Design, synthesis and molecular docking studies of novel triazole as antifungal agent

Article abstract of DOI:10.1016/j.ejmech.2011.04.022

In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4- difluorophenyl)-3-[(4-substituted trifluoromethyl phenyl)-piperazin-1-yl]- propan-2-ols were designed,

Full text of DOI:10.1016/j.ejmech.2011.04.022

European Journal of Medicinal Chemistry 46 (2011) 3167e3176
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Design, synthesis and molecular docking studies of novel triazole as antifungal
agent
,
,
Xiaoyun Chai a 1, Jun Zhang c 1, Yongbing Cao b, Yan Zou a, Qiuye Wu a, Dazhi Zhang a, Yuanying Jiang b,
,
Qingyan Sun a
*
a Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People’s Republic of China
b Drug Research Center, School 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:
In order to meet the urgent need for novel antifungal agents with improved activity and broader
spectrum, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted trifluoromethyl
phenyl)-piperazin-1-yl]-propan-2-ols were designed, synthesized and evaluated as antifungal agents.
The MIC80 values indicate that the compounds 7ae7q, 8ae8d showed higher antifungal activities against
Candida albicans than 5ae5i, 6ae6j. Moreover, the molecular model for the binding between compound
5a, 7a and the active site of CACYP51 was provided based on the computational docking results, and the
structureeactivity relationship was analyzed.
Received 2 February 2011
Received in revised form
7 April 2011
Accepted 7 April 2011
Available online 15 April 2011
Keywords:
Triazole
Ó 2011 Elsevier Masson SAS. All rights reserved.
Antifungal agents
Synthesis
Molecular docking
1. Introduction
One of the most common classes of antifungal agents are azoles.
For over a decade, azoles have been a mainstay of the antifungal
The incidence of infections caused by fungi pathogenic has
increased significantly over the years [1]. Many fungal infections
are caused by opportunistic pathogens that may be endogenous
(Candida infections) or acquired from the environment (Crypto-
coccus, Aspergillus infections). However, besides these known
fungal species, new emerging fungal pathogens appear every year
as the cause of morbidity and life-threatening infections in the
immunocompromised hosts [1,2]. Nowadays, numerous antifungal
drugs with various structures and scaffolds are known and avail-
able. These drugs are amphotericin B [3], 5-fluorocytosine, azoles
(such as fluconazole and itraconazole) [4], and echinocandins (such
as caspofungin and micafungin) [5]. However, their clinical uses
have been limited by the emergence of drug resistance, high risk of
toxicity, insufficiencies in their antifungal activity and undesirable
side effects [6,7]. Hence, there is still a need to develop and extend
the safe and efficient chemotherapeutic agents with potent broad
spectrum antifungal activities [7].
armamentarium. These antigugal drugs act by inhibiting CYP51,
a necessary enzyme in the biosynthesis of ergosterol, through
a mechanism in which the heterocyclic nitrogen atom (N-4 of tri-
azole) binds to the heme iron atom [8]. As a member of the cyto-
chrome P450 superfamily, CYP51 catalyzes the oxidative removal of
the 14
a
-methyl group of (C-32) lanosterol via three successive
monooxygenation reactions to give
6
14,15-desaturated intermedi-
ates in ergosterol biosynthesis. The first two of these reactions are
conventional cytochrome P450 hydroxylations that produce the
14-hydroxymethyl and 14-carboxyaldehyde derivatives of lano-
sterol [9,10]. In the final step, the 14-aldehyde group is eliminated
as formic acid with concomitant introduction of a 614,15 double
bond [11e13].
Unfortunately, the broad use of azoles has led to development of
severe resistance, which significantly reduced their efficacy [14,15].
The emergence of resistance shows the need of the discovery of
new antifungal compounds which have broader antifungal spectra
and higher therapeutic indexes than fluconazole. And we could also
study more about the structureeactivity for the inhibition of CYP51.
Researches indicated that the structurally and functionally
important regions, such as the heme group, the hydrophilic
H-bonding region, the narrow hydrophobic cleft- substrate access
* Corresponding author. Tel.: þ86 21 81871228 15; fax: þ86 21 81871225.
E-mail address: sqy_2000@163.com (Q. Sun).
1
These authors contributed equally to this work.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.04.022

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X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
channel 2 (FG loop), and the active site have been recognized
accurately. The binding mode of azoles with CACYP51 has been
investigated by flexible molecular docking [16e19]. The molecular
modeling, which gives the utilization of structural information of
fungal CYP51s can accelerate the discovery of novel antifungal
agents. In our previous research, we introduced the phenyl group
and fluorophenyl group to the piperazinyl of the side chain, most of
the compounds exhibited higher activity against nearly all fungi
tested. In this paper, we introduce the trifluoromethyl phenyl group
following the conclusion of the previous and the strategy of
structure-based rational drug design.
Hospital. C. albicans and C. neoformans were purchased from ATCC,
and other strains were clinic isolates. C. albicans (ATCCY0109) and C.
neoformans (ATCCBLS108) were used as the quality-controlled
strains, and tested in each assay. Fluconazole (FLC), itraconazole
(ICZ), voriconazole (VCZ) served as the positive control were
obtained from their respective manufacturers.
The in vitro minimal inhibitory concentrations (MICs) of the
compounds were determined by the micro-broth dilution method
in 96-well microtestplates according to the methods defined by the
National Committee for Clinical Laboratory Standards (NCCLS) [21].
The MIC80 was defined as the first well with an approximate 80%
reduction in growth compared to the growth of the drug-free well.
For assays, 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 C. albicans and at 72 h for C. neoformans. Fluconazole (FLC),
itraconazole (ICZ) and voriconazole (VCZ) served as the positive
control were obtained from their respective manufacturers. The
results of assays are summarized in Table 1. The data points from
the mean of replicates. All of our susceptibility tests were per-
formed three times by each antifungal agent.
2. Chemistry
The general synthetic methodology for the preparation of title
compounds 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-
substituted trifluoromethyl phenyl)-piperazin-1-yl]-propan-2-ols
(5ae5i, 6ae6j, 7ae7q, 8ae8d) is outlined in Scheme 1. As a key
intermediate of our designed triazole antifungals, the oxirane
compound 1 was synthesized by the reported procedure [10]. And
compound 2 were synthesized according to the literature [20]. The
title compound 3 was synthesized by ring-open reaction of oxirane
1 with compound 2. The good yield was obtained when the reac-
tion was performed in a protic solvent ethanol in the presence of
triethylamine as a base at 80 ꢀC. Then the nitro group on the phenyl
ring of compound 3 was reduced to an amino group in the presence
of Raney Ni and hydrazine hydrate. In the presence of DMAP
(4-dimethylaminopyridine) and EDCI (1-ethyl-3-(3-dimethylam-
inopropyl) carbodiimide HCl) in dichloromethane at room
temperature, the aniline 4 was converted to title compounds by
reacting with various acids. All the new compounds (5ae5i, 6ae6j,
7ae7q, 8ae8d) described above were characterized by IR, LC-MS
and NMR spectroscopic analysis.
4. Results and discussion
The results of antifungal activities in vitro showed that all the
compounds showed only moderate activity or no activity against
nearly all fungi tested. Only several compounds exhibited excellent
activity against C. albicans. Among the compounds tested, 5a, 6j, 7a,
7b, 7d, 7e, 7p, 8a, 8b and 8c showed higher activity against
C. albican than FCZ and ICZ. The series of 7ae7q and 8ae8d showed
no activity against nearly all fungi tested except C. albicans,
C. neoformans and A. fumigatus. And the series of 5ae5i and 6ae6j
exhibited moderate activity against nearly all fungi tested. Notice-
ably, the MIC80 values indicate that the compounds 7ae7q, 8ae8d
showed higher antifungal activities against C. albicans than 5ae5i,
6ae6j. Compound 7a showed 16 times higher activity (with the
3. Pharmacology
The in vitro antifungal activities of all title compounds were
evaluated against eight human pathogenic fungi, Candida albicans,
Cryptococcus neoformans, Candida parapsilosis, Candida tropicalis,
Trichophyton rubrum, Fonsecaea compacta, Microsporum gypseum,
Aspergillus fumigatus, which are often encountered clinically, and
were compared with fluconazole, itraconazole, voriconazole.
