Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase

Article abstract of DOI:10.1016/j.ejmech.2008.11.007

Based on the results of computational docking to the active site of the cytochrome P450 14α-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC₈₀ values indicate that compounds 1a-n exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2a-f, 3a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC₈₀ value of 0.0039 μg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.

Full text of DOI:10.1016/j.ejmech.2008.11.007

European Journal of Medicinal Chemistry 44 (2009) 1913–1920
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis, and biological evaluation of novel triazole derivatives
as inhibitors of cytochrome P450 14 -demethylase
a
Xiaoyun Chai a, Jun Zhang a, Honggang Hu a, Shichong Yu a, Qingyan Sun a, Zhigang Dan a,
**
,
a,
*
Yuanying Jiang b , Qiuye Wu
a Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People’s Republic of China
b Department of Pharmacology, College of Pharmacy, Second Military Medical University, Guohe Road 325, 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:
Based on the results of computational docking to the active site of the cytochrome P450 14a-demethylase
Received 18 September 2008
Received in revised form
5 November 2008
Accepted 11 November 2008
Available online 24 November 2008
(CYP51),
a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as
analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC80 values
indicate that compounds 1a–n exhibited higher activity against nearly all fungi tested except Aspergillus
fumigatus than fluconazole, while compounds 2a–f, 3a–f showed no activity or only moderate activity
against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that
of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times
Keywords:
Triazole
higher activity (with the MIC80 value of 0.0039 mg/mL) than that of fluconazole against Candida albicans
and also showed higher activity than that of the other positive controls. Computational docking
experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme
group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In
addition, the activity of the compounds would be enhanced when the side chains were shorter.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Synthesis
Antifungal activity
CYP51
Molecular docking
1. Introduction
administration of antifungal agents has led to the development of
fungal resistance. Survey reveals genetic mutations that result in
In recent years, life-threatening systemic fungal infections have
become increasingly common, especially in the immunocompro-
mised hosts suffering from tuberculosis, cancer or AIDS and in
organ transplant cases [1,2]. Several clinical drugs, such as azoles,
amphotericin B, 5-fluorocytosine, and caspofungin, have been
developed to reduce the impact of fungal diseases. Among those,
azoles, especially triazole antifungal agents, were used widely and
efficiently. For example, fluconazole, voriconazole and itraconazole
(Fig. 1), presently play a leading role in the treatment of invasive
fungal infections. These antifungal 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 [3]. However, the increasing
resistance to clinically used drugs, especially fluconazole, may also
result in resistance to new structurally related azoles such as vor-
iconazole and ravuconazole [4–6]. 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
structure–activity for the inhibition of CYP51.
CYP51 is a member of the cytochrome P450 superfamily, which
catalyzes the oxidative removal of the 14
lanosterol via three successive monooxygenation reactions to give
14,15-desaturated intermediates in ergosterol biosynthesis. The
a-methyl group of (C-32)
d
first two of these reactions are conventional cytochrome P450
hydroxylations that produce the 14-hydroxymethyl and 14-car-
boxyaldehyde derivatives of lanosterol [7,8]. In the final step, the
14-aldehyde group is eliminated as formic acid with concomitant
introduction of a d
14,15 double bond [9–11]. The crystal structure of
Abbreviations: C. alb, Candida albicans; Cry. neo, Cryptococcus neoformans; C. par,
Candida parapsilosis; C. tro, Candida tropicalis; T. rub, Trichophyton rubrum; C. kri,
Candida Krusei; M. gyp, Microsporum gypseum; A. fum, Aspergillus fumigatus; ICZ,
itraconazole; KCZ, ketoconazole; FCZ, fluconazole; VCZ, voriconazole; AMB,
amphotericin B; TRB, terbinafine.
CYP51 of fungi has not been obtained. Ji et al. constructed a 3D
model of Candida albicans CYP51. In general, the active site of CYP51
for ligand binding can be divided into four subsites: a coordination
bond with iron of the heme group, the hydrophilic H-bonding
region, the hydrophobic region, and the narrow hydrophobic
cleft formed by the residues in the helix B’-meander 1 loop and
* Corresponding author. Tel./fax: þ86 21 25070381.
** Corresponding author.
E-mail address: wuqy6439@sohu.com (Q. Wu).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.11.007

1914
X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
(Fig. 3) containing a triazole ring, a difluorophenyl group, a
hydroxyl group and a side chain. In the design, the N atom of the
triazole was coordinated to iron atom of the heme, and the 2,
4-difluorophenyl group could be located into the hydrophobic
pocket. The side chain was designed to be oriented to the narrow
hydrophobic cleft.
2. Chemistry
Compounds 1a–n were prepared according to a very efficient
and straightforward synthetic route outlined in Scheme 1. And
compounds 2a–f and 3a–f were synthesized according to Scheme
2. After the key intermediate oxirane 7 was synthesized by
a known procedure [13], the title compound 8 was synthesized by
ring-open reaction of oxirane 7 with allylamine, and then was
formed by adding the HCl gas. In the presence of KI and K2CO3 in
acetonitrile at room temperature, the compound 8 was converted
to the target compounds by reacting with various substituted
benzyl bromide.
Fig. 1. Triazole antifungal agents used in clinical therapy.
