Azide-enolate 1,3-dipolar cycloaddition in the synthesis of novel triazole-based miconazole analogues as promising antifungal agents

Article abstract of DOI:10.1016/j.ejmech.2016.02.013

Seven miconazole analogs involving 1,4,5-tri and 1,5-disubstituted triazole moieties were synthesized by azide-enolate 1,3-dipolar cycloaddition. The antifungal activity of these compounds was evaluated in vitro against four filamentous fungi, including A

Full text of DOI:10.1016/j.ejmech.2016.02.013

European Journal of Medicinal Chemistry 112 (2016) 60e65
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Azide-enolate 1,3-dipolar cycloaddition in the synthesis of novel
triazole-based miconazole analogues as promising antifungal agents
a
,
Davir Gonzalez-Calderon *, María G. Mejía-Dionicio a, Marco A. Morales-Reza a,
ꢀ
ꢀ
Alejandra Ramírez-Villalva a, Macario Morales-Rodríguez b, Bertha Jauregui-Rodríguez b,
Eduardo Díaz-Torres , Carlos Gonzalez-Romero , Aydee Fuentes-Benítes
a
a
a, **
ꢀ
ꢀ
a
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Química Organica, Facultad de Química, Universidad Autonoma del Estado de Mexico, Paseo Colon/Paseo Tollocan s/n,
ꢀ
Toluca, Estado de Mexico, 50120, Mexico
b
ꢀ
ꢀ
ꢀ
Departamento de Microbiología, Facultad de Química, Universidad Autonoma del Estado de Mexico, Paseo Colon/Paseo Tollocan s/n,
ꢀ
Toluca, Estado de Mexico, 50120, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Seven miconazole analogs involving 1,4,5-tri and 1,5-disubstituted triazole moieties were synthesized by
azide-enolate 1,3-dipolar cycloaddition. The antifungal activity of these compounds was evaluated
in vitro against four filamentous fungi, including Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus
oryzae, and Mucor hiemalis as well as three species of Candida spp. as yeast specimens. These pre-clinical
studies suggest that compounds 4b, 4d and 7b can be considered as drug candidates for future com-
plementary biological studies due to their good/excellent antifungal activities.
Received 23 October 2015
Received in revised form
19 January 2016
Accepted 4 February 2016
Available online xxx
© 2016 Elsevier Masson SAS. All rights reserved.
Keywords:
Miconazole analogs
1,2,3-Triazole derivatives
Antifungal activity
Azide-enolate cycloaddition
1. Introduction
[11], leishmaniasis [12], HIV [13], influenza [14], dengue [15], pain
(analgesic) [16], epilepsy [17], obesity [18], inflammation [19] and
Miconazole is an azole-type drug with a broad spectrum of
antifungal activity [1]. Due to the development of fungal resistance
to this drug [2], the medicinal chemistry of anti-fungal agents has
become an important field of study in organic synthesis [3]. To
design new agents free of antibiotic resistance, the modification of
functional groups in lead molecules has been an efficient strategy
[4].
The triazole ring system, is a very well-recognized pharmaco-
phore [5], this nitrogen heterocycle is prominent among U.S. FDA
approved pharmaceuticals [6]. In particular, the 1,2,3-triazole core
has been an increasingly important heterocycle with successful
application in medicinal chemistry [7]. There are reports in litera-
ture about the biological activity of 1,2,3-triazole derivatives
against cancer [8], malaria [9], tuberculosis [10], trypanosomiasis
bacterial infection [20]. On the other hand, the study of 1,2,3-
triazole scaffolds for the synthesis of antifungals [21], and partic-
ularly for miconazole analogs [22] has represented an ongoing and
promising field of research in the last few years.
Cu-catalyzed azide-alkyne cycloaddition (CuAAC) represents
the conventional method for obtaining 1,2,3-triazole moieties [23].
In recent years, azide-enolate 1,3-dipolar cycloaddition has
emerged as a novel and potent tool for the synthetic approach to
these valuable heterocycles [24]. Its application in medicinal
chemistry has already been demonstrated [25].
