Synthesis and evaluation of novel 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols as antifungal agents

Article abstract of DOI:10.1016/j.ejmech.2006.11.003

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents

Full text of DOI:10.1016/j.ejmech.2006.11.003

European Journal of Medicinal Chemistry 42 (2007) 1151e1157
http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and evaluation of novel
-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-
piperazin-1-yl]-propan-2-ols as antifungal agents
1
a,
b
a
c
Qing-Yan Sun *, Wan-Nian Zhang , Jian-Ming Xu , Yong-Bing Cao ,
Qiu-Ye Wu , Da-Zhi Zhang , Chao-Mei Liu ,
a
a
a
a
Shi-Chong Yu , Yuan-Ying Jiang
c
a
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
b
Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
c
Department of Pharmacology, College of Pharmacy, Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
Received 5 August 2006; received in revised form 31 October 2006; accepted 13 November 2006
Available online 24 November 2006
Abstract
A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and
synthesized on the basis of the structureeactivity relationships and antimycotic mechanism of azole antifungal agents. Their structures were
1
13
confirmed by elemental analysis, IR, MS, H NMR and C NMR. Results of preliminary antifungal tests against six human pathogenic fungi
Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, inherently fluconazole-resistant Candida krusei, Can-
(
dida glabrata) in vitro showed that all title compounds exhibited activity against fungi tested to some extent except against C. tropicalis. Com-
pound 5b showed higher activity against C. albicans, C. parapsilosis and C. krusei than fluconazole, and its MIC values were determined to be
0
.5 mg/mL, 1 mg/mL and 4 mg/mL, respectively. Compound 5k showed higher activities against Torulopsis glabrata than fluconazole (with the
MIC value of 2 mg/mL). Compounds 5a, 5c, 5f, 5g, 5i exhibited higher activities against C. parapsilosis than fluconazole (with the MIC values of
mg/mL, 2 mg/mL, 2 mg/mL, 1 mg/mL and 2 mg/mL, respectively).
2
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Triazole; Synthesis; Antifungal activity
1
. Introduction
transplant cases [1,2]. Triazole antifungals (e.g. fluconazole
and itraconazole) which act by inhibiting cytochrome P450
14a-demethylase (CYP51), a key enzyme in the fungal
ergosterol biosynthesis, now become the most rapidly expand-
ing group of antifungal compounds. However, their clinical
value has been limited by their relatively high risk of toxicity,
the emergence of drug resistance, pharmacokinetic defi-
ciencies, and/or insufficiencies in their antifungal activities.
Despite recent developments [3e6], there is still a need for
genuinely broad-spectrum and low-toxicity antifungal agents.
In the past two or three decades, fungal infections have be-
come an important complication and a major cause of morbid-
ity and mortality in immunocompromised individuals
suffering from tuberculosis, cancer or AIDS and in organ
*
Corresponding author. Tel.: þ86 21 25070382; fax: þ86 21 25070381.
E-mail address: sqy2000@sohu.com (Q.-Y. Sun).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.11.003

1152
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
N
OH
N
O
N
O
N
N
N
N
N
N
N
F
N
O
N
N
O
N
F
F
F
Fluconazole
Itraconazole
Ji’s [7] study indicated that the triazole ring in the parent
3. Bioassays of antifungal activities
structure of triazole antifungal agents was positioned perpen-
dicularly to the porphyrin plane with a ring nitrogen atom co-
ordinated to the heme iron and was of key importance for the
antifungal activity. The halogenated phenyl group was deep in
the same hydrophobic binding cleft in the active site of the tar-
get enzyme CYP51 and long chains of some antifungals such
as itraconazole and ketoconazole surpassed the active site and
interacted with residues in the substrate access channel.
We herein designed a novel series of 1-(1H-1,2,4-triazol-1-
yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-
The in vitro minimal inhibitory concentrations (MICs) of
the title compounds were determined by the microbroth dilu-
tion method according to the methods defined by the National
Committee for Clinical Laboratory Standards [11]. Fungi
strains for testing: Candida albicans, Candida parapsilosis,
Cryptococcus neoformans, Candida tropicalis, Candida kru-
sei, Torulopsis glabrata were provided through Shanghai
Changhai Hospital. C. krusei and C. parapsilosis are ATCC
standard strains, others are clinic isolates. C. krusei
(ATCC6258) and C. parapsilosis (ATCC22019) were qual-
ity-controlled strains, and tested in each assay. Fluconazole
(FLC) and itraconazole (ICZ) obtained from their respective
manufacturers served as the positive control. The drug
MIC80 was defined as the first well with an approximate
80% reduction in growth compared to the growth of the
drug-free well. The title compounds to be tested were dis-
solved in dimethyl sulfoxide (DMSO), serially diluted in
1
-yl]-propan-2-ols containing a triazole ring, a difluorogenated
phenyl group and a long side chain, to find potent systemic an-
tifungal agents that have a broad antifungal spectrum but with
less potential to develop resistance. The 4-(4-substituted-
phenyl) piperazine was chosen as side chains to adjust the
physicochemical properties of the whole molecule to avoid
the dissatisfying side effects and/or improve the pharmacoki-
netic and pharmacodynamic behavior. The structures of this
series of compounds are shown in Scheme 1 and Table 1.