C. albicans and C. neoformans were provided by Shanghai Changz-
heng Hospital; C. parapsilosis, C. tropicalis, T. rubrum, F. compacta,
M. gypseum, and A. fumigatus were provided by Shanghai Changhai
MIC80 value of 0.00097
C. albicans. And compound 7d, 7p showed the same activity (with
the MIC80 value of 0.0156 g/mL) as that of voriconazole against
C. albicans. Besides, the series of 6ae6j, 7ae7q and 8ae8d exhibited
higher activity against A. fumigatus than 5ae5i. Compounds 7g, 7i,
7j, 8a and 8c exhibited the same activities against A. fumigatus as
voriconazole (with the MIC80 value of 1 mg/mL). The MIC80 value of
compound 6d is four times lower than that of itraconazole (with
the MIC80 value of 0.25 mg/mL) against A. fumigatus in vitro.
mg/mL) than that of voriconazole against
m
Scheme 1. Reagents and conditions: (a) CH3CH2OH, Et3N, 80 ꢀC, 5 h; (b) Raney Ni, NH2NH2ꢁH2O, CH3CH2OH, 80 ꢀC, 3.5 h; (c) Various acids, DMAP, EDCI, CH2Cl2, 8 h.

X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
3169
Table 1
Antifungal in vitro activities of the title compounds (MIC80
,
m
g/mL)a.
C. par.
Compd
R
C. alb.
C. tro.
C. neo.
T. rub.
F. com.
M. gyp.
A. fum.
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3
CH2CH3
CH2CH2CH3
CH(CH3)2
CH2(CH2)2CH3
C(CH3)3
CH2(CH2)3CH3
CH2(CH2)4CH3
CH2(CH2)5CH3
0.0625
0.25
1
0.25
1
0.25
1
1
0.25
1
0.25
0.25
0.25
1
1
4
4
0.25
0.25
1
1
1
1
4
4
16
0.25
1
1
1
4
1
1
1
16
1
1
4
1
4
4
4
4
4
1
4
4
4
4
4
16
16
4
1
1
1
1
4
0.25
4
4
0.25
>64
16
>64
64
>64
>64
64
>64
>64
0.25
6a
6b
1
4
0.25
0.25
1
1
0.25
16
1
4
4
4
1
1
4
4
F
6c
4
0.25
1
>64
0.25
1
4
4
0.25
4
Cl
Cl
6d
0.25
e
e
e
e
e
0.25
Cl
6e
6f
1
0.25
e
1
4
16
e
1
64
4
CH
3
0.25
4
e
1
0.0625
e
4
e
4
CH CH
2
3
6g
6h
6i
0.25
1
0.25
1
4
>64
4
C(CH )
3 3
1
1
1
16
16
e
1
OCH
3
16
4
4
16
16
e
e
4
64
16
4
OCF
3
CF
3
6j
0.0625
0.00097
e
e
e
0.0625
0.25
e
e
7a
e
e
F
7b
7c
7d
7e
0.0625
0.25
e
e
e
e
e
e
e
e
0.25
e
e
e
e
e
e
e
e
e
e
e
e
4
16
4
F
0.25
0.25
0.25
0.0156
0.0625
F
Cl
4
Cl
7f
0.25
e
e
0.25
e
e
e
4
7g
7h
7i
1
e
e
e
e
e
e
e
e
0.25
0.25
0.25
0.25
e
e
e
e
e
e
e
e
e
e
e
e
1
4
1
1
Cl
Cl
0.25
0.25
1
Cl
Br
7j
Br
(continued on next page)

3170
X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
Table 1 (continued )
Compd
R
C. alb.
C. par.
C. tro.
C. neo.
T. rub.
F. com.
M. gyp.
A. fum.
7k
0.25
e
e
1
e
e
e
4
CH
3
OCH
3
7l
1
e
e
e
e
1
1
e
e
e
e
e
e
4
OCH
3
OCH
3
7m
0.25
>64
OCH
3
H3CO
H3CO
7n
0.25
e
e
0.25
e
e
e
>64
O N
2
7o
7p
0.25
e
e
e
e
0.0625
e
e
e
e
e
e
4
4
NO
2
0.0156
0.25
7q
8a
8b
0.25
e
e
e
e
e
e
0.25
0.25
0.25
e
e
e
e
e
e
e
e
e
4
1
4
0.0625
0.0625
8c
0.0625
0.25
e
e
e
e
0.25
0.25
e
e
e
e
e
e
1
4
8d
FCZ
ICZ
VCZ
4
1
1
0.25
1
1
0.25
0.25
1
1
0.25
0.0156
0.0039
16
0.25
0.0156
0.25
0.0156
0.0039
64
1
>64
0.0156
0.0156
a
Abbreviations: C. alb., C. albicans; C. par.; C. parapsilosis; C. tro., C. tropicalis; C. neo., C. neoformans; T. rub., T. rubrum; F. com., F. compacta; M. gyp., M. gypseum; A. fum.,
A. fumigatus; FCZ: fluconazole; ICZ: itraconazole; VCZ: voriconazole.
In our previous research, the molecular docking result indicated
that the 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
p
e
p
face-to-edge interaction.
To clarify the binding mode of our synthesized compounds in
this paper, compound 5a and 7a were docked into the active site of
CACYP51 respectively by the Builder module within InsightII 2000
software package (Fig. 1). The compound 7a docking result revealed
that the triazole group and the difluorophenyl group can bind to the
active site of CACYP51 through the former binding mode. Although
the side chain of the compound 5a is also oriented into the
substrate access channel 2, the amide side chain were too short to
form hydrophobic and van der waals interactions with surrounding
Fig. 1. Computed binding geometry of the new inhibitors 5a and 7a in the active site of
CACYP51.

X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
3171
hydrophobic residues. From the figure we can see the difluor-
ophenyl group of compound 5a diverged from the hydrophobic
binding cleft slightly. That is because the big trifluoromethyl group
attached to the piperazinyl of the side chain and the short side
chain blocks the compounds combinding with the active site
compatibly. And the trifluoromethyl phenyl group of the side chain
can interact with the phenyl group of Phe380 through the forma-
the residue, which was then extracted with ethyl acetate
(80 mL ꢂ 3). The extract was washed with saturated NaCl solution
(30 mL ꢂ 3), dried over anhydrous Na2SO4 and concentrated. The
residue was crystallized to afford a white solid 2 32.2 g, in 78%
yield: m.p. 51e53 ꢀC.
tion of pep face-to-edge interaction.
6.2. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(2-fluoro-
4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (3)
5. Conclusion
To
a stirred mixture of 1-[2-(2,4-difluorophenyl)-2,3-epox-
ypropyl]-1H-1,2,4-triazole methanesulfonate (1) (1.65 g, 0.005 mol),
C2H5OH (30 mL) and N(C2H5)3 (3 mL), 1-[4-nitro-2-(trifluoromethyl)
phenyl]piperazine (2) (1.65 g, 0.006 mol) was added and heated at
70e80 ꢀC for 5 h. The reaction was monitored by TLC. After filtration,
the filtrate was evaporated under reduced pressure. Water (30 mL)
was added to the residue, which was then extracted with ethyl
acetate (80 mL ꢂ 3). The extract was washed with saturated NaCl
solution (20 mL ꢂ 3), dried over anhydrous Na2SO4 and evaporated.
The residue was crystallized from C2H5OH to afford a white solid 3
1.92 g, in 75% yield: m.p. 115e117 ꢀC. 1H NMR (DMSO-d6): 6.80e8.48
(6H, m, Ar-H), 7.81, 8.13 (2H, ss, triazoleeH), 4.51e4.60 (2H, dd,
J ¼ 15 Hz, triazoleeCH2e), 2.50e3.01 (8H, m, piperazineeH),
2.73e3.17 (2H, dd, J ¼ 15 Hz, CH2epiperazinee), 5.10 (1H, s, OH). IR
(KBr): 3200, 2940, 2893, 1605, 1514, 1338, 1257, 1136, 918 cmꢃ1. LC-
MS, m/z Calcd. for C22H21F5N6O3, 512.2, found [M þ H]þ 513.3.
In summary, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoro
-phenyl)-3-[(4-substituted trifluoromethyl phenyl)-piperazin-1-
yl]-propan-2-ols were successfully designed and synthesized.
In vitro antifungal activity assay indicated that the trifluoromethyl
phenyl group of the side chain greatly influences the antifungal
activity of these analogs against Candida species. This observation
was explainable by a molecular model resulting from the compu-
tational docking simulation. The piperazinyl side chain of the
compound 7a is oriented into substrate access channel 2 (FG loop)
and forms hydrophobic and van der waals interactions with
surrounding hydrophobic residues. The trifluoromethyl phenyl
group of the side chain can interacts with the phenyl group of
Phe380 through the 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.
6.3. 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[4-(4-amino-
2-(trifluoromethyl)phenyl)piperazin-1-yl]-propan-2-ol (4)
6. Experimental part
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluor-
ophenyl)-3-[4-(2-fluoro-4-nitro-phenyl)-piperazin-1-yl]-propan-
2-ol (3) (2.56 g, 0.005 mol), C2H5OH (30 mL) and 85% hydrazine
hydrate (8 mL), freshly prepared Raney Ni (0.5 g) was added and
was heated at 70e80 ꢀC for 3 h. The reaction was monitored by TLC.