N-terminus of helix I [12]. The analysis of the binding between
fluconazole and CYP51 was shown in Fig. 2. Fluconazole binds to the
active site of CYP51 via coordination of the N atom of the triazole
nucleus with iron of the heme group. The difluorophenyl group is
located in the hydrophobic binding cleft lined with Ala114, Phe126,
Leu139, Met140, Phe145, Ile304, Met306 and Gly307. Several resi-
dues lined with Leu121, Thr122, Phe228, Thr311, Pro375, Leu376,
His377, Ser378, Met508, Val509 and Val510 were observed to form
indirect nonbonding interactions with another triazolyl ring.
Researches indicated that the triazole ring, the difluorophenyl
group and the hydroxyl group were the pharmacophores of anti-
fungal agents. But the side chains located in the narrow hydro-
phobic cleft were also important. We intended to alter the side
chains to find potent systemic antifungal agents with a broad
antifungal spectrum and less potential to develop resistance.
Based on the above results, we designed a series of 1-(1H-1,2,
4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols
3. Pharmacology
The in vitro antifungal activities of all title compounds were
evaluated against eight human pathogenic fungi, C. albicans, Cryp-
tococcus neoformans, Candida parapsilosis, Candida tropicalis, Tri-
chophyton rubrum, Candida Krusei, Microsporum gypseum,
Aspergillus fumigatus, which are often encountered clinically, and
were compared with fluconazole, itraconazole, ketoconazole,
voriconazole, amphotericin B and terbinafine. C. albicans and Cry.
neoformans were provided by Shanghai Changzheng Hospital;
C. parapsilosis, C. tropicalis, T. rubrum, C. Krusei, M. gypseum, and
A. fumigatus were provided by Shanghai Changhai Hospital. C.
albicans and Cry. neoformans were purchased from ATCC, and other
strains were clinic isolates. C. albicans (ATCC76615) and Cry. neo-
formans (ATCC32609) were used as the quality-controlled strains,
and tested in each assay. Fluconazole (FLC), itraconazole (ICZ),
ketoconazole (KCZ), voriconazole (VCZ), amphotericin B (AMB) and
Fig. 2. Computed binding geometry of the clinical used inhibitor fluconazole in the active site of CYP51.

X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
1915
Fig. 3. All the compounds we designed and synthesized.
terbinafine (TRB) served as the positive control were obtained from
their respective manufacturers.
than fluconazole, while compounds 2a–f, 3a–f showed no activity
or only moderate activity against nearly all fungi tested. Notice-
ably, the MIC value of compounds 1a, 1b and 1g is 64 times lower
than that of fluconazole against M. gypseum in vitro. And
compounds 1a, 1b and 2b showed 128 times higher activity (with
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) [14].
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 Cry. neoformans. The results of
assays are summarized in Table 1. The data points form the mean of
replicates. All of our susceptibility tests were performed three
times by each antifungal agents.
the MIC80 value of 0.0039 mg/mL) than that of fluconazole against
C. albicans and also showed higher activities than that of the other
positive controls. These results clearly indicated that the
substituted benzyl side chain greatly enhanced the antifungal
activity of these analogs against Candida species, and that the
amine side chain showed higher activity as it is shortened. In
addition, despite the positive controls itraconazole and vor-
iconazole showing cross-resistance to fluconazole-resistant
strains of C. albicans, our target compounds 1a–n, 2a, 2b and 3b
displayed certain extent of activities against these fluconazole-
resistant strains. The trichophyton species T. rubrum was found to
be much less sensitive to these derivatives, as indicated by their
MIC80 values showing moderate to no activity. Because of the
intrinsic mechanism resistant to triazole antifungals, the anti-
fungal agents showed no activity to A. fumigatus.
4. Results and discussion
The MIC80 values indicate that compounds 1a–n exhibited
higher activity against nearly all fungi tested except A. fumigatus
Scheme 1. Synthesis of the benzyl derivatives 1a–n. Conditions: (a) ClCH2COCl, AlCl3, 50 ꢀC, 5 h, in 87% yield; (b) C6H5CH3, NaHCO3, 1H-1,2,4-triazole, reflux, 5 h, in 87% yield;
(c) C6H5CH3, (CH3)3SOI, NaOH, centylmethylammonium bromide, 60 ꢀC, 3 h, in 86% yield; (d) CH3SO3H, 0 ꢀC, 1 h, in 89% yield; (e) CH3CH2OH, Et3N, allylamine, reflux, 6 h; (f) HCl(g)
in 80–90% yield; (g) CH3CN, KI, K2CO3, substituted benzyl bromide, rt, 5–6 h, in 50–70% yield.
,

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X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
Scheme 2. Synthesis of the para-benzoate derivatives 2a–f, 3a–f. Conditions: (a) SOCl2, reflux, 4–5 h, in 95% yield; (b) alcohol or substituted phenol, CH2Cl2, Et3N, 0–5 ꢀC, 5–6 h, in
75–80% yield; (c) N-bromosuccimide, peroxybenzoic acid, CCl4, reflux, 12 h,, in 70–78% yield; (d/e) compound 8, CH3CN, KI, K2CO3, rt, 5–8 h, in 40–60% yield.
