Synthesis and Biological Activity of Novel 1-Substituted Phenyl-4-[N-[(2'-morpholinothoxy)phenyl]aminomethyl]-1H-1,2,3-Triazoles

Article abstract of DOI:10.1111/j.1747-0285.2011.01172.x

In an attempt to search for potent antifungal agents, a series of novel 1-substituted phenyl-4-[N-[(2'-morpholinothoxy)phenyl]aminomethyl]-1H-1,2,3-triazoles 5a-m was designed and synthesized via Huisgen cycloaddition reaction between various (2-morpholin

Full text of DOI:10.1111/j.1747-0285.2011.01172.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01172.x
Chem Biol Drug Des 2011; 78: 695–699
Research Letter
Synthesis and Biological Activity of Novel
1-Substituted Phenyl-4-[N-[(2¢-
morpholinothoxy)phenyl]aminomethyl]-1H-1,2,3-
Triazoles
Huisgen cycloaddition reaction using azides and alkynes is an impor-
tant method for atom economic synthesis of 1,2,3-triazoles. The
advantages of 100% atom economy and simple purification process
of the resulting products in this reaction have led to a high status
in synthetic organic chemistry (11). Owing to their expected potent
bioactivity, a series of new triazole derivatives were designed and
synthesized via Huisgen cycloaddition reaction. Both morpholine and
substituted aromatic rings were combined to 1,2,3-triazoles systems
in the same matrix to serve as a novel scaffold and with the hope
of discovering better fungicidal activity. The fungicide activity of
these final compounds was evaluated in vitro against five fungi.
Ming-Zhen Mao, Yu-Xin Li*, Yun-Yun Zhou,
Wei Chen, Tuan-Wei Liu, Shu-Jing Yu,
Su-Hua Wang and Zheng-Ming Li*
State Key Laboratory of Elemento-Organic Chemistry, Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
*Corresponding authors: Yu-Xin Li, liyx128@nankai.edu.cn and
Zheng-Ming Li, nkzml@vip.163.com
In an attempt to search for potent antifungal
agents, a series of novel 1-substituted phenyl-4-[N-
[(2¢-morpholinothoxy)phenyl]aminomethyl]-1H-1,2,3-
triazoles 5a–m was designed and synthesized via
Huisgen cycloaddition reaction between various (2-
morpholinoethoxy)-N-(prop-2-ynyl)aniline and dif-
ferent azidobenzene. Their chemical structures
were characterized by 1H NMR and elemental
analysis. A cleaner reaction with milder conditions
and satisfactory yields was observed in the micor-
wave-assisted synthesis of 4a–c. The fungicidal
activity of some target compounds were evaluated
in vitro against Fusarium omysporum, Physalos-
pora piricola, Alternaria solani, Cercospora arachid-
icola and Gibberella zeae at 50 lg ⁄ mL. The bioassay
results indicated that some compounds exhibited
moderate fungicidal activities. Furthermore, com-
pound 5h displayed equal activity to the positive
control compounds against Alternaria solani.
Experimental
Instruments
Melting points were conducted on a Yanaco MP-500 micromelting
point apparatus. 1H NMR spectra were measured on a Bruker
AC-400 instrument (400 MHz) using tetramethylsilane as an internal
standard and CDCl3 as solvent. Elemental analyses were performed
on MF-3 automatic elemental analyzer.
Synthesis
Compounds 2 to 3 were prepared according to the literature proce-
dures (12–14).
Key words: 1,2,3-Triazoles, antifungal activities, Huisgen cycloaddi-
tion reaction, synthesis
General procedure for the synthesis of
compounds 4a–c
Received 7 December 2010, revised 25 April 2011 and accepted for
publication 27 June 2011
To a solution of 3a (5.6 mmol) in 30 mL of THF, 0.157 g (2.8 mmol) of
potassium hydroxide and 0.862 g (2.8 mmol) of tetrabutyl ammonium
bromide were added with stirring. The mixture was stirred at room
temperature for 10 min, then 0.41 g (2.8 mmol) of propargyl bromide
(80% in toluene) was added dropwise and heated under microwave
for 1 h on 45 ꢀC. The solvent was filtered and then evaporated in
vacuum. The crude product was purified by silica gel column eluted
with petroleum ether–ethyl acetate (V:V, 2:1) to afford 4a.
