Design, synthesis and antifungal activities of novel 1,2,4-triazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.02.042

A series of novel 1,2,4-triazole derivatives with a 4-(4-substitutedphenyl) piperazine side chain were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). Their antifungal activities against eight human pathogenic fungi

Full text of DOI:10.1016/j.ejmech.2011.02.042

European Journal of Medicinal Chemistry 46 (2011) 3142e3148
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Design, synthesis and antifungal activities of novel 1,2,4-triazole derivatives
,
Jianming Xu a, Yongbing Cao b 1, Jun Zhang c, Shichong Yu a, Yan Zou a, Xiaoyun Chai a,
,
a
b
a,
**
Qiuye Wu a , Dazhi Zhang , Yuanying Jiang , Qingyan Sun
*
a Department of Organic Chemistry, Second Military Medical University, Guohe Road 325, Shanghai 200433, People’s Republic of China
b Department of Pharmacology, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People’s Republic of China
c Overseas Education Faculty of the Second Military Medical University, Xiangyin Road 800, Shanghai 200433, People’s Republic of 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 novel 1,2,4-triazole derivatives with a 4-(4-substitutedphenyl) piperazine side chain were
designed and synthesized based on the structure of lanosterol 14a-demethylase (CYP51). Their antifungal
activities against eight human pathogenic fungi were evaluated in vitro by measuring the minimal
inhibitory concentrations. Nearly all tested compounds were found to be more potent against Candida
albicans than control drug fluconazole. Noticeably, the MIC80 value of compounds 6,7,9,14 and 29 is 16
times lower than that of voriconazole against C. albicans. The activities of compounds 7 and 21 against
Received 15 September 2009
Received in revised form
27 January 2011
Accepted 16 February 2011
Available online 24 February 2011
Cryptococcus neoformans in vitro are comparable to that of voriconazole with a MIC80 value of 0.0156 mg/
mL. Moreover, the molecular model for the binding between compound 7 and the active site of CACYP51
was provided based on the computational docking results.
Keywords:
Synthesis
Antifungal activity
1,2,4-Triazole
Piperazine
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
oxidative removal of the lanosterol 14a -
-methyl group to give D14,15
desaturated intermediates in fungal ergosterol biosynthesis. Recent
studies showed that typical azole inhibitors were able to fit the
putative active site of CYP51 bya combination of heme coordination,
During the past two decades, the growing population of
immuno-compromised patients due to organ transplantation,
tuberculosis, AIDS and cancer chemotherapy has resulted in an
increase in severe fungal infections. In many cases, it is not the AIDS
or cancer itself but the mycoses that are lethal to these patients
[1,2]. Azole compounds (e.g. fluconazole, voriconazole and itraco-
hydrogen bonding,
pep stacking and hydrophobic interactions
[7e9]. Ji’s study [9]indicated thatin the activesiteofCYP51the 1,2,4-
triazole ring in the scaffold of 1,2,4-triazole antifungal agent was
positioned perpendicularly to the porphyrin plane with a ring
nitrogen atom (N-4 of 1,2,4-triazole) coordinated tothe heme iron of
CYP51 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 target 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. Based on these properties of the active site
of CYP51, it provides us an attempt to design newtriazole derivatives
to find potent systemic antifungal agents that have a broad anti-
fungal spectrum but with less potential to develop drug resistance.
In our previous research [10e12], we designed and synthesized
a series of novel 1-(1H-1,2,4- triazole-1-yl)-2-(2,4-difluorophenyl)-3-
substituted-2-propanols containing a 1,2,4-triazole ring, a difluor-
ogenatedphenyl group, a hydroxyl group and a long side chain
connected by a 4-(4-substitutedphenyl) piperazine linker. Their
minimal inhibitory concentration (MIC) value indicates that it is very
helpful to introduce 4-(4-substitutedphenyl) piperazine as a side
chain linker to adjust the physicochemical properties of the whole
target molecule to avoid the dissatisfying side effects and/or improve
nazole) which act by competitive inhibition of the lanosterol 14a-
demethylase (CYP51) are an important class of antifungal agents as
they have fungistatic, orally effective and broad-spectrum activities
against most yeasts and filamentous fungi, which now become the
most rapidly expanding group of antifungal compounds. However,
their clinical application value has been limited by their relatively
high risk of toxicity, the emergence of drug resistance, pharmaco-
kinetic deficiencies and/or insufficiencies in their antifungal activ-
ities. Despite recent developments [3e6], there is still an urgent
need for authentically genuinely broad-spectrum and low-toxicity
antifungal agents.
CYP51 is a member of the cytochrome P450 super family and
a key enzyme in the biosynthesis of ergosterol, which catalyzes the
* Corresponding author. Tel./fax: þ86 21 81871225.
** Corresponding author. Tel./fax: þ86 21 81871228/81871225.
E-mail addresses: wuqy6439@sohu.com (Q. Wu), sqy_2000@163.com (Q. Sun).
1
Author contributed equally to this work.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.042

J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
3143
the pharmacokinetic and pharmacodynamic behavior. Hereby in our
present work, we designed, synthesized some analogous amides of
alkyl carboxylic acids and evaluated their antifungal activities against
eight human pathogenic fungi in vitro. The structures of this series of
compounds are shown in Scheme 1 and all compounds are
racemates.
Committee for Clinical Laboratory Standards [14]. Fungi strains for
testing: Candida albicans, Candida parapsilosis, Candida tropicalis,
Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton
rubrum, Fonsecaea compacta, Microsporum gypseum were provided
by Shanghai Changhai Hospital. C. albicans, C. neoformans and
C. parapsilosis are ATCC standard strains, others are clinic
isolates. C. albicans (ATCCY0109), C. neoformans (ATCCBLS108) and
C. parapsilosis (ATCC0306392) were quality controlled strains, and
tested in each assay. Fluconazole (FCZ), itraconazole (ICZ), ketoco-
nazole (KCZ), voriconazole (VCZ) and amphotericin B (AMB)
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 dissolved
in dimethyl sulfoxide (DMSO), serially diluted in growth medium,
inoculated and incubated at 35 ꢀC. Growth MIC was determined at
24 h for Candida albicans, 72 h for Cryptococcus neoformans and at 7
days for filamentous fungi. The results of antifungal assays are
summarized in Table 1. These data are the mean of three replicate
tests performed with each antifungal compound.