ꢀ
growth medium, inoculated and incubated at 35 C. Growth
MIC was determined at 24 h for C. albicans and at 72 h for
Cr. neoformans.
2
. Chemistry
4. Results and discussion
The general synthetic route of title compounds 1-(1H-1,2,4-
triazol-1-yl)-2-(2,4-difluoro-phenyl)-3-[(4-substitutedphenyl)-
piperazin-1-yl]-propan-2-ols (5ae5q) is outlined in Scheme 1.
The important intermediate oxirane 1, compounds 2a and 2b
were synthesized with known procedures [8e10].
The in vitro antifungal activities of all title compounds
were evaluated against six human pathogenic fungi (C. albi-
cans, C. parapsilosis, Cr. neoformans, C. tropicalis, inherently
fluconazole-resistant C. krusei, Candida glabrata) which are
R
O
N
OH
N
N
R
N
N
F
N
NO2
N
F
a
N
CH SO H
+
H N
N
NO2
3
3
F
1
2a: R=H
2b: R=F
3a: R=H
3b: R=F
F
R
R
R1
OH
OH
F
N
N
N
N
F
N
NH2
c
N
N
F
N
N
b
N
N
NH NH2 H O
R1
2
2
OHC
4
a: R=H
F
5a~5q
4
b: R=F
ꢀ ꢀ
3 2 3 2 2 2 3 2
Scheme 1. Synthetic route to the title compounds. Conditions: (a) CH CH OH, Et N, 80 C, 5 h; (b) Raney Ni, NH NH $H O, CH CH OH, 8 0 C, 3.5 h; (c) HAc,
reflux, 0.5e4 h.

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
1153
Table 1
Some characteristics of the title compounds
fluconazole-resistant C. krusei than fluconazole (with the
same MIC values of 4 mg/mL). Compounds 5a and 5g showed
higher activities against Cr. neoformans than fluconazole (with
the same MIC values of 4 mg/mL). Compound 5k showed
higher activities against T. glabrata than fluconazole (with
the MIC values of 2 mg/mL).
ꢀ
Compound
R
R
1
Yield (%)
Mp ( C)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
F
4-Fluoro
4-Chloro
4-Bromo
85
87
83
93
85
88
70
76
72
68
66
80
81
76
75
72
74
184e186
194e196
190e192
195e196
176e178
174e176
204e206
171e173
180e182
184e185
169e171
195e197
185e186
166e168
192e193
188e190
186e188
2,4-Dichloro
3,4-Dichloro
4-Methyl
5. Experimental part
g
h
i
4-Hydroxy
2-Hydroxy-3-methoxy
3,4-Methylenedioxy
4-Benzyloxy
4-(3-Chloro-benzyloxy)
4-Nitro
Melting points were measured on a Yamato MP-21 melt-
ing-point apparatus and are uncorrected. Infrared spectra
were recorded in potassium bromide disks on a HITACHI
j
k
l
1
70-50 spectrophotometer. H and C NMR spectra were
13
2
m
n
o
p
q
3-Nitro
4-Fluoro
recorded in CDCl or DMSO-d6 unless otherwise indicated
3
F
4-Chloro
4-Bromo
4-Methyl
with a Bruker AC-300P spectrometer, using TMS as internal
standard. Elemental analysis was undertaken with an Italian
MOD 1106 analyzer at the Analysis Center of Shanghai Insti-
tute of Pharmaceutical Industry. The solvents and reagents
were used as received or dried prior to use as needed.
F
F
often encountered clinically and are summarized in Table 2.
The MIC values (in mg/mL) against different pathogenic fungi,
in comparison with fluconazole (FLC) and itraconazole (ICZ),
are given.
5.1. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (3a)
The results of antifungal activities in vitro showed that
the title compounds were active against nearly all fungi tested
to some extent except against C. tropicalis. Among the
compounds tested, Compound 5b showed higher activity
against C. albicans, C. parapsilosis and C. krusei than flucona-
zole, and its MIC values were determined to be 0.5 mg/mL,
To a stirred mixture of 1-[2-(2,4-difluorophenyl)-2,3-epox-
ypropyl]-1H-1,2,4-triazole methanesulfonate
0.005 mol), CH CH OH (30 mL) and N(C H ) (3 mL), 1-
1
(1.65 g,
3
2
2 5 3
(4-nitro-phenyl)-piperazine (2a, 1.3 g, 0.006 mol) was added
ꢀ
and was heated at 70e80 C for 5 h. The reaction was moni-
1
5
mg/mL and 4 mg/mL, respectively. Compounds 5a, 5c, 5f,
g, 5i exhibited higher activities against C. parapsilosis than
tored by TLC. After filtration, the filtrate was evaporated
under reduced pressure. Water (30 mL) was added to the res-
idue, which was then extracted with ethyl acetate (80 mL ꢁ 3).