After filtration, the filtrate was evaporated under reduced pressure.
Water (20 mL) was added to the residue, which was then extracted
with ethyl acetate (60 mL ꢂ 3). The extract was washed with
saturated NaCl solution (20 mL ꢂ 3), dried over anhydrous Na2SO4
and evaporated. The residue was crystallized from ethyl acetate to
afford a white solid 4 2.00 g, in 83% yield: m.p. 161e163 ꢀC. 1H NMR
(DMSO-d6): 6.75e7.60 (6H, m, Ar-H), 7.78, 8.16 (2H, ss, triazoleeH),
4.52e4.54 (2H, dd, J ¼ 15 Hz, triazoleeCH2e), 2.44e2.72 (8H, m,
piperazineeH), 2.70e3.16 (2H, dd, J ¼ 15 Hz, CH2epiperazinee),
5.28 (1H, s, OH), 3.52 (2H, s, NH2). IR (KBr): 3404, 3212, 3117, 3053,
2950, 2835, 1616, 1514, 1274, 1139, 965 cmꢃ1. LC-MS, m/z Calcd. for
C22H21F5N6O3, 482.2, found [M þ H]þ 483.3.
In our studies, the 3D structures of the designed azoles were
built by the Builder module within InsightII 2000 software package.
Then, the flexible ligand docking procedure in the Affinity module
within InsightII was used to define the lowest energy position for
the substrate using a Monte Carlo docking protocol. All the atoms
within a defined radius (8 Å) of the substrate were allowed to move.
The solvation grid supplied with the affinity Program was used. If
the resulting substrate/enzyme system was within a predefined
energy tolerance of the previous structure, the system was sub-
jected to minimization. The resulting structure was accepted on the
basis of energy check, which used the Metropolis criterion, and also
a check of RMS distance of the new structure versus the structure
found so far. The final conformation were obtained through
a simulation annealing procedure from 500 to 300 K, and then
5000 rounds of energy minimization were performed to reach
a convergence, where the resulting interaction energy values were
used to define a rank order.
Melting points were measured on a Yamato MP-21 melting-point
apparatus and are uncorrected. Infrared spectra were recorded in
potassium bromide disks on a HITACHI270-50 spectrophotometer.
1H NMR spectra were recorded in CDCl3/DMSO unless otherwise
indicated with a Bruker AC-300P spectrometer, using TMS as
internal standard. The HPLC-MS were recorded on Agilent 1100
series LC/MS. The solvents and reagents were used as received or
dried prior to use as needed.
6.4. General procedure for the target compound 5ae5i, 6ae6j,
7ae7q, 8ae8d
To a stirred mixture of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluor-
ophenyl)-3-[4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-
yl]-propan-2-ol (4) (0.001 mol), DMAP (100 mg) and EDCI (200 mg)
in 50 mL dichloromethane under 0 ꢀC and substituted acid
(0.001 mol) were added and stirred for 8e12 h. The reaction was
monitored by TLC. After filtration, the filtrate was evaporated under
reduced pressure. The residue was then extracted with ethyl
acetate (60 mL ꢂ 3). The extract was washed with saturated NaCl
solution (20 mL ꢂ 3), dried over anhydrous Na2SO4 and evaporated.
The residue was crystallized from ethyl acetate to afford the title
compounds.
6.1. 1-[4-nitro-2-(trifluoromethyl)phenyl]piperazine (2)
To a stirred mixture of 1-chloro-4-nitro-2-(trifluoromethyl)
benzene (33.9 g, 150 mmol) and CH3CN (300 mL), piperazine
anhydrous (26.94 g, 300 mmol) was added and reflux for 10 h. The
reaction was monitored by TLC. After filtration, the filtrate was
evaporated under reduced pressure. Water (60 mL) was added to

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X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
6.5. The title compounds were characterized as follows
(s, 2H, triazoleeCH2), 2.48e2.77 (m, 8H, piperazineeH), 2.71e3.18
(d, 2H, CH2epiperazine), 2.32e2.37 (t, 2H, eCH2e), 1.67e1.72 (m,
6.5.1. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
acetamide (5a)
2H, eCH2e),1.35e1.43 (m, 2H, eCH2e), 0.91e0.96 (t, 3H, eCH3); 13
C
NMR (75 MHz, CDCl3) d: 171.54, 150.37, 146.86, 144.79, 136.49,
129.82, 126.35, 126.28, 125.65, 124.87, 123.44, 122.32, 117.01, 110.87,
110.50, 104.08, 103.65, 103.33, 74.54, 63.65, 55.73, 54.62, 53.27,
36.30, 30.84, 23.82, 13.79. IR (KBr): 3255, 3185, 3116, 3066, 2960,
2934, 2875, 1689, 1616, 1550, 1504, 1271, 1134 cmꢃ1. LC-MS, m/z
Calcd. for C27H31F5N6O2, 566.2, found [M þ H]þ 567.4.
Mp: 168e170 ꢀC; Yield: 81%; 1H NMR (300 MHz, CDCl3)
d: 6.78e7.78 (6H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.53e4.54
(2H, dd, triazoleeCH2e), 2.46e2.76 (8H, m, piperazineeH),
2.74e3.17 (2H, dd, CH2epiperazinee), 2.17 (s, 3H, eCH3); 13C NMR
(75 MHz, CDCl3) d: 168.51, 150.42, 146.94, 144.89, 136.37, 129.75,
126.27, 126.10, 125.63, 124.97, 123.43, 122.01, 116.89, 110.80, 110.54,
104.09, 103.72, 103.38, 74.54, 63.61, 55.70, 54.61, 53.25, 23.89. IR
(KBr): 3420, 3302, 3186, 3069, 2947, 2827, 1694, 1616, 1547, 1503,
1232, 1135 cmꢃ1. LC-MS, m/z Calcd. for C24H25F5N6O2, 524.2, found
[M þ H]þ 525.3.
6.5.6. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
pivalamide (5f)
Mp: 99e101 ꢀC; Yield: 76%; 1H NMR (300 MHz, CDCl3)
d:
6.78e7.76 (m, 6H, Ar-H), 7.79, 8.17 (ss, 2H, triazoleeH), 4.53e4.54
(s, 2H, triazoleeCH2), 2.50e2.78 (m, 8H, piperazineeH), 2.69e3.18
(d, 2H, CH2epiperazine), 1.30 (s, 9H, eCH3); 13C NMR (75 MHz,
6.5.2. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
propionamide (5b)
CDCl3) d: 174.92, 150.46, 146.60, 144.56, 136.59, 129.86, 126.34,
126.19, 125.99, 125.61, 124.88, 123.53, 117.08, 110.78, 110.51, 104.05,
103.69, 103.34, 74.61, 74.54, 63.66, 55.72, 54.61, 53.28, 34.93, 19.22.
IR (KBr): 3374, 3123, 2965, 2875, 2824, 1669, 1617, 1503, 1383, 1273,
1137 cmꢃ1. LC-MS, m/z Calcd. for C27H31F5N6O2, 566.2, found
[M þ H]þ 567.3.
Mp: 173e175 ꢀC; Yield: 71%; 1H NMR (300 MHz, CDCl3)
d:
6.78e7.76 (6H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.53e4.54
(2H, dd, triazoleeCH2e), 2.46e2.77 (8H, m, piperazineeH),
2.68e3.17 (2H, dd, CH2epiperazinee), 2.35e2.42 (q, 2H, eCH2e),
1.21e1.24 (t, 3H, eCH3); 13C NMR (75 MHz, CDCl3)
d: 172.21, 150.42,
146.86, 144.89,136.43,129.78,126.27, 125.62,124.96, 123.43,116.90,
110.82, 110.56, 103.73, 74.61, 63.61, 55.69, 54.61, 53.26, 29.44, 9.51.
IR (KBr): 3420, 3300, 3186, 3066, 2977, 2943, 2848, 1685, 1616,
1550, 1504, 1271, 1135 cmꢃ1. LC-MS, m/z Calcd. for C25H27F5N6O2,
538.2, found [M þ H]þ 539.3.