2. Chemistry
The general synthetic route of target compounds 1-(1H-1,2,4-tri-
azol-1-yl)-2-(2,4-difluoro -phenyl)-3-[(4-substitutedphenyl)-piper-
azin-1-yl]-2-propanols(5e31) is outlined in Scheme 1. The important
intermediate oxirane 1, compounds 2a and 2b were synthesized by
known procedures [10e13]. Compounds 3a and 3b were obtained as
racemates via ring-opening reactions of oxirane 1 with compounds
2a and 2b. Good yields were obtained when the nucleophilic reac-
tions were performed in a protic solvent ethanol in the presence of
triethylamine as a base at 80 ꢀC. The nitro group on the phenyl ring of
compounds3a and 3bwasreducedto anamino groupin thepresence
of Ranney Ni and 85% hydrazine hydrate. In the presence of 4-dime-
thylaminopyridine (DMAP) and 1-(3-dimethylamino-propyl)-3-eth-
ylcarbodiimide hydrochloride (EDCI) in dichloromethane, the
anilines 4a and 4b were converted to target compounds 5e31 by
reacting with various alkyl carboxylic acids at ambient temperature.
4. Results and discussion
The results of antifungal activities in vitro showed that all the title
compounds were active against all fungi tested to some extent.
Among the compounds tested, most of them showed higher activity
against C. albicans than fluconazole, itraconazole and amphotericin B
in vitro. Noticeably, the MIC80 value of compounds 6,7,9,14,29 is 16
times lower than that of voriconazole against C. albicans in vitro. The
activities of compounds 8, 11e13, 15, 16, 22, 24, 26, 27 and 31 are
3. Antifungal assay
The in vitro minimal inhibitory concentrations (MICs) of the
target compounds were determined by the micro-broth dilution
method according to the methods defined by the National
R
O
N
OH
N
N
R
N
N
F
N
NO2
F
N
N
a
H N
N
NO2
CH3SO3H +
F
1
3a: R=H
3b: R=F
2a: R=H
2b: R=F
F
O
R
R
OH
R'
OH
N
N
N
N
F
N
NH
N
N
F
N
NH2
c
b
N
N
NH2NH2 H2O
HOOC
R'
4a: R=H
4b: R=F
F
5~31
F
Conditions: (a)CH3CH2OH,Et3N,80 ºC,5h; (b)Ranney Ni,NH2NH2 H2O,CH3CH2OH,80 ºC,3.5h; (c)DMAP,EDCI,CH2Cl2,8h.
Compd.
R
R’
Compd.
R
R’
Compd.
R
R’
5
6
H
H
H
H
H
H
H
H
H
CH2Cl
CF2Cl
CF3
14
15
16
17
18
19
20
21
22
H
H
H
H
H
F
CH2(CH2)4CH3
CH2(CH2)5CH3
CH2(CH2)7CH3
CH2(CH2)9CH3
CH2(CH2)13CH3
CH3
23
24
25
26
27
28
29
30
31
F
F
F
F
F
F
F
F
F
CH2CH3
CH2CH2CH3
CH(CH3)2
7
8
CH2CH3
CH2(CH2)2CH3
C(CH3)3
9
CH2CH2CH3
CH(CH3)2
10
11
12
13
CH2(CH2)3CH3
CH2(CH2)4CH3
CH2(CH2)5CH3
CH2Ph
CH2(CH2)2CH3
CH2(CH2)3CH3
C(CH3)3
F
CH2Cl
F
CF2Cl
F
CF3
Scheme 1. Synthetic route of the title compounds.

3144
J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
Table 1
Antifungal Activities of The Title Compounds in vitro (MIC80
m
g/mL).a
C. tro.
compd.
C. alb.
C. par.
C. neo.
A. fum.
T. rub.
F. com.
M. gyp.
5
6
7
8
0.0039
0.00097
0.00097
0.0156
0.00097
0.0039
0.0156
0.0156
0.0156
0.00097
0.0156
0.0156
0.0625
0.25
0.0156
0.0039
0.0039
0.0156
0.0156
0.0156
0.0625
0.25
0.0156
0.0156
0.0625
1
0.0156
0.0039
0.00097
0.0156
0.0625
0.0156
0.0625
0.25
0.0156
0.0156
0.0625
0.25
0.25
0.0625
0.0156
1
0.25
1
4
1
1
4
4
4
1
>64
16
>64
1
1
1
>64
4
1
1
1
4
1
>64
1
64
1
1
1
64
64
1
1
>64
4
0.0625
0.0156
0.0156
0.0625
0.0625
0.25
0.0625
0.0625
0.0039
0.0039
0.0625
0.0625
0.0625
0.25
0.0625
0.0625
0.0156
0.25
0.25
0.25
0.25
1
0.0625
0.0039
0.0039
0.25
0.0625
0.0625
0.25
0.0625
0.0156
0.0039
0.0156
0.0156
0.0156
0.25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
FCZ
ICZ
KCZ
VCZ
AMB
0.25
1
0.25
0.0625
0.0625
0.0625
0.0625
16
1
0.0625
1
1
0.25
4
0.25
0.0625
0.0156
0.25
1
0.25
1
1
0.0625
0.25
0.25
0.25
0.0625
16
0.25
0.0625
0.0156
16
0.25
1
1
1
0.0625
0.0039
64
0.0625
0.0156
0.0039
0.0039
0.0625
0.0156
0.25
0.25
0.0156
0.25
0.0625
0.0625
0.0625
1
0.25
0.0625
1
0.0625
0.0156
0.0039
0.0039
0.0625
0.0156
4
1
0.25
1
0.0625
0.0156
0.0625
1
0.25
16
0.0625
0.0039
0.0156
0.0625
0.0156
0.0625
0.25
0.0156
0.0156
0.0156
0.0039
0.0039
0.25
0.0156
0.0039
>64
0.0156
0.0625
0.0156
0.0625
0.0156
0.0156
0.0039
0.00097
0.0625
0.0156
4
0.25
0.0156
0.0625
0.25
0.0156
0.25
0.0625
0.0625
0.0156
0.25
0.0156
0.0039
0.0039
0.0039
0.25
1
0.0156
0.0625
0.0625
0.0625
0.0625
1
0.25
0.0625
0.25
0.25
0.0625
0.0625
0.25
1
1
1
1
0.0156
0.0625
0.0039
1
0.0625
0.0156
1
0.0625
0.0156
1
0.0156
0.0625
a
Abbreviations: C. alb., Candida albicans; C. par., Candida paropsilosis; C. tro., Candida tropicalis; C. neo., Cryptococcus neoformans; A. fum., Aspergillus fumigatus; T. rub.,
Trichophyton rubrum; F. com., Fonsecaea compacta; M. gyp., Microsporum gypseum; FCZ, fluconazole; ICZ, itraconazole; KCZ, ketoconazole; VCZ, voriconazole; AMB, ampho-
tericin B.
