1,2,4-triazoles containing flurophenyl and trifluoromethanephenyl moieties
Li-Ya Wang a, Wen-Che Tseng b, Tian-Shung Wu a,c, Kimiyoshi Kaneko d, Hiroyuki Takayama d,
a,b,
Masayuki Kimura d, Wen-Chin Yang e, Jin Bin Wu b, Shin-Hun Juang a,b, , Fung Fuh Wong
⇑
⇑
a The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
c School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
d Department of Medico Pharmaceutical Science, Nihon Pharmaceutical University, 10281, Komuro, Inamachi, Kita-Adachigun, Saitama, Japan
e Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient 1,3-dipolar cycloaddition method was performed for the synthesis of a series of monofluoro-
and trifluoromethane-3,5-disubstituted 1,2,4-triazoles. This efficient cycloaddition method was to react
hydrazonoyl hydrochlorides with a series of aldehydes in the presence of NEt3 as catalytic basic agent to
provide the corresponding product in 28–94%. Their growth inhibitory results against cancer cells indicated
that some of the fluorine- and trifluoromethane-containing compounds could effectively inhibit the growth
of NCI-H226 and T-cell leukemia (Jurkat) cells. Among the compounds, trifluoromethane-containing 1,2,
4-triazoles possessed the five-membered ring groups on the C-5 position of the triazolic ring, including
cyclopentyl, 3-furyl, 3-thienyl, and 2-pyrrolyl, possessed the significant inhibitory activity for NCI-H226
cancer cells.
Received 1 April 2011
Revised 4 July 2011
Accepted 6 July 2011
Available online 14 July 2011
Keywords:
1,2,4-Triazoles
Aldehydes
Antiproliferative activity
Fluorine-containing compounds
Nitrilimine
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Cycloaddition
Triazoles are an important class of heterocyclic compounds
which show various biological activities including antifungal,1,2
antimicrobial,3 antiviral,4 anti-inflammatory,5 anti-asthmatic,6
anticonvulsant activities,7 antiproliferative,8 hypotonic activities,9
antibacterial, antifungal, and antihelmintic activities.10 Triazole-
based agonists or antagonists targeting different receptors were de-
scribed recently,11,12 especially the 3,5-disubstituted 1,2,4-triazole
scaffold.13–17
heterocyclic derivatives.20 Herein, we give an efficient cycloaddi-
tion for the conversion of a series of aldehydes to fluorine-
or trifluoromethane-containing 3,5-disubstituted 1,2,4-triazoles
using hydrazonoyl hydrochlorides and hydroxylamine hydrate in
the presence of triethylamine as a catalyst. The reaction mechanism
involved the 1,3-dipolar cycloaddition reaction. Furthermore, the
cytotoxicities of these 3,5-disubstituted 1,2,4-triazole derivatives
were explored for realizing the structure–activity relationship and
identifying the structural fragments responsible for the biological
activity.
Aldehydes 1–12 are the commercially available materials and
hydrazonoyl chloride materials 13–22 were prepared following
the reported procedure.21 Scheme 1 shows the efficient 1,3-dipolar
cycloaddition methodology using nitrilimine as an efficient 1,3-
dipolar. The reliable model procedure involved the treatment of a
toluene solution of aldehydes 1–12 with 1.0 equiv of hydroxyl-
amine hydrochloride with excess amount of triethylamine at room
temperature for 30 min. When the aldehydes were completely
consumed and converted to the oxime intermediates,22 hydrazo-
noyl chloride was then added to the reaction mixture and the solu-
tion was heated at reflux for 1–2 h. After aqueous work up and
purified by column chromatography on silica gel, the correspond-
ing cycloaddition products 23–48 were isolated in moderate to
good yields (28–94%, see Table 1 and Chart 1).
Fluorine-18 and trifluoromethane-containing19 compounds are
well known to play an important role in wide fields, including bio-
chemistry and agrochemistry. For example, replacement of hydro-
gen atoms by fluorines or trifluoromethane groups in pheromones
has been shown to produce a variety of effects on the insect
response, some of them are a priori unpredictable. As a result,
we focused to synthesize a series of fluorine- or trifluorome-
thane-containing 3,5-disubstituted 1,2,4-triazoles derivatives in
this work.