To explain the results, we proposed a likely binding mode for 1b
to the active site of CYP51 based on computational docking results
(Fig. 4). As usual, the triazole interacts with iron of the heme group,
while the 2,4-difluorophenyl group in the designed compound
could be placed into the hydrophobic pocket formed by Ala114,
Phe126, Leu139, Met140, Phe145, Ile304, Met306 and Gly307 and
The side chains of the compounds 1a–n we designed were
rather short but the activity was very good. One reason was that the
allyl group could improve the flexibility of the molecule making the
phenyl group more easily lock its proper position, and the allyl
group could form additional van der Waals interactions with the
surrounding Ala117, Leu376, and Ile379. In addition, all of the side
chains were of the pharmacophores, and the spatial orientations of
the pharmacophores were just oriented in the hydrophobic pocket.
The side chains of inhibitors were not the determinants for activity,
but were very important. They played a role in adjusting the
physico-chemical properties of the whole molecule to avoid some
dissatisfying side effects and improve their pharmacokinetic and
pharmacodynamic behaviors.
the 2-chlorobenzyl group would generate
p–p stacking interac-
tions with the Tyr118. The latter two groups also incorporate to
adjust the overall physical–chemical properties of the molecules
and orientation of aromatic rings. In addition, the N-substituted
group of the linker would be oriented to interact with a hydro-
phobic pocket formed by Leu121, Thr122, Phe228, Thr311, Pro375,
Leu376, His377, Ser378, Met508, Val509 and Val510.
Table 1
Antifungal activities of the title compounds in vitro (MIC80
,
mg/mL).
Compound
C. alb
Cry. neo
0.0625
C. par
C. tro
T. nru
C. kru
M. gyp
A. fum
1a
1b
1c
1d
1e
1f
1g
1h
1i
1g
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
ICZ
KCZ
FCZ
VCZ
AMB
TRB
0.0039
0.0039
0.0156
0.0156
0.0156
0.0156
0.25
0.0625
0.0625
0.0156
0.0156
0.0156
0.25
0.0625
0.0156
0.0625
0.0625
0.0625
0.25
0.25
0.25
0.25
0.0625
0.25
0.0625
1
0.25
0.25
1
1
1
0.25
1
1
0.25
1
1
0.0625
0.0625
0.0625
0.0625
0.25
0.0625
0.25
0.0625
0.25
0.0625
0.25
0.25
0.0156
0.25
0.0625
0.25
1
0.25
0.25
0.25
1
1
1
0.25
0.25
0.25
0.0625
1
0.25
1
1
0.0625
0.0156
0.0625
0.0625
0.0625
0.0625
0.0625
0.25
0.0625
0.0625
0.0625
0.0625
0.25
0.25
0.0625
0.0625
0.25
1
1
1
1
4
1
4
16
4
0.0039
0.0039
0.0156
0.0156
0.0625
0.0625
0.0625
0.0156
0.0625
0.0039
0.0156
0.0156
0.0625
1
0.0156
0.25
0.0156
1
0.25
1
1
1
0.25
0.25
4
1
0.0625
0.0156
0.25
0.0039
2
>64
>64
>64
>64
>64
>64
16
0.0625
0.0625
0.0625
0.25
0.25
0.25
0.25
0.25
0.0625
0.0625
0.25
0.25
1
0.25
1
1
1
1
1
1
1
1
16
>64
4
0.125
0.0625
1
0.0156
2
1
>64
4
>64
>64
>64
>64
16
1
0.0625
0.0039
0.25
0.25
1
1
1
0.25
0.25
0.25
0.25
1
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
0.5
1
1
1
1
1
0.0625
0.25
16
4
4
4
64
1
0.125
0.0625
4
0.0625
2
0.0625
1
4
1
0.0625
1
0.0625
0.0156
0.5
0.0156
2
4
4
16
0.25
0.125
0.0625
1
0.0039
2
0.25
0.125
0.0625
1
0.0039
2
0.5
0.25
4
0.0625
2
16
1
>64
0.25
64
0.25
0.0625
0.0625
4
0.0625

X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
1917
Fig. 4. Computed binding geometry of the new inhibitor 1b in the active site of CYP51.
5. Conclusion
6.1. (1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-
(allylamine)-propan-2-ols muriate (8)
In conclusion,
a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-
difluorophenyl)-3-substituted-2-propanols as analogs of flucona-
zole were synthesized and their antifungal activities were screened
for eight human pathogenic fungi. The compounds 1a–n exhibited
higher and broader spectrum antifungal activities with high
activity against nearly all fungi tested except A. fumigatus. The
obtained results indicated that for antifungal activity of these novel
triazole derivatives it is very helpful to introduce the allyl group and
the substituted benzyl bromide as side chains to interact with
To a stirred mixture of 1-[2-(2,4-difluorophenyl)-2,3-epox-
ypropyl]-1H-1,2,4-triazole methanesulfonate 7 (3.33 g, 10 mmol),
CH3CH2OH (50 mL), N(C2H5)3 (5 mL), and allylamine (0.89 g,
15 mmol) were added and was refluxed at 80–90 ꢀC for 6 h. The
reaction was monitored by TLC. After filtration, the filtrate was
evaporated under reduced pressure. Water (50 mL) was added to
the residue, which was then extracted with ethylacetate
(80 mL ꢁ 3). The extract was washed with saturated NaCl solution
(30 mL ꢁ 3), dried over anhydrous Na2SO4 and evaporated. The
residue was dissolved with 20 mL ethylacetate, then added HCl gas
to the solution. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-
3-(allylamine)-propan-2-ols muriate was separated from ethyl-
acetate to afford 8 (2.63 g, 79.5%).