We previously reported the antifungal activity of benzyloxy de-
rivatives of miconazole [26]. As part of our ongoing research, we
herein describe the synthesis/evaluation of triazolic analogs (1,4,5-
and 1,5-substituted derivatives) that maintain the 1-(2-
phenylethyl)imidazole core responsible for the biological activity
of this compound [27] (Fig. 1).
* Corresponding author.
** Corresponding author.
2. Chemistry
ꢀ
ꢀ
E-mail addresses: qfb_dgonzalez@yahoo.com.mx (D. Gonzalez-Calderon),
mpagfuentesb@uaemex.mx (A. Fuentes-Benítes).
From 2,4-dichlorobenzaldehyde 1 [Eq. (1)], the 1-(2,4-
http://dx.doi.org/10.1016/j.ejmech.2016.02.013
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.

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D. Gonzalez-Calderon et al. / European Journal of Medicinal Chemistry 112 (2016) 60e65
61
Table 1
Synthesis of 1,4,5-trisubstituted 1,2,3-triazole 4aed (miconazole analogs) from
alcohol 2 by coupling with active ketones 3.
N
N
N
N
N
N
N
R2
(PhO)2P(O)N3
O
OH
(DPPA)
R2
+
R1
R1
Fig. 1. Proposed triazolic analogs of miconazole.
Cl
Cl
DBU
3
4a-d
dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol
2 (key precursor)
2
Cl
Cl
was obtained in two steps according to our previous report [26].
Previously we published a novel method for preparing 1,4,5-
trisubstituted 1,2,3-triazoles from benzylic alcohols via an azide-
enolate 1,3-dipolar cycloaddition [28]. For this purpose we used
diphenylphosphoryl azide (DPPA) as an azidating agent, followed
by an efficient cycloaddition in the presence of active ketones.
Miconazole analogs 4aed (1,4,5-trisubstituted derivatives) were
synthesized in good yields (Table 1) by coupling acetylacetone 3a,
2-benzoylacetophenone 3b, benzoylacetonitrile 3c and 1-(phenyl-
sulfonyl)heptan-2-one 3d under the aforementioned protocol.
Entrya
Ketone
Triazoleb (Yield%)c
1
2
3
4
3a: R1 ¼ CH3, R2 ¼ COCH3
4a (75%)
4b (67%)
4c (63%)
4d (78%)
3b: R1 ¼ Ph, R2 ¼ COPh
3c: R1 ¼ Ph, R2 ¼ CN
3d: R1 ¼ CH3(CH2)4e, R2 ¼ SO2Ph
a
Reaction conditions: A mixture of compound 2 (1.0 eq), DPPA (1.1 eq), and DBU
(2.0 eq) in DMF was stirred at r.t. for 3 h. Then 3 (1.0 eq) was added and the reaction
continued at 60 ꢀC for 3 h.
b
Confirmed by 1H NMR, 13C NMR, and MS.
Yields refer to chromatographically pure isolated compounds.
c
N
CHO
N
3. Microbiology
Cl
[Ref. 26]
OH
(1)
Compounds 4a-d and 7a-c were evaluated for their in vitro
antifungal activity against four filamentous fungi (Aspergillus
fumigatus ATCC-16907, Trichosporon cutaneum ATCC-28592,
Rhizopus oryzae ATCC-10329 and Mucor hiemalis ATCC-8690) as
well as three yeast specimens (Candida utilis ATCC-9226, Candida
albicans ATCC-10231 and Candida tropicalis ATCC-13803).
CLSI standardized methods were adopted to carry out the
microbiological tests. The M38-A microdilution method [31] was
used to determine the sensitivity of filamentous fungi, and the
M27-A3 method [32] for Candida yeasts.
The antifungal activity of compounds 4aed and 7aec was
compared with itraconazole, a standard antifungal drug. The min-
imum inhibitory concentration (MIC) values of the compounds and
standard drugs, expressed in micrograms per millilitre, were
determined in 96-well plates by using RPMI 1640 medium buffered
with MOPS (3-[N-morpholino]propane sulfonic acid; Sigma-
Aldrich).