6.5.7. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
hexanamide (5g)
Mp: 107e109 ꢀC; Yield: 72%; 1H NMR (300 MHz, CDCl3)
d:
6.78e7.76 (m, 6H, Ar-H), 7.79,8.17 (ss, 2H, triazoleeH), 4.53e4.54 (s,
2H, triazoleeCH2), 2.48e3.19 (m, 8H, piperazineeH), 3.14e3.19 (d,
2H, CH2epiperazine), 2.31e2.36 (t, 2H, eCH2e), 1.68e1.73 (m, 2H,
eCH2e), 1.26e1.37 (m, 4H, eCH2e), 0.87e0.92 (t, 3H, eCH3); 13C
6.5.3. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
butyramide (5c)
NMR (75 MHz, CDCl3) d: 171.54, 150.39, 146.86, 144.89, 136.49,
Mp: 189e191 ꢀC; Yield: 68%; 1H NMR (300 MHz, CDCl3)
d:
129.80, 126.35, 126.18, 125.65, 124.87, 123.44, 122.02, 117.01, 110.77,
110.50, 104.04, 103.68, 103.33, 74.54, 63.65, 55.73, 54.61, 53.27,
36.30, 30.84, 24.71, 21.88, 13.79. IR (KBr): 3420, 3307, 3261, 3119,
3066, 2957, 2933, 2859, 1693, 1616, 1542, 1503, 1383, 1136,
1013 cmꢃ1. LC-MS, m/z Calcd. for C28H33F5N6O2, 580.3, found
[M þ H]þ 581.4.
6.78e7.63 (m, 6H, Ar-H), 7.79, 8.16 (ss, 2H, triazoleeH), 4.53e4.54
(s, 2H, triazoleeCH2), 2.47e2.77 (m, 8H, piperazineeH), 2.71e3.17
(d, 2H, CH2epiperazine), 2.30e2.35 (t, 2H, eCH2e), 1.71e1.78 (m,
2H, eCH2e), 0.97e1.01 (t, 3H, eCH3); 13C NMR (75 MHz, CDCl3)
d:
171.35, 150.42, 146.90, 144.87, 136.38, 129.76, 126.29, 126.01, 125.63,
124.95, 123.45, 116.93, 110.82, 110.54, 104.08, 103.73, 103.37, 74.59,
74.52, 63.61, 55.71, 54.61, 53.25, 18.45, 13.52. IR (KBr): 3301, 3254,
3184, 3110, 3065, 2875, 1688, 1616, 1551, 1505, 1383, 1134,
1017 cmꢃ1. LC-MS, m/z Calcd. for C26H29F5N6O2, 552.2, found
[M þ H]þ 553.3.
6.5.8. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
heptanamide (5h)
Mp: 83e85 ꢀC; Yield: 71%; 1H NMR (300 MHz, CDCl3)
d:
6.77e7.63 (m, 6H, Ar-H), 7.79,8.16 (ss, 2H, triazoleeH), 4.53e4.54 (s,
2H, triazoleeCH2), 2.47e2.76 (m, 8H, piperazineeH), 2.70e3.18 (d,
2H, CH2epiperazine), 2.32e2.37 (t, 2H, eCH2e), 1.65e1.73 (m, 2H,
eCH2e), 1.29e1.38 (m, 6H, eCH2-), 0.86e0.91 (t, 3H, eCH3); 13C
6.5.4. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
isobutyramide (5d)
Mp: 189e191 ꢀC; Yield: 69%; 1H NMR (300 MHz, CDCl3)
d:
NMR (75 MHz, CDCl3) d: 171.56, 150.39, 146.85, 144.91, 136.53,
6.78e7.79 (m, 6H, Ar-H), 7.80, 8.16 (ss, 2H, triazoleeH), 4.53e4.55
(s, 2H, triazoleeCH2), 2.50e2.76 (m, 8H, piperazineeH),
2.69e3.18(d, 2H, CH2epiperazine), 2.45e2.48 (m, H, eCHe),
129.84, 126.37, 125.99, 125.63, 124.93, 123.46, 116.91, 110.77, 110.51,
104.05, 103.68, 103.33, 74.56, 63.70, 55.70, 54.62, 53.28, 36.34,
31.04, 28.30, 24.99, 21.98, 13.91. IR (KBr): 3310, 3121, 3065, 2957,
2931, 2856, 2824, 1670, 1617, 1541, 1503, 1383, 1136, 1057 cmꢃ1. LC-
MS, m/z Calcd. for C29H35F5N6O2, 594.3, found [M þ H]þ 595.4.
1.22e1.26 (d, 6H, eCH3); 13C NMR (75 MHz, CDCl3)
d: 175.50,
150.40, 146.90, 144.90, 136.58, 129.81, 126.37, 126.19, 125.99, 125.63,
124.88, 123.57, 117.08, 110.78, 110.51, 104.05, 103.69, 103.34, 74.61,
74.54, 63.66, 55.72, 54.61, 53.28, 34.93, 19.37. IR (KBr): 3310, 3120,
3166, 2969, 2879, 2823, 1672, 1616, 1540, 1502, 1273, 1137 cmꢃ1. LC-
MS, m/z Calcd. for C26H29F5N6O2, 552.2, found [M þ H]þ 553.3.
6.5.9. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
octanamide (5i)
Mp: 62e64 ꢀC; Yield: 65%; 1H NMR (300 MHz, CDCl3)
d:
6.5.5. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
pentanamide (5e)
6.78e7.63 (m, 6H, Ar-H), 7.79,8.17 (ss, 2H, triazoleeH), 4.53e4.54 (s,
2H, triazoleeCH2), 2.47e2.76 (m, 8H, piperazineeH), 2.70e3.17 (d,
2H, CH2epiperazine), 2.31e2.36 (t, 2H, eCH2e), 1.68e1.73 (m, 2H,
eCH2e), 1.26e1.37 (m, 8H, eCH2e), 0.85e0.89 (t, 3H, eCH3); 13C
Mp: 168e170 ꢀC; Yield: 78%; 1H NMR (300 MHz, CDCl3)
d:
6.78e7.76 (m, 6H, Ar-H), 7.79, 8.17 (ss, 2H, triazoleeH), 4.53e4.54

X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
3173
NMR (75 MHz, CDCl3)
d
: 171.52, 150.44, 146.78, 144.96, 136.52,
6.5.14. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-methylbenzamide (6e)
129.84, 126.34, 125.88, 125.60, 124.95, 123.42, 116.87, 110.68, 110.59,
104.05, 103.68, 103.37, 74.56, 63.70, 55.73, 54.62, 53.24, 36.34,
31.04, 28.28, 24.99, 22.33, 21.98, 13.94. IR (KBr): 3307, 3120, 3064,
2955, 2929, 2855, 1670, 1616, 1541, 1502, 1383, 1136, 1013 cmꢃ1. LC-
MS, m/z Calcd. for C30H37F5N6O2, 608.3, found [M þ H]þ 609.4.
Mp: 174e176 ꢀC; Yield: 74%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.97 (10H, m, Ar-H), 7.79,8.15 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.48e2.79 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 2.43 (3H, s, eCH3); 13C NMR
(75 MHz, CDCl3) d: 165.40, 159.94, 150.43, 147.41, 144.88, 141.83,
6.5.10. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
benzamide (6a)
136.28, 131.58, 129.75, 128.92, 127.68, 126.27, 126.10, 125.88, 125.51,
124.69, 122.07, 118.37, 110.81, 110.56, 104.10, 103.75, 103.38, 74.60,
74.53, 63.62, 55.71, 54.62, 53.26, 20.98. IR (KBr): 3291, 3131, 3078,
2955, 2884, 2815, 1669, 1615, 1541, 1505, 1420, 1383, 1137,
1041 cmꢃ1. LC-MS, m/z Calcd. for C30H29F5N6O2, 600.2, found
[M þ H]þ 601.3.
Mp: 173e175 ꢀC; Yield: 78%; 1H NMR (300 MHz, CDCl3)
d:
6.82e7.88 (11H, m, Ar-H), 7.79, 8.15 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.49e2.80 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d:
165.61, 163.21, 157.28, 150.44, 147.54, 144.89, 136.22, 134.49, 131.76,
129.76, 128.40, 127.66, 126.29, 125.91, 125.55, 124.74, 122.07, 118.41,
110.84, 110.55, 104.10, 103.75, 103.39, 74.54, 63.62, 55.73, 54.62,
53.27. IR (KBr): 3295, 3110, 3075, 3015, 2951, 2888, 2813, 2750,
1668, 1615, 1541, 1505, 1384, 1135, 1042 cmꢃ1. LC-MS, m/z Calcd. for
C29H27F5N6O2, 586.2, found [M þ H]þ 587.3.