a hydrophobic pocket and also generate p–p stacking interactions
with the Tyr118. 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. Experimental part
6.2. General procedure for the preparation of the compounds 1a–n
Inourstudies, weconstructeda3DmodelofC. albicansCYP51onthe
basis of Ji et al. [15]. All the molecular modeling calculations were per-
formed using SYBYL 6.9 version. And the structures of the compounds
were assigned with Gasteiger–Hu¨ckle partial atomic charges. Energy
minimization was performed using the Tripos force field, Powell opti-
mization method, and MAXIMIN2 minimizer with a convergence
criterion 0.001 Kcal/mol Å. Simulated annealing was then performed.
The system was heated to 1000 K for 1.0 ps and then annealed to 250 K
for 1.5 ps. The annealing function was exponential; 50 such cycles of
annealing were run and the resulting 50 conformers were optimized
using methods described above. The lowest energy conformation was
selected. All the other parameters were default values.
To
a stirred mixture of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-
difluorophenyl)-3-(allyl-mine)-propan-2-ols muriate (8, 1.0 mmol)
and CH3CN (25 mL), KI (0.5 mmol), K2CO3 (2.5 mmol), substituted
benzyl bromide (1.2 mmol) were added and stirred for 5–6 h. The
reaction was monitored by TLC. After filtration, the filtrate was
evaporated under reduced pressure. Then the compounds 1a–n
were separated and purified readily by chromatography on silica
gel.
6.3. General procedure for the preparation of the compounds 2a–f,
3a–f
Melting points were measured on a Yamato MP-21 melting-
point apparatus and are uncorrected. Infrared spectra were
recorded using potassium bromide disks on a HITACHI270-50
spectrophotometer. 1H NMR spectra were recorded in CDCl3 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.
4-Methylbenzoic acid (9, 1.36 g, 10.0 mmol) and thionyl chloride
(10 mL) were added and stirred for 4–5 h until no gas released. Then
evaporated the reagent under reduced pressure to afford compound
10 (1.47 g, 95.0%). The compound 10 (1.47 g, 9.5 mmol) was dropped
in 25 mL CH2Cl2 which dissolved alcohol or substituted phenol
(19.0 mmol) and Et3N at 0w5 ꢀC for 5w6 h to afford compound 11
(75–80%). The compound 11 (5.0 mmol), N-bromosuccimide

1918
X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
(6.0 mmol), peroxybenzoic acid (0.2 mmol) and CCl4 (20 mL) were
added and refluxed for 12 h to afford compound 12 (70–78%). To
a stirred mixture of compound 8 (0.3420 g, 1.0 mmol), and CH3CN
(25 mL), KI (0.5 mmol), K2CO3 (2.5 mmol), the compound 12
(1.2 mmol) were added and stirred for 5–8 h. The reaction was
monitored by TLC. After filtration, the filtrate was evaporated under
reduced pressure. Then the compounds 2a–f, 3a–f were separated
and purified readily by chromatography on silica gel.
J ¼ 13.6 Hz, Ar–CH2–), 2.98–3.17 (2H, m, CCH2N), 2.83–2.88 (2H, m,
NCH*2CH]CH2); IR (KBr): 3215, 3108, 3073, 2950, 1654, 1553, 1432,
1270, 994, 897; LC–MS, m/z: 419.1 (M þ H)þ.
6.3.7. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(4-chlorobenzyl)-amino]-2-propanol (1g)
Mp: 74.4–75.9 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.04 (1H, s, tri-
azole-H), 7.74 (1H, s, triazole-H), 6.74–7.59 (7H, m, Ar-H), 5.59–5.70
(1H, m, CH*]CH2), 5.10 (1H, br, OH), 4.98–5.12 (2H, m, CH]CH*2),
4.40–4.53 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.34–3.52 (2H, dd,
J ¼ 13.6 Hz, Ar–CH2–), 2.97–3.17 (2H, m, CCH2N), 2.81–2.88 (2H, m,
NCH*2CH]CH2); IR (KBr): 3295, 3180, 3074, 2955, 1648, 1527, 1435,
1258, 993, 905; LC–MS, m/z: 419.1 (M þ H)þ.
The title compounds were characterized as follows.
6.3.1. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-benzyl-amino]-2-propanol (1a)
Mp: 67.2–68.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.04 (1H, s, tri-
azole-H), 7.73 (1H, s, triazole-H), 6.76–7.63 (8H, m, Ar-H), 5.63–5.72
(1H, m, CH*]CH2), 5.61 (1H, br, OH), 4.98–5.12 (2H, m, CH]CH*2),
4.39–4.50 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.35–3.57 (2H, dd,
J ¼ 13.2 Hz, Ar–CH2–), 2.99–3.16 (2H, m, CCH2N), 2.82–2.89 (2H, m,
NCH*2CH]CH2); IR (KBr): 3250, 3110, 3080, 2975, 1645, 1520, 1450,
1263, 990, 910; LC–MS, m/z: 385.1 (M þ H)þ.