Nitrilimine cycloadditions to ethylenic or ethylynic dipolaro-
philes are of great interest due to their potential application for
the synthesis of various bioactive 5-substituted-4,5-dihydrpyrazole
⇑
Corresponding authors. Tel.: +886 4 2205 3366x5603; fax: +886 4 2207 8083.
E-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F.
Wong).
0960-894X/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.07.009

L.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5358–5362
5359
(51–94%, see the entries 20–24 in Table 1 and Chart 1). For further
investigation of the substituent effect, we extended the same
reaction condition toward [(4-trifluoromethylphenyl)-hydrazon-
o]-chloroacetic acid ethyl ester (21) and [(4-fluorophenyl)-hydraz-
ono]-chloroacetic acid ethyl ester (22), having ethyl carboxylate
group at the C-3 position of 1,2,4-triazole ring. The desired prod-
ucts 47 and 48 were produced in 66% and 86% yields, respectively.
As a result, this efficient cycloaddition method can be successfully
applied to the various aldehydes as a dipolarophile including ali-
phatic, aryl, and heterocyclic aldehydes and assorted hydrazonoyl
hydrochloride compounds as the 1,3-dipole reactants.
R2
O
1. NH2OH.HCl, toluene
N
R
R2
N
R1
H
2.
Cl
N
N
CO2R3
23-48
NH CO2R3
1-12
13-22
NEt3, toluene, at reflux, 2 h
Scheme 1.
The growth inhibitory activity of all methnimidamide com-
pounds is evaluated against a panel of human cancer cell lines
in vitro, including lung carcinoma (NCI-H226), nasopharyngeal
(NPC-TW01), and T-cell leukemia (Jurkat) cells. The GI50 value indi-
cates the concentration of the compound that results in a 50% de-
crease in the cell growth relative to the vehicle. The results are
presented in Table 2 and indicated that trifluoro- and monoflu-
oro-3,5-disubstituted 1,2,4-triazoles 23–48 compounds showed
the better inhibitory potency against nasopharyngeal (NPC-
TW01) and T-cell leukemia (Jurkat) cell.
Acetaldehyde 1 was used as the model dipolarophile and al-
lowed to react with various aromatic hydrazonoyl hydrochlorides
13–20 bearing various substituents including F, Cl, Br, CF3, and
OMe at the ortho or meta or para position to the nitrilimine group.
The reaction gave the corresponding 3,5-disubstituted 1,2,4-tria-
zoles 23–30 in good to excellent yields (82–91%, see the entries
1–8 in Table 1 and Chart 1). For realizing the effect of the dipolaro-
philes’ property on the 1,3-dipolar cycloaddition, we applied the
same reaction condition to p-fluorophenylchlorohydrazone 20
and various aliphatic, cyclic aliphatic, aryl, and heterocyclic alde-
hyde substrates 2–7 to prepare a series of fluorine-containing
3,5-disubstituted 1,2,4-triazoles. The desired fluorine-containing
products 31–41 were obtained in 28–91% yields (see the entries
8–19 in Table 1 and Chart 1). The poor isolated yields were found
for aromatic and heterocyclic aldehyde 8–12 as the reactants.
The synthetic strategy was also applicable to p-trif-
luoromethylphenylchlorohydrazone (17) as the 1,3-dipole reactant
with cyclopentanecarbaldehyde (6), cyclohexanecarbaldehyde (7),
furan-3-carbaldehyde (8), thiophene-3-carbaldehyde (9), and 1H-
pyrrole-3-carbaldehyde (10) to prepare the trifluormethane-con-
taining desired products (see Table 1). The corresponding 3,
5-disubstituted 1,2,4-triazoles 42–46 were obtained in good yield
Methyl 1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazole-3-car-
boxylate 30 was selected as the compared model for the inhibitory
activity study. Their GI50 values are 11.7
lM (NCI-H226), 15.2 lM
(NPC-TW01), and 8.70 M (Jurkat), respectively. In comparison
l
with compounds 23–29 containing various substituents, including
H, o-CF3, m-F, m-Cl, p-Cl, p-F, p-CF3, and p-OMe, at N-1 of the phe-
nyl ring, The results showed that only compound 24, 26, and 27
with o-, m-, and p-CF3Ph substituents on N-1 position of triazole
ring possessed the better inhibitory activity against NCI-H226
and Jurkat with GI50 values between 6.13 lM and 16.6 lM. How-
ever, methyl 5-methyl-1-aryl-1H-1,2,4-triazole-3-carboxylate 24–
30 displayed reduced inhibitory activity for NPC-TW01 cell line,
expect for compound 28–30 (see Table 2).