The extract was washed with saturated NaCl solution
(20 mL ꢁ 3), dried over anhydrous Na SO and evaporated.
fluconazole (with the MIC values of 2 mg/mL, 2 mg/mL,
mg/mL, 1 mg/mL and 2 mg/mL, respectively). Especially,
2
the MIC value of compound 5b is 4 times lower than that of
fluconazole against C. parapsilosis in vitro. Compounds 5f,
5
2
4
The residue was crystallized from DMF/H O to afford 3a
2
ꢀ ꢀ
g, 5i, 5l showed higher activities against inherently
(1.78 g, 80.3%). Mp 186e187 C [lit. [12] 186e187 C].
Table 2
Antifungal activities of the title compounds in vitro (MIC80, mg/mL)
Compound
C. albicans
C. parapsilosis ATCC22019
Cr. neoformans
C. tropicalis
C. krusei ATCC6258
T. glabrata
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
64
0.5
64
2
1
4
32
32
64
>64
>64
4
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
16
4
>64
>64
>64
8
2
8
>64
1
8
8
8
16
4
>64
16
8
1
32
2
g
h
i
1
4
>64
16
4
64
32
16
64
>64
16
8
16
4
16
16
32
2
2
j
64
>64
16
4
8
k
l
>64
>64
64
32
4
8
m
n
o
p
q
4
8
4
4
16
32
16
8
8
8
32
32
8
16
8
32
16
16
8
32
16
32
4
16
8
FLC
ICZ
1
0.25
32
2
0.25
32
2
1

1154
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
5
.2. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-
The title compounds were characterized as follows.
(
2-fluoro-4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (3b)
5.5.1. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
The reaction was run similarly to that used to synthesize 3a.
A white solid was obtained, and it was crystallized from DMF/
(4-{4-[(4-fluoro-benzylidene)-amino]-phenyl}-piperazin-1-
yl)-propan-2-ol (5a)
ꢀ
1
H O to afford 3b in 78% yield, mp 166e167 C. H NMR
1
H NMR (DMSO-d ): d 8.42 (1H, s, N]CH), 6.78e7.87
2
6
(
DMSO-d ): 6.80e7.96 (6H, m, Ar-H), 7.81, 8.13 (2H, ss,
(11H, m, Ar-H), 7.79, 8.12 (2H, ss, triazole-H), 4.50e4.59
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.49e3.10 (8H, m, piper-
6
triazole-H), 4.52e4.61 (2H, dd, J ¼ 18 Hz, triazole-CH -),
2
2
2
.50e3.18 (8H, m, piperazine-H), 2.73e3.17 (2H, dd,
azine-H), 2.73e3.14 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
2
1
3
J ¼ 17 Hz, CH -piperazine-). IR (KBr): 3200, 2940, 2893,
C NMR (DMSO-d ): d 165.5, 163.9, 163.8, 163.5, 161.9,
6
2
ꢂ1
1
(
605, 1514, 1338, 1257, 1136, 918 cm . EIMS, m/z: 463
161.8, 160.0, 158.1, 158.0, 156.1, 151.2, 149.6, 144.7,
143.8, 133.0, 130.5, 130.4, 129.4, 126.2, 126.1, 122.0,
M þ 1).
116.5, 116.0, 115.8, 111.7, 111.6, 104.6, 104.4, 104.1, 77.3,
77.1, 76.8, 72.4, 62.4, 56.3, 54.3, 51.0, 49.3, 48.3. IR (KBr):
5
[
.3. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
4-(4-amino-phenyl)-piperazin-1-yl]-propan-2-ol (4a)
ꢂ1
3130, 2943, 2878, 2829, 1619, 1508, 1233 cm . EIMS, m/z:
5
21 (M þ 1). Anal. calcd for C H F N O: C, 64.60; H,
2
8 27 3 6
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-di-
5.23; N, 16.14. Found: C, 64.30; H, 5.15; N, 15.72.
fluorophenyl)-3-[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-2-
ol (2.22 g, 0.005 mol), CH CH OH (20 mL) and 85% hydra-
zine hydrate (8 mL), freshly prepared Raney Ni (0.5 g) was
5.5.2. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-
{4-[(4-chloro-benzylidene)-amino]-phenyl}-piperazin-1-yl)-
propan-2-ol (5b)
3
2
ꢀ
added and heated at 70e80 C for 3 h. The reaction was mon-
1
itored by TLC. After filtration, the filtrate was evaporated
under reduced pressure. Water (20 mL) was added to the res-
idue, which was then extracted with ethyl acetate (60 mL ꢁ 3).
The extract was washed with saturated NaCl solution
H NMR (DMSO-d ): d 8.42 (1H, s, N]CH), 6.78e7.83
6
(11H, m, Ar-H), 7.78, 8.12 (2H, ss, triazole-H), 4.50e4.59
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.48e3.10 (8H, m, piper-
2
azine-H), 2.73e3.14 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
2
1
3
(
The residue was crystallized from ethyl acetate to afford 4a
20 mL ꢁ 3), dried over anhydrous Na SO and evaporated.
C NMR (DMSO-d ): d 163.8, 161.9, 159.9, 158.1, 158.0,
6
2
4
156.0, 151.2, 149.8, 144.7, 143.6, 136.8, 135.1, 129.6,
129.5, 129.4, 129.0, 126.1, 122.1, 116.5, 111.8, 111.6,
ꢀ ꢀ
1.45 g, 70.1%). Mp 129e130 C [lit. [12] 129e130 C].