6.3.8. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(2-bromobenzyl)-amino]-2-propanol (1h)
Mp: 67.3–68.8 ꢀC; 1H NMR(400 MHz, CDCl3)
d: 7.97 (1H, s, tri-
azole-H), 7.71 (1H, s, triazole-H), 6.72–7.54 (7H, m, Ar-H), 5.70–5.77
(1H, m, CH*]CH2), 5.03 (1H, br, OH), 4.94–5.12 (2H, m, CH]CH*2),
4.30–4.46 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.54–3.68 (2H, dd,
J ¼ 13.6 Hz, Ar–CH2–), 2.98–3.23 (2H, m, CCH2N), 2.81–2.87 (2H, m,
NCH*2CH]CH2); IR (KBr): 3256, 3090, 3045, 2997, 1650, 1533, 1457,
1235, 989, 908; LC–MS, m/z: 463.0 (M þ H)þ.
6.3.2. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(2-fluorobenzyl)-amino]-2-propanol (1b)
Mp: 77.0–78.3 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.02 (1H, s, tri-
azole-H), 7.69 (1H, s, triazole-H), 6.71–7.57 (7H, m, Ar-H), 5.58–5.66
(1H, m, CH*]CH2), 5.13 (1H, br, OH), 4.95–5.07 (2H, m, CH]CH*2),
4.35–4.48 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.43–3.58 (2H, dd,
J ¼ 13.2 Hz, Ar–CH2–), 2.83–2.98 (2H, m, CCH2N), 2.78–2.82 (2H, m,
NCH*2CH]CH2); IR (KBr): 3215, 3108, 3070, 2990, 1640, 1510, 1475,
1230, 980, 908; LC–MS, m/z: 403.1 (M þ H)þ.
6.3.9. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(4-bromobenzyl)-amino]-2-propanol (1i)
Mp: 78.5–80.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s,
triazole-H), 7.73 (1H, s, triazole-H), 6.73–7.58 (7H, m, Ar-H), 5.58–
5.67 (1H, m, CH*]CH2), 5.12 (1H, br, OH), 4.97–5.09 (2H, m,
CH]CH*2), 4.39–4.52 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.32–
3.49 (2H, dd, J ¼ 13.2 Hz, Ar–CH2–), 2.82–3.16 (2H, m, CCH2N),
2.80–3.00 (2H, m, NCH*2CH]CH2); IR (KBr): 3255, 3175, 3077,
2990, 1648, 1536, 1455, 1220, 998, 905; LC–MS, m/z: 463.0
(M þ H)þ.
6.3.3. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(3-fluorobenzyl)-amino]-2-propanol (1c)
Mp: 72.6–74.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.73 (1H, s, triazole-H), 6.73–7.61 (7H, m, Ar-H), 5.60–5.69
(1H, m, CH*]CH2), 5.02 (1H, br, OH), 4.98–5.12 (2H, m, CH]CH*2),
4.40–4.98 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.36–3.55 (2H, dd,
J ¼ 13.2 Hz, Ar–CH2–), 2.98–3.18 (2H, m, CCH2N), 2.82–2.88 (2H, m,
NCH*2CH]CH2); IR (KBr): 3220, 3106, 3082, 2995, 1638, 1543, 1462,
1217, 992, 905; LC–MS, m/z: 403.1 (M þ H)þ.
6.3.10. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-
allyl-N-(2-methylbenzyl)-amino]-2-propanol (1j)
Mp: 70.8–72.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 7.95 (1H, s,
triazole-H), 7.71 (1H, s, triazole-H), 6.71–7.53 (7H, m, Ar-H), 5.70–
5.72 (1H, m, CH*]CH2), 4.97–5.12 (2H, m, CH]CH*2), 4.93 (1H, br,
OH), 4.29–4.41 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.37–3.60 (2H,
dd, J ¼ 13.6 Hz, Ar–CH2–), 2.99–3.17 (2H, m, CCH2N), 2.81–2.88
(2H, m, NCH*2CH]CH2), 2.23 (3H, s, Ar–CH3); IR (KBr): 3285, 3108,
3080, 2975, 1668, 1545, 1430, 1286, 998, 895; LC–MS, m/z: 399.1
(M þ H)þ.
6.3.4. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(4-fluorobenzyl)-amino]-2-propanol (1d)
Mp: 69.3–71.3 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.72 (1H, s, triazole-H), 6.74–7.60 (7H, m, Ar-H), 5.59–5.68
(1H, m, CH*]CH2), 5.02 (1H, br, OH), 4.97–5.11 (2H, m, CH]CH*2),
4.39–4.51 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.33–3.52 (2H, dd,
J ¼ 13.6 Hz, Ar–CH2–), 2.96–3.17 (2H, m, CCH2N), 2.80–2.86 (2H, m,
NCH*2CH]CH2); IR (KBr): 3230, 3145, 3073, 2990, 1647, 1550, 1477,
1240, 990, 915; LC–MS, m/z: 403.1 (M þ H)þ.
6.3.11. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-
allyl-N-(4-methylbenzyl)-amino]-2-propanol (1k)
Mp: 63.1–64.3 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.05 (1H, s,
triazole-H), 7.72 (1H, s, triazole-H), 6.73–7.58 (7H, m, Ar-H), 5.35–
5.77 (1H, m, CH*]CH2), 5.22 (1H, br, OH), 4.96–5.10 (2H, m,
CH]CH*2), 4.37–4.48 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.29–3.50
(2H, dd, J ¼ 13.2 Hz, Ar–CH2–), 2.96–3.17 (2H, m, CCH2N), 2.81–2.87
(2H, m, NCH*2CH]CH2), 2.32 (3H, s, Ar–CH3); IR (KBr): 3245, 3118,
3075, 2996, 1645, 1535, 1466, 1230, 990, 910; LC–MS, m/z: 399.1
(M þ H)þ.
