Design, synthesis and antimicrobial activities of 1,2,3-triazole derivatives

Article abstract of DOI:10.1016/j.cclet.2012.06.014

Fifteen 1-(4-substituted phenyl)-4-(4-bromophenyl)-5-(halo-o-hydroxyphenyl) imino-1,2,3-triazoles were designed and synthesized based on rational combination of 1,2,3-triazoles and (halo)o-hydroxyphenyl group according to the superposition principle of re

Full text of DOI:10.1016/j.cclet.2012.06.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 933–935
www.elsevier.com/locate/cclet
Design, synthesis and antimicrobial activities of
1,2,3-triazole derivatives
a
a
a
Xu Zhao a, Bo Wei Lu b, Jun Rui Lu a, , Chun Wei Xin , Jian Fa Li , Ya Liu
*
a College of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China
b College of Chemistry, Nankai University, Tianjin 300071, China
Received 27 April 2012
Available online 4 July 2012
Abstract
Fifteen 1-(4-substituted phenyl)-4-(4-bromophenyl)-5-(halo-o-hydroxyphenyl)imino-1,2,3-triazoles were designed and synthe-
sized based on rational combination of 1,2,3-triazoles and (halo)o-hydroxyphenyl group according to the superposition principle of
reinforcement of biological activities. All the compounds were tested to an in vitro antimicrobial screening against M.a. and E.c..
Compounds IIe–IIo exhibited more potent antimicrobial activities against M.a. and E.c. than triclosan and fluconazole, which
provided valuable information to further study of novel antimicrobial research.
# 2012 Jun Rui Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 1-(4-Substituted phenyl)-4-(4-bromophenyl)-5-(halo-o-hydroxyphenyl)imino-1,2,3-triazoles; 1-(4-Substituted phenyl)-4-(4-bromo-
phenyl)-5-amino-1,2,3-triazoles; Synthesis; Antimicrobial activity
Some studies have showed that many triazoles had strong affinity and specificity to the targets of pathogen like
lanosterol 14a-demethylase and HIV-RT and possessed brilliant application prospects in antibacterial [1–3],
antifungal [4–6], anti-tumor [7] and anti-HIV [8] fields. Meanwhile, they also had many highlights like low
cytotoxicity to human. As a result, triazoles in the design of novel biological and medical agents became more and
more outstanding. Furthermore, the o-hydroxydiphenyl ethers were important compounds in broad-spectrum
antibacterial fields. The key structures in these compounds like o-hydroxyphenyl or halo-o-hydroxyphenyl showed
strong affinity and specificity to the targets of pathogen like FabI gene and NAD+ coenzyme [9,10]. In addition, many
Schiff base derivatives had good antibacterial, anticancer and antitumor activities [11,12].Based on the studies above,
fifteen 1-(4-substituted phenyl)-4-(4-bromophenyl)-5-(halo-o-hydroxyphenyl)-imino-1,2,3-triazoles were designed
and synthesized in this paper. The intermediates and all target compounds were screened for their in vitro antibacterial
activities against E.c. and M.a. The results showed that the target compounds (II) possessed efficient antimicrobial
activities at the concentration of 0.1 mg/mL. Under a lower concentration of 0.01 mg/mL, most of compounds still
exhibited the antimicrobial activities against M.a. and E.c., and higher than fluconazole and triclosan. Especially, the
inhibitory ratio of IIm against E.c. came up to 79.9%, and IIn against M.a. reach up to 80.1%. These compounds were
* Corresponding author.
E-mail address: lujunrui@tjut.edu.cn (J.R. Lu).
1001-8417/$ – see front matter # 2012 Jun Rui Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.014