(
104.6, 104.4, 104.2, 77.3, 77.0, 76.8, 72.3, 62.4, 56.3, 54.3,
49.3. IR (KBr): 3128, 2955, 2877, 2830, 1619, 1506, 1233,
5
.4. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-
ꢂ1
(2-fluoro-4-amino-phenyl)-piperazin-1-yl]-propan-2-ol (4b)
1141, 829 cm . EIMS, m/z: 537 (M þ 1). Anal. calcd for
C H ClF N O: C, 62.63; H, 5.07; N, 15.65. Found: C,
2
8
27
2 6
The reaction was run similarly to that used to synthesize 4a.
A white solid was obtained, and it was recrystallized from
62.76; H, 5.05; N, 15.52.
ꢀ
1
ethyl acetate to afford 4b in 75% yield, mp 134e135 C. H
5.5.3. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-
{4-[(4-bromo-benzylidene)-amino]-phenyl}-piperazin-1-yl)-
NMR (DMSO-d ): 6.35e7.56 (6H, m, Ar-H), 7.79, 8.15
6
(
2H, ss, triazole-H), 4.52e4.54 (2H, dd, J ¼ 18 Hz, triazole-
propan-2-ol (5c)
1
CH -), 2.49e2.84 (8H, m, piperazine-H), 2.69e3.14 (2H,
H NMR (DMSO-d ): d 8.41 (1H, s, N]CH), 6.78e7.73
6
2
dd, J ¼ 17 Hz, CH -piperazines-), 5.28 (1H, s, OH). IR
(11H, m, Ar-H), 7.79, 8.12 (2H, ss, triazole-H), 4.50e4.59
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.49e3.10 (8H, m, piper-
2
(
KBr): 3404, 3212, 3117, 3053, 2950, 2835, 1616, 1514,
274, 1139, 965 cm . EIMS, m/z: 433 (M þ 1).
2
ꢂ1
1
azine-H), 2.73e3.14 (2H, dd, J ¼ 17 Hz, CH -piperazine-),
2
1
3
5
.13 (1H, s, OH). C NMR (DMSO-d ): d 163.8, 161.8,
6
5
1
.5. General procedure for the preparation of 1-(1H-
,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-{4-
160.0, 158.1, 156.0, 151.2, 149.8, 144.7, 143.5, 135.5,
132.0, 129.8, 129.4, 126.2, 126.1, 125.3, 122.1, 116.4,
111.8, 111.6, 104.6, 104.4, 104.2, 77.3, 77.0, 76.8, 72.3,
[(substitutedbenzylidene)-amino]-phenyl}-piperazin-1-yl)-
propan-2-ol (5ae5q)
62.4, 56.2, 54.3, 49.3. IR (KBr): 3320, 3128, 3049, 2948,
ꢂ1
2877, 2828, 1618, 1506, 1233, 1140, 1010, 825 cm
.
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-
difluorophenyl)-3-[4-(4-amino-phenyl)-piperazin-1-yl]-propan-2-
ol (4a, 0.001 mol) or 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluor-
ophenyl)-3-[4-(2-fluoro-4-amino-phenyl)-piperazin-1-yl]-propan-
EIMS, m/z: 583 (M þ 1). Anal. calcd for C H BrF N O:
2
8
27
2 6
C, 57.84; H, 4.68; N, 14.45. Found: C, 57.81; H, 4.66; N,
14.29.
2
-ol (4b, 0.001 mol) and CH COOH (10 mL) substituted benz-
3
5.5.4. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
(4-{4-[(2,4-dichloro-benzylidene)-amino]-phenyl}-
aldehyde (0.001 mol) was dropwise added and refluxed for
.5e4 h. The reaction was monitored by TLC. After filtration,
0
piperazin-1-yl)-propan-2-ol (5d)
1
the filtrate was evaporated under reduced pressure. The residue
was recrystallized from ethanol to afford the title compounds
H NMR (DMSO-d ): d 8.82 (1H, s, N]CH), 6.90e8.12
6
(10H, m, Ar-H), 7.74, 8.28 (2H, ss, triazole-H), 5.64 (1H, s,
OH), 4.60 (2H, s, triazole-CH -), 2.48e3.06 (8H, m,
5
ae5q.
2

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
1155
piperazine-H), 2.73e2.95 (2H, dd, J ¼ 17 Hz, CH -pipera-
C H F N O : C, 64.85; H, 5.44; N, 16.21. Found: C,
28 28 2 6 2
64.83; H, 5.48; N, 16.04.