Cl
Cl
1
2
Cl
Recently [29] we reported a novel method for obtaining 1,5-
disubstituted triazoles from azides by coupling them with -keto-
b
phosphonates. Therefore, we decided to begin with the synthesis of
benzyl azide 5 [Eq. (2)] as a precursor. The azidation of benzyl
alcohol 2 was achieved using DPPA and DBU in dry DMF with good
yields [30]. The synthesis of alkyl (7a and 7b) and aryl (7c) 1,5-
disubstituted triazole derivatives was carried out via an azide-
enolate 1,3-dipolar cycloaddition (Table 2).
N
N
N
N
DPPA, DBU
OH
N3
Table 2
(2)
Synthesis of 1,5-disubstituted 1,2,3-triazole 7aec (miconazole analogs) from azide 5
by coupling with
DMF
87%
Cl
Cl
b
-ketophosphonates 6.
N
N
2
Cl
5
Cl
N
N
N
N
KOH
CH3CN
N
O
P
O
N3
+
R
OMe
R
Cl
Cl
An outstanding aspects for compounds 7aec is a singlet signal
in the range
7.6e7.4 ppm (1H NMR spectra) attributable to the
OMe
6
d
triazolic hydrogen [Eq. (3)]. Likewise, for all final compounds, the
7a-c
Cl
Cl
hydrogens Ha, Hb and Hc on the imidazole moiety can be observed
5
in the ranges
d
7.7e7.4, 7.0e6.9 and 6.9e6.6 ppm respectively.
Entrya
Ketone
Triazoleb (Yield%)c
b
H
1
2
3
6a: R ¼ cyclohexyl
7a (64%)
7b (70%)
7c (72%)
H
R2
6b: R ¼ CH3(CH2)3C(CH3)2e
6c: R ¼ p-(CH3S)phenyl
N
N
c
H
a
N
(3)
H
a
N
R1
N
R
Reaction conditions: A mixture of compound 5 (1.0 eq), 6 (1.0 eq), and KOH (3.0
eq), in CH3CN was stirred at 60 ꢀC for 5 h.
b
Confirmed by 1H NMR, 13C NMR, and MS.
Yields refer to chromatographically pure isolated compounds.
c

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D. Gonzalez-Calderon et al. / European Journal of Medicinal Chemistry 112 (2016) 60e65
Table 3
Table 4
In vitro antifungal activities of synthetized compounds (MIC,
m
g/mL).
Determination of the sensitivity of yeast (according to document M27-A3): Sus-
ceptible (S), dose-dependent sensitive (SDD) and resistant (R).
Compound
Yeast fungi
Filamentous fungi
Compound
C. uti.
C. alb.
C. trop.
C. uti.
C. alb.
C. trop.
A. fum.
T. cut.
R. ory.
M. hie
4a
4b
4c
4d
7a
7b
R
R
R
SDD
R
R
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
SDD
S
4a
4b
4c
4d
7a
7b
16
16
16
0.25
16
2
16
0.06
16
16
0.06
16
0.06
8
0.03
1
16
16
16
2
16
0.5
16
0.25
16
16
16
0.12
16
8
8
8
16
0.5
2
8
16
16
16
0.25
0.12
16
16
1
0.03
16
0.06
16
0.03
7c
7c
4
0.03
16
1
16
0.5
Standarda
Standarda
0.03
a
Itraconazole. Interpretive criteria: Breakpoints (MIC,
m
g/mL) ¼ 0.12 [S], 0.25e0.5
Abbreviations: C. uti., Candida utilis; C. alb., Candida albicans; C. trop., Candida tro-
picalis; A. fum., Aspergillus fumigatus; T. cut., Trichosporon cutaneum; R. ory., Rhizopus
oryzae; M. hie., Mucor hiemalis.