comparable tothatofvoriconazole invitroagainst C. albicans with the
MIC80 value of 0.0156 g/ml. The MIC80 value of compound 7 is 64
times lower than that of amphotericin B against C. tropicalis in vitro.
Compounds 7, 21 exhibited the same activities against C. neoformans
improvement of the antifungal activity, suggesting that the
hydrophobic interactions of the aliphatic group with CYP51 were
important for its binding affinity.
m
Although Sheng’s study [15] indicated that the piperazinyl
group is not the best linker for the design of azole antifungal side
chain, according to our preliminary in vitro antifungal assay we still
think that the piperazinyl group is a good choice for the new
candidate design. Up to now, the crystal structure of CYP51 from
C. albicans is unclear, so we can just clarify our design by using
computational docking method based on the homonology
modeling structure of CYP51.
as voriconazole (with the MIC80 values of 0.0156 mg/mL).
Fluconazole is not effective against A. fumigatus, while our
compounds exhibit moderate activity. For example, compounds 5,
8e10, 19, 23 exhibited the same activities against A. fumigatus as
amphotericin B (with the MIC80 values of 4 mg/mL). Compounds 6, 7,
11, 15e17, 20e22, 24, 26, 28e30 exhibited the same activities
against A. fumigatus as itraconazole and ketoconazole (with the
MIC80 values of 1
been known that A. fumigatus possesses an intrinsic mechanism
resistant to triazole antifungal agents.
Moreover, our compounds also showed excellent activity
against dermatophytes (i.e. T. rubrum and M. gypseum). Compound
13,14,21,30,31 exhibited the same activities against T. rubrum as
voriconazole (with the MIC80 values of 0.0039 mg/mL). Compounds
6, 7, 14, 21 showed the same activity against M. gypseum as keto-
conazole, voriconazole and amphotericin B (with the MIC80 values
of 0.0039 mg/mL). Compound 7 showed the highest activity with
m
g/mL). The result is encouraging because it has
In previous research, the molecular docking results indicated
that the azole compound binds to the active site of CACYP51
through the formation of a coordination bond with iron of heme
group. The difluorophenyl group is located in the hydrophobic
binding cleft lined with Phe126, Ile304, Met306, Gly307 and
Gly308. The piperazinyl side chain is oriented into substrate access
channel 2 (FG loop) and forms hydrophobic and van der waals
interactions with surrounding hydrophobic residues such as Tyr64,
Gly65, Leu87, Leu88, Met92, Ala117, Tyr118, Pro230, Ile231, Phe233,
Val234, Leu376, His377, Ser378, Ile379, Phe380, Met508. Further-
more, the phenyl group attached to the piperazinyl of the side chain
interacts with the phenyl group of Phe380 through the formation of
broad antifungal spectrum, which is a good candidate for further
evaluation.
The results of preliminary antifungal assays indicated that the
introduction of fluorine atom to the phenyl group of side chain did
not improve the antifungal activities effectively. However, the
length of alkyl side chain is essential to their antifungal activities.
Compounds with a short or moderate-length side chain present
higher antifungal activities than those with longer side chains.
Compared with the aromatic analogues studied previously [12], the
introduction of an aliphatic side chain resulted in a better
p
e
p
face-to-edge interaction.
To clarify the binding mode of our synthesized compounds in
this paper, compound 7 was docked into the active site of CACYP51
by the Builder module within Insight II 2000 software package
(Fig. 1). The compound 7 docking result revealed that the triazole
group, the difluorophenyl group and the piperazinyl side chain can
bind to the active site of CACYP51 through the former binding
mode.

J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
3145
Chemical, China). Silica gel column chromatography was per-
formed with Silica gel 60G (Qindao Haiyang Chemical, China).
Commercial solvents were used without any pretreatment.
The important intermediates 1-[4-(4-amino-phenyl)-piperazin-1-
yl]-2-(2,4-difluorophenyl)-3-(1H- 1,2,4-triazol-1-yl)-propan-2-ol (4a)
and 2-(2,4-difluorophenyl)-1-[4-(2-fluoro-4-amino-phenyl) -piper-
azin-1-yl]-3-(1H-1,2,4-triazol-1-yl)-propan-2-ol (4b) were prepared
according to an established procedure [10,11].