Table 1
Synthesis of 3,5-disubstituted 1,2,4-triazoles using aldehydes with hydrazonoyl hydrochlorides
R2
O
Cl
NH CO2R3
Aldehydes
R1
H
Hydrazones
N
Entry
1,2,4-Triazoles
Yield (%)
No.
R1
No.
R2
H
R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
13
14
15
16
17
18
19
20
20
20
20
20
20
20
20
20
20
20
20
17
17
17
17
17
21
22
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
88
87
86
85
87
82
86
91
91
90
89
91
88
86
62
57
41
33
28
94
91
64
62
51
66
86
o-CF3
m-Br
m-CF3
p-CF3
p-OMe
p-Cl
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
Ethyl
i-Propyl
n-Butyl
Cyclopropyl
Cyclopentyl
Cyclohexyl
3-Furyl
3-Thienyl
2-pyrrolyl
Phenyl
2-Naphthyl
Cyclopentyl
Cyclohexyl
3-Furyl
3-Thienyl
2-Pyrrolyl
2-Pyrrolyl
2-Pyrrolyl
10
11
12
6
7
8
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-F
9
10
10
10
Et

5360
L.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5358–5362
X
N
X
CF3
N
N
N
Me
Me
Me
Me
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
23
24
27. X = CF3, 28. X = OMe
29. X = Cl, 30. X = F
25. X = Br
26. X = CF3
F
F
X
X
N
N
N
N
N
N
R
N
N
CO2Me
N
N
N
N
CO2Me
CO2Me
CO2Me
31. R = Et
34
35. X = F
42. X = CF3
36. X = F
43. X = CF3
32. R = i-Pr
33. R = n-Bu
X
X
N
X
F
N
N
N
N
N
N
N
O
S
R
N
N
N
H
N
N
CO2Me
CO2Me
CO2Y
CO2Me
40. R = Ph
37. X = F
44. X = CF3
38. X = F
45. X = CF3
39. X = F, Y = Me
46. X = CF3, Y = Me
47. X = CF3, Y = Et
48. X = F, Y = Et
41. R = 2-Naphthyl
Chart 1.
For the further structure–activity relationship study, we modi-
fied monofluorine-containing 1,2,4-triazole-3-carboxylate 30 to
31–41 with various substituents at C-5 position in 1,2,4-triazole
ring, such as ethyl (31), i-propyl (32), n-butyl (33), cyclopropyl
(34), cyclopentyl (35), cyclohexyl (36), 3-furyl (37), 3-thienyl (38),
2-pyrroyl (39), phenyl (40), and 2-naphthyl group (41). Their anti-
proliferative activities were presented in Table 2. Most of the mod-
ified monofluorine-containing 1,2,4-triazole-3-carboxylates 31–41
exhibited significant inhibition against T-cell leukemia cell (Jurkat,
Table 2 and Chart 1). Most of the compounds 42–46 were more po-
tent than monofluorine-containing 1,2,4-triazole compounds 31–
41 against NCI-H226 cell line with GI50 values between 5.65
and 6.01 M. However, trifluormethane-containing 1,2,4-triazole
compounds 42–46 provided the less satisfactory antiproliferative
activity results against NPC-TW01 (>97.2 M) and T-cell leukemia
cell (Jurkat, >34.9 M, see Table 2).