[SDD], 1 [R].
a
Itraconazole.
light at 254 nm m.p.: Fischer-Johns Scientific melting point appa-
ratus; uncorrected. 1H and 13C-NMR spectra: Bruker Avance
300 MHz and Varian 500 MHz;
d in ppm rel. to Me4Si as internal
4. Results and discussion
standard, J in Hz. MS: Shimadzu GCMS-QP2010 Plus; in m/z (rel. %).
The antifungal activity of the evaluated compounds is summa-
rized in Table 3. Compounds 4b, 4d and 7b showed good activity
6.2. Experimental procedures
against C. albicans and C. tropicalis (MIC 0.03e0.06
mg/mL) as
compared to itraconazole (MIC 0.03
m
g/mL). Such compounds
6.2.1. 1-(1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-
methyl-1H-1,2,3-triazol-4-yl)ethanone 4a
proved to be ‘sensitive’1 according to the sensitivity parameters of
document M27-A3 (Table 4). On the other hand, the antifungal
screening of compound 4d showed that it was either better than or
comparable to itraconazole against filamentous fungi T. cutaneum,
R. oryzae, and M. hiemalis (MIC 0.12 versus 1.0, 0.5 versus 0.5, and
To a cold solution (0 ꢀC) of benzylic alcohol 2 (0.35 g, 1.36 mmol)
and diphenylphosphoryl azide (0.32 mL, 1.5 mmol) in anhydrous
DMF (3.5 mL) was added DBU (0.4 mL, 2.72 mmol). The solution
was stirred for 15 min at 0 ꢀC under nitrogen atmosphere, and then
brought to room temperature with continuous stirring for 3 h. At
this time, TLC indicated the disappearance of the starting material.
Acetylacetone 3a, (0.14 mL, 1.36 mmol) was then added to the re-
action mixture, which was stirred for 3 h at 60e70 ꢀC. Brine
(~40 mL) was added and then the reaction mixture was washed
with EtOAc (3 ꢁ 10 mL). The organic layer was dried (Na2SO4) and
the solvent evaporated under reduced pressure. The crude extract
was purified by flash column chromatography, eluting with DCM/
MeOH 95/5 to afford the thick yellow oil 4a (0.37 g, 75%). Rf: 0.3
0.25 versus 1.0
moderate growth inhibition of A. fumigatus (MIC 0.5
compared with the standard drug (MIC 0.25 g/mL). In contrast
mg/mL respectively). Compound 7b demonstrated
mg/mL)
m
with the results observed for an aryl substituent, these outcomes
clearly indicate that an alkyl group in the 5-substituted triazole
promotes the biological activity of this type of compound. Addi-
tionally, substituent probably allows for a better interaction with
the 14-a-demethylase (P45014DM, CYP51) enzyme [33], leading to
its selective inhibition and therefore the growth inhibition of the
fungal cell.
(DCM/MeOH 95/5). 1H NMR: (500 MHz, CDCl3)
d
¼ 7.51 (d,
J ¼ 1.7 Hz, 1Im-H), 7.33e7.26 (m, 3AreH), 7.01 (s, 1ImeH), 6.86 (s,
1ImeH), 6.03 (dd, J ¼ 9.9, 4.0 Hz, 1H), 5.25 (dd, J ¼ 14.7, 10.0 Hz, 1H),
4.62 (dd, J ¼ 14.7, 3.9 Hz, 1H), 2.69 (s, 3H), 2.31 (s, 3H) ppm. 13C
5. Conclusion
NMR: (125 MHz, CDCl3)
d
¼ 193.91 (C]O),143.86 (C),137.94 (CeCl),
In summary, azide-enolate 1,3-dipolar cycloaddition allowed for
the synthesis of seven miconazole analogs with 1,4,5-tri and 1,5-
disubstituted triazole moieties. The pre-clinical studies showed
that compounds 4b, 4d and 7b have a good scope against C. albicans
and C. tropicalis. A broader spectrum of 4d against filamentous
fungi (T. cutaneum, R. oryzae, and M. hiemalis) has been demon-
strated. Due to their good/excellent activity, these miconazole an-
alogs can be considered as drug candidates for future
complementary biological studies.