6.1. General procedure for the preparation of title compounds 5e31
To a stirred mixture of 4a or 4b (0.001 mol), DMAP (100 mg) and
EDCI (200 mg) in 50 mL dichloromethane under 0 ꢀC and alkyl
carboxylic acid (0.001 mol)was added and stirred for 8e12 h. The
reaction was monitored by TLC (dichloromethane/methanol, 1/
20e1/10, v/v). After filtration, the filtrate was evaporated under
reduced pressure. The residue was then extracted with ethyl
acetate (50 mL ꢁ 3). The extract was washed with saturated NaCl
solution (20 mL ꢁ 3), dried over anhydrous Na2SO4 and evaporated.
The residue was crystallized from absolute alcohol to afford the title
compounds 5e31.
The title compounds 5e31 were characterized as follows.
Fig. 1. Computed binding geometry of the new inhibitor
7 in the active site of
CACYP51.
6.2. Data for 2-chloro-N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-
3-(1H-1,2,4-triazol-1-yl)propyl] piperazin-1-yl}phenyl)acetamide
(5)
5. Conclusion
On the basis of the active site of CACYP51, a series of novel tri-
azole derivatives with a 4-(4-substitutedphenyl) piperazine side
chain have been successfully designed and synthesized as anti-
fungal agents. The in vitro antifungal activities of all title
compounds were evaluated against eight human pathogenic fungi
which are often encountered clinically. Compared with their
aromatic analogues, our present results clearly showed that the
introduction of aliphatic side chain with a proper length greatly
enhanced the antifungal activity of these title compounds against
Candida species and the introduction of fluorine atom to the phenyl
group of side chain is not necessary to improve their antifungal
activities. The obtained results demonstrated that our effort which
maintains the pharmacophores (a 1,2,4-triazole ring, a difluoro-
genated phenyl group and a hydroxyl group), substituted one tri-
azole ring of fluconazole with a 4-(4-substitutedphenyl) piperazine
linking a series of aliphatic side chain is encouraging. This obser-
vation was explainable by a molecular model resulting from the
computational docking simulation. The piperazinyl side chain of
the compound 7 is oriented into substrate access channel 2 (FG
loop) and forms hydrophobic and van der waals interactions with
surrounding hydrophobic residues. The phenyl group of the side
chain can interacts with the phenyl group of Phe380 through the
Yield: 78%; m.p. 77e80 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s,1H, triazoleC5eH), 7.58e6.79 (m, 7H, AreH), 4.56
(d, 1H, J ¼ 15 Hz, triazoleeCH2), 4.54 (d, 1H, J ¼ 15 Hz, triazoleeCH2),
4.16 (s, 2H, eCH2e), 3.04e2.49 (m, 8H, piperazine-H), 3.16 (d, 1H,
J ¼ 15 Hz, CH2epiperazine), 2.69 (d,1H, J ¼ 13.8 Hz, CH2epiperazine).
EIMS, m/z: 491 (M þ 1). IR (KBr): 3265,3193,3128,3051,2952,
2825,1664,1614,1514,1271,1139,1014,848 cmꢂ1
.
Anal. calcd for
C23H25ClF2N6O2: C, 56.27; H, 5.13; N,17.12. Found: C, 56.43; H, 5.15; N,
17.08.
6.3. Data for 2-chloro-N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-
3-(1H-1,2,4-triazol-1-yl)propyl] piperazin-1-yl}phenyl)-2,2-
difluoroacetamide (6)
Yield: 68%; m.p. 176e178 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 8.01e6.79 (m, 7H, AreH),
5.16 (1H, s,OH), 4.61 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.49 (d, 1H,
J ¼ 14.4 Hz, triazoleeCH2), 3.06e2.50 (m, 8H, piperazine-H), 3.16 (d,
1H, J ¼ 13.5 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.5 Hz,
CH2epiperazine). EIMS, m/z: 527 (M
þ
1). IR (KBr):
3271,3112,2826,1716,1616,1537,1309,1139,1007 cmꢂ1. Anal. calcd for
C23H23ClF4N6O2: C, 52.43; H, 4.40; N, 15.95. Found: C, 52.63; H,
4.52; N, 15.68.
formation of
pep face-to-edge interaction. Further evaluations are
necessary to determine the antifungal activities of these title
compounds in vivo and help us to optimize these new leading
compounds.
6.4. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)-2,2,2-
trifluoroacetamide (7)
6. Experimental part
Melting points were measured on a Yamato MP-21 melting-
point apparatus and are uncorrected. Infrared spectra were recor-
ded in potassium bromide disks on a HITACHI 270-50 spectro-
photometer. 1H NMR spectra were recorded in CDCl3 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 Institute of Pharmaceutical Industry.
Mass spectra were recorded on an Agilent 1100 HPLC-MS. TLC
analysis was carried out on silica gel plates GF254 (Qindao Haiyang
Yield: 74%; m.p. 103e105 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 8.48e6.79 (m, 7H, AreH),
4.60 (d, 1H, J ¼ 14.1 Hz, triazoleeCH2), 4.54 (d, 1H, J ¼ 14.1 Hz,
triazoleeCH2), 2.97e2.51 (m, 8H, piperazine-H), 3.18 (d, 1H,
J
¼
13.8 Hz, CH2epiperazine), 2.69 (d, 1H,
CH2epiperazine). EIMS, m/z: 511 (M
3118,2947,2828,2359,1710,1548,1422,1211,1186,1138,965
J
¼
13.8 Hz,
1). IR (KBr):
cmꢂ1
þ
.
Anal. calcd for C23H23F5N6O2: C, 54.12; H, 4.54; N, 16.46. Found: C,
53.98; H, 4.68; N, 16.57.

3146
J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
6.5. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)propionamide (8)
1532,1415,1139 cmꢂ1. nal. calcd for C27H34F2N6O2: C, 63.26; H, 6.69;
N, 16.40. Found: C, 63.38; H, 6.58; N, 16.58.