2
1
3
zine-). C NMR (DMSO-d ): d 163.9, 161.8, 160.0, 158.1,
6
1
1
1
6
2
58.0, 152.5, 151.2, 150.1, 144.7, 143.3, 137.0, 136.1,
32.3, 129.6, 129.4, 129.2, 127.6, 126.1, 122.4, 116.3,
11.8, 111.6, 104.6, 104.4, 104.2, 77.3, 77.3, 76.8, 72.3,
5.5.8. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
(4-{4-[(2-hydroxy-3-methoxy-benzylidene)-amino]-phenyl}-
2.4, 56.3, 54.3, 49.1. IR (KBr): 3070, 3051, 2944, 2881,
ꢂ1
836, 1614, 1587, 1511, 1384, 1269, 1141, 831 cm
.
piperazin-1-yl)-propan-2-ol (5h)
1
EIMS, m/z: 572 (M þ 1). Anal. calcd for C H Cl F N O:
H NMR (DMSO-d ): d 13.85 (1H, s, OH), 8.58 (1H, s,
2
8
26
2
2
6
6
C, 58.85; H, 4.59; N, 14.71. Found: C, 58.84; H, 4.62; N,
1
N]CH), 6.78e7.61 (10H, m, Ar-H), 7.79, 8.12 (2H, ss, tria-
zole-H), 4.51e4.60 (2H, dd, J ¼ 18 Hz, triazole-CH -), 2.48e
4.83.
2
3
.09 (8H, m, piperazine-H), 2.73e3.10 (2H, dd, J ¼ 17 Hz,
1
3
CH -piperazine-), 3.92 (3H, s, eOCH ). C NMR (DMSO-
2
3
5
.5.5. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
d6): d 163.8, 161.8, 159.9, 159.5, 157.9, 151.4, 151.2, 150.1,
48.5, 144.7, 140.0, 129.4, 129.3, 126.0, 123.5, 122.1,
119.4, 118.4, 116.4, 114.4, 111.8, 111.6, 104.6, 104.4,
04.2, 77.3, 77.0, 76.8, 72.4, 62.4, 56.2, 54.3, 49.1. IR
(
4-{4-[(3,4-dichloro-benzylidene)-amino]-phenyl}-
1
piperazin-1-yl)-propan-2-ol (5e)
1
H NMR (DMSO-d ): d 8.42 (1H, s, N]CH), 6.82e8.02
6
1
(
(
10H, m, Ar-H), 7.83, 8.17 (2H, ss, triazole-H), 4.55e4.64
2H, dd, J ¼ 18 Hz, triazole-CH -), 2.53e3.15 (8H, m, piper-
(
1
KBr): 3383, 3120, 3058, 2934, 2884, 2821, 1615, 1509,
ꢂ1
2
466, 1242, 1139, 966, 828, 735 cm . EIMS, m/z: 549
azine-H), 2.62e3.18 (2H, dd, J ¼ 16.5 Hz, CH -piperazine-).
2
1
3
(M þ 1). Anal. calcd for C H F N O : C, 63.49; H, 5.51;
2
9 30 2 6 3
C NMR (DMSO-d ): d 163.8, 161.9, 161.8, 158.1, 158.0,
6
N, 15.32. Found: C, 63.37; H, 5.45; N, 15.28.
1
1
1
6
2
54.3, 151.2, 150.0, 144.7, 143.0, 136.7, 134.7, 133.2,
30.7, 129.9, 129.4, 127.5, 126.2, 122.2, 116.6, 116.4,
11.8, 111.6, 104.6, 104.4, 104.2, 77.3, 77.0, 76.8, 72.4,
5.5.9. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
2.4, 56.2, 54.3, 49.1. IR (KBr): 3361, 3131, 2953, 2881,
ꢂ1
(4-{4-[(benzo[1,3]dioxol-5-yl-methylene)-amino]-phenyl}-
828, 1618, 1507, 1243, 1168, 967, 821, 698, 579 cm
þ
.
piperazin-1-yl)-propan-2-ol (5i)
EIMS, m/z: 571 (M ). Anal. calcd for C H Cl F N O: C,
2
5
8
26
2 2 6
1
H NMR (DMSO-d ): d 8.33 (1H, s, N]CH), 6.78e7.60
6
8.85; H, 4.59; N, 14.71. Found: C, 58.89; H, 4.58; N, 14.58.
(
(
10H, m, Ar-H), 7.78, 8.12 (2H, ss, triazole-H), 4.50e4.59
2H, dd, J ¼ 18 Hz, triazole-CH -), 2.48e3.10 (8H, m, piper-
2
5
{
.5.6. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-(4-
4-[(4-methyl-benzylidene)-amino]-phenyl}-piperazin-1-yl)-
azine-H), 2.72e3.13 (2H, dd, J ¼ 17.5 Hz, CH -piperazine-),
2
13
6
.00e6.01 (2H, d, OeCH eO). C NMR (DMSO-d ):
2
6
propan-2-ol (5f)
1
d 163.9, 161.8, 158.1, 158.0, 156.9, 151.2, 150.2, 149.3,
H NMR (DMSO-d ): d 8.42 (1H, s, N]CH), 6.78e7.76
6
1
1
1
5
2
6
48.4, 144.7, 144.2, 131.6, 129.4, 129.3, 126.2, 126.1,
25.2, 121.9, 116.6, 111.7, 111.6, 108.2, 106.8, 104.6,
04.3, 104.1, 101.5, 77.3, 77.0, 76.8, 72.3, 72.2, 62.4, 56.3,
6.2, 54.4, 49.4. IR (KBr): 3418, 3118, 2938, 2888, 2826,
777, 1620, 1507, 1446, 1242, 1140, 1036, 928, 830, 675,
(
(
11H, m, Ar-H), 7.79, 8.12 (2H, ss, triazole-H), 4.50e4.59
2H, dd, J ¼ 18 Hz, triazole-CH -), 2.49e3.10 (8H, m, piper-
2
azine-H), 2.72e3.13 (2H, dd, J ¼ 17 Hz, CH -piperazine-),
2
1
3
2
1
1
1
5
2
5
5
.39 (3H, s, eCH ). C NMR (DMSO-d ): d 163.9, 163.8,
3 6
58.1, 157.9, 151.2, 149.4, 144.7, 144.4, 141.3, 134.1,
29.5, 128.5, 126.2, 126.1, 122.0, 116.8, 116.6, 111.7,
11.6, 104.6, 104.4, 104.1, 77.3, 77.0, 76.8, 72.3, 62.4, 56.3,
4.4, 51.1, 49.4, 21.6. IR (KBr): 3407, 3138, 2939, 2881,
ꢂ1
13 cm . EIMS, m/z: 547 (M þ 1). Anal. calcd for
C H F N O : C, 63.73; H, 5.16; N, 15.38. Found: C,
2
9 28 2 6 3
63.87; H, 5.19; N, 15.48.