136.42 (C), 133.09 (C), 131.03 (CH), 130.91 (CeCl), 130.20 (CH),
129.94 (CH), 129.18 (CH), 128.78 (CH), 128.72 (CH), 59.52 (CH),
49.25 (CH2), 27.77 (CH3), 8.56 (AreCH3) ppm. MS-EIþ m/z (%): 364
[Mþþ1], 212 (100), 203 (45), 149 (63), 81 (20), 57 (19), 43 (83).
6.2.2. (1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-
phenyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone 4b
Following the synthetic procedure for 4a, compound 2 (0.35 g,
1.36 mmol) and 3b (0.305 g,1.36 mmol) were coupled in the presence
of diphenylphosphoryl azide (0.32 mL, 1.5 mmol) and DBU (0.4 mL,
2.72 mmol). The crude extract was purified by flash column chro-
matography, eluting with DCM/MeOH 95/5 to afford the thick yellow
oil 4b (0.445 g, 67%). Rf: 0.35 (DCM/MeOH 95/5). 1H NMR: (500 MHz,
6. Experimental section
6.1. General
CDCl3)
d
¼ 8.28e8.20 (m, 2AreH), 7.73 (d, J ¼ 8.5 Hz, 1ImeH),
Flash column chromatography: SiO2 60 (230e400 mesh). TLC:
Silica-gel plates (SiO2; 0.20-mm thickness); visualization with UV
7.64e7.56 (m, 1AreH), 7.53e7.32 (m, 8AreH), 7.01 (s, 1ImeH),
6.87e6.80 (m, 2AreH), 6.71 (s,1ImeH), 5.98 (dd, J ¼ 10.6, 3.7 Hz,1H),
5.18 (dd, J ¼ 14.6,10.6 Hz, 1H), 4.48 (dd, J ¼ 14.6, 3.8 Hz, 1H) ppm. 13
C
1
NMR: (125 MHz, CDCl3)
d
¼ 185.81 (C]O),143.73 (C), 143.37 (CeCl),
‘S’, ‘SDD’ and ‘R’ are represented by standardized values (breakpoints) used to
appreciate the clinical value of the in vitro antifungal testing result and predicting
the response of patients infected. Sensitivity is dependent on achieving the
maximum dosages in plasma (breakpoints) to obtain optimal response. For itra-
conazole, an MIC within the susceptible-dose dependent (SDD) range indicates the
137.31 (C), 136.77 (C), 136.23 (C), 133.23 (C), 132.93 (CeCl), 131.34
(CH), 130.57 (2CH), 130.40 (CH), 130.13 (C), 129.89 (CH), 129.59 (CH),
129.57 (CH), 129.39 (CH), 129.35 (2CH), 128.92 (2CH), 128.58 (CH),
128.28 (2CH), 60.02(CH), 49.84 (CH2) ppm. MS-EIþ m/z (%): 487 [Mþ],
105 [C7H5Oꢂ] (100), 84 (25), 77 [C6Hꢂ5] (61), 43 (47).
need for plasma concentrations 0.25e0.5
mg/mL for an optimal response. Actual
breakpoints are described in Table 4 (See Ref. [32b]).