Yield: 82%; m.p. 147e149 ꢀC [10]; 1HNMR (CDCl3): 8.15 (s, 1H,
triazoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.77 (m, 7H, AreH),
5.20 (1H, s,OH), 4.60 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.49 (d, 1H,
J ¼ 14.4 Hz, triazoleeCH2), 3.02e2.49 (m, 8H, piperazine-H), 3.16 (d,
1H, J ¼ 12.3 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 12.3 Hz, CH2epi-
perazine), 2.39e2.31 (q, 2H, eCH2e), 1.25e1.20 (t, 3H, eCH3). EIMS,
m/z: 471 (M þ 1). IR (KBr): 3278,3118,3066,2966,2880,2825,1655,
1603,1543,1514,1453, 1205,1137 cmꢂ1. Anal. calcd for C24H28F2N6O2:
C, 61.26; H, 6.00; N, 17.86. Found: C, 61.11; H, 5.93; N, 17.82.
6.10. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)pivalamide (13)
Yield: 63%; m.p. 129e131 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.77 (m, 7H, AreH),
4.60 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.49(d, 1H, J ¼ 14.4 Hz, tri-
azoleeCH2), 3.02e2.49 (m, 8H, piperazine-H), 3.16 (d, 1H,
J ¼ 14.4 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 14.4 Hz, CH2epiper-
azine), 1.29 (s, 9H, eCH3). EIMS, m/z: 499 (M þ 1). IR (KBr):
3374,3135, 2954,2836,1671,1615,1519,1497,1393,1154 cmꢂ1. Anal.
calcd for C26H32F2N6O2: C, 62.64; H, 6.47; N, 16.86. Found: C, 62.53;
H, 6.31; N, 16.93.
6.6. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)butanamide (9)
Yield: 80%; m.p. 163e165 ꢀC [10]; 1HNMR (CDCl3): 8.15 (s, 1H,
triazoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.78 (m, 7H, AreH),
4.57 (d, 1H, J ¼ 14.1 Hz, triazoleeCH2), 4.49 (d, 1H, J ¼ 14.1 Hz, tri-
azoleeCH2), 3.01e2.49 (m, 8H, piperazine-H), 3.16 (d,1H, J ¼ 13.5 Hz,
CH2epiperazine), 2.69 (d, 1H, J ¼ 13.5 Hz, CH2epiperazine),
2.31e2.26 (t, 2H, eCH2e), 1.77e1.70 (m, 2H, eCH2e), 1.01e0.96 (t,
3H, eCH3). EIMS, m/z: 485 (M þ 1). IR (KBr): 3351,3133, 3071,2962,
2869,2834,1655,1617,1594, 1515,1498,1454,1276 cmꢂ1. Anal. calcd
for C25H30F2N6O2: C, 61.97; H, 6.24; N,17.34. Found: C, 61.82; H, 6.32;
N, 17.18.
6.11. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)heptanamide (14)
Yield: 62%; m.p. 169e171 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.57e6.77 (m, 7H, AreH),
4.58 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.4 Hz, tri-
azoleeCH2), 2.99e2.49 (m, 8H, piperazine-H), 3.15 (d,1H, J ¼ 13.5 Hz,
CH2epiperazine), 2.69(d, 1H,
J
¼
13.5 Hz, CH2epiperazine),
2.32e2.27 (t, 2H, eCH2e), 1.71e1.66 (m, 2H, eCH2e), 1.30e1.26 (m,
6H, eCH2e), 0.89e0.85 (t, 3H, eCH3). EIMS, m/z: 527 (M þ 1). IR
(KBr): 3405,3324,2955,2927, 2851,2826,1653,1513,1140 cmꢂ1. Anal.
calcd for C28H36F2N6O2: C, 63.86; H, 6.89; N, 15.96. Found: C, 63.71;
H, 6.73; N, 16.05.
6.7. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)isobutanamide (10)
Yield: 76%; m.p. 128e130 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.78 (m, 7H, AreH),
4.60 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.49 (d, 1H, J ¼ 14.4 Hz,
triazoleeCH2), 3.01e2.49 (m, 8H, piperazine-H), 3.16 (d, 1H,
J ¼ 12.6 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 12.6 Hz, CH2epiper-
azine), 2.46e2.42 (m, H, eCHe), 1.24e1.21 (d, 6H, eCH3). EIMS, m/z:
6.12. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)octanamide (15)
Yield: 66%; m.p. 96e98 ꢀC; 1HNMR (CDCl3): 8.19 (s, 1H, tri-
azoleC3eH), 7.81 (s, 1H, triazoleC5eH), 7.60e6.77 (m, 7H, AreH),
4.60 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.54 (d, 1H, J ¼ 14.4 Hz,
triazoleeCH2), 3.00e2.49 (m, 8H, piperazine-H), 3.16 (d, 1H,
J ¼ 13.5 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 13.5 Hz, CH2epiper-
azine), 2.35e2.27 (t, 2H, eCH2e), 1.71e1.65 (m, 2H, eCH2e),
1.34e1.26 (m, 8H, eCH2e), 0.89e0.85 (t, 3H, eCH3). EIMS, m/z: 541
485 (M
þ
1). IR (KBr): 3443,3271,3113,3062,2972,2936,2875,
2811,1658,1604, 1546,1513,1498 cmꢂ1. Anal. calcd for C25H30F2N6O2:
C, 61.97; H, 6.24; N, 17.34. Found: C, 61.91; H, 6.28; N, 17.39.
6.8. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)pentanamide (11)
(M þ 1). IR (KBr): 3396, 3134,2920,2851,1674,1514,1498,1139 cmꢂ1
.
Anal. calcd for C29H38F2N6O2: C, 64.42; H, 7.08; N, 15.54. Found: C,
64.32; H, 7.13; N, 15.29.