In recent years, 1,2,3-triazoles have a wide range of applications
in the development of new drugs, such as antibacterial (1), an-
tiviral (2), antimicrobial (3), cytostatic (4), anti-HIV (5), antineo-
plastic (6) and anti-inflammatory agents (7). It was also reported
that 1,2,3-triazoles had the capacity of activating potassium chan-
nel (8) and inhibiting inosine monophosphate dehydrogenase (9).
In addition, it was noted that many biological compounds con-
taining halogen atoms exhibited enhanced fungicidal activities
(10).
General procedure for the synthesis of
compounds 5a–m (15)
To a solution of 4a (1 mmol) in a 1:1 mixture of t-butanol and
water (10 mL), 0.125 g (0.5 mmol) of copper sulphate and 0.198 g
695

Mao et al.
(1 mmol) of sodium ascorbate were added to the mixture. After stir-
red for 10 min at room temperature, 1.0 mmol azidobenzene was
added and the resulting mixture was stirred for further 6 h at the
room temperature (monitored by thin-layer chromatography (TLC)).
After completion of the reaction, water was added and the mixture
was extracted with ethyl acetate (2 · 20 mL). The combined
organic extracts were washed with brine and dried over magnesium
sulphate. The solvent was evaporated in vacuum, and the residue
was purified on silica gel with ether petroleum–ethyl acetate (V:V,
1:1) and 5a was obtained. The data of all obtained compounds 5
are shown in Table 1.
N-CH2), 2.58 (s, 4H, CH2-N-CH2). Anal. Calcd for C21H24ClN5O2: C,
60.94; H, 5.844; N, 16. 92. Found: C, 60.07; H, 6.15; N,16.53.
1-(2¢-Chloro)phenyl-4-[N-[3-chloro-4-(2¢-morphol-
inothoxy)]phenyl]aminomethyl]-1H-1,2,3-
triazoles 5d
1H NMR (CDCl3, 400 MHz), d: 7.80 (s, 1H, triazolyl-H), 7.59 (d, 2H,
J = 8.7, Ar-H), 6.97 (d, 2H, J = 8.7, Ar-H), 6.81 (d, 2H, J = 8.7,
2 · Ar-H), 6.72 (d, 1H, J = 1.5, Ar-H), 6.54 (t, 2H, 2 · Ar-H), 4.42 (s,
2H, CH2), 4.29 (s, 1H, NH), 4.05 (t, 2H, O-CH2), 3.83 (s, 3H, CH3),
3.73 (t, 4H, CH2-O-CH2), 2.78 (t, 2H, N-CH2), 2.59 (s, 4H, CH2-N-
CH2). Anal. Calcd for C22H27N5O2: C, 66.47; H, 6.64; N, 18.46.
Found: C, 66.61; H, 6.47; N, 18.69.
1-Phenyl-4-[N-[4-(2¢-morpholinothoxy)]
phenyl]aminomethyl]-1H-1,2,3-triazoles 5a
1H NMR (CDCl3, 400 MHz), d: 7.87 (s, 1H, triazolyl-H), 7.70 (d, 2H,
J = 8.0, 2 · Ar-H), 7.51 (t, 2H, 2 · Ar-H), 7.43 (t, 1H, Ar-H), 6.87 (d,
J = 8.9, 2H, 2 · Ar-H), 6.66 (d, 2H, J = 8.9, 2 · Ar-H), 4.50 (s, 2H,
CH2), 4.04 (t, 2H, O-CH2), 3.73 (t, 4H, CH2-O-CH2), 2.77 (t, 2H, N-
CH2), 2.58 (t, 4H, CH2-N-CH2). Anal. Calcd for C21H25N5O2: C, 66.47;
H, 6.64; N, 18.46. Found: C, 66.61; H, 6.47; N, 18.69.
