Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates

Article abstract of DOI:10.1016/j.ejmech.2014.01.009

A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl dithiocarbamates as new analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these compounds, 2a-f and 3a-q exhibited higher activities than fluconazole against nearly all fungi tested except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3h-k, and 3o-q against Candida species were much better than those of fluconazole and ketoconazole. Also, 2a-d, 3a-d, 3e-f, 3h-k, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft.

Full text of DOI:10.1016/j.ejmech.2014.01.009

European Journal of Medicinal Chemistry 74 (2014) 366e374
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antifungal activities and molecular docking studies of novel
2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl
dithiocarbamates
Yan Zou 1, Shichong Yu 1, Renwu Li, Qingjie Zhao, Xiang Li, Maocheng Wu, Ting Huang,
*
**
Xiaoxun Chai, Honggang Hu , Qiuye Wu
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates as new
analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these
compounds, 2aef and 3aeq exhibited higher activities than fluconazole against nearly all fungi tested
except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3hek, and 3oeq
against Candida species were much better than those of fluconazole and ketoconazole. Also, 2aed, 3aed,
3eef, 3hek, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking
experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme
group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft.
Ó 2014 Elsevier Masson SAS. All rights reserved.
Received 18 September 2013
Received in revised form
27 December 2013
Accepted 1 January 2014
Available online 16 January 2014
Keywords:
Triazole
Dithiocarbamate
Antifungal activity
CYP51
SAR
1. Introduction
develop new antifungal compounds with broader spectrum and
lower toxicities.
Azoles, such as fluconazole, itraconazole, voriconazole and
posaconazole (Fig. 1), are so far the mostly used fungicides in
clinical practice. Their mode of action, pharmacological properties,
and the resistance mechanisms are also mostly learned [1]. In
general, Azole drugs target the ergosterol biosynthetic pathway
through inhibiting the lanosterol 14 alpha demethylase (CYP51), a
key enzyme encoded by ERG11 gene. This kind of inhibition occurs
through the binding of a nitrogen atom of the azole ring to the iron
atom of the heme group of the enzyme. Therefore, the accumula-
tion of 14 alpha methylated sterol species leads to the synthesis of
toxic compounds, which are unable to successfully replace ergos-
terol, a kind of primary membrane sterol in fungi [2,3]. However,
owing to the relatively high risk of toxicity, serious drug resistance,
some nonnegligible drug interactions with chemotherapy agents
and insufficiencies in their antifungal activities, the clinical appli-
cation of azoles has been limited. Therefore, it is necessary to
On the other hand, dithiocarbamates have attracted consid-
erable attention recently due to their occurrence in a variety of
biologically active compounds [4]. It is reported that di-
thiocarbamates had antifungal, anti-bacterial and anti-tumor
effects [5e18]. In an effort to develop new type of antifungal
azoles, we were interested in the incorporation of dithiocarba-
mate moiety with triazoles (Fig. 2). Therefore, in the present
studies,
a series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-
1,2,4-triazol-1-yl)propyl dithiocarbamates were designed, syn-
thesized and evaluated for their antifungal activities. In addition,
a docking study of these compounds was conducted in an
attempt to understand their mechanism of action on the target
enzyme.
2. Chemistry
Herein, a new one-pot three-component method for the syn-
thesis of compounds 1aei, 2aeg and 3aeq was developed, which
started from readily available carbon disulfide, amines (primary or
secondary), and oxirane 6 (Scheme 1). In this method, the impor-
tant intermediate oxirane 6 was synthesized by the known proce-
dure in Scheme 2 [19] and the target compounds were obtained by
* Corresponding author. Tel./fax: þ86 (21) 8187 1228.
** Corresponding author. Tel./fax: þ86 (21) 8187 1225.
E-mail addresses: huhonggang_fox@msn.com (H. Hu), wuqy6439@sohu.com
(Q. Wu).
1
Yan Zou and Shichong Yu contributed equally to this work.
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.009

Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
367
Fig. 1. Triazole antifungal agents used in clinical therapy.
the initial nucleophilic addition of primary or secondary amines to
carbon disulfide, and the second nucleophilic attack of the resulted
carbamodithioic acid to the oxirane. All the target compounds were
obtained as racemates.
approximate 80% reduction in growth compared to the growth of
the drug-free well. For assays, the compounds to be tested were
dissolved in dimethyl sulfoxide (DMSO), serially diluted in growth
medium and incubated at 35 ꢀC. Growth MIC was determined at
24 h for C. albicans and at 72 h for C. neoformans. In vitro minimal
80% inhibitory concentration values are summarized in Table 1.
These data are the mean of three replicate tests with each anti-
fungal compound.
3. Antifungal assay
The in vitro antifungal activities of 1aei, 2aeg and 3aeq were
evaluated against eight human pathogenic fungi including Candida
albicans Y0109, C. albicans SC5314, Cryptococcus neoformans,
Candida parapsilosis, Candida glabrata, Trichophyton rubrum,
Microsporumgypseum and Aspergillus fumigatus. The positive con-
trols, including itraconazole, fluconazole, terbinafine and ketoco-
nazole, were obtained from their respective manufacturers.
The in vitro minimal inhibitory concentrations (MICs) of these
compounds were determined by the micro-broth dilution method
defined by the National Committee for Clinical Laboratory Standard
(NCCLS) [20]. The MIC80 was defined as the first well with an
4. Results and discussion
The results of in vitro antifungal activities of 1aei, 2aeg and
3aeq showed that most compounds were active against several
fungi tested to some extent and some of them showed even
higher activities than fluconazole, itraconazole, terbinafine and
ketoconazole. For example, the in vitro activities of 2b, 3a, 3c, 3he
k, and 3oeq against Candida species were much better than those
of fluconazole and ketoconazole. Compounds 2aed, 3aed, 3eef,
Fig. 2. All the compounds we designed and synthesized.