Yield: 77%; m.p. 191e193 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.57e6.77 (m, 7H, AreH),
5.21(1H, s,OH), 4.58 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H,
J ¼ 14.4 Hz, triazoleeCH2), 2.99e2.49 (m, 8H, piperazine-H), 3.15 (d,
1H, J ¼ 13.5 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 13.5 Hz, CH2epi-
perazine), 2.33e2.28 (t, 2H, eCH2e), 1.71e1.65 (m, 2H, eCH2e),
1.41e1.26 (m, 2H, eCH2e), 0.95e0.90 (t, 3H, eCH3). EIMS, m/z: 499
6.13. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)decanamide (16)
Yield: 71%; m.p. 117e119 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.57e6.75 (m, 7H, AreH),
4.58 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.4 Hz,
triazoleeCH2), 2.91e2.50 (m, 8H, piperazine-H), 3.17 (d, 1H,
J ¼ 13.5 Hz, CH2epiperazine), 2.69 (d, 1H, J ¼ 13.5 Hz, CH2epiper-
azine), 2.33e2.28 (t, 2H, eCH2e), 1.70e1.63 (m, 2H, eCH2e),
1.29e1.25 (m,12H, eCH2e), 0.89e0.84 (t, 3H, eCH3). EIMS, m/z: 569
(M þ 1). IR (KBr): 3333, 2927,2853,1670,1512,1272,1139 cmꢂ1. Anal.
calcd for C31H42F2N6O2: C, 65.47; H, 7.44; N, 14.78. Found: C, 65.33;
H, 7.35; N, 14.62.
(M
þ
1). IR (KBr): 3351,3133,3070,2955,2834,1655,1617,1594,
1515,1454,1389,1141 cmꢂ1. Anal. calcd for C26H32F2N6O2: C, 62.64; H,
6.47; N, 16.86. Found: C, 62.46; H, 6.39; N, 16.79.
6.9. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)hexanamide (12)
Yield: 67%; m.p. 199e201 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.78 (m, 7H, AreH),
4.58 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.4 Hz,
triazoleeCH2), 3.00e2.50 (m, 8H, piperazine-H), 3.17 (d, 1H,
J ¼ 14.4 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 14.4 Hz, CH2epiper-
azine), 2.33e2.28 (t, 2H, eCH2e), 1.73e1.68 (m, 2H, eCH2e),
1.36e1.23 (m, 4H, eCH2e), 0.92e0.87 (t, 3H, eCH3). EIMS, m/z: 513
(M þ 1). IR (KBr): 3342,3132,2957, 2931,2859, 2829,1654,1616,1596,
6.14. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)dodecanamide (17)
Yield: 70%; m.p. 88e90 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.58e6.76 (m, 7H, AreH),
4.55 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.49 (d, 1H, J ¼ 14.4 Hz,
triazoleeCH2), 2.92e2.51 (m, 8H, piperazineeH), 3.17 (d, 1H,

J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
3147
J ¼ 13.5 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.5 Hz, CH2epiper-
6.19. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)-2,2,2-
trifluoroacetamide (22)
azine), 2.33e2.28 (t, 2H, eCH2e), 1.71e1.64 (m, 2H, eCH2e),
1.30e1.25 (m,18H, eCH2e), 0.89e0.85 (t, 3H, eCH3). EIMS, m/z: 597
(M þ 1). IR (KBr): 3306,2919, 2851,1665, 1516,1417,1254,1138 cmꢂ1
.
Anal. calcd for C33H46F2N6O2: C, 66.42; H, 7.77; N, 14.08. Found: C,
66.28; H, 7.89; N, 13.99.
Yield: 88%; m.p. 169e171 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.61e6.78 (m, 6H, AreH), 5.16
(1H, s,OH), 4.61 (d, 1H, J ¼ 14.1 Hz, triazoleeCH2), 4.49 (d, 1H,
J ¼ 14.1 Hz, triazoleeCH2), 3.06e2.50 (m, 8H, piperazine-H), 3.16 (d,
1H, J ¼ 13.5 Hz, CH2epiperazine), 2.74 (d, 1H, J ¼ 13.5 Hz, CH2epi-
6.15. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} phenyl)palmitamide (18)
perazine).
EIMS,
m/z:
529
(M
þ
1).
IR
(KBr):
3275,3117,2829,1716,1617,1540,1454,1114 cmꢂ1
.
Anal. calcd for
Yield: 63%; m.p. 71e73 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.57e6.78 (m, 7H, AreH),
4.57 (d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.4 Hz, tri-
azoleeCH2), 3.01e2.49 (m, 8H, piperazine-H), 3.16 (d,1H, J ¼ 13.5 Hz,
CH2epiperazine), 2.68 (d, 1H, J ¼ 13.5 Hz, CH2epiperazine),
2.33e2.28 (t, 2H, eCH2e), 1.72e1.67 (m, 2H, eCH2e), 1.29e1.24 (m,
24H, eCH2e), 0.89e0.85 (t, 3H, eCH3). EIMS, m/z: 653 (M þ 1). IR
(KBr): 3302, 2919,2850,1653, 1516,1417,1272,1138 cmꢂ1. Anal. calcd
for C37H54F2N6O2: C, 68.07; H, 8.34; N,12.87. Found: C, 67.95; H, 8.16;
N, 12.69.
C23H22F6N6O2: C, 52.27; H, 4.20; N, 15.90. Found: C, 52.09; H, 4.28; N,
16.03.
6.20. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
propionamide (23)
Yield: 80%; m.p. 98e100 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.57e6.78 (m, 6H, AreH),
5.21(1H, s,OH), 4.58 (d, 1H, J ¼ 14.25 Hz, triazoleeCH2), 4.50 (d, 1H,
J ¼ 14.25 Hz, triazoleeCH2), 2.92e2.50 (m, 8H, piperazine-H), 3.15 (d,
1H, J ¼ 13.5 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.5 Hz, CH2epi-
perazine), 2.37e2.33 (q, 2H, eCH2e), 1.24e1.21 (t, 3H, eCH3). EIMS,
6.16. Data for N-(4-{4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
acetamide (19)
m/z: 489 (M
þ
1). IR (KBr): 3274,3115,2828,1664,1606,1514,
1421,1224,1138 cmꢂ1. Anal. calcd for C24H27F3N6O2: C, 59.01; H, 5.57;
N, 17.20. Found: C, 58.93; H, 5.48; N, 16.99.