ꢂ1
823, 1619, 1498, 1233, 1141, 967, 824 cm . EIMS, m/z:
17 (M þ 1). Anal. calcd for C H F N O: C, 67.43; H,
2
9 30 2 6
5.5.10. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
.85; N, 16.27. Found: C, 67.51; H, 5.87; N, 16.04.
(4-{4-[(4-benzyloxy-benzylidene)-amino]-phenyl}-
piperazin-1-yl)-propan-2-ol (5j)
1
5
.5.7. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
H NMR (DMSO-d ): d 8.39 (1H, s, N]CH), 6.79e7.80
6
(
1
4-{4-[(4-hydroxy-benzylidene)-amino]-phenyl}-piperazin-
(16H, m, Ar-H), 7.75, 8.15 (2H, ss, triazole-H), 4.57 (2H, s,
triazole-CH -), 2.54e3.07 (8H, m, piperazine-H), 2.75e3.11
-yl)-propan-2-ol (5g)
1
2
H NMR (DMSO-d ): d 9.30 (1H, s, OH), 8.35 (1H, s,
6
(2H, dd, J ¼ 17 Hz, CH -piperazine-), 5.12 (2H, s, OeCH e
2
2
1
3
N]CH), 6.79e7.71 (11H, m, Ar-H), 7.74, 8.16 (2H, ss, tria-
zole-H), 4.58 (2H, s, triazole-CH -), 2.55e3.07 (8H, m, piper-
), 5.20 (1H, s, OH). C NMR (DMSO-d ): d 163.8, 161.8,
6
161.1, 158.0, 157.9, 157.2, 151.2, 149.3, 144.7, 144.5,
136.6, 130.2, 128.6, 128.1, 127.5, 126.1, 121.9, 116.6,
116.4, 115.1, 111.7, 111.6, 104.6, 104.3, 104.1, 78.4, 77.3,
77.0, 76.8, 72.3, 72.2, 70.1, 62.4, 56.3, 54.4, 49.5. IR (KBr):
3318, 3128, 3033, 2826, 1604, 1510, 1236, 1012, 834,
2
azine-H), 2.75e3.11 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
2
1
3
C NMR (DMSO-d ): d 160.7, 160.6, 160.0, 159.9, 156.5,
6
1
1
1
2
6
50.4, 149.1, 144.8, 142.9, 130.0, 129.8, 129.7, 127.9,
26.2, 121.6, 115.6, 115.5, 110.7, 110.6, 103.9, 103.6,
03.4, 74.5, 74.4, 63.4, 55.6, 54.0, 48.3. IR (KBr): 3122,
950, 2877, 2821, 1607, 1514, 1233, 1136, 966, 827,
ꢂ1
733 cm . EIMS, m/z: 609 (M þ 1). Anal. calcd for
C H F N O : C, 69.06; H, 5.63; N, 13.81. Found: C,
3
5 34 2 6 2
ꢂ1
78 cm . EIMS, m/z: 519 (M þ 1). Anal. calcd for
69.26; H, 5.61; N, 13.61.

1156
Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
1
3
5
.5.11. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
C NMR (DMSO-d ): d 165.3, 163.3, 158.6, 156.4, 154.4,
6
[
4-(4-{[4-(3-chloro-benzyloxy)-benzylidene]-amino}-
150.9, 145.7, 145.6, 145.3, 138.6, 138.5, 133.2, 131.2,
131.1, 130.2, 119.6, 118.6, 116.3, 116.2, 111.2, 109.2,
109.0, 104.1, 103.9, 75.1, 75.0, 64.0, 56.1, 54.6, 50.6. IR
(KBr): 3396, 3134, 2830, 1615, 1510, 1249, 1139, 966, 834,
phenyl)-piperazin-1-yl]-propan-2-ol (5k)
1
H NMR (DMSO-d ): d 8.38 (1H, s, N]CH), 6.78e7.86
6
(
(
15H, m, Ar-H), 7.81, 8.13 (2H, ss, triazole-H), 4.50e4.59
2H, dd, J ¼ 18 Hz, triazole-CH -), 2.48e3.07 (8H, m, piper-
ꢂ1
680 cm . EIMS, m/z: 539 (M þ 1). Anal. calcd for
2
azine-H), 2.72e3.13 (2H, dd, J ¼ 17 Hz, CH -piperazine-),
C H F N O: C, 62.45; H, 4.87; N, 15.61. Found: C, 62.35;
28 26 4 6
2
1
3
5
d 163.9, 161.0, 160.7, 158.7, 158.1, 157.1, 151.2, 150.0,
.07e5.10 (2H, d, OeCH e).