6.3.5. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(2-chlorobenzyl)-amino]-2-propanol (1e)
Mp: 72.4–73.7 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 7.99 (1H, s, tri-
azole-H), 7.72 (1H, s, triazole-H), 6.73–7.56 (7H, m, Ar-H), 5.69–5.77
(1H, m, CH*]CH2), 5.13 (1H, br, OH), 4.96–5.10 (2H, m, CH]CH*2),
4.33–4.48 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.55–3.70 (2H, dd,
J ¼ 13.2 Hz, Ar–CH2–), 2.97–3.24 (2H, m, CCH2N), 2.82–3.23 (2H, m,
NCH*2CH]CH2); IR (KBr): 3285, 3153, 3080, 2950, 1645, 1527, 1440,
1235, 987, 905; LC–MS, m/z: 419.1 (M þ H)þ.
6.3.12. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-
allyl-N-(4-nitrobenzyl)-amino]-2-propanol (1l)
Mp: 95.5–97.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.00 (1H, s, tri-
6.3.6. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-allyl-
N-(3-chlorobenzyl)-amino]-2-propanol (1f)
azole-H), 7.75 (1H, s, triazole-H), 6.73–8.13 (7H, m, Ar-H), 5.61–5.71
(1H, m, CH*]CH2), 5.00 (1H, br, OH), 5.00–5.15 (2H, m, CH]CH*2),
4.45–4.58 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.54–3.69 (2H, dd,
J ¼ 14.4 Hz, Ar–CH2–), 2.99–3.19 (2H, m, CCH2N), 2.86–2.91 (2H, m,
NCH*2CH]CH2); IR (KBr): 3215, 3108, 3073, 2950, 1645, 1553, 1432,
1280, 994, 897; LC–MS, m/z: 430.1 (M þ H)þ.
Mp: 76.0–77.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.74 (1H, s, triazole-H), 6.73–7.60 (7H, m, Ar-H), 5.60–5.69
(1H, m, CH*]CH2), 5.10 (1H, br, OH), 4.98–5.12 (2H, m, CH]CH*2),
4.40–4.53 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.35–3.53 (2H, dd,

X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
1919
6.3.13. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-
6.3.19. Isobutyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2e)
Mp: 67.3–68.5 ꢀC; 1H NMR (400 MHz, CDCl3)
: 8.03 (1H, s, tri-
allyl-N-(4-ethylbenzyl)-amino]-2-propanol (1m)
Mp: 87.7–89.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.05 (1H, s, tri-
d
azole-H), 7.72 (1H, s, triazole-H), 6.71–7.54 (7H, m, Ar-H), 5.63–5.69
(1H, m, CH*]CH2), 5.10 (1H, br, OH), 4.97–5.12 (2H, m, CH]CH*2),
4.30–4.48 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.47–3.61 (2H, dd,
J ¼ 14.0 Hz, Ar–CH2–), 2.96–3.20 (2H, m, CCH2N), 2.81–2.94 (2H, m,
NCH*2CH]CH2); 2.57–2.67 (2H, q, Ar–CH2*CH3), 1.12–1.23 (3H, t, Ar–
CH2CH*3); IR (KBr): 3254, 3175, 3030, 2990, 1683, 1544, 1445, 1296,
986, 905; LC–MS, m/z: 413.1 (M þ H)þ.
azole-H), 7.95 (1H, s, triazole-H), 6.72–7.93 (7H, m, Ar-H), 5.63–5.65
(1H, m, CH*]CH2), 5.12 (1H, br, OH), 4.98–5.09 (2H, m, CH]CH*2),
4.41–4.52 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 4.09–4.10 (2H, d,
J ¼ 6.4 Hz, OCH2–), 3.43–3.59 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.98–
3.18 (2H, m, CCH2N), 2.82–2.89 (2H, m, NCH*2CH]CH2), 2.04–2.11
(1H, m, OCH2CH*), 1.01–1.02 (6H, d, J ¼ 6.8 Hz, 2 ꢁ CH3); IR (KBr):
3285, 3102, 3040, 2975, 1738, 1668, 1545, 1430, 1286, 992, 915; LC–
MS, m/z: 485.1 (M þ H)þ.
6.3.14. 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-difluorophenyl)-3-[N-
allyl-N-(2,4-dichlorobenzyl)-amino]-2-propanol (1n)
6.3.20. Pentyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2f)
Mp: 83.6–85.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.00 (1H, s,
triazole-H), 7.73 (1H, s, triazole-H), 6.71–7.52 (6H, m, Ar-H), 5.64–
5.73 (1H, m, CH*]CH2), 5.00 (1H, br, OH), 4.96–5.12 (2H, m,
CH]CH*2), 4.33–4.48 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.53–3.63
(2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.96–3.20 (2H, m, CCH2N), 2.81–2.94
(2H, m, NCH*2CH]CH2); IR (KBr): 3246, 3123, 3055, 2997, 1640,
1563, 1426, 1208, 1002, 910; LC–MS, m/z: 453.1 (M þ H)þ.