6.5.15. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-ethylbenzamide (6f)
Mp: 98e100 ꢀC; Yield: 71%; 1H NMR (300 MHz, CDCl3)
d:
6.84e7.86 (10H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.48e2.84 (8H, m, piperazineeH),
2.69e3.17 (2H, dd, CH2epiperazinee), 2.69e2.77 (2H, m, CH2),
6.5.11. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-fluorobenzamide (6b)
1.25e1.30 (3H, t, CH3); 13C NMR (75 MHz, CDCl3)
d: 165.40, 159.88,
150.37, 147.92, 147.34, 144.82, 136.25, 131.83, 129.70, 129.16, 127.71,
126.21, 126.07, 125.83, 125.63, 124.73, 122.00, 118.20, 110.75, 110.49,
104.03, 103.68,103.32, 74.54, 74.48, 63.57, 55.64, 54.56, 53.21, 28.01,
15.26. IR (KBr): 3417, 3274, 3117, 2962, 2876, 2819, 1652, 1615, 1541,
1499, 1384, 1186, 1015 cmꢃ1. LC-MS, m/z Calcd. for C31H31F5N6O2,
614.2, found [M þ H]þ 615.3.
Mp: 204e206 ꢀC; Yield: 75%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.90 (10H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.53e4.54
(2H, dd, triazoleeCH2e), 2.48e2.79 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 5.30 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) d: 164.55, 163.32, 157.26, 150.44, 147.61, 144.82,
136.68, 133.17, 129.63, 129.35, 128.43, 126.35, 126.13, 125.95, 125.48,
124.79, 122.07, 118.45, 110.80, 110.54, 104.33, 103.21, 103.16, 74.67,
74.58, 63.69, 55.76, 54.66, 53.27. IR (KBr): 3294, 3113, 3078, 3016,
2949, 2887, 2847, 2821, 2753, 1669, 1607, 1547, 1506, 1384, 1164,
1041 cmꢃ1. LC-MS, m/z Calcd. for C29H26F6N6O2, 604.2, found
[M þ H]þ 605.3.
6.5.16. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-isopropylbenzamide (6g)
Mp: 101e103 ꢀC; Yield: 70%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.90 (10H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.50e2.81 (8H, m, piperazineeH),
2.72e3.18 (2H, dd, CH2epiperazinee), 1.36 (9H, s, CH3); 13C NMR
6.5.12. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-chlorobenzamide (6c)
(75 MHz, CDCl3) d: 167.62, 155.04, 150.42, 147.41, 144.88, 136.31,
131.74, 129.76, 129.12, 127.52, 126.27, 126.10, 125.89, 125.69, 125.51,
124.80, 118.21, 110.81, 110.54, 104.09, 103.73, 74.60, 74.53, 63.62,
55.72, 54.61, 53.26, 34.66, 30.88. IR (KBr): 3420, 3124, 2963, 2907,
2870, 2824, 1653, 1615, 1539, 1504, 1384, 1136, 1013 cmꢃ1. LC-MS,
m/z Calcd. for C33H35F5N6O2, 642.3, found [M þ H]þ 643.4.
Mp: 201e203 ꢀC; Yield: 76%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.89 (10H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.49e4.59
(2H, dd, triazoleeCH2e), 2.49e2.80 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d:
164.47, 163.39, 157.28, 150.44, 147.66, 144.89, 136.68, 133.16, 129.61,
129.30, 128.46, 126.31, 126.13, 125.95, 125.68, 124.79, 122.05, 118.45,
110.83, 110.55, 104.09, 103.74, 103.38, 74.60, 74.54, 63.63, 55.75,
54.63, 53.27. IR (KBr): 3289, 3253, 3189, 3136, 3077, 2952, 2843,
2750, 1672, 1614, 1548, 1504, 1384, 1135, 1041 cmꢃ1. LC-MS, m/z
Calcd. for C29H26ClF5N6O2, 620.2, found [M þ H]þ 621.3.
6.5.17. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-methoxybenzamide (6h)
Mp: 139e141 ꢀC; Yield: 68%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.87 (10H, m, Ar-H), 7.79, 8.16 (2H, ss, triazoleeH), 4.53e4.54
(2H, dd, triazoleeCH2e), 2.48e2.79 (8H, m, piperazineeH),
2.70e3.19(2H, dd, CH2epiperazinee), 3.87 (3H, s, eOCH3); 13C NMR
6.5.13. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
2,4-dichlorobenzamide (6d)
(75 MHz, CDCl3) d: 164.98, 162.08, 159.95, 150.45, 147.30, 144.90,
136.45, 129.64, 126.49, 126.30, 125.92, 125.73, 125.54, 124.76,
124.66, 122.11, 118.32, 113.63, 110.83, 110.57, 104.11, 103.76, 103.38,
74.61, 63.64, 55.73, 55.40, 54.65, 53.29. IR (KBr): 3432, 3284, 3245,
3185, 3129, 3069, 2951, 2821, 1673, 1607, 1577, 1504, 1383, 1175,
1022 cmꢃ1. LC-MS, m/z Calcd. for C30H29F5N6O3, 616.2, found
[M þ H]þ 617.3.
Mp: 193e195 ꢀC; Yield: 80%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.97 (9H, m, Ar-H), 7.80, 8.17 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.45e2.80 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 5.36 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) d: 164.18, 159.92, 150.40, 147.84, 146.30, 144.88,
135.83, 131.26, 130.35, 129.79, 127.43, 126.34, 126.17, 125.69,
124.20, 121.95, 117.69, 110.79, 110.53, 104.06, 103.70, 103.35, 74.61,
74.53, 63.65, 55.75, 54.81, 54.58, 53.25. IR (KBr): 3420, 3254, 3121,
2954, 2883, 2823, 1670, 1616, 1541, 1501, 1456, 1383, 1137,
1050 cmꢃ1. LC-MS, m/z Calcd. for C29H25Cl2F5N6O2, 654.1, found
[M þ H]þ 655.2.
6.5.18. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
4-(trifluoromethoxy)-benzamide (6i)
Mp: 177e179 ꢀC; Yield: 75%; 1H NMR (300 MHz, CDCl3)
d:
6.79e7.91 (10H, m, Ar-H), 7.79, 8.15 (2H, ss, triazoleeH), 4.49e4.54
(2H, dd, triazoleeCH2e), 2.48e2.79 (8H, m, piperazineeH),

3174
X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
2.70e3.19 (2H, dd, CH2epiperazinee), 5.33 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) : 165.04, 152.44, 147.86, 144.89, 135.63, 135.30,
103.37, 74.61, 74.54, 63.64, 55.74, 54.62, 53.25. IR (KBr): 3420, 3299,
3121, 3066, 2952, 2884, 2823, 1683, 1616, 1584, 1541, 1501, 1383,
1321, 1137, 1012 cmꢃ1. LC-MS, m/z Calcd. for C31H28F6N6O2, 630.2,
found [M þ H]þ 631.3.
d
131.83, 129.73, 129.57, 129.07, 128.38, 126.37, 126.15, 125.93, 125.58,
124.86, 124.23, 122.09, 118.58, 110.82, 110.54, 104.09, 103.77, 103.30,
74.62, 63.63, 55.73, 54.61, 53.27. IR (KBr): 3394, 3113, 3078, 3026,
2949, 2887, 2847, 2811, 2753, 1660, 1607, 1547, 1511, 1384, 1134,
1028 cmꢃ1 LC-MS, m/z Calcd. for C30H26F8N6O3, 670.2, found
[M þ H]þ 671.3.
6.5.23. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(4-fluorophenyl)-acrylamide (7d)
Mp: 179e181 ꢀC; Yield: 74%; 1H NMR (300 MHz, CDCl3)
d:
6.5.19. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(trifluoromethyl)-benzamide (6j)
6.43e7.90 (10H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.82, 7.56
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.47e2.78
(8H, m, piperazineeH), 2.70e3.19 (2H, dd, CH2epiperazinee); 13C
Mp: 109e111 ꢀC; Yield: 79%; 1H NMR (300 MHz, CDCl3)
d:
NMR (75 MHz, CDCl3) d: 163.52, 160.68, 159.90, 157.25, 150.43,
6.80e8.12 (10H, m, Ar-H), 7.80, 8.17 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.49e2.81 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 5.32 (1H, s, OH); 13C NMR
147.29, 144.87, 139.19, 134.32, 133.51, 129.74, 128.40, 126.46, 125.72,
125.02, 123.68, 122.60, 121.97, 117.22, 110.74, 110.53, 104.07, 103.71,
103.36, 74.53, 63.60, 55.71, 54.64, 53.20. IR (KBr): 3420, 3245, 3195,
3129, 3056, 2952, 2881, 2829, 1672, 1630, 1601, 1544, 1505, 1383,
1326, 1180, 1012 cmꢃ1. LC-MS, m/z Calcd. for C31H28F6N6O2, 630.2,
found [M þ H]þ 631.3.
(75 MHz, CDCl3) d: 164.04, 150.44, 147.85, 144.89, 135.83, 135.33,
131.83, 129.73, 129.47, 129.04, 128.30, 126.30, 126.14, 125.93,
125.56, 124.86, 124.23, 122.04, 118.58, 110.82, 110.55, 104.09,
103.74, 103.38, 74.62, 63.63, 55.72, 54.60, 53.27. IR (KBr): 3289,
3120, 3070, 2957, 2884, 2823, 2678, 1663, 1616, 1599, 1500, 1384,
1164, 1012 cmꢃ1. LC-MS, m/z Calcd. for C30H26F8N6O2, 654.2, found
[M þ H]þ 655.3.