Yield: 81%; m.p. 104e106 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.58e6.78 (m, 6H, AreH),
5.21(1H, s,OH), 4.58 (d, 1H, J ¼ 14.25 Hz, triazoleeCH2), 4.50 (d, 1H,
J ¼ 14.25 Hz, triazoleeCH2), 2.92e2.51 (m, 8H, piperazine-H), 3.16
(d, 1H, J ¼ 13.45 Hz, CH2epiperazine), 2.71 (d, 1H, J ¼ 13.45 Hz,
CH2epiperazine), 2.14 (s, 3H, eCH3). EIMS, m/z: 475 (M þ 1). IR
6.21. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
butanamide (24)
Yield: 78%; m.p. 113e115 ꢀC; 1HNMR (CDCl3): 8.16 (s, 1H, tri-
azoleC3eH), 7.80 (s,1H, triazoleC5eH), 7.58e6.76 (m, 6H, AreH), 4.58
(d, 1H, J ¼ 14.4 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.4 Hz, tri-
azoleeCH2), 2.93e2.51 (m, 8H, piperazine-H), 3.17 (d,1H, J ¼ 12.6 Hz,
CH2epiperazine), 2.70 (d, 1H, J ¼ 12.6 Hz, CH2epiperazine),
2.32e2.27 (t, 2H, eCH2e), 1.77e1.67 (m, 2H, eCH2e), 1.01e0.96 (t,
3H, eCH3). EIMS, m/z: 503 (M þ 1). IR (KBr): 3443,3271, 3110,
2963,2826,1661,1604,1513,1137 cmꢂ1. Anal. calcd for C25H29F3N6O2:
C, 59.75; H, 5.82; N, 16.72. Found: C, 59.68; H, 5.79; N, 16.77.
(KBr): 3456,3117,2828,1669,1608,1515,1271,1254,1138,1015 cmꢂ1
.
Anal. calcd for C23H25F3N6O2: C, 58.22; H, 5.31; N, 17.71. Found: C,
58.09; H, 5.23; N, 17.87.
6.17. Data for 2-chloro-N-(4-{4-[2-(2,4-difluorophenyl)-2-
hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl] piperazin-1-yl}-3-fluoro-
phenyl)acetamide (20)
Yield: 75%; m.p. 91e93 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.57e6.80 (m, 6H, AreH),
5.21(1H, s,OH), 4.58 (d, 1H, J ¼ 14.3 Hz, triazoleeCH2), 4.50 (d, 1H,
J ¼ 14.3 Hz, triazoleeCH2), 4.16 (s, 2H, eCH2e), 2.94e2.51 (m, 8H,
piperazine-H), 3.16 (d, 1H, J ¼ 13.45 Hz, CH2epiperazine), 2.71 (d,
1H, J ¼ 13.45 Hz, CH2epiperazine). EIMS, m/z: 509 (M þ 1). IR (KBr):
3483,3255,2950,2830,1683,1617,1514,1419, 1225,1138 cmꢂ1. Anal.
calcd for C23H24ClF3N6O2: C, 54.28; H, 4.75; N, 16.51. Found: C,
54.13; H, 4.68; N, 16.49.
6.22. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
isobutanamide (25)
Yield: 79%; m.p. 126e128 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.56e6.78 (m, 6H, AreH),
4.57 (d, 1H, J ¼ 14.3 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.3 Hz,
triazoleeCH2), 2.92e2.51 (m, 8H, piperazine-H), 3.16 (d, 1H,
J ¼ 13.42 Hz, CH2epiperazine), 2.71 (d, 1H, J ¼ 13.42 Hz, CH2epi-
perazine), 2.48e2.45 (m, H, eCHe), 1.25e1.22 (d, 6H, eCH3). EIMS,
m/z: 503 (M þ 1). IR (KBr): 3443,3272,3112,2829,1664,1606,1498,
1254,1137 cmꢂ1. Anal. calcd for C25H29F3N6O2: C, 59.75; H, 5.82; N,
16.72. Found: C, 59.62; H, 5.86; N, 16.82.
6.18. Data for 2-chloro-N-(4-{4-[2-(2,4-difluorophenyl)-2-
hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl] piperazin-1-yl}-3-fluoro-
phenyl)-2,2-difluoroacetamide (21)
6.23. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
pentanamide (26)
Yield: 77%; m.p. 117e119 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.80 (s, 1H, triazoleC5eH), 7.60e6.79 (m, 6H, AreH), 4.60
(d,1H, J¼ 14.1 Hz, triazoleeCH2),4.49(d,1H, J¼ 14.1Hz,triazoleeCH2),
2.97e2.52 (m, 8H, piperazine-H), 3.18 (d, 1H, J ¼ 13.2 Hz, CH2epiper-
azine), 2.70 (d, 1H, J ¼ 13.2 Hz, CH2epiperazine). EIMS, m/z: 545
(M þ 1). IR (KBr): 3542,3115,2947,2829,1706,1658,1515,1274,1179,
1137 cmꢂ1. Anal. calcd for C23H22ClF5N6O2: C, 50.70; H, 4.07; N, 15.42.
Found: C, 50.58; H, 4.13; N, 15.29.