9[(Schme_1)TD$FIG] 34
X. Zhao et al. / Chinese Chemical Letters 23 (2012) 933–935
Br
Br
X
Y
N
N
a
N
N
d
c
R
NH
R
N
3
2
NH
2
N
CH
N
R
N
R
b
HO
R=H, Br, CH3
X=H, Cl, Br
Y=H, Cl, Br
¢ò
I
Scheme 1. The synthetic route of target compounds. Reagents and conditions: (a) NaNO2, HCl, 0 to 5 8C; (b) NaN3, À5 to 0 8C; (c) 4-bromophenyl-
acetonitrile, MeOH, MeONa; (d) (halo)salicylaldehyde, toluene, reflux.
a series of excellent antimicrobial compounds. Further biological evaluation of all compounds is progressing. The
structure–activity relationship and action mode of this class of compounds will be explored by molecular modeling.
1. Experimental
All the reagents were purchased from commercial sources and used without further purification. The monitoring of
the progress of all reactions and homogeneity of the synthesized compounds were carried out by thin chromatography
(TLC), TLC analysis was performed on silica gel plate, which was obtained from Qingdao Ocean Chemicals. The
melting point was taken in open capillary tubes and the thermometer was uncorrected. IR spectrum was recorded on
Nicolet 370 DTGS spectrometer via KBr pellets. NMR spectrum was measured on a Bruker AVANCE III spectrometer
operated at 400 MHz with CDCl3 or DMSO-d6 as the solvent and TMS as the internal standard. Elemental analysis
was carried out on a Perkin-Elmer 2400 elemental analyzer. Mass spectra were scanned on a shimadzu LCMS 2010
spectrometer (shimadzu, Tokyo, Japan).
Substituted aminobenzene was used as raw material, azidobenzene was synthesized through diazotization and
azidation, then 1-(4-substituted phenyl)-4-(4-bromophenyl)-5-amino-1,2,3-triazoles (I) was obtained by the reaction
of azidobenzene and 4-bromophenylacetonitrile in the MeOH in the presence of MeONa. The target compounds were
prepared by the reaction of (I) and (halo) salicylaldehyde in toluene, the solution was adjusted to pH 4–5 with acetic
acid. The synthetic route of target compounds was outline in Scheme 1.
According to the national standard GB15979-2002, the antimicrobial activity was evaluated against different
bacterial strains such as Monilia albicans (M.a.) (ATCC10231) and Escherichia coli (E.c.) (8099) at the concentration
of 0.1 mg/mL and 0.01 mg/mL. Fluconazole and triclosan were used as a standard for the comparison of antimicrobial
activity.
2. Results and discussions
All the target compounds are first reported and their structure were confirmed by IR, 1H NMR, 13C NMR, MS and
elemental analysis. The spectra of IIa exhibited absorptions at 3513 cmÀ1 for (str. of –OH), 3130 cmÀ1 for (str. of Ar–
H), 1618 cmÀ1 for (str. of C C), 1556 cmÀ1 for (str. of N N), 1267 cmÀ1 for (str. of C–OH), 1141 cmÀ1 for (str. of C–
N). 1H NMR (400 MHz, DMSO-d6): d 11.74 (s, 1H, OH), 8.687 (s, 1H, N CH), 7.78–7.77 (d, 2H, J = 7.2 Hz, Ar–H),
7.74–7.71 (d, 2H, J = 8.8 Hz, Ar–H), 7.58–7.56 (d, 2H, J = 8.8 Hz, Ar–H), 7.50–7.40 (m, 4H, Ar–H), 7.15–7.13 (dd,
1H, J1 = 8.0 Hz, J2 = 2.4 Hz, Ar–H), 7.04–7.02 (d, 1H, J = 8.4 Hz, Ar–H), 6.96–6.92 (t, 1H, J = 7.2 Hz, Ar–H). The
13C NMR (100 MHz, DMSO-d6) of compound IIa showed singlet at d 168.92 for (N CH), 139.31 and 136.00 for
(triazole), 161.29, 135.33, 134.63, 133.35, 132.81, 130.13, 129.19, 128.55, 127.38, 125.95, 123.54, 119.85, 118.22,
117.70 for aromatic carbon. Anal. calcd. for C21H15BrN4O: C 60.16, H 3.61, N 13.36%; found: C 60.23, H 3.76, N
13.41%. MS m/z: 419.04 [M+1]+. Similarly, all these compounds were characterized on the basis of spectral studies.
The structures and the results of antimicrobial activities (inhibitory ratios = (No. of Colony in control group À No.
of Colony in experimental group)/No. of Colony in control group  100%) in vitro of target compounds were listed in
Table 1.

X. Zhao et al. / Chinese Chemical Letters 23 (2012) 933–935
935
Table 1
The structures and antibacterial activity of the compounds (inhibitory ratio %).
Compounds
Substituents
Yield
(%)
Melting
Inhibitory
Inhibitory
point (8C)
(0.1 mg/mL)
(0.01 mg/mL)
R
X
Y
E.c.
M.a.
E.c.
M.a.
IIa
IIb
H
H
H
87.0
89.4
87.9
91.3
90.5
89.3
91.5
92.3
90.7
90.7
90.1
89.7
93.6
93.7
94.0
164–166
191–193
184–186
187–189
187–188
207–208
229–231
256–257
194–196
172–174
194–195
200–202
215–216
254–256
255–257
96.9
97.1
96.0
97.8
98.0
98.1
98.1
99.2
98.6
98.3
98.9
98.3
100
99.6
100
99.0
100
100
100
100
100
100
100
100
100
100
100
100
86.7
99.2
<50
<50
<50
50.9
60.2
66.2
64.2
70.0
65.4
70.0
70.6
62.3
79.9
72.8
70.3
51.9
41.0
<50
50.1
<50
60.2
Br
H
H
IIc
IId
CH3
H
H
H
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
H
IIe
IIf
Br
H
65.7
60.3
70.8
76.5
69.7
63.4
65.6
63.1
71.9
80.1
71.9
43.8
42.6
CH3
H
H
IIg
IIh
Br
Br
Br
H
Br
IIi
IIj
CH3
H
IIk
IIl
Br
H
CH3
H
H
IIm
IIn
Cl
Cl
Cl
Br
99.1
99.0
90.7
95.5
IIo
Triclosan
Fluconazole
CH3
The results showed that all target compounds possessed efficient antimicrobial activities at the concentration of
0.1 mg/mL. They had above 96.0% inhibitory ratio against E.c., especially, IIm reached up to 100%; except IIa and
IIc, other compounds had 100% inhibitory ratio against M.a. Moreover, under a lower concentration of 0.01 mg/mL,
except IIa and IIc, other compounds still exhibited the antifungal activity against M.a., which were much better than
that of fluconazole (42.6%) and triclosan (43.8%), the inhibitory ratio of IIn reached up to 80.1%; compounds IIe–IIo
still had antibacterical activity against E.c. and higher than triclosan (51.9%) and fluconazole (41.0%), especially, the
inhibitory ratio of IIm reached up to 79.9%. These results may provide some guidance for novel antimicrobial
research.
Further biological evaluation of all compounds is in progress. The structure–activity relationship and action mode
of this class of compounds will be explored by molecular modeling.
Acknowledgment
The work was supported by the National Natural Science Foundation of China (No. 20976135).
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