6.5.24. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(2-chlorophenyl)-acrylamide (7e)
Mp: 146e148 ꢀC; Yield: 76%; 1H NMR (300 MHz, CDCl3)
d:
6.5.20. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
cinnamamide (7a)
6.53e8.17 (10H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.82,7.56
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.48e2.78
(8H, m, piperazineeH), 2.71e3.19 (2H, dd, CH2epiperazinee); 13C
Mp: 193e195 ꢀC; Yield: 71%; 1H NMR (300 MHz, CDCl3)
d:
NMR (75 MHz, CDCl3) d: 160.20, 157.54, 156.95, 154.43, 154.27,
6.52e7.92 (11H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.85, 7.56
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.47e2.77
(8H, m, piperazineeH), 2.70e3.18 (2H, dd, CH2-piperazine-); 13C
147.43, 144.42, 141.88, 133.14, 130.54, 129.38, 128.22, 126.76, 124.78,
123.28, 122.74, 120.76, 118.99, 114.32, 107.81, 107.55, 101.09, 100.72,
100.37, 71.61, 71.54, 60.63, 52.73, 51.61, 50.25. IR (KBr): 3395, 3117,
3056, 2953, 2881, 2820, 1655, 1616, 1550, 1499, 1384, 1323, 1180,
1015 cmꢃ1. LC-MS, m/z Calcd. for C31H28ClF5N6O2, 646.2, found
[M þ H]þ 647.3.
NMR (75 MHz, CDCl3) d: 163.73, 160.32, 159.87, 150.43, 147.25,
144.90, 140.57, 136.38, 134.58, 129.87, 129.00, 127.78, 126.30,
125.72, 123.71, 122.02, 121.87, 117.22, 110.82, 110.55, 104.10, 103.74,
103.38, 74.62, 74.56, 63.66, 55.73, 54.63, 53.26. IR (KBr): 3420,
3300, 3120, 3062, 2952, 2884, 2823, 1669, 1598, 1510, 1300, 1178,
1015 cmꢃ1. LC-MS, m/z Calcd. for C31H29F5N6O2, 612.2, found
[M þ H]þ 613.3.
6.5.25. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3-chlorophenyl)-acrylamide (7f)
Mp: 159e161 ꢀC; Yield: 70%; 1H NMR (300 MHz, CDCl3)
d:
6.5.21. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(2-fluorophenyl)-acrylamide (7b)
6.51e7.90 (10H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.82, 7.56
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.48e2.78
(8H, m, piperazineeH), 2.71e3.15 (2H, dd, CH2epiperazinee); 13C
Mp: 142e144 ꢀC; Yield: 73%; 1H NMR (300 MHz, CDCl3)
d:
NMR (75 MHz, CDCl3) d: 163.34, 160.53, 160.12, 157.26, 150.42,
6.68e7.84 (10H, m, Ar-H), 7.81,8.18 (2H, ss, triazoleeH), 6.85, 7.56
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.48e2.78
(8H, m, piperazineeH), 2.69e3.18 (2H, dd, CH2epiperazinee); 13C
147.32, 144.87, 138.88, 136.87, 133.75, 130.70, 129.77, 126.83, 126.27,
126.12, 124.96, 123.70, 121.98, 117.34, 110.80, 110.53, 104.06, 103.71,
103.35, 74.58, 74.51, 63.62, 55.75, 54.61, 53.24. IR (KBr): 3395, 3108,
3057, 2948, 2883, 2820, 1668, 1624, 1551, 1499, 1383, 1321, 1181,
1015 cmꢃ1. LC-MS, m/z Calcd. for C31H28ClF5N6O2, 646.2, found
[M þ H]þ 647.3.
NMR (75 MHz, CDCl3) d: 160.23, 158.21, 156.95, 154.43, 154.27,
147.43, 144.42, 141.88, 133.14, 130.54, 129.38, 128.22, 126.76, 124.78,
123.28, 122.74, 120.76, 118.99, 114.32, 107.81, 107.55, 101.09, 100.72,
100.37, 71.61, 71.54, 60.63, 52.73, 51.41, 50.35. IR (KBr): 3374, 3116,
3061, 2953, 2882, 2820, 1670, 1617, 1549, 1499, 1383, 1135,
1014 cmꢃ1. LC-MS, m/z Calcd. for C31H28F6N6O2, 630.2, found
[M þ H]þ 631.3.
6.5.26. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(4-chlorophenyl)-acrylamide (7g)
Mp: 202e204 ꢀC; Yield: 77%; 1H NMR (300 MHz, CDCl3)
d:
6.5.22. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3-fluorophenyl)-acrylamide (7c)
6.48e7.89 (10H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.83,
7.57(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e),
2.48e2.83 (8H, m, piperazineeH), 2.69e3.19 (2H, dd,
Mp: 145e147 ꢀC; Yield: 75%; 1H NMR (300 MHz, CDCl3)
d:
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 163.47, 160.68,
6.50e7.90 (10H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.82, 7.57
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.40e2.79
(8H, m, piperazineeH), 2.72e3.18 (2H, dd, CH2epiperazinee); 13C
NMR (75 MHz, CDCl3) d: 164.08, 160.84, 160.71, 160.55, 150.43,
147.35, 144.89, 139.20, 137.24, 134.24, 130.97, 129.77, 126.32, 125.74,
125.03, 123.47, 122.00, 117.29, 116.34, 110.82, 110.55, 104.09, 103.73,
159.93, 157.25, 150.43, 147.29, 144.87, 139.19, 134.32, 133.51, 129.74,
128.40, 126.46, 125.72, 125.02, 123.68, 122.60, 121.97, 117.22, 110.79,
110.53, 104.07, 103.71, 103.36, 74.53, 63.60, 55.71, 54.60, 53.23. IR
(KBr): 3420, 3246, 3115, 3057, 2952, 2883, 2826, 2756, 1673, 1629,
1542, 1503, 1383, 1318, 1143, 1012 cmꢃ1. LC-MS, m/z Calcd. for
C31H28ClF5N6O2, 646.2, found [M þ H]þ 647.3.

X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
3175
6.5.27. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-
phenyl)-3-(2,3-dichlorophenyl)-acrylamide (7h)
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 3.92,
3.93(6H, ss, eOCH3), 2.47e2.79 (8H, m, piperazineeH), 2.72e3.18
(2H, dd, CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 164.11,
Mp: 147e149 ꢀC; Yield: 69%; 1H NMR (300 MHz, CDCl3)
d:
160.73, 160.17, 160.00, 157.41, 150.47, 148.98, 144.92, 140.75, 136.60,
129.81, 127.40, 126.33, 125.69, 125.00, 123.59, 121.93, 119.48, 117.20,
110.57, 110.02, 104.11, 103.76, 103.40, 74.62, 74.56, 63.68, 55.77,
55.38, 54.68, 53.30. IR (KBr): 3445, 3123, 3063, 2996, 2944, 2813,
1669, 1622, 1599, 1549, 1501, 1383, 1314, 1225, 1136, 1026 cmꢃ1. LC-
MS, m/z Calcd. for C33H33F5N6O4, 672.3, found [M þ H]þ 673.5.
6.40e7.74 (9H, m, Ar-H), 7.81,8.19 (2H, ss, triazoleeH), 6.83,7.57(2H,
ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.49e2.79 (8H, m,
piperazineeH), 2.68e3.19 (2H, dd, CH2epiperazinee); 13C NMR
(75 MHz, CDCl3) d: 163.22, 160.68, 159.93, 157.25, 150.42, 147.36,
144.88,139.37,135.50,132.00,129.66,128.03,126.29,125.71,125.02,
123.74, 122.85, 121.97, 117.27, 110.81, 110.53, 104.07, 103.71, 103.36,
74.53, 63.60, 55.71, 54.60, 53.24. IR (KBr): 3419, 3274, 3116, 3059,
2951, 2883, 2823, 1684, 1617, 1542, 1500, 1384, 1319, 1134,
1012 cmꢃ1. LC-MS, m/z Calcd. for C31H27Cl2F5N6O2, 680.2, found
[M þ H]þ 681.3.
6.5.32. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(2,6-dimethoxyphenyl)-acrylamide (7m)
Mp: 109e111 ꢀC; Yield: 65%; 1H NMR (300 MHz, CDCl3)
d:
6.64e7.99 (9H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.83, 7.33
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 3.80, 3.85(6H,
ss, eOCH3), 2.49e2.81 (8H, m, piperazineeH), 2.71e3.17 (2H, dd,
CH2epiperazinee); IR (KBr): 3299, 3120, 3067, 3000, 2949, 2833,
1682, 1618, 1540, 1499, 1383, 1316, 1136, 1013 cmꢃ1. LC-MS, m/z
Calcd. for C33H33F5N6O4, 672.3, found [M þ H]þ 673.4.