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63
6.2.3. 1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-
phenyl-1H-1,2,3-triazole-4-carbonitrile 4c
the reaction mixture and washed with EtOAc (3 ꢁ 30 mL). The
organic layer was dried (Na2SO4) and the solvent evaporated under
reduced pressure. The crude extract was purified by flash column
chromatography, eluting with DCM/MeOH 95/5 to afford the thick
yellow oil 7a (0.31 g, 64%). Rf: 0.3 (DCM/MeOH 95/5). 1H NMR:
Following the synthetic procedure for 4a, compound 2 (0.35 g,
1.36 mmol) and 3c (0.197 g, 1.36 mmol) were coupled in the pres-
ence of diphenylphosphoryl azide (0.32 mL, 1.5 mmol) and DBU
(0.4 mL, 2.72 mmol). The crude extract was purified by flash column
chromatography, eluting with DCM/MeOH 95/5 to afford the thick
yellow oil 4c (0.35 g, 63%). Rf: 0.3 (DCM/MeOH 95/5). 1H NMR:
(300 MHz, CDCl3)
d
¼ 7.50 (d, J ¼ 2.0 Hz, 1ImeH), 7.45 (s, 1AreH),
7.42 (s, 1AreH), 7.31e7.29 (m, 2AreH), 6.96 (s, 1ImeH), 6.76 (s,
1ImeH), 6.03 (dd, J ¼ 9.9, 3.9 Hz, 1H), 5.22 (dd, J ¼ 14.5, 9.9 Hz, 1H),
4.55 (dd, J ¼ 14.5, 3.9 Hz, 1H), 2.64e2.50 (m, 1H), 1.90e1.47 (m, 5H),
(500 MHz, CDCl3)
d
¼ 7.68 (d, J ¼ 8.5 Hz, 1AreH), 7.59e7.55 (m,
1AreH), 7.52e7.47 (m, 3AreH), 7.39 (dd, J ¼ 8.5, 2.1 Hz, 1AreH),
7.34 (s, 1AreH), 7.01 (s, 1AreH), 6.95e6.90 (m, 2AreH), 6.64 (s,
1AreH), 6.07 (dd, J ¼ 10.5, 3.7 Hz,1H), 5.13 (dd, J ¼ 14.7,10.5 Hz,1H),
4.52 (dd, J ¼ 14.7, 3.8 Hz, 1H) ppm. 13C NMR: (125 MHz, CDCl3)
1.43e1.01 (m, 5H) ppm. 13C NMR: (75 MHz, CDCl3)
d
¼ 143.80
(CeCl), 135.94 (C), 132.75 (C), 132.19 (CH), 131.23 (CeCl), 129.80
(CH), 129.67 (CH), 129.58 (CH), 128.64 (CH), 122.56 (CH), 118.99
(CH), 59.41 (CH), 51.56 (CH2), 33.22 (CH), 32.37 (2CH2), 25.71 (CH),
25.44 (2CH2) ppm.
d
¼ 145.35 (C), 136.76 (CeCl), 132.92 (C), 131.73 (CH), 130.57 (C),
130.23 (CeCl), 130.15 (CH), 129.79 (2CH), 129.59 (CH), 129.43 (CH),
128.83 (CH), 128.75 (2CH), 124.73 (CH), 121.97 (CH), 120.89 (C),
111.21 (C^N), 60.97 (CH), 49.99 (CH2) ppm. MS-EIþ m/z (%): 409
[Mþ], 373 (20), 299 (30), 229 (31), 203 (100), 149 (36), 81 (85).
6.2.7. 1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-(2-
methylhexan-2-yl)-1H-1,2,3-triazole 7b
Following the synthetic procedure for 7a, compound 5 (0.35 g,
1.24 mmol) and 6b (0.311 g, 1.24 mmol) were coupled in the
presence of KOH (0.2 g, 3.73 mmol). The crude extract was purified
by flash column chromatography, eluting with DCM/MeOH 95/5 to
afford the thick yellow oil 7b (0.35 g, 70%). Rf: 0.3 (DCM/MeOH 9/1).