1-(4¢-Methoxy)phenyl-4-[N-[2-(2¢-morpholino-
thoxy)]phenyl]aminomethyl-1H-1,2,3-triazoles
5e
1H NMR (CDCl3, 400 MHz), d: 7.80 (s, 1H, triazolyl-H), 7.58 (d, 2H,
J = 8.7, Ar-H), 7.00 (d, 2H, J = 8.7, Ar-H), 6.88 (t, 1H, Ar-H), 6.82 (d,
1H, J = 1.5, Ar-H), 6.71 (d, 2H, 2 · Ar-H), 4.57 (s, 2H, CH2), 4.14 (t,
2H, O-CH2), 3.85 (s, 3H, CH3), 3.73 (t, 4H, CH2-O-CH2), 2.82 (t, 2H,
N-CH2), 2.59 (s, 4H, CH2-N-CH2). Anal. Calcd for C23H29N5O3: C,
65.23; H, 6.90; N, 16.54. Found: C, 65.52; H, 6.60; N, 16.78.
1-Phenyl-4-[N->[2-(2¢-morpholinothoxy>)]
phenyl]aminomethyl]-1H-1,2,3-triazoles 5b
1H NMR (CDCl3, 400 MHz), d: 7.88 (s, 1H, triazolyl-H), 7.69 (d, 2H,
J = 8.1, 2 · Ar-H), 7.49 (t, 2H, 2 · Ar-H), 7.41 (t, 1H, Ar-H), 6.88 (t,
1H, Ar-H), 6.82 (d, 1H, J = 7.7, Ar-H), 6.68 (t, 2H, 2 · Ar-H), 4.58 (s,
2H, CH2), 4.14 (t, 2H, O-CH2), 3.73 (t, 4H, CH2-O-CH2), 2.82 (s, 2H,
N-CH2), 2.58 (s, 4H, CH2-N-CH2). Anal. Calcd for C22H27N5O2:C,
66.47; H, 6.64; N, 18.46. Found: C, 66.12; H, 6.23; N, 18.91.
1-(4¢-Trifluoromethyl)phenyl-4-[N-[4-(2¢-
morpholinothoxy)]phenyl]aminomethyl]-1H-
1,2,3-triazoles 5f
1H NMR (CDCl3, 400 MHz), d: 7.94 (s, 1H, triazolyl-H), 7.85 (d, 2H,
J = 8.2, Ar-H), 7.76 (d, 2H, J = 8.1, Ar-H), 6.79 (d, 2H, J = 8.5,
2 · Ar-H), 6.64 (d, 2H, J = 8.5, 2 · Ar-H), 4.50 (s, 2H, CH2), 4.04 (t,
2H, O-CH2), 3.73 (s, 4H, CH2-O-CH2), 2.76 (t, 2H, N-CH2), 2.56 (s, 4H,
CH2-N-CH2). Anal. Calcd for C22H24F3N5O2: C, 59.02; H, 5.41; N,
15.65. Found: C, 58.91; H, 5.36; N, 15.52.
1-(4¢-Methoxy)phenyl-4-[N-[2-(2¢-morpholino-
thoxy)]phenyl]aminomethyl]-1H-1,2,3-triazoles
5c
1H NMR (CDCl3, 400 MHz), d: 7.86 (s, 1H, triazolyl-H), 7.56 (d, 1H,
J = 8.2, Ar-H), 7.56 (t, 1H, Ar-H), 7.43 (t, 2H, 2 · Ar-H), 6.79 (d, 2H,
J = 8.4, Ar-H), 6.66 (d, 2H, J = 8.2, 2 · Ar-H), 4.51 (s, 2H, CH2),
4.04 (t, 2H, O-CH2), 3.73 (d, 4H, J = 3.5, CH2-O-CH2), 2.76 (t, 2H,
1-(2¢-Nitro)phenyl-4-[N-[2-(2¢-morpholinothoxy)]
phenyl]aminomethyl]-1H-1,2,3-triazoles 5g
1H NMR (CDCl3, 400 MHz), d: 8.03 (s, 1H, triazolyl-H), 7.78 (d, 1H,
J = 7.6, Ar-H), 7.74 (t, 1H, J = 8.1, Ar-H), 6.79 (t, 1H, Ar-H), 6.60 (d,
1H, J = 7.8, 2 · Ar-H), 6.88 (t, 1H, Ar-H), 6.81 (d, 1H, J = 7.7, Ar-
H), 6.68 (t, 2H, 2 · Ar-H), 4.61 (s, 2H, CH2), 4.13 (t, 2H, O-CH2),
3.73 (s, 4H, CH2-O-CH2), 2.83 (t, 2H, N-CH2), 2.60 (s, 4H, CH2-N-
CH2). Anal. Calcd for C21H24N6O4: C, 59.42; H, 5.70; N, 19.80.