6.5.28. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3-bromophenyl)-acrylamide (7i)
Mp: 168e170 ꢀC; Yield: 68%; 1H NMR (300 MHz, CDCl3)
d:
6.50e7.86 (10H, m, Ar-H), 7.81,8.18 (2H, ss, triazoleeH),
6.83,7.57(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e),
2.41e2.79 (8H, m, piperazineeH), 2.71e3.19 (2H, dd,
6.5.33. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(2-nitrophenyl)-acrylamide (7n)
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 163.33, 160.70,
160.54, 157.27, 150.43, 147.31, 144.87, 138.79, 136.22, 132.24, 129.24,
126.52, 126.30, 126.16, 125.62, 125.43, 122.30, 121.99, 117.31, 110.82,
110.55, 104.07, 103.71, 103.36, 74.56, 74.50, 63.63, 55.77, 54.63,
53.25. IR (KBr): 3404, 3264, 3109, 3060, 2947, 2883, 2820, 1669,
1617, 1548, 1499, 1383, 1320, 1179, 1014 cmꢃ1. LC-MS, m/z Calcd. for
C31H28BrF5N6O2, 690.1, found [M þ H]þ 691.3.
Mp: 175e177 ꢀC; Yield: 75%; 1H NMR (300 MHz, CDCl3)
d:
6.42e8.12 (10H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.83, 7.57
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.48e2.79
(8H, m, piperazineeH), 2.71e3.19 (2H, dd, CH2epiperazinee); 13C
NMR (75 MHz, CDCl3) d: 163.24, 162.86, 160.71, 157.29, 150.44,
148.25, 147.50, 144.89, 136.05, 130.43, 129.86, 128.75, 126.14, 125.77,
125.01, 124.72, 123.80, 121.99, 117.43, 110.82, 110.56, 104.08, 103.72,
103.37, 74.60, 74.54, 63.64, 55.76, 54.63, 53.25. IR (KBr): 3420, 3274,
3112, 3058, 2948, 2882, 2825, 1674, 1616, 1571, 1516, 1501, 1384,
1320, 1227, 1137, 1011 cmꢃ1. LC-MS, m/z Calcd. for C31H28F5N7O4,
657.2, found [M þ H]þ 658.4.
6.5.29. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(4-bromophenyl)-acrylamide (7j)
Mp: 183e185 ꢀC; Yield: 71%; 1H NMR (300 MHz, CDCl3)
d:
6.50e7.90 (10H, m, Ar-H), 7.81,8.18 (2H, ss, triazoleeH), 6.83,7.57
(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.47e2.78
(8H, m, piperazineeH), 2.70e3.19 (2H, dd, CH2epiperazinee); 13C
6.5.34. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3-nitrophenyl)-acrylamide (7o)
NMR (75 MHz, CDCl3) d: 163.42, 160.32, 160.21, 157.46, 150.36,
147.23, 144.81, 139.19, 136.18, 133.80, 131.87, 129.20, 126.20, 126.03,
125.65, 123.00, 122.65, 121.92, 117.17, 110.76, 110.48, 104.02, 103.67,
103.31, 74.53, 74.47, 63.56, 55.65, 54.55, 53.18. IR (KBr): 3420, 3256,
3113, 3062, 2951, 2882, 2824, 1678, 1628, 1541, 1502, 1383, 1318,
1137, 1010 cmꢃ1. LC-MS, m/z Calcd. for C31H28BrF5N6O2, 690.1, found
[M þ H]þ 691.3.
Mp: 208e210 ꢀC; Yield: 77%; 1H NMR (300 MHz, CDCl3)
d:
6.66e8.44 (10H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.83,
7.58(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e),
2.48e2.79 (8H, m, piperazineeH), 2.70e3.19 (2H, dd,
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 163.04, 162.74,
160.55, 157.29, 150.43, 148.18, 147.37, 144.87, 136.12 130.42, 129.77,
126.28, 126.11, 125.74, 125.59, 124.73, 123.92, 121.96, 117.19, 110.81,
110.54, 104.07, 103.71, 103.36, 74.60, 74.53, 63.63, 55.74, 54.62,
53.23. IR (KBr): 3420, 3251, 3101, 3047, 2956, 2881, 2828, 1682,
1636, 1615, 1534, 1500, 1384, 1351, 1225, 1132, 1010 cmꢃ1. LC-MS, m/
z Calcd. for C31H28F5N7O4, 657.2, found [M þ H]þ 658.4.
6.5.30. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(4-methyl)-acrylamide (7k)
Mp: 176e178 ꢀC; Yield: 80%; 1H NMR (300 MHz, CDCl3)
d:
6.45e7.90 (10H, m, Ar-H), 7.87, 8.18 (2H, ss, triazoleeH), 6.83,
7.57(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e),
2.48e2.79 (8H, m, piperazineeH), 2.73e3.18 (2H, dd,
6.5.35. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(4-nitrophenyl)-acrylamide (7p)
CH2epiperazinee), 2.38 (3H, s, eCH3); 13C NMR (75 MHz, CDCl3)
d:
163.86, 160.70, 159.95, 157.26, 150.42, 147.17, 144.87, 139.70, 136.41,
131.84, 129.58, 127.74, 126.48, 126.27, 125.36, 124.99, 122.02, 120.77,
117.25, 110.81, 110.54, 104.08, 103.72, 103.37, 74.59, 74.52, 63.63,
55.73, 54.62, 53.25, 20.93. IR (KBr): 3353, 3123, 3024, 2947, 2881,
2819,1655,1617,1549,1383,1318,1225,1181,1016 cmꢃ1. LC-MS, m/z
Calcd. for C32H31F5N6O2, 626.2, found [M þ H]þ 627.4.
Mp: 229e231 ꢀC; Yield: 81%; 1H NMR (300 MHz, CDCl3)
d:
6.57e8.11 (10H, m, Ar-H), 7.80, 8.17 (2H, ss, triazoleeH), 6.83, 7.56
(2H, ss, C]CeH), 5.36 (1H, s, OH), 4.54e4.55 (2H, dd, tri-
azoleeCH2e), 2.48e2.79 (8H, m, piperazineeH), 2.70e3.19 (2H, dd,
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 163.04, 162.94,
160.73, 157.41, 150.47, 147.65, 147.48, 144.86, 136.01, 129.74, 128.77,
126.29, 126.06, 125.57, 125.07, 124.09, 123.76, 121.95, 117.35, 110.80,
110.54, 104.08, 103.72, 103.36, 74.60, 74.53, 63.61, 55.70, 54.59,
53.22. IR (KBr): 3445, 3110, 3058, 2950, 2885, 2826, 1682, 1617,
1600, 1541, 1501, 1384, 1315, 1223, 1138, 1013 cmꢃ1. LC-MS, m/z
Calcd. for C31H28F5N7O4, 657.2, found [M þ H]þ 658.3.
6.5.31. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3,4-dimethoxyphenyl)-acrylamide (7l)
Mp: 191e193 ꢀC; Yield: 72%; 1H NMR (300 MHz, CDCl3)
d:
6.38e7.73 (9H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.83, 7.44

3176
X. Chai et al. / European Journal of Medicinal Chemistry 46 (2011) 3167e3176
6.5.36. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-3-
(3-cyanophenyl)-acrylamide (7q)
6.5.40. (E)-N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-
phenyl)-3-(furan-2-yl)-acrylamide (8d)
Mp: 183e185 ꢀC; Yield: 80%; 1H NMR (300 MHz, CDCl3)
d:
Mp: 212e214 ꢀC; Yield: 85%; 1H NMR (300 MHz, CDCl3)
d:
6.58e7.90 (10H, m, Ar-H), 7.81, 8.18 (2H, ss, triazoleeH), 6.83,
7.56(2H, ss, C]CeH), 4.54e4.55 (2H, dd, triazoleeCH2e),
2.48e2.79 (8H, m, piperazineeH), 2.70e3.19 (2H, dd,
6.38e7.55 (9H, m, Ar-H), 7.80, 8.18 (2H, ss, triazoleeH), 6.83, 7.55
(2H, ss, C]CeH), 5.36 (1H, s, OH), 4.54e4.55 (2H, dd, tri-
azoleeCH2e), 2.47e2.78 (8H, m, piperazineeH), 2.75e3.17 (2H, dd,
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d
: 163.55, 160.70,
CH2epiperazinee); 13C NMR (75 MHz, CDCl3)
d: 163.56, 160.71,
160.54, 157.42, 150.43, 147.40, 144.87, 138.31, 136.12, 135.93, 130.12,
129.76, 126.31, 126.11, 125.25, 125.02, 124.29, 123.76, 121.98, 117.31,
110.82, 110.54, 104.08, 103.73, 103.37, 74.60, 74.52, 63.64, 55.76,
54.83, 53.24. IR (KBr): 3339, 3125, 3072, 2944, 2885, 2823, 2234,
157.44, 150.78, 147.24, 145.31, 144.88, 136.29, 129.77, 127.68, 126.07,
125.62, 125.10, 118.85, 117.14, 114.88, 112.60, 110.83, 110.57, 104.11,
103.74, 103.39, 74.61, 74.54, 63.62, 55.70, 54.61, 53.25. IR (KBr):
3420, 3299, 3120, 2944, 2884, 2825, 2755, 1734, 1685, 1634, 1542,
1685, 1635,1617, 1600, 1514, 1501, 1384, 1318, 1226, 1133, 1012 cmꢃ1
.