368
Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
5. Conclusion
A series of novel triazole derivatives with substituted amine
dithiocarbamic acid esters as side chains have been successfully
designed and synthesized as antifungal agents. In vitro antifungal
activities of all title compounds were evaluated against eight hu-
man pathogenic fungi usually encountered clinically. The results
showed that the introduction of dithiocarbamate with proper side
chains enhanced the antifungal activities of these title compounds
against Candida species. Among the amines studied, the secondary
amines were shown to be more active than the primary amines. The
results also demonstrated that 3eeq, with substituted phenyl pi-
perazines as side chains, are highly active and worth for further
evaluation.
Scheme 1. Reagents and conditions: (a) ClCH2COCl, AlCl3, r.t.,
5 h; (b) C6H5CH3,
NaHCO3, 1H-1,2,4-triazole, reflux,
5 h; (c) C6H5CH3, NaOH, (CH3)3SOI, acetyl-
trimethylammonium bromide, 60 ꢀC, 3 h.
3hek, 3p and 3q exhibited higher activities against A. fumi than
fluconazole. From the results, it seems that compounds 2aef and
3aed, which have N, N-disubstituted dithiocarbamates in their
structures, showed higher antifungal activities than 1aei con-
taining N-monosubstituted dithiocarbamate groups. To further
demonstrate the finding, a series of substituted phenyl pipera-
zines were introduced to the side chain of target compounds to
make 3eeq. The antifungal activities of compounds 3eeq were
tested and shown to be better than those of compounds 1aei and
2aeg.
It has been reported that fluconazole is not effective against
A. fumigatus because A. fumigatus possesses an intrinsic mechanism
resistant to triazole antifungal agents [21]. Most interestingly, our
compounds exhibit moderate activity against A. fumigatus. For
example, compounds 3e and 3f exhibited the same activities
against A. fumigatus as ketoconazole (with the MIC80 values of
4 mg/mL). Compounds 2a, 2b, 3c, 3d, 3h, 3i, 3p and 3q exhibited the
same activities against A. fumigatus as itraconazole (with the MIC80
values of 8 mg/mL).
6. Experiment part
Melting points were measured on a Yamato MP-21 melting-
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 unless otherwise indicated with a Bruker AC-
300P spectrometer, using TMS as internal standard. ESI mass
spectra were performed on an API-3000 LC-MS spectrometer. TLC
analysis was carried out on silica gel plates GF254 (Yantai Huanghai
chemical, china). Amines and piperazine were purchased from
Energy-Chemical. The solvents and reagents were purchased from
commercial vendors and were used as received or dried prior to use
as needed.
6.1. General procedure for the synthesis of title compounds 1aei,
2aeg and 3aeq
Moreover, our compounds also showed excellent activities
against C. neoformans and C. glabrata. For example, compounds 3a,
3e and 3hek exhibited higher antifungal activities against
C. neoformans than all positive controls with the MIC80 values of
<0.125 mg/mL. The antifungal activities of compounds 2aeb, 2eef,
3aee, 3p against C. glabrata were stronger than those of all positive
controls (with the MIC80 values of <0.125 mg/mL). Compared to
other tested compounds, the highest activities with broad anti-
fungal spectra of 3aeb, 3i and 3p make them good candidates for
further evaluation.
To further understand the mechanism of action of the syn-
thesized compounds, 3b and 3i were docked into the active site
of CACYP51 by the Builder module within Insight II 2000 soft-
ware package (Fig 3). The docking result revealed that the tri-
azole group, the difluorophenyl group and the piperazinyl side
chain can bind to the active site of CACYP51 through the former
binding mode. The substituted phenyl piperazine side chain of
compound 3i forms hydrophobic and van der Waals interactions
with surrounding hydrophobic residues such as Ile-131, Met-306,
Ile-304, Tyr-118, Phe-126 and Tyr-132. The sulfur atom of di-
thiocarbamates would generate H-bond with the Phe-228. The
oxygen atom of morpholine of compound 3b would also form H-
bond with the Ser-378.
The solution of amine (2.0 mmol), triethylamine (3.0 mmol) and
carbon disulfide (2.0 mmol) in CH3CH2OH (7 ml) was stirred under
0
ꢀC for 1 h and then oxirane 6 (1.0 mmol) was added, and the
mixture was stirred under r.t. for about 5 h. The reaction was
monitored by TLC (dichloromethane/methanol, 50/1, V/V). The
solvent was removed under reduced pressure. The residue was
then extracted with ethyl acetate, washed with 10% citric acid,
saturated Na2CO3 solution and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated. The viscous residue was
crystallized from diethyl ether to afford the title compound 1aei,
2aeg and 3aeq.
The characterization data of the compounds are given below.
6.1.1. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl methylcarbamodithioate (1a)
Yield: 90.8%; m. p. 94.2e95.9 ꢀC. 1H NMR (300 MHz, DMSO-d6):
dH 9.97 (dd, J ¼ 32.1, 4.7 Hz, 1H), 8.29 (s, 1H), 7.75 (s, 1H), 7.32 (td,
J ¼ 9.0, 7.0 Hz, 1H), 7.19 (ddd, J ¼ 11.9, 9.2, 2.5 Hz, 1H), 6.95 (td,
J ¼ 8.5, 2.5 Hz, 1H), 6.27 (d, J ¼ 21.5 Hz, 1H), 4.80e4.50 (m, 2H),
3.99e3.79 (m, 2H), 2.97e2.78 (d, J ¼ 4.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dC 196.66, 163.94e164.11, 160.85e161.11, 157.67e157.83,
151.10, 145.44, 130.42e130.63, 125.45e125.69, 111.11e111.43,
104.13e104.84, 73.90, 56.72, 44.04, 34.28. HRMS (m/z): calcd. for
C13H15F2N4OS2: 345.4107; found: 345.4129.
6.1.2. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl ethylcarbamodithioate (1b)
Yield: 88.0%; m. p. 93.2e94.8 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.10 (d, J ¼ 12.5 Hz, 1H), 7.84 (s, 1H), 7.60e7.50 (m, 1H), 6.90e6.74
(m, 2H), 5.42e5.23 (m, 1H), 4.71 (s, 2H), 4.33e3.39 (m, 5H), 1.27e
0.97 (m, 3H). 13C NMR (75 MHz, CDCl3): dC 197.66, 164.42e164.69,
161.08e161.29, 160.08e160.18, 156.80e156.89, 150.89, 144.44,
130.14, 124.26e124.43, 111.47e111.75, 103.85e104.56, 75.35,
Scheme 2. Reagents and conditions: (a) Et3N, CH3CH2OH, ice bath to r.t.

Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
369
Table 1
Antifungal activities of the target compounds in vitro.
Compd
R
MICa
(mg/mL)
C. abl Y0109
C. abl SC5314
C. par.
C. neo.
C. gla.
A. fum.
T. rub.
M. gyp.
1a
1b
1c
1d
1e
CH3NH
1
1
0.25
1
0.5
1
1
0.25
2
0.5
>64
>64
>64
1
64
64
64
64
64
2
4
2
4
16
>64
>64
>64
>64
>64
4
4
32
64
>64
>64
>64
>64
>64
>64
CH3CH2NH
CH3 (CH2)2NH
(CH3)2CHNH
CH3 (CH2)3NH
0.25
1f
0.5
0.5
2
64
4
>64
64
64
1g
1
1
1
64
8
>64
64
>64
1h
1i
0.25
1
0.25
0.5
64
8
16
16
4
8
>64
>64
64
>64
0.5
32
2a
2b
(CH3)2N
(CH3 CH2)2N
ꢁ0.125
ꢁ0.125
ꢁ0.125
ꢁ0.125
0.5
0.5
0.5
0.25
ꢁ0.125
ꢁ0.125
8
8
0.5
8
2
4
2c
0.25
0.5
32
1
0.5
64
2
2
2d
2e
0.25
0.25
0.5
1
8
0.25
16
>64
>64
ꢁ0.125
ꢁ0.125
ꢁ0.125
ꢁ0.125
>64
4
16
2f
0.25
0.25
0.25
2
ꢁ0.125
>64
>64
2
1
32
1
2g
8
8
>64
64
0.25
3a
3b
ꢁ0.125
ꢁ0.125
ꢁ0.125
ꢁ0.125
0.5
ꢁ0.125
ꢁ0.125
ꢁ0.125
16
16
8
8
8
8
0.25
0.25
3c
ꢁ0.125
ꢁ0.125
ꢁ0.125
ꢁ0.125
0.25
1
0.25
2
ꢁ0.125
ꢁ0.125
8
8
1
2
4
3d
32
3e
3f
0.25
0.25
0.25
1
ꢁ0.125
ꢁ0.125
4
4
2
2
2
2
ꢁ0.125
ꢁ0.125
0.25
0.25
(continued on next page)

370
Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
Table 1 (continued )
Compd
R
MICa
(mg/mL)
C. abl Y0109
C. abl SC5314
C. par.
C. neo.
C. gla.
A. fum.
T. rub.
M. gyp.
3g
3h
0.5
0.5
2
0.5
0.5
>64
1
>64
ꢁ0.125
ꢁ0.125
0.5
ꢁ0.125
0.25
8
0.5
4
3i
3j
ꢁ0.125
ꢁ0.125
0.25
0.25
ꢁ0.125
ꢁ0.125
0.25
0.5
16
8
1
1
2
2
ꢁ0.125
0.5
3k
3l
ꢁ0.125
ꢁ0.125
ꢁ0.125
0.5
1
ꢁ0.125
0.25
0.5
16
1
2
4
0.25
0.5
>64
16
3m
3n
0.5
0.5
0.5
1
1
0.5
0.5
0.5
0.5
>64
>64
1
>64
ꢁ0.125
0.5
16
3o
ꢁ0.125
ꢁ0.125
0.5
0.25
0.25
16
1
4
3p
3q
ꢁ0.125
ꢁ0.125
ꢁ0.125
ꢁ0.125
0.25
0.5
0.25
0.25
ꢁ0.125
8
8
1
1
4
2
2
4
0.25
ICZ
8
16
0.25
0.25
4
4
8
1
0.5
2
4
1
2
0.5
2
8
0.25
4
TBLR
KCZ
FCZ
0.25
0.25
1
0.0625
0.125
4
0.0625
1
32
ꢁ0.125
0.25
>64
Abbreviations: C. alb, Candida albicans; C. neo, Cryptococcus neoformans; C. par, Candida parapsilosis; C. gla, Candida glabrata; T. rub, Trichophyton rubrum; M. gyp, Microsporum
gypseu;. A. fum, Aspergillus fumigates. ICZ, Itraconazole; TBLR, terbinafine; KCZ, Ketoconazole; FCZ, fluconazole.
a
Minimum inhibitory concentration for 80% inhibition of growth.
56.767, 43.08, 41.80, 13.16. HRMS (m/z): calcd. for C14H17F2N4OS2:
359.0806; found: 359.0838.
196.02, 163.99e164.15, 160.67e160.84, 159.66e159.81, 156.39e
156.55, 150.45, 143.98, 129.65, 123.85, 110.96e111.23, 103.42e
104.12, 74.90, 56.30, 49.51, 42.07, 21.72, 20.96. HRMS (m/z): calcd.
for: C15H19F2N4OS2: 373.0963; found: 373.0987.
6.1.3. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl propylcarbamodithioate (1c)
Yield: 72.4%; m. p. 94.2e95.1 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.12 (d, J ¼ 13.9 Hz, 1H), 7.86 (d, J ¼ 2.4 Hz, 1H), 7.65e7.49 (m, 1H),
6.93e6.75 (m, 2H), 5.35 (d, J ¼ 28.4 Hz, 1H), 4.82e4.67 (m, 2H),
4.35e3.34 (m, 5H), 1.72e1.56 (m, 2H), 0.99e0.78 (m, 3H). 13C NMR
(75 MHz, CDCl3): dC 197.89, 164.48e164.64, 161.16e161.32, 160.12e
160.28, 156.85e157.01,150.76,144.34,130.08,124.24,111.46e111.74,
103.91e104.61, 74.50, 56.73, 49.74, 42.62, 21.45, 11.37. HRMS (m/z):
calcd. for C15H19F2N4OS2: 373.0963; found: 373.0990.