lM
l
l
l
On the other hand, compounds 47 and 48 with 2-pyrroyl group
at C-5 position in pyrazole ring were modified from methyl carbox-
ylate to ethyl carboxylate group at C-3 position of 1,2,4-triazole
ring. We found the ethyl carboxylate group grafted at C-3 position
in triazolic ring promoted the inhibitory activity against NCI-H226
<11.0
(>100
l
l
M, see Table 2), except for compound 32 (>100 M), 33
l
M), 36 (>100 M), 38 (54.0 M) and 41 (18.5 lM) with
l
l
bulky groups including i-propyl, t-butyl, cyclohexyl, 3-thienyl or
2-naphthyl groups at C-5 position on the triazole ring. In addition,
compounds 32–33, 36, and 38 also showed the better antiprolifer-
cell line from 72.0 to 5.71
activity was observed between compound 46 (5.65
pound 47 (5.61 M). As a result, monofluoro-containing 3,5-disub-
lM. Nevertheless, only little change in
l
M) and com-
ative activity against NCI-H226 (<6.90
l
M, see Table 2), which pos-
l
sess the flexible i-propyl, n-butyl and cyclohexyl alkyl groups and
3-thienyl at C-5 position on the triazole ring. Finally, monofluoro-
containing 1,2,4-triazoles compounds 35 and 37–39 having the
five-membered ring groups on the C-5 position of triazole ring,
including cyclopentyl, 3-furyl, 3-thienyl, and 2-pyrrolyl, possessed
the good inhibitory activity for NPC-TW01cell near between 9.58
stituted 1,2,4-triazole compounds 32–33, 36, and 48 and
trifluormethane-containing 3,5-disubstituted 1,2,4-triazole com-
pounds 42–47 may be regarded as the potent leads against NCI-
H226 in future investigation.
In conclusion, we have performed an efficient 1,3-dipolar cyclo-
addition method to prepare a series of monofluoro- and trifluo-
romethane-3,5-disubstituted 1,2,4-triazole compounds by using
an efficient 1,3-dipolar cycloaddition from hydrazonoyl hydrochlo-
rides with aldehydes and excess amount of NEt3. Based on their
growth inhibitory activity data on cancer cells, monofluoro- and
trifluormethane-containing 1,2,4-triazole compounds were found
to effectively inhibit the growth of NCI-H226 cancer cells. More-
over, monofluoro-containing 1,2,4-triazoles possessed phenyl and
and 11.7 lM (see Table 2).
Since fluorine-18 and trifluoromethane-containing19 compounds
are well known to play an important role in wide fields, including
biochemistry and agrochemistry, we prepared a series of trif-
luormethane-containing 1,2,4-triazole-3-carboxylates 42–46 pos-
sessing five- or six-membered ring at the C-5 position of the
triazole ring for further structure–activity relationship study (see

L.-Y. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5358–5362
5361
Table 2
The inhibitory activity of the 3,5-disubstituted 1,2,4-triazoles derivatives in NCI-H226, NPC-TW01, and Jurkat
R2
N
R1
N
N
CO2R3
a,b
Compounds
1,2,4-Triazoles (23–48)
R2 (N-1)
GI50
(lM)
R1 (C-5)
R3 (C-3)
NCI-H226
NPC-TW01
Jurkat
1.25
>100
>100
>100
Reference
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Methotrexate
Me
Me
Me
Me
Me
Me
Me
Me
10.25
>100
6.13
7.35
14.3
16.6
>100
84.0
11.7
71.3
6.17
6.40
16.3
70.5
6.26
91.6
6.94
72.0
89.3
79.3
5.71
5.76
6.01
5.74
5.65
5.61
5.71
0.10
>100
>100
>100
>100
>100
9.92
17.5
15.2
15.8
>100
>100
95.9
10.4
30.5
11.7
10.7
9.58
15.6
>100
56.4
>100
>100
34.9
>100
76.4
64.3
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
o-CF3
m-Br
m-CF3
p-CF3
p-OMe
p-Cl
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
p-F
10.6
9.10
>100
65.9
8.70
11.0
>100
>100
9.42
9.55
>100
9.32
54.0
9.01
10.0
18.5
>100
>100
97.2
Et
i-Pr
n-Bu
Cyclopropyl
Cyclopentyl
Cyclohexyl
3-Furyl
3-Thienyl
2-Pyrrolyl
Phenyl
2-Naphthyl
Cyclopentyl
Cyclohexyl
3-Furyl
3-Thienyl
2-Pyrrolyl
2-Pyrroryl
2-Pyrroryl
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-F
>100
>100
>100
>100
47
48
Et
a
NCI-H226: human lung carcinoma; NPC-TW01: human nasopharyngeal carcinoma; Jurkat: human T-cell leukemia.
All tested compounds were dissolved in 100% DMSO at a concentration of 20 mM as the stock solution. Cells were cultured without or in the presence of the
b
methnimidamide derivatives at different concentrations for 72 h. Cell survival was determined by MTT assay. Drug molar concentration causing 50% cell growth inhibition
(GI50) was calculated. Each value represents the mean SD of three independent experiments.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.07.009.
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