C NMR (DMSO-d ):
H, 4.87; N, 15.39.
2
6
1
1
1
6
1
49.3, 144.7, 144.4, 142.5, 138.7, 134.6, 130.2, 129.9,
28.2, 127.4, 125.3, 121.9, 121.8, 116.6, 115.0, 111.7,
11.6, 104.6, 104.3, 104.1, 78.3, 77.3, 77.0, 76.8, 72.3, 69.2,
2.4, 56.3, 54.4, 49.5. IR (KBr): 3129, 3040, 2914, 2823,
5.5.15. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
(4-{2-fluoro-4-[(4-chloro-benzylidene)-amino]-phenyl}-
piperazin-1-yl)-propan-2-ol (5o)
ꢂ1
1
604, 1510, 1238, 1012, 832 cm . EIMS, m/z: 643 (M þ 1).
H NMR (DMSO-d ): d 8.39 (1H, s, N]CH), 6.82e7.80
6
Anal. calcd for C H ClF N O : C, 65.36; H, 5.17; N,
3
(10H, m, Ar-H), 7.81, 8.16 (2H, ss, triazole-H), 4.51e4.59
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.52e2.99 (8H, m, piper-
5
33
2 6 2
1
3.07. Found: C, 65.18; H, 5.00; N, 12.51.
2
azine-H), 2.73e3.17 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
2
1
3
5
.5.12. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
C NMR (DMSO-d ): d 167.7, 160.5, 157.9, 155.7, 153.8,
6
(
propan-2-ol (5l)
4-{4-[(4-nitro-benzylidene)-amino]-phenyl}-piperazin-1-yl)-
150.2, 144.8, 144.6, 138.1, 135.6, 134.8, 129.8, 129.6,
128.6, 119.0, 118.0, 110.5, 110.4, 108.6, 108.4, 103.4, 74.4,
63.3, 55.8, 55.6, 53.9, 50.2, 50.0. IR (KBr): 3394, 3135,
1
H NMR (DMSO-d ): d 8.55 (1H, s, N]CH), 6.79e8.29
6
ꢂ1
(
(
11H, m, Ar-H), 7.79, 8.12 (2H, ss, triazole-H), 4.51e4.60
2H, dd, J ¼ 17.5 Hz, triazole-CH -), 2.49e3.11 (8H, m, pi-
2828, 1615, 1508, 1249, 1139, 966, 825, 679 cm . EIMS,
m/z: 555 (M þ 1). Anal. calcd for C H ClF N O: C, 60.60;
2
28 26
3 6
perazine-H), 2.73e3.14 (2H, dd, J ¼ 17 Hz, CH -piperazine-
H, 4.72; N, 15.14. Found: C, 60.33; H, 4.90; N, 14.96.
2
1
3
)
.
C NMR (DMSO-d ): d 163.9, 163.8, 161.8, 160.0,
6
1
1
1
5
1
58.1, 153.8, 151.2, 150.5, 148.9, 144.7, 142.4, 142.2,
29.4, 129.0, 126.1, 126.0, 124.0, 122.5, 116.2, 111.8,
11.6, 104.6, 104.4, 104.2, 77.3, 77.0, 76.8, 72.4, 62.4, 56.2,
4.3, 48.9. IR (KBr): 3130, 3075, 2951, 2881, 2830, 1619,
5.5.16. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
(4-{2-fluoro-4-[(4-bromo-benzylidene)-amino]-phenyl}-
piperazin-1-yl)-propan-2-ol (5p)
ꢂ1
1
509, 1341, 1234, 1139, 854 cm . EIMS, m/z: 548 (M þ 1).
H NMR (DMSO-d ): d 8.37 (1H, s, N]CH), 6.82e7.80
6
Anal. calcd for C H F N O : C, 61.42; H, 4.97; N, 17.91.
2
Found: C, 61.50; H, 4.95; N, 17.76.