6.1.5. 2-(2, 4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl butylcarbamodithioate (1e)
Yield: 74.2%; m. p. 93.9e95.6 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.12 (d, J ¼ 13.5 Hz, 1H), 7.86 (s, 1H), 7.62e7.50 (m, 1H), 6.94e6.75
(m, 2H), 5.35 (d, J ¼ 25.0 Hz, 1H), 4.73 (d, J ¼ 3.7 Hz, 2H), 4.38e3.34
(m, 5H),1.64 (m, 2H),1.50e1.31 (m, 2H),1.04e0.90 (m, 3H). 13C NMR
(75 MHz, CDCl3): dC 197.81, 164.54e164.70, 161.22e161.38, 160.16e
160.34, 156.92e157.07, 150.61, 144.31, 130.21, 124.39, 111.56e111.83,
103.96e104.66, 75.45, 56.81, 47.91, 42.75, 30.18, 20.10, 13.70. HRMS
(m/z): calcd. for C16H21F2N4OS2: 387.1119; found: 387.1130.
6.1.4. 2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl isopropylcarbamodithioate (1d)
Yield: 84.2%; m. p. 94.5e96.0 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.10 (d, J ¼ 12.5 Hz, 1H), 7.84 (s, 1H), 7.67e7.48 (m, 1H), 6.81e6.23
(m, 2H), 5.42e5.27 (m, 1H), 4.71 (s, 2H), 4.60e4.42 (m, 1H), 4.35e
3.42 (m, 3H), 1.26e1.02 (m, 6H). 13C NMR (75 MHz, CDCl3): dC
6.1.6. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl allylcarbamodithioate (1f)
Yield: 71.2%; m. p. 94.8e96.2 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.11 (d, J ¼ 12.6 Hz, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.64e7.50 (m, 1H),

Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
371
Fig. 3. A: Computed binding geometry of the new inhibitor 3b in the active site of CYP51, B: computed binding geometry of the new inhibitor 3i in the active site of CYP51.
6.92e6.77 (m, 2H), 5.87 (m, 1H), 5.42e5.21 (m, 3H), 4.73 (s, 2H),
4.34 (dd, J ¼ 7.7, 3.5 Hz, 2H), 4.14e4.02 (m, 1H), 3.84 (d, J ¼ 15.2 Hz,
1H). 13C NMR (75 MHz, CDCl3): dC 198.48, 164.55e164.71, 161.23e
161.39, 156.72e156.87, 151.57, 144.49, 131.47, 130.15e130.35,
124.20e124.40, 118.88, 111.55e111.87, 103.98e104.68, 75.63, 56.57,
50.17, 42.84. MS (ESI): m/z 371.48 [M þ H]þ.
(d, J ¼ 14.9 Hz, 1H), 4.76e4.59 (m, 2H), 4.24 (d, J ¼ 15.1 Hz, 1H), 3.98
(d, J ¼ 15.1 Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). 13C NMR (75 MHz,
CDCl3): dC 198.19, 164.47e164.63, 161.15e161.32, 160.29e160.45,
157.02e157.18, 151.40, 144.59, 130.29e130.49, 124.61e124.83,
111.41e111.72, 103.88e104.59, 75.55, 57.12, 46.39, 44.12, 42.10,
HRMS (m/z): calcd. for C15H19F2N4OS2: 373.0963; found:373.0985.
6.1.7. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl cyclopropylcarbamodithioate (1g)
6.1.11. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl diethylcarbamodithioate (2b)
Yield: 85.2%; m. p. 96.2e97.9 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.85 (d, J ¼ 4.2 Hz, 1H), 7.58e7.23 (m, 1H), 6.91e6.76 (m,
2H), 5.30e4.98 (m, 1H), 4.81e4.66 (m, 2H), 4.15e3.88 (m, 1H),
3.88e3.62 (m, 1H), 1.00e0.86 (m, 2H), 0.80e0.64 (m, 2H). 13C NMR
(75 MHz, CDCl3): dC 199.60, 164.45e164.61, 161.147e161.30,
160.28e160.40, 156.98e157.13, 150.99, 144.47, 130.24, 124.27e
124.49, 111.44e111.68, 103.90e104.60, 75.45, 56.99, 42.83, 30.45,
27.68, 8.42. HRMS (m/z): calcd. for C15H17F2N4OS2: 371.0806; found:
371.0831.
Yield: 84.6%; m. p. 95.7e96.9 ꢀC. 1H NMR (600 MHz, CDCl3): dH
8.21 (s, 1H), 7.89 (s, 1H), 7.65 (dd, J ¼ 15.3, 8.1 Hz, 1H), 6.89e6.68 (m,
2H), 5.47 (s, 1H), 4.74 (dd, J ¼ 34.8, 14.0 Hz, 2H), 4.30 (d, J ¼ 15.2 Hz,
1H), 4.14e3.96 (m, 3H), 3.77 (d, J ¼ J ¼ 6.8 Hz, 2H), 1.36e1.28 (m,
6H). 13C NMR (75 MHz, CDCl3): dC 196.45, 164.44e164.61, 161.13e
161.30, 160.30e160.46, 157.03e157.19, 150.62, 144.47, 130.44,
124.63e124.85, 111.34e111.65, 103.85e104.55, 75.38, 57.41, 50.81,
47.53, 43.51, 12.39, 11.53. MS (ESI): m/z 387.43 [M þ H]þ.
6.1.8. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl cyclohexylcarbamodithioate (1h)
6.1.12. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl methyl(phenyl)carbamodithioate (2c)
Yield: 87.7%; m. p. 96.4e97.9 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.12 (d, J ¼ 12.7 Hz, 1H), 7.86 (d, J ¼ 1.9 Hz, 1H), 7.62e7.52 (m, 1H),
6.83e6.54 (m, 2H), 5.45e5.29 (m, 1H), 4.73 (s, 2H), 4.43e4.21 (m,
1H), 4.00 (t, J ¼ 16.4 Hz, 1H), 3.81 (d, J ¼ 15.3 Hz, 1H), 2.09 (d,
J ¼ 12.3 Hz, 2H), 1.85e1.59 (m, 4H), 1.52e1.12 (m, 6H). 13C NMR
(75 MHz, CDCl3): dC 196.39, 164.49e164.70, 161.33e161.40, 161.13,
156.83e157.00, 151.21, 144.52, 130.27, 124.33e124.50, 111.52e
111.79, 103.89e104.60, 75.47, 56.74, 42.65, 31.69, 25.25, 24.54.