Found: C, 59.63; H, 5.44; N, 19.54.
Table 1: Data of compounds 5
Compound
X
R1
R2
R3
Yield(%)
Mp(ꢀC)
5a
5b
5c
5d
5e
5f
p-NH
o-NH
o-NH
p-NH
o-NH
p-NH
o-NH
p-NH
p-NH
p-NH
p-NH
p-NH
p-NH
H
H
H
Cl
H
H
H
Cl
Cl
H
H
H
Cl
H
H
H
NO2
H
NO2
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
76.4
77.3
68.6
78.5
69.7
82.6
64.9
76.6
65.7
72.5
76.8
74.9
72.4
111–112
Syrup
Syrup
137–138
Syrup
150–151
Syrup
110–111
Syrup
Syrup
88–89
Syrup
97–98
OCH3
OCH3
CF3
H
CF3
H
NO2
Cl
Cl
1-(4¢-Trifluoromethyl)phenyl-4-[N-[3-chloro-4-(2¢-
morpholinothoxy)]phenyl]aminomethyl]-1H-
1,2,3-triazoles 5h
1H NMR (CDCl3, 400 MHz), d: 7.96 (s, 1H, triazolyl-H), 7.85 (d, 2H,
J = 9.4, 2 · Ar-H), 7.77 (d, 2H, J = 9.4, 2 · Ar-H), 6.82 (d, 1H,
J = 8.7, Ar-H), 6.73 (d, 1H, J = 3.7, Ar-H), 6.54 (q, 1H, Ar-H), 6.81
(d, 1H, J = 7.7, Ar-H), 4.47 (s, 2H, CH2), 4.06 (t, 2H, O-CH2), 3.72 (t,
4H, CH2-O-CH2), 2.79 (t, 2H, N-CH2), 2.60 (s, 4H, CH2-N-CH2). Anal.
5g
5h
5i
5j
5k
5l
H
Cl
Cl
5m
NO2
696
Chem Biol Drug Des 2011; 78: 695–699

Synthesis and Biological Activity of Novel 1,2,3-Triazoles
Calcd for C22H23ClF3N5O2 : C, 54.83; H, 4.81; N, 14.53. Found: C,
54.37; H, 4.81; N, 14.28.
1-(2¢-Chloro-4¢-nitro)phenyl-4-[N-[3-chloro-4-(2¢-
morpholinothoxy)]phenyl]aminomethyl]-1H-
1,2,3-triazoles 5m
1H NMR (CDCl3, 400 MHz), d: 8.46 (s, 1H, triazolyl-H), 8.29 (m, 1H,
Ar-H), 8.04 (s, H, Ar-H), 7.93 (d, 1H, J = 8.8, Ar-H), 6.80 (d, 1H,
J = 8.7, 2 · Ar-H), 6.66 (d, 1H, J = 8.7, Ar-H), 6.55 (m, 1H, J = 8.9,
Ar-H), 4.53 (s, 2H, CH2), 4.07 (t, 2H, O-CH2), 3.73 (t, 4H, CH2-O-CH2),
2.81 (t, 2H, N-CH2), 2.61 (t, 4H, CH2-N-CH2). Anal. Calcd for
C21H22Cl2N6O4: C, 51.13; H, 4.49; N, 17.03. Found: C, 51.34; H, 4.68;
N, 17.22.
1-(2¢-Nitro)phenyl-4-[N-[4-(2¢-morpholinothoxy)]
phenyl]aminomethyl]-1H-1,2,3-triazoles 5i
1H NMR (CDCl3, 400 MHz), d: 8.07 (s, 1H, triazolyl-H), 7.80 (m, 1H,
Ar-H), 7.70 (m, 2H, 2 · Ar-H), 6.97 (m, 1H, Ar-H), 6.85 (d, 1H,
J = 8.8, Ar-H), 6.75 (d, 1H, J = 8.8, Ar-H), 6.81 (q, 1H, Ar-H), 4.50
(s, 2H, CH2), 4.08 (t, 2H, O-CH2), 3.73 (t, 4H, CH2-O-CH2), 2.81 (t,
2H, N-CH2), 2.61 (t, 4H, CH2-N-CH2). Anal. Calcd for