(10H, m, Ar-H), 7.80, 8.15 (2H, ss, triazole-H), 4.51e4.59
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.51e2.99 (8H, m, piper-
8 27 2 7 3
2
azine-H), 2.72e3.16 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
2
1
3
5
.5.13. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
C NMR (DMSO-d ): d 168.0, 162.6, 158.3, 155.8, 153.9,
6
(
propan-2-ol (5m)
4-{4-[(3-nitro-benzylidene)-amino]-phenyl}-piperazin-1-yl)-
150.4, 144.9, 144.8, 135.1, 131.8, 130.2, 129.7, 124.7,
119.1, 118.4, 110.7, 110.5, 108.7, 103.9, 103.7, 74.5, 63.4,
55.6, 54.1, 54.0, 50.3, 50.0. IR (KBr): 3395, 3135, 2946,
1
H NMR (DMSO-d ): d 8.69 (1H, s, N]CH), 6.79e8.27
6
ꢂ1
(
(
11H, m, Ar-H), 8.13, 8.55 (2H, ss, triazole-H), 4.51e4.60
2H, dd, J ¼ 17.5 Hz, triazole-CH -), 2.50e3.11 (8H, m, pi-
2826, 1615, 1507, 1248, 1139, 966, 822 cm . EIMS, m/z:
599 (M þ 1). Anal. calcd for C H BrF N O: C, 56.10; H,
2
28 26
3 6
perazine-H), 2.74e3.14 (2H, dd, J ¼ 16.5 Hz, CH -pipera-
4.37; N, 14.02. Found: C, 55.81; H, 4.45; N, 13.95.
2
13
zine-). C NMR (DMSO-d ): d 163.9, 163.8, 161.9, 161.8,
6
1
1
1
7
3
6
60.0, 158.1, 153.9, 151.2, 150.3, 148.8, 144.7, 142.5,
38.4, 133.7, 129.7, 129.4, 126.0, 125.0, 123.2, 122.4,
16.5, 116.3, 111.8, 111.6, 104.6, 104.4, 104.2, 77.3, 77.0,
6.8, 72.4, 62.4, 56.2, 54.3, 49.0. IR (KBr): 3181, 3117,
069, 2975, 2877, 2830, 1613, 1529, 1349, 1235, 964, 819,
5.5.17. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
(4-{2-fluoro-4-[(4-methyl-benzylidene)-amino]-phenyl}-
piperazin-1-yl)-propan-2-ol (5q)
1
H NMR (DMSO-d ): d 8.38 (1H, s, N]CH), 6.81e7.76
6
ꢂ1
74 cm . EIMS, m/z: 548 (M þ 1). Anal. calcd for
(10H, m, Ar-H), 7.80, 8.16 (2H, ss, triazole-H), 4.51e4.58
(2H, dd, J ¼ 18 Hz, triazole-CH -), 2.41e2.98 (8H, m, piper-
C H F N O : C, 61.42; H, 4.97; N, 17.91. Found: C,
3
6
2
8
27
2
7
2
1.22; H, 4.96; N, 17.89.
azine-H), 2.73e3.17 (2H, dd, J ¼ 17 Hz, CH -piperazine-),
2
1
3
2
.41 (3H, s, eCH ). C NMR (DMSO-d ): d 163.0, 161.0,
3 6
5
.5.14. 1-(1H-1,2,4-Triazol-1-yl)-2-(2,4-difluorophenyl)-3-
159.8, 156.4, 154.4, 150.9, 146.1, 145.3, 141.7, 138.4,
138.3, 133.9, 130.2, 129.8, 129.0, 119.6, 118.4, 111.2,
111.0, 109.1, 109.0, 104.3, 104.1, 75.1, 75.0, 64.0, 56.4,
(
4-{2-fluoro-4-[(4-fluoro-benzylidene)-amino]-phenyl}-
piperazin-1-yl)-propan-2-ol (5n)
1
H NMR (DMSO-d ): d 8.39 (1H, s, N]CH), 6.83e7.87
6
56.1, 54.6, 50.8, 50.6, 24.2. IR (KBr): 3387, 3136, 2946,
ꢂ1
(
(
10H, m, Ar-H), 7.81, 8.16 (2H, ss, triazole-H), 4.54e4.60
2H, dd, J ¼ 18 Hz, triazole-CH -), 2.53e3.00 (8H, m, piper-
2885, 2821, 1614, 1497, 1249, 1139, 966, 819, 679 cm
.
EIMS, m/z: 535 (M þ 1). Anal. calcd for C H F N O: C,
29 29 3 6
2
azine-H), 2.71e3.14 (2H, dd, J ¼ 17 Hz, CH -piperazine-).
65.16; H, 5.47; N, 15.72. Found: C, 65.04; H, 5.60; N, 15.09.
2

Q.-Y. Sun et al. / European Journal of Medicinal Chemistry 42 (2007) 1151e1157
1157
Acknowledgement
[5] A. Chen, J.D. Sobel, Expert Opin. Emerg. Drugs 10 (2005) 21e33.
[
[
6] S. Sundriyal, R.K. Sharma, R. Jain, Curr. Med. Chem. 13 (2006) 1321e1335.
7] H. Ji, W. Zhang, Y. Zhou, M. Zhang, J. Zhu, Y. Song, J. Lu, J. Med.
Chem. 43 (2000) 2493e2505.
We wish to express our thanks to the National Natural Sci-
ence Foundation of China (Grant No. 30300437) for financial
support.
[
8] K. Richardson, US Patent 4,404,216, 1983.
[9] J. Yang, L. Liu, X. Wang, J. Lu, C. Sun, H. Zhang, Y. Zhou, Z. Zhang,
Yiyao Gongye 5 (1984) 1e4.
[
[
10] D.K. Hutchinson, M.R. Barbachyn, S.J. Brickner, R.B. Gammill, M.V.
Patel, US Patent 8,804,32, 1996.
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