HRMS (m/z): calcd. for C18H23F2N4OS2: 413.1276; found: 413.1299.
Yield: 74.3%; m. p. 101.9e103.4 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.86 (s, 1H), 7.70e7.53 (m, 1H), 7.79e7.21 (m, 6H), 7.36
(d, J ¼ 6.8 Hz, 3H), 7.21e7.20 (m, 2H), 6.95e6.75 (m, 2H), 5.34e5.15
(m, 2H), 5.08e4.88 (m, 1H), 4.84e4.62 (m, 2H), 4.32 (dd, J ¼ 15.0,
4.5 Hz, 1H), 4.05 (dd, J ¼ 15.0, 7.4 Hz, 1H), 3.48 (s, 1H), 3.26 (s, 2H).
13C NMR (75 MHz, CDCl3): dC 200.58, 164.41e164.57, 161.10e161.26,
160.24e160.40, 156.97e157.13, 151.40, 144.52, 130.13e130.33,
129.93, 129.35, 126.56, 124.63e124.85, 111.31e111.63, 103.84e
104.54, 75.54, 56.96, 47.21, 44.62. HRMS (m/z): calcd. for
C20H21F2N4OS2: 435.1119; found: 435.1140.
6.1.9. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl benzylcarbamodithioate (1i)
Yield: 87.1%; m. p. 101.2e103.6 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.13 (s, 1H), 7.79 (s, 1H), 7.62e7.40 (m, 4H), 7.25e7.15 (m, 2H), 6.90e
6.68 (m, 2H), 5.28e5.03 (m, 1H), 4.65 (s, 2H), 4.15 (d, J ¼ 15.0 Hz,
1H), 3.87 (d, J ¼ 15.1 Hz, 1H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3):
dC 198.20, 164.55e164.76, 161.36e161.45, 160.23e160.43, 156.94e
157.06, 149.94, 144.13, 135.64, 130.27, 128.97, 128.32, 111.62e111.85,
104.01e104.71, 75.37, 56.84, 52.00, 42.98. MS (ESI): m/z 421.44
[M þ H]þ.
6.1.13. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl benzyl(methyl)carbamodithioate (2d)
Yield: 70.6%; m. p. 103.6e105.1 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.86 (s, 1H), 7.75e7.49 (m, 1H), 7.36 (d, J ¼ 6.8 Hz, 3H),
7.26 (d, J ¼ 7.4 Hz, 1H), 7.15 (d, J ¼ 6.9 Hz, 1H), 6.83 (dd, J ¼ 16.0,
7.6 Hz, 2H), 5.52e5.35 (m, 1H), 5.35e5.17 (m, 1H), 5.06e4.88 (m,
1H), 4.83e4.63 (m, 2H), 4.32 (dd, J ¼ 15.0, 4.5 Hz, 1H), 4.05 (dd,
J ¼ 15.0, 7.4 Hz,1H), 3.37e3.12 (m, 3H). 13C NMR (75 MHz, CDCl3): dC
199.76, 164.46e164.59, 161.19e161.35, 160.34e160.49, 157.07e
157.23, 150.69, 144.35, 134.93, 133.99, 130.34, 128.89, 128.10, 127.79,
127.08, 124.66, 111.44e111.71, 103.92e104.62, 75.48, 60.71, 58.21,
6.1.10. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl dimethylcarbamodithioate (2a)
Yield: 79.9%; m. p. 96.7e98.0 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.12 (s, 1H), 7.82 (s, 1H), 7.69e7.43 (m, 1H), 6.98e6.72 (m, 2H), 5.32
57.29, 44.34, 39.48. HRMS (m/z): calcd. for C21H23F2N4OS2:
449.1276; found:449.1296.

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Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
6.1.14. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl (2-hydroxyethyl)methylcarbamodithioate (2e)
111.43e111.75, 103.89e104.59, 75.38, 57.05, 54.29, 52.40, 50.38,
45.52, 43.73, 29.70. HRMS (m/z): calcd. for
C17H22F2N5OS2:
Yield: 80.1%; oil. 1H NMR (300 MHz, CDCl3): dH 8.17 (s, 1H), 7.86
(s, 1H), 7.61e7.49 (m, 1H), 6.93e6.79 (m, 2H), 5.32 (t, J ¼ 3.1 Hz, 1H),
4.70e4.53 (m, 2H), 4.35e4.20 (m, 2H), 3.94 (dd, J ¼ 20.9, 12.5 Hz,
3H), 3.59 (s, 1H), 3.43 (s, 2H). 13C NMR (75 MHz, CDCl3): dC 198.98,
164.44e164.60, 161.13e161.29, 160.27e160.43, 157.00e157.15,
150.66, 144.54, 130.15, 124.52, 111.40e111.67, 103.90e104.60, 75.22,
65.80, 59.85, 57.21, 44.02, 42.19. HRMS (m/z): calcd. for
414.1228; found:414.1251.
6.1.20. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-oxopiperidine-1-carbamodithioate (3d)
Yield: 90.9%; m. p. 111.8e113.2 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.13 (s, 1H), 7.87 (s, 1H), 7.60e7.41 (m, 1H), 7.01e6.73 (m, 2H), 5.27
(d, J ¼ 28.4 Hz, 1H), 4.83e4.65 (m, 2H), 4.64e4.10 (m, 5H), 4.03 (d,
J ¼ 14.9 Hz,1H), 2.64 (t, J ¼ 6.0 Hz, 4H). 13C NMR (75 MHz, CDCl3): dC
204.97, 198.83, 164.55e164.71, 161.23e161.39, 160.27e160.43,
157.00e157.16, 151.62, 144.59, 130.19e130.39, 124.34e124.56,
111.53e111.84, 104.00e104.69, 75.37, 56.91, 53.44, 44.41, 39.55.
HRMS (m/z): calcd. for C17H19F2N4O2S2: 413.0912; found:413.0948.
C
16H21F2N4O2S2: 403.1069; found:403.1092.