Mp: 65.3–68.1 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.95 (1H, s, triazole-H), 6.72–7.93 (7H, m, Ar-H), 5.61–5.68
(1H, m, CH*]CH2), 5.12 (1H, br, OH), 4.98–5.10 (2H, m, CH]CH*2),
4.42–4.52 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 4.30–4.33 (2H, t,
OCH2–), 3.43–3.59 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.98–3.19 (2H, m,
CCH2N), 2.82–2.89 (2H, m, NCH*2CH]CH2), 1.71–1.79 (2H, m,
OCH2CH*2CH2CH2CH3), 1.43–1.53 (2H, m, OCH2CH2CH*2CH2CH3),
1.26–1.33 (2H, m, OCH2CH2CH2CH*2CH3), 0.96–1.00 (3H, t, CH3); IR
(KBr): 3265, 3158, 3074, 2996, 1735, 1645, 1531, 1435, 1245, 990,
905; LC–MS, m/z: 499.1 (M þ H)þ.
6.3.15. Methyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2a)
Mp: 66.4–68.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s,
triazole-H), 7.95 (1H, s, triazole-H), 6.72–7.93 (7H, m, Ar-H), 5.60–
5.68 (1H, m, CH*]CH2), 5.13 (1H, br, OH), 4.98–5.10 (2H, m,
CH]CH*2), 4.41–4.52 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.91 (3H,
s, OCH3), 3.43–3.60 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.98–3.19 (2H, m,
CCH2N), 2.83–2.89 (2H, m, NCH*2CH]CH2); IR (KBr): 3255, 3118,
3075, 2985, 1735, 1645, 1535, 1466, 1230, 987, 905; LC–MS, m/z:
443.1 (M þ H)þ.
6.3.21. Phenyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (3a)
Mp: 72.2–73.4 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.09 (1H, s,
triazole-H), 7.75 (1H, s, triazole-H), 6.74–8.11 (12H, m, Ar-H), 5.62–
5.72 (1H, m, CH*]CH2), 5.15 (1H, br, OH), 5.00–5.15 (2H, m,
CH]CH*2), 4.44–4.55 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.49–
3.64 (2H, dd, J ¼ 14.0 Hz, Ar–CH2–), 3.02–3.49 (2H, m, CCH2N),
2.86–2.92 (2H, m, NCH*2CH]CH2); IR (KBr): 3245, 3150, 3054,
2998, 1738, 1645, 1531, 1423, 1210, 995, 905; LC–MS, m/z: 505.1
(M þ H)þ.
6.3.16. Ethyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2b)
Mp: 60.4–62.1 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.95 (1H, s, triazole-H), 6.72–7.94 (7H, m, Ar-H), 5.61–5.68
(1H, m, CH*]CH2), 5.13 (1H, br, OH), 4.98–5.10 (2H, m, CH]CH*2),
4.41–4.52 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 4.34–4.40 (2H, dd,
J ¼ 14.0 Hz, OCH2–), 3.44–3.59 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.99–
3.19 (2H, m, CCH2N), 2.83–2.90 (2H, m, NCH*2CH]CH2), 1.37–1.40
(3H, t, CH3); IR (KBr): 3235, 3145, 3053, 2990, 1760, 1648, 1555,
1477, 1240, 980, 912; LC–MS, m/z: 457.1 (M þ H)þ.
6.3.22. 3-Nitrophenyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-
3-(1H-1,2,4-triazol-1-yl)-propyl]-amino}-methyl)-benzoate (3b)
Mp: 74.5–75.9 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.09 (1H, s,
triazole-H), 7.76 (1H, s, triazole-H), 6.77–8.17 (11H, m, Ar-H), 5.48–
5.79 (1H, m, CH*]CH2), 5.13 (1H, br, OH), 5.02–5.17 (2H, m,
CH]CH*2), 4.39–4.52 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.50–
3.65 (2H, dd, J ¼ 14.0 Hz, Ar–CH2–), 2.99–3.42 (2H, m, CCH2N),
2.80–2.95 (2H, m, NCH*2CH]CH2); IR (KBr): 3236, 3177, 3056,
2996, 1745, 1638, 1531, 1435, 1245, 992, 898; LC–MS, m/z: 550.1
(M þ H)þ.
6.3.17. Isopropyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-
(1H-1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2c)
Mp: 58.3–59.7 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.04 (1H, s,
triazole-H), 7.94 (1H, s, triazole-H), 6.72–7.92 (7H, m, Ar-H), 5.61–
5.66 (1H, m, CH*]CH2), 5.13 (1H, br, OH), 5.21–5.27 (1H, m,
OCH), 4.98–5.12 (2H, m, CH]CH*2), 4.42–4.52 (2H, dd, J ¼ 14.4 Hz,
triazole–CH2–), 3.44–3.58 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.98–
3.19 (2H, m, CCH2N), 2.82–2.90 (2H, m, NCH*2CH]CH2), 1.36–1.37
(6H, d, J ¼ 6.0 Hz, 2 ꢁ CH3); IR (KBr): 3262, 3208, 3096, 2998,
1744, 1677, 1580, 1477, 1220, 988, 915; LC–MS, m/z: 471.1
(M þ H)þ.