Yield: 76%; m.p. 176e178 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.58e6.76 (m, 6H, AreH),
5.23(1H, s,OH), 4.58 (d, 1H, J ¼ 14.3 Hz, triazoleeCH2), 4.50 (d, 1H,
J ¼ 14.3 Hz, triazoleeCH2), 2.91e2.51 (m, 8H, piperazine-H), 3.15 (d,
1H, J ¼ 13.4 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.4 Hz,

3148
J. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 3142e3148
CH2epiperazine), 2.32e2.29 (t, 2H, eCH2e), 1.70e1.64 (m, 2H,
eCH2e), 1.41e1.25 (m, 2H, eCH2e), 0.93e0.90 (t, 3H, eCH3). EIMS,
4.58 (d, 1H, J ¼ 14.3 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.3 Hz,
triazoleeCH2), 2.91e2.50 (m, 8H, piperazine-H), 3.15 (d, 1H,
J ¼ 13.55 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.55 Hz, CH2epi-
perazine), 2.32e2.29 (t, 2H, eCH2e), 1.71e1.66 (m, 2H, eCH2e),
1.32e1.27 (m, 8H, eCH2e), 0.88e0.85 (t, 3H, eCH3). EIMS, m/z: 559
m/z:
517
(M
þ
1).
IR
(KBr):
3352,2957,2820,1662,1597,1531,1509,1138 cmꢂ1
.
Anal. calcd for
C26H31F3N6O2: C, 60.45; H, 6.05; N,16.27. Found: C, 60.29; H, 5.98; N,
16.41.
(M þ 1). IR (KBr): 3301,2929,2854,1661,1598,1511,1422,1139 cmꢂ1
.
Anal. calcd for C29H37F3N6O2: C, 62.35; H, 6.68; N, 15.04. Found: C,
62.45; H, 6.57; N, 15.23.
6.24. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
pivalamide (27)
6.28. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)-2-
phenylacetamide (31)
Yield: 78%; m.p. 115e117 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.58e6.78 (m, 6H, AreH),
4.57 (d, 1H, J ¼ 14.25 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.25 Hz,
triazoleeCH2), 2.92e2.50 (m, 8H, piperazine-H), 3.15 (d, 1H,
J ¼ 13.6 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.6 Hz, CH2epiper-
azine), 1.28 (s, 9H, eCH3). EIMS, m/z: 517 (M þ 1). IR (KBr):
3258,2968,2827,1648,1616,1513,1419,1272,1137 cmꢂ1. Anal. calcd
for C26H31F3N6O2: C, 60.45; H, 6.05; N, 16.27. Found: C, 60.39; H,
6.12; N, 16.18.
Yield: 76%; m.p. 183e185 ꢀC; 1HNMR (CDCl3): 8.14 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.55e6.74 (m, 11H, AreH),
5.21(1H, s,OH), 4.57 (d, 1H, J ¼ 14.3 Hz, triazoleeCH2), 4.49 (d, 1H,
J ¼ 14.3 Hz, triazoleeCH2), 4.70 (s, 2H, eCH2e), 2.89e2.49 (m, 8H,
piperazine-H), 3.14 (d, 1H, J ¼ 13.45 Hz, CH2epiperazine), 2.69 (d,
1H, J ¼ 13.45 Hz, CH2epiperazine). EIMS, m/z: 551 (M þ 1). IR (KBr):
3344,3027,2953,2817,1664,1599,1508,1453, 1384,1137 cmꢂ1. Anal.
calcd for C29H29F3N6O2: C, 63.26; H, 5.31; N, 15.26. Found: C, 63.09;
H, 5.25; N, 15.43.
6.25. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
hexanamide (28)
Acknowledgements
Yield: 72%; m.p. 182e184 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.58e6.77 (m, 6H, AreH),
4.57 (d, 1H, J ¼ 14.24 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.24 Hz,
triazoleeCH2), 2.91e2.50 (m, 8H, piperazine-H), 3.15 (d, 1H,
J ¼ 13.47 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.47 Hz, CH2epi-
perazine), 2.32e2.29 (t, 2H, eCH2e), 1.71e1.68 (m, 2H, eCH2e),
1.34e1.33 (m, 4H, eCH2e), 0.91e0.88 (t, 3H, eCH3). EIMS, m/z: 531
(M þ 1). IR (KBr): 3354,2957,2932,2857,1662,1617,1529,1509,1421,
1138 cmꢂ1. Anal. calcd for C27H33F3N6O2: C, 61.12; H, 6.27; N, 15.84.
Found: C, 61.05; H, 6.15; N, 15.63.
This work was supported by the National Natural Science
Foundation of China (Grant No. 30300437 and 20772153), the
Eleventh Five Year Military Medicine and Public Health Research
Projects (Grant No. 06MB206) and by Shanghai Leading Academic
Discipline Project (Project No. B906).
References
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Yield: 74%; m.p. 160e162 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.56e6.77 (m, 6H, AreH),
4.58 (d, 1H, J ¼ 14.27 Hz, triazoleeCH2), 4.50 (d, 1H, J ¼ 14.27 Hz,
triazoleeCH2), 2.91e2.51 (m, 8H, piperazine-H), 3.15 (d, 1H,
J ¼ 13.47 Hz, CH2epiperazine), 2.70 (d, 1H, J ¼ 13.47 Hz, CH2epi-
perazine), 2.32e2.29 (t, 2H, eCH2e), 1.72e1.67 (m, 2H, eCH2e),
1.35e1.30 (m, 6H, eCH2e), 0.89e0.86 (t, 3H, eCH3). EIMS, m/z: 545
(M þ 1). IR (KBr): 3356,2931,2851,1663,1597,1529,1508,1421,1385,
1138 cmꢂ1. Anal. calcd for C28H35F3N6O2: C, 61.75; H, 6.48; N, 15.43.
Found: C, 61.58; H, 6.59; N, 15.48.
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6.27. Data for N-(4-{4-[2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl]piperazin-1-yl} -3-fluoro-phenyl)
octanamide (30)
Yield: 75%; m.p. 122e124 ꢀC; 1HNMR (CDCl3): 8.15 (s, 1H, tri-
azoleC3eH), 7.79 (s, 1H, triazoleC5eH), 7.58e6.77 (m, 6H, AreH),