6.1.15. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl benzyl(2-hydroxyethyl)carbamodithioate (2f)
Yield: 75.9%; oil. 1H NMR (300 MHz, CDCl3): dH 8.18 (d, J ¼ 6.0 Hz,
1H), 7.87 (s, 1H), 7.70e7.52 (m, 1H), 7.36e7.28 (m, 3H), 7.26 (d,
J ¼ 6.6 Hz, 1H), 7.16 (d, J ¼ 6.7 Hz, 1H), 6.83 (dd, J ¼ 18.0, 8.9 Hz, 2H),
5.47e5.37 (m, 1H), 5.19e4.98 (m, 2H), 4.70 (d, J ¼ 14.1 Hz, 2H), 4.35
(d, J ¼ 15.0 Hz, 1H), 4.24e3.79 (m, 5H). 13C NMR (75 MHz, CDCl3): dC
199.74, 164.43e164.59, 161.11e161.28, 160.20e160.35, 156.95e
157.11, 151.29, 144.63, 135.11, 134.53, 134.04, 130.20, 128.91, 128.23,
127.69, 126.94, 111.39e111.66, 103.88e104.57, 75.41, 65.89, 60.01,
6.1.21. 2-(2, 4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-phenyl piperazine-1-carbodithioate (3e)
Yield: 87.5%; m. p. 157.1e160.3 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.15 (s, 1H), 7.87 (s, 1H), 7.61e7.42 (m, 1H), 7.33e7.26 (m, 2H), 6.88e
6.59 (m, 5H), 5.33 (s, 1H), 4.79e4.65 (m, 2H), 4.60e4.28 (m, 3H),
4.06 (t, J ¼ 13.1 Hz, 3H), 3.31 (s, 4H). 13C NMR (75 MHz, CDCl3): dC
198.20, 164.51e164.67, 161.19ee161.36, 160.29e160.44, 157.02e
157.17, 151.50, 150.03, 144.60, 130.29e130.49, 129.38, 126.14,
124.51e124.72, 120.76, 116.33, 111.48e111.79, 103.93e104.63, 75.47,
57.01, 52.17, 50.23, 49.24, 43.71. HRMS (m/z): calcd. for:
52.11, 47.27, 44.25. HRMS (m/z): calcd. for
C22H25F2N4O2S2:
479.1382; found: 479.1399.
6.1.16. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl bis(2-hydroxyethyl)carbamodithioate (2g)
Yield: 75.6%; oil. 1H NMR (300 MHz, CDCl3): dH 8.19 (s, 1H), 7.86
(s, 1H), 7.60e7.43 (m, 1H), 6.95e6.80 (m, 2H), 5.32 (s, 1H), 4.76 (d,
J ¼ 14.1 Hz, 1H), 4.61 (d, J ¼ 14.1 Hz, 1H), 4.51e4.15 (m, 4H), 4.15e
3.79 (m, 8H). 13C NMR (75 MHz, CDCl3): dC 199.54, 164.54e164.70,
161.22e161.39, 160.32e160.47, 157.04e157.20, 151.11, 144.66,
130.08e130.28, 124.58e124.80, 111.53e111.84, 104.03e104.73,
75.29, 59.00e60.28, 58.10, 57.10, 43.99. HRMS (m/z): calcd. for
C22H24F2N5OS2: 476.1385; found:476.1398.
6.1.22. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-benzylpiperazine-1-carbodithioate (3f)
Yield: 85.4%; m. p.158.8e162.6 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.85 (s, 1H), 7.59e7.41 (m, 1H), 7.36 (s, 5H), 6.92e6.78
(m, 2H), 5.32 (s, 1H), 4.81e4.63 (m, 2H), 4.29 (d, J ¼ 15.0 Hz, 3H),
4.00 (d, J ¼ 15.0 Hz, 3H), 3.62 (s, 2H), 2.60 (s, 4H). 13C NMR (75 MHz,
CDCl3): dC 197.99, 164.50e164.66, 161.18e161.35, 160.28e160.43,
157.00e157.16, 151.49, 144.61, 130.23e130.43, 129.72, 128.76,
128.35, 124.43e124.65, 111.47e111.78, 103.93e104.63, 75.33, 61.98,
C
17H23F2N4O3S2: 433.1174; found: 433.1198.
6.1.17. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl piperidine-1-carbamodithioate (3a)
Yield: 87.8%; m. p. 99.7e101.6 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.84 (s, 1H), 7.60e7.46 (m, 1H), 6.96e6.73 (m, 2H), 5.44
(s, 1H), 4.83e4.59 (m, 2H), 4.26 (t, J ¼ 14.3 Hz, 3H), 4.10e3.73 (m,
3H), 1.71 (s, 6H). 13C NMR (75 MHz, CDCl3): dC 196.34, 164.45e
164.61, 161.14e161.30, 160.30e160.46, 157.03e157.19, 151.35,
144.59, 130.35e130.55, 124.71e124.93, 111.36e111.68, 103.84e
104.54, 75.44, 57.28, 54.31, 52.07, 43.61, 25.47, 26.00, 24.06. HRMS
(m/z): calcd. for C17H21F2N4OS2: 399.119; found: 399.1143.
56.92, 51.82, 44.06. HRMS (m/z): calcd. for
490.1541; found: 490.1568.
C23H26F2N5OS2:
6.1.23. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (3g)
Yield: 81.3%; m. p. 160.3e164.1 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.87 (s, 1H), 7.62e7.45 (m, 1H), 7.42e7.35 (m, 1H), 7.28e
7.23 (m, 1H), 7.05e6.98 (m, 2H), 6.97e6.74 (m, 2H), 5.33 (d,
J ¼ 5.2 Hz, 1H), 4.80e4.67 (m, 2H), 4.52 (d, J ¼ 16.6 Hz, 2H), 4.34 (d,
J ¼ 15.0 Hz, 1H), 4.07 (t, J ¼ 15.2 Hz, 3H), 3.20e2.98 (m, 4H). 13C
NMR (75 MHz, CDCl3): dC 198.09, 164.53e164.70, 161.21e161.38,
160.32e160.47, 157.05e157.20, 147.79, 130.76, 130.28e130.48,
128.98, 127.81, 120.60, 111.50e111.81, 103.96e104.66, 75.31, 57.33,
52.74, 50.67, 43.82. MS (ESI): m/z 494.41 [M þ H]þ.