1384, 1320, 1215, 1135, 1013 cmꢃ1
. LC-MS, m/z Calcd. for
LC-MS, m/z Calcd. for C32H28F5N7O2, 637.2, found [M þ H]þ 638.4.
C29H27F5N6O3, 602.2, found [M þ H]þ 603.4.
6.5.37. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
furan-2-carboxamide (8a)
Acknowledgment
Mp: 193e195 ꢀC; Yield: 76%; 1H NMR (300 MHz, CDCl3)
d:
This work was supported by the National Natural Science
Foundation of China (Nos. 30300437), the Eleventh Five Year
Military Medicine and Public Health Research Projects (Nos.
06MB206) and by Shanghai Leading Academic Discipline Project
Number: B906.
6.57e7.93 (9H, m, Ar-H), 7.80, 8.17 (2H, ss, triazoleeH), 4.54e4.55
(2H, dd, triazoleeCH2e), 2.48e2.79 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 5.36 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) d: 163.42, 160.58, 157.46, 150.45, 147.59, 147.30,
144.91, 135.66, 129.80, 126.36, 125.30, 124.77, 122.05, 118.45, 115.07,
110.84, 110.57, 104.09, 103.73, 103.38, 74.59, 74.52, 63.66, 55.77,
54.65, 53.27. IR (KBr): 3252, 3116, 3076, 3015, 2951, 2889, 2817,
2750, 1681, 1615, 1541, 1506, 1384, 1325, 1225, 1137, 1016 cmꢃ1. LC-
MS, m/z Calcd. for C27H25F5N6O3, 576.2, found [M þ H]þ 577.3.
References
[1] T.J. Walsh, A. Groll, J. Hiemenz, R. Fleming, E. Roilides, E. Anaissie, Clin.
Microbiol. Infect. 10 (2004) 48e66.
[2] M.A. Pfaller, D.J. Diekema, Clin. Microbiol. Rev. 20 (2007) 133e163.
[3] H.A. Gallis, R.H. Drew, W.W. Pickard, Rev. Infect. Dis. 12 (1990) 308e329.
[4] D.J. Sheehan, C.A. Hitchcock, C.M. Sibley, Clin. Microbiol. Rev. 12 (1999)
40e79.
[5] D.W. Denning, J. Antimicrob. Chemother. 49 (2002) 889e891.
[6] A. Kleeman, J. Engel, B. Kutscher, D. Reichert, Bioseparation 8 (1999) 335.
[7] D.S. Johnson, J.J. Li, The Art of Drug Synthesis (2007) 71.
[8] N.H. Georgopapadakou, T.J. Walsh, Antimicrob. Agents Chemother. 40 (1996)
279e291.
[9] J.M. Trzaskos, R.T. Fischer, M.F. Favata, J. Biol. Chem. 261 (1986) 16937e16942.
[10] Y. Aoyama, Y. Yoshida, Y. Sonoda, Y. Sato, J. Biol. Chem. 262 (1987)
1239e1243.
[11] Y. Aoyama, Y. Yoshida, Y. Sonoda, Y. Sato, J. Biol. Chem. 264 (1989)
18502e18505.
[12] R.T. Fischer, J.M. Trzaskos, R.L. Magolda, S.S. Ko, C.S. Brosz, B. Larsen, J. Biol.
Chem. 266 (1991) 6124e6132.
[13] A.Z. Shyadehi, D.C. Lamb, S.L. Kelly, D. E Kelly, W.H. Schunck, J.N. Wright,
D. Corina, M. Akhtar, J. Biol. Chem. 271 (1996) 12445e12450.
[14] I.A. Casalinuovo, P. Di Francesco, E. Garaci, Eur. Rev. Med. Pharmacol. Sci.
8 (2004) 69e77.
[15] H.L. Hoffman, E.J. Ernst, M.E. Klepser, Expert Opin. Investig. Drugs 9 (2000)
593e599.
[16] H.T. Ji, W.N. Zhang, Y.J. Zhou, M. Zhang, J. Zhu, Y.L. Song, J. Lu, J. Zhu, J. Med.
Chem. 43 (2000) 2493e2505.
6.5.38. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
nicotinamide (8b)
Mp: 163e165 ꢀC; Yield: 81%; 1H NMR (300 MHz, CDCl3)
d:
6.79e9.10 (10H, m, Ar-H), 7.88, 8.22 (2H, ss, triazoleeH), 5.36 (1H, s,
OH), 4.54e4.55 (2H, dd, triazoleeCH2e), 2.44e2.81 (8H, m,
piperazineeH), 2.71e3.19 (2H, dd, CH2epiperazinee); 13C NMR
(75 MHz, CDCl3) d: 164.14, 160.11, 157.43, 150.43, 148.74, 147.78,
144.90, 140.27, 135.95, 130.20, 126.31, 125.94, 124.86, 122.04, 118.44,
117.71,110.81,110.56,104.09,103.74,103.38, 74.55, 63.66, 55.74, 54.83,
53.47, 53.27. IR (KBr): 3385, 3298, 3252, 3122, 3065, 3051, 2950, 2883,
2822,1679,1617,1554,1502,1384,1319,1224,1136,1015 cmꢃ1. LC-MS,
m/z Calcd. for C28H26F5N7O2, 587.2, found [M þ H]þ 588.3.
6.5.39. N-(4-{4-[2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-
triazol-1-yl)-propyl]-piperazin-1-yl}-3-(trifluoromethyl)-phenyl)-
isonicotinamide (8c)
Mp: 169e171 ꢀC; Yield: 80%; 1H NMR (300 MHz, CDCl3)
d:
[17] C. Sheng, W. Zhang, H. Ji, Chin. Chem. Lett. 15 (2004) 404e407.
[18] C.Q. Sheng, W.N. Zhang, H.T. Ji, M. Zhang, Y.L. Song, H. Xu, J. Zhu, Z.Y. Miao,
Q.F. Jiang, J.Z. Yao, Y.J. Zhou, J. Zhu, J.G. Lü, J. Med. Chem. 49 (2006)
2512e2525.
[19] Z.J. Guan, X.Y. Chai, S.C. Yu, H.G. Hu, Y.Y. Jiang, Q.G. Meng, Q.Y. Wu, Chem. Biol.
Drug Des. 76 (2010) 496e504.
6.80e8.83 (10H, m, Ar-H), 7.80, 8.17 (2H, ss, triazoleeH), 4.49e4.55
(2H, dd, triazoleeCH2e), 2.48e2.81 (8H, m, piperazineeH),
2.70e3.19 (2H, dd, CH2epiperazinee), 5.35 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) d: 164.02, 160.71, 157.44, 150.44, 147.99, 144.89,
141.49, 135.64, 129.78, 126.31, 126.15, 125.57, 125.20, 122.01, 121.53,
118.58, 110.83, 110.56, 104.09, 103.74, 103.38, 74.62, 74.55, 63.63,
55.73, 54.60, 53.25. IR (KBr): 3293, 3110, 3075, 2949, 2886, 2821,
1673, 1616, 1595, 1542, 1383, 1322, 1237, 1135, 1016 cmꢃ1. LC-MS,
m/z Calcd. for C28H26F5N7O2, 587.2, found [M þ H]þ 588.3.
[20] W.K. Sang, G.L. Jung, J.L. Eun, P.C. Hea-Young, Y.Y. Chung, Y.L. Dae,
R.R. Kyoung, K.K. Eon, J. Comb. Chem. 6 (2004) 851e854.
[21] National Committee for Clinical Laboratory Standards, Reference Method for
Broth Dilution Antifungal Susceptibility Testing of Yeasts Approved Standard.
Document M27eA2. National Committee for Clinical Laboratory Standards,
Wayne, PA, 2002.