6.2.4. 1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-
pentyl-4-(phenylsulfonyl)-1H-1,2,3-triazole 4d
Following the synthetic procedure for 4a, compound 2 (0.35 g,
1.36 mmol) and 3d (0.346 g, 1.36 mmol) were coupled in the
presence of diphenylphosphoryl azide (0.32 mL,1.5 mmol) and DBU
(0.4 mL, 2.72 mmol). The crude extract was purified by flash column
chromatography, eluting with DCM/MeOH 95/5 to afford the thick
yellow oil 4d (0.54 g, 78%). Rf: 0.4 (DCM/MeOH 9/1). 1H NMR:
1H NMR: (500 MHz, CDCl3)
d
¼ 7.54e7.53 (m, 1ImeH), 7.44 (s,
1AreH), 7.28e7.27 (m, 1AreH), 7.27e7.25 (m, 2AreH), 6.96 (s,
1ImeH), 6.78 (s, 1ImeH), 6.23 (dd, J ¼ 10.6, 3.0 Hz, 1H), 5.29 (dd,
J ¼ 14.6, 10.6 Hz, 1H), 4.50 (dd, J ¼ 14.6, 3.0 Hz, 1H), 1.37e1.21 (m,
2H), 1.10 (s, 3H), 1.03 (s, 3H), 0.97e0.82 (m, 2H), 0.75e0.64 (m, 1H),
0.61e0.54 (m, 3H), 0.43e0.31 (m, 1H) ppm. 13C NMR: (75 MHz,
(500 MHz, CDCl3)
d
¼ 8.07e8.01 (m, 2AreH), 7.68e7.63 (m,
1ImeH), 7.60e7.54 (m, 2AreH), 7.51 (dd, J ¼ 1.6, 0.8 Hz, 1AreH),
7.39 (s, 1H), 7.31e7.29 (m, 2AreH), 6.92 (s, 1ImeH), 6.70 (s, 1ImeH),
6.03 (dd, J ¼ 9.7, 4.2 Hz, 1H), 5.15 (dd, J ¼ 14.7, 9.7 Hz, 1H), 4.56 (dd,
J ¼ 14.9, 4.3 Hz, 1H), 2.88e2.68 (m, 2H), 1.23e1.09 (m, 6H), 0.78 (t,
CDCl3)
d
¼ 145.93 (CeCl), 137.33 (C), 135.81 (CH), 133.29 (CH),
132.53 (CeCl), 132.26 (CH), 130.90 (C), 129.73 (CH), 129.50 (CH),
128.45 (CH), 118.89 (CH), 62.20 (CH), 49.80 (CH2), 41.07 (CH2), 33.47
(C), 27.77 (CH3), 27.67 (CH3), 26.73 (CH2), 22.76 (CH2), 13.65 (CH3)
ppm. MS-EIþ m/z (%): 406 [Mþ], 296 (11), 240 (28), 203 (53), 172
(25), 159 (33), 124 (34), 81 (45), 57 (100), 41 (71).
J ¼ 6.9 Hz, 3H) ppm. 13C NMR: (125 MHz, CDCl3)
¼ 145.12 (CeCl),
d
141.44 (C), 140.43 (C), 137.25 (C), 136.62 (C), 134.00 (C), 132.82 (CH),
130.90 (CeCl), 129.91 (CH), 129.35 (2CH), 129.21 (CH), 128.91 (CH),
128.79 (CH), 127.90 (2CH), 118.76 (CH), 60.31 (CH), 49.52 (CH2),
31.29 (CH2), 28.49 (CH2), 22.50 (CH2), 22.02 (CH2), 13.70 (CH3) ppm.
MS-EIþ m/z (%): 518 [Mþ], 376 (13), 280 (19), 203 (64), 172 (36), 159
(37), 149 (49), 125 (58), 77 (100), 41 (49).