6.1.18. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl morpholine-4-carbamodithioate (3b)
Yield: 91.4%; m. p. 102.1e103.8 ꢀC. 1H NMR (600 MHz, CDCl3): dH
8.19 (s, 1H), 7.91 (s, 1H), 7.64e7.47 (m, 1H), 6.89e6.71 (m, 2H), 5.31
(s, 1H), 4.83e4.68 (m, 2H), 4.36 (d, J ¼ 15.0 Hz, 3H), 4.06 (d,
J ¼ 15.0 Hz, 1H), 3.89e3.42 (m, 6H). 13C NMR (75 MHz, CDCl3): dC
198.27, 164.47e164.61, 161.13e161.31, 160.25e160.40, 156.98e
157.19, 151.28, 144.05, 130.26e130.39, 124.45e124.62, 111.48e
111.75, 104.02e104.55, 75.35, 65.90, 57.01, 53.64, 51.76, 43.71, 14.32.
MS (ESI): m/z 401.47 [M þ H]þ.
6.1.24. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(3-fluorophenyl)piperazine-1-carbodithioate (3h)
Yield: 82.0%; m. p.161.6e166.9 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.87 (s, 1H), 7.61e7.39 (m, 1H), 7.24 (dd, J ¼ 15.2, 8.2 Hz,
1H), 6.94e6.77 (m, 2H), 6.72e6.48 (m, 3H), 5.31 (d, J ¼ 6.0 Hz, 1H),
4.80e4.65 (m, 2H), 4.59e4.27 (m, 3H), 4.05 (t, J ¼ 11.6 Hz, 3H), 3.33
(s, 4H). 13C NMR (75 MHz, CDCl3): dC 198.01, 165.41, 164.55, 162.17,
161.23e161.39, 160.32e160.48, 157.05e157.21, 151.32e151.45,
150.38, 130.21e130.58, 124.34e124.51, 111.28e111.83, 106.93e
107.22, 103.97e104.68, 102.86e103.20, 75.23, 57.24, 51.67, 49.89,
48.08, 43.90. HRMS (m/z): calcd. for C22H23F3N5OS2: 494.1291;
found: 494.1308.
6.1.19. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-methylpiperazine-1-carbamodithioate (3c)
Yield: 75.4%; m. p. 149.8e151.7 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.85 (s, 1H), 7.59e7.42 (m, 1H), 6.98e6.72 (m, 2H), 5.33
(d, J ¼ 6.7 Hz, 1H), 4.82e4.61 (m, 2H), 4.58e4.19 (m, 3H), 4.15e3.80
(m, 3H), 2.48 (d, J ¼ 4.3 Hz, 4H), 2.33 (s, 3H). 13C NMR (75 MHz,
CDCl3): dC 197.72, 164.48e164.64, 161.17e161.33, 160.28e160.44,
157.01e157.17, 151.45, 144.58, 130.30e130.50, 124.56e124.78,

Y. Zou et al. / European Journal of Medicinal Chemistry 74 (2014) 366e374
373
6.1.25. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(4-fluorophenyl)piperazine-1-carbodithioate (3i)
Yield: 88.5%; m. p.168.0e169.8 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.87 (s, 1H), 7.61e7.40 (m, 1H), 7.28e7.23 (m, 2H), 6.91e
6.78 (m, 4H), 5.31 (d, J ¼ 8.5 Hz, 1H), 4.81e4.64 (m, 2H), 4.60e4.28
(m, 3H), 4.05 (t, J ¼ 12.6 Hz, 3H), 3.27 (s, 4H). 13C NMR (75 MHz,
CDCl3): dC 198.12, 164.56e164.71, 161.23e161.38, 160.33e160.45,
157.03e157.18, 151.18, 148.35, 130.24e130.44, 129.31, 126.08,
124.40e124.62, 117.70, 111.52e111.83, 103.97e104.68, 75.34, 57.18,
51.60, 49.88, 48.85, 43.82. HRMS (m/z): calcd. for C22H23F3N5OS2:
494.1291; found: 494.1303.
6.80 (m, 3H), 5.32 (d, J ¼ 1.8 Hz, 1H), 4.80e4.66 (m, 2H), 4.43e4.25
(m, 3H), 4.07 (t, J ¼ 16.7 Hz, 3H), 3.66e3.33 (m, 2H), 3.14 (s, 4H). 13
C
NMR (75 MHz, CDCl3): dC 198.20, 164.54e164.70, 161.23e161.39,
160.33e160.49, 157.05e157.21, 150.44, 134.35, 130.36, 130.24,
127.67, 125.66, 124.33e124.55, 118.81, 111.50e111.81, 103.97e
104.67, 75.30, 75.24, 57.42, 52.59, 50.73, 48.24, 43.91. HRMS (m/z):
calcd. for C22H22Cl2F2N5OS2: 544.0605; found: 544.0629.
6.1.31. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(3-methoxyphenyl)piperazine-1-carbodithioate (3o)
Yield: 83.4%; m. p.170.1e174.6 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.15 (s, 1H), 7.86 (s, 1H), 7.61e7.52 (m, 1H), 7.22 (t, J ¼ 8.2 Hz, 1H),
6.93e6.78 (m, 2H), 6.55e6.42 (m, 3H), 5.32 (s, 1H), 4.79e4.65 (m,
2H), 4.59e4.27 (m, 3H), 4.03 (d, J ¼ 15.0 Hz, 3H), 3.81 (s, 3H), 3.31 (s,
4H). 13C NMR (75 MHz, CDCl3): dC 198.02, 164.52, 160.72e161.20,
150.76e151.18, 144.57, 130.19, 124.58, 111.53e111.80, 109.12, 106.00,
103.12e104.65, 75.35, 57.12, 55.30, 51.76, 49.96, 48.87, 43.87. HRMS
(m/z): calcd. for C23H26F2N5O2S2: 506.1490; found: 506.1519.