6.3.23. 4-Nitrophenyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-
3-(1H-1,2,4-triazol-1-yl)-propyl]-amino}-methyl)-benzoate (3c)
Mp: 82.3–84.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.11 (1H, s,
triazole-H), 7.76 (1H, s, triazole-H), 6.74–8.34 (11H, m, Ar-H),
5.63–5.73 (1H, m, CH*]CH2), 5.12 (1H, br, OH), 5.01–5.16 (2H, m,
CH]CH*2), 4.43–4.57 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 3.52–
3.68 (2H, dd, J ¼ 14.4 Hz, Ar–CH2–), 2.92–3.22 (2H, m, CCH2N),
2.87–2.90 (2H, m, NCH*2CH]CH2); IR (KBr): 3283, 3135, 3066,
2985, 1740, 1665, 1542, 1446, 1220, 996, 912; LC–MS, m/z: 550.1
(M þ H)þ.
6.3.18. Butyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazole-1-yl)-propyl]-amino}-methyl)-benzoate (2d)
Mp: 43.1–45.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.03 (1H, s, tri-
azole-H), 7.95 (1H, s, triazole-H), 6.72–7.93 (7H, m, Ar-H), 5.61–5.68
(1H, m, CH*]CH2), 5.12 (1H, br, OH), 4.98–5.10 (2H, m, CH]CH*2),
4.42–4.52 (2H, dd, J ¼ 14.0 Hz, triazole–CH2–), 4.30–4.33 (2H, t,
OCH2–), 3.43–3.59 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 2.98–3.19 (2H, m,
CCH2N), 2.82–2.89 (2H, m, NCH*2CH]CH2), 1.73–1.82 (2H, m,
OCH2CH*2CH2CH3), 1.32–1.46 (2H, m, OCH2CH2CH2*CH3), 0.98–1.20
(3H, t, CH3); IR (KBr): 3250, 3135, 3065, 2988, 1730, 1643, 1552,
1450, 1263, 987, 895; LC–MS, m/z: 485.1 (M þ H)þ.
6.3.24. 4-Chlorophenyl-4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-
3-(1H-1,2,4-triazol-1-yl)-propyl]-amino}-methyl)-benzoate (3d)
Mp: 85.2–86.9 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.04 (1H, s,
triazole-H), 7.75 (1H, s, triazole-H), 6.74–8.09 (11H, m, Ar-H), 5.62–
5.71 (1H, m, CH*]CH2), 5.20 (1H, br, OH), 5.00–5.15 (2H, m,
CH]CH*2), 4.43–4.55 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.49–3.65
(2H, dd, J ¼ 14.0 Hz, Ar–CH2–), 3.00–3.21 (2H, m, CCH2N), 2.85–
2.91 (2H, m, NCH*2CH]CH2); IR (KBr): 3265, 3102, 3030, 2995,

1920
X. Chai et al. / European Journal of Medicinal Chemistry 44 (2009) 1913–1920
1738, 1668, 1545, 1443, 1286, 982, 896; LC–MS, m/z: 539.1
(M þ H)þ.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 20772153) and by Shanghai Leading
Academic Discipline Project Number: B906. We thank Dr. Wannian
Zhang for his advice and discussions.
6.3.25. Methyl-2-[4-({allyl[2-(2,4-difluorophenyl)-2-hydroxy-3-
(1H-1,2,4-triazol-1-yl)-propyl]-amino}-methyl)-benzoyloxy]-
benzoate (3e)
Mp: 99.3–101.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.06 (1H, s,
References
triazole-H), 7.75 (1H, s, triazole-H), 6.74–8.13 (11H, m, Ar-H), 5.63–
5.70 (1H, m, CH*]CH2), 5.20 (1H, br, OH), 5.00–5.14 (2H, m,
CH]CH*2), 4.44–4.55 (2H, dd, J ¼ 14.4 Hz, triazole–CH2–), 3.78 (3H,
s, OCH3), 3.49–3.64 (2H, dd, J ¼ 14.0 Hz, Ar–CH2–), 3.02–3.21 (2H,
m, CCH2N), 2.86–2.93(2H, m, NCH*2CH]CH2); IR (KBr): 3265, 3198,
3066, 2998, 1734, 1657, 1580, 1477, 1230, 990, 915; LC–MS, m/z:
563.1 (M þ H)þ.
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6.3.26. 4-(Propoxycarbonyl)-phenyl-[4-({allyl[2-(2,4-
difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-
yl)propyl]amino}methyl)]benzoate (3f)
Mp: 90.4–91.9 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.04 (1H, s, tri-
azole-H), 7.76 (1H, s, triazole-H), 6.74–8.14 (11H, m, Ar-H), 5.64–
5.71 (1H, m, CH*]CH2), 5.12 (1H, br, OH), 5.01–5.16 (2H, m,
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(2H, t, OCH2), 3.51–3.66 (2H, dd, J ¼ 13.6 Hz, Ar–CH2–), 3.02–3.51
(2H, m, CCH2N), 2.86–2.92 (2H, m, NCH*2CH]CH2), 1.76–1.85 (2H,
m, OCH2CH*2), 1.02–1.06 (3H, t, CH3); IR (KBr): 3245, 3214, 3096,
2985, 1735, 1657, 1570, 1477, 1220, 978, 910; LC–MS, m/z: 591.1
(M þ H)þ.
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