6.2.8. 1-(1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-5-(4-
(methylthio)phenyl)-1H-1,2,3-triazole 7c
Following the synthetic procedure for 7a, compound 5 (0.35 g,
1.24 mmol) and 6c (0.341 g, 1.24 mmol) were coupled in the
presence of KOH (0.2 g, 3.73 mmol). The crude extract was purified
by flash column chromatography, eluting with DCM/MeOH 95/5 to
afford the thick yellow oil 7c (0.385 g, 72%). Rf: 0.3 (DCM/MeOH 9/
6.2.5. 1-(2-Azido-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole 5
To a cold solution (0 ꢀC) of benzylic alcohol 2 (1.5 g, 5.83 mmol)
and diphenylphosphoryl azide (1.25 mL, 5.83 mmol) in anhydrous
DMF (13.0 mL), was added DBU (0.872 mL, 5.83 mmol). The solution
was stirred for 15 min at 0 ꢀC under nitrogen atmosphere, and then
brought to room temperature with continuous stirring for 3 h. Brine
(~100 mL) was added to the reaction mixture and washed with
EtOAc (3 ꢁ 30 mL). The organic layer was dried (Na2SO4) and the
solvent evaporated under reduced pressure. The crude extract was
purified by flash column chromatography, eluting with DCM/MeOH
95/5 to afford the thick yellow oil 5 (1.43 g, 87%). Rf: 0.4 (DCM/
1). 1H NMR: (300 MHz, CDCl3)
d
¼ 7.69 (m, 1ImeH), 7.68 (s, 1AreH),
7.47 (d, J ¼ 2.1 Hz, 2AreH), 7.36e7.19 (m, 4AreH), 6.96 (s, 1ImeH),
6.75 (d, J ¼ 8.4 Hz, 2AreH), 6.64 (s, 1ImeH), 6.01 (dd, J ¼ 10.5,
3.5 Hz, 1H), 5.15 (dd, J ¼ 14.5, 10.5 Hz, 1H), 4.48 (dd, J ¼ 14.5, 3.6 Hz,
1H), 2.49 (s, 3H) ppm. 13C NMR: (75 MHz, CDCl3)
d
¼ 141.81 (C),
139.43 (CeCl), 136.05 (CeS), 133.21 (C), 132.72 (CH), 131.83 (CH),
130.91 (CeCl), 129.83 (CH), 129.77 (C), 129.40 (CH), 128.94 (2CH),
128.79 (CH), 128.55 (CH), 126.14 (2CH), 118.83 (CH), 59.98 (CH),
50.20 (CH2), 15.05 (CH3) ppm.
MeOH 95/5). 1H NMR: (300 MHz, CDCl3)
d
¼ 7.46 (d, J ¼ 2.0 Hz,
1ImeH), 7.38e7.20 (m, 3AreH), 7.05 (s, 1ImeH), 6.91 (s, 1ImeH),
5.26 (dd, J ¼ 7.6, 3.5 Hz, 1H), 4.22 (dd, J ¼ 14.4, 3.5 Hz, 1H), 4.01 (dd,
J ¼ 14.4, 7.6 Hz, 1H) ppm. 13C NMR: (75 MHz, CDCl3)
d
¼ 137.62
Acknowledgments
(CeCl), 135.46 (C), 133.03 (CH), 132.32 (CeCl), 129.81 (CH), 129.68
(CH), 128.81 (CH), 128.14 (CH), 119.45 (CH), 62.65 (CHeN3), 50.51
(CH2) ppm.
ꢀ
Financial support from Secretaría de Investigacion y Estudios
ꢀ
Avanzados/UAEMex (project No. 3804/2014/CID) and CONACYT-
Mexico (postgraduate scholarship No. 227581 and No. 273644) is
gratefully acknowledged. The authors would like to thank the ref-
erees for valuable comments and suggestions, Signa S.A. de C.V. for
some graciously donated solvents and reagents, and M.N. Zavala-
Segovia and L. Triana-Cruz (CCIQS UAEMex‒UNAM) for technical
support, and Prof. Bruce Allan Larsen for proofreading the
manuscript.
6.2.6. 5-Cyclohexyl-1-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-
yl)ethyl)-1H-1,2,3-triazole 7a
To a solution of benzyl azide 5 (0.35 g, 1.24 mmol) and b-keto-
phosphonate 6a (0.29 g, 1.24 mmol) in acetonitrile grade reagent
(3.5 mL) was added potassium hydroxide (0.2 g, 3.73 mmol). The
solution was stirred for 5 h at 60 ꢀC. Brine (~40 mL) was added to

ꢀ
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64
D. Gonzalez-Calderon et al. / European Journal of Medicinal Chemistry 112 (2016) 60e65
(b) M.H. Shaikh, D.D. Subhedar, L. Nawale, D. Sarkar, F.A. Kalam Khan,
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J.N. Sangshetti, B.B. Shingate, 1,2,3-Triazole derivatives as antitubercular
agents: synthesis, biological evaluation and molecular docking study, Med.
Chem. Commun. 6 (2015) 1104e1116.
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