6.1.26. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(2-chlorophenyl)piperazine-1-carbodithioate (3j)
Yield: 85.4%; m. p.164.9e168.3 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.17 (d, J ¼ 20.4 Hz, 1H), 7.87 (s, 1H), 7.59 (tt, J ¼ 20.6, 10.3 Hz, 1H),
7.21 (t, J ¼ 8.1 Hz, 1H), 6.99e6.62 (m, 5H), 5.31 (d, J ¼ 6.4 Hz, 1H),
4.83e4.66 (m, 2H), 4.62e4.25 (m, 3H), 4.05 (t, J ¼ 12.3 Hz, 3H), 3.32
(s, 4H). 13C NMR (75 MHz, CDCl3): dC 198.05, 164.54e164.67,
161.22e161.36, 160.30e160.46, 157.03e157.19, 150.89, 135.20,
130.41, 124.31e124.52, 124.49, 116.07, 114.08, 111.51e111.83,
103.97e104.67, 75.33, 57.37, 57.74, 51.75, 49.83, 43.82. HRMS (m/z):
calcd. for C22H24ClF2N5OS2: 510.0995; found: 510.1019.
6.1.32. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(4-methoxyphenyl)piperazine-1-carbodithioate (3p)
Yield: 72.9%; m. p. 173.1e176.9 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.15 (s, 1H), 7.86 (s, 1H), 7.61 (td, J ¼ 9.1, 6.7 Hz, 1H), 6.91e6.80 (m,
6H), 5.34 (s, 1H), 4.84e4.65 (m, 2H), 4.58e4.27 (m, 3H), 4.03 (d,
J ¼ 15.0 Hz, 3H), 3.79 (d, J ¼ 3.1 Hz, 3H), 3.16 (s, 4H). 13C NMR
(75 MHz, CDCl3): dC 197.97, 155.16, 151.41, 130.33e130.52, 124.51e
124.69, 119.19, 114.71, 111.44e111.78, 103.97e104.69, 75.43, 57.12,
6.1.27. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(4-chlorophenyl)piperazine-1-carbodithioate (3k)
Yield: 86.0%; m. p.165.1e169.9 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.87 (s, 1H), 7.61e7.41 (m, 1H), 7.26 (d, J ¼ 8.9 Hz, 2H),
6.93e6.79 (m, 4H), 5.30 (s, 1H), 4.80e4.65 (m, 2H), 4.58e4.27 (m,
3H), 4.05 (t, J ¼ 12.6 Hz, 3H), 3.27 (s, 4H). 13C NMR (75 MHz, CDCl3):
dC 198.10, 164.68e164.92, 161.23e161.36, 160.23e160.37, 157.01e
157.16, 151.52, 148.58, 130.32e130.44, 130.24, 129.25, 125.76,
124.45e125.67, 117.53, 111.48e111.80, 103.94e104.64, 75.38, 57.06,
51.84, 49.93, 48.68, 43.78. HRMS (m/z): calcd. for C22H24ClF2N5OS2:
510.0995; found: 510.1012.
55.59, 50.83, 43.85. HRMS (m/z): calcd. for
C23H26F2N5O2S2:
506.1490; found: 506.1513.
6.1.33. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(3-trifluoromethylphenyl)piperazine-1-carbodithioate (3q)
Yield: 73.5%; m. p. 178.1e180.5 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.14 (s, 1H), 7.87 (s, 1H), 7.61 (dd, J ¼ 9.1, 6.6 Hz, 1H), 7.41 (t,
J ¼ 7.9 Hz, 1H), 7.20e7.02 (m, 3H), 6.94e6.79 (m, 2H), 5.30 (s, 1H),
4.80e4.65 (m, 2H), 4.60e4.28 (m, 3H), 4.06 (t, J ¼ 16.3 Hz, 3H), 3.38
(s, 4H). 13C NMR (75 MHz, CDCl3): dC 198.10, 155.09, 151.04, 149.60,
144.08, 131.37, 131.02, 129.75e129.96, 129.35, 123.91e124.12,
118.37, 116.24e116.45, 111.74, 110.95e111.28, 103.41e104.11, 74.92,
6.1.28. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(2-methylphenyl)piperazine-1-carbodithioate (3l)
Yield: 77.5%; m. p. 166.8e169.4 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.87 (s, 1H), 7.62e7.39 (m, 1H), 7.21 (dd, J ¼ 11.7, 7.5 Hz,
2H), 7.12e6.97 (m, 2H), 6.94e6.79 (m, 2H), 5.37 (s, 1H), 4.85e4.64
(m, 2H), 4.63e4.28 (m, 3H), 4.05 (d, J ¼ 15.0 Hz, 3H), 3.00 (s, 4H),
2.35 (s, 3H). 13C NMR (75 MHz, CDCl3): dC 198.10, 164.49e164.63,
161.15e161.35, 160.29e160.45, 151.43, 149.92, 132.74, 131.30,
130.50, 130.29e130.42, 126.81, 124.25e124.76, 119.28, 111.45e
111.77, 103.91e104.61, 75.45, 57.10, 52.96, 51.26, 43.74, 17.80. HRMS
(m/z): calcd. for C23H26F2N5OS2: 490.1541; found: 490.1568.
56.47, 47.60, 43.21. HRMS (m/z): calcd. for
C23H23F5N5OS2:
544.1259; found: 544.1281.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.01.009.
References
6.1.29. 2-(2, 4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)
propyl 4-(2,3-dimethylphenyl)piperazine-1-carbodithioate (3m)
Yield: 80.4%; m. p. 168.1e171.4 ꢀC. 1H NMR (300 MHz, CDCl3): dH
8.16 (s, 1H), 7.87 (s, 1H), 7.62e7.49 (m, 1H), 7.11 (t, J ¼ 7.7 Hz, 1H),
6.98 (d, J ¼ 7.3 Hz, 1H), 6.85e6.68 (m, 3H), 5.35 (d, J ¼ 11.8 Hz, 1H),
4.82e4.64 (m, 2H), 4.58e4.28 (m, 2H), 4.05 (d, J ¼ 15.0 Hz, 3H), 2.97
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138.31, 131.34, 130.26e130.46, 125.95e126.01, 124.50e124.72,
116.83, 111.41e111.72, 103.87e104.57, 75.41, 65.81, 57.05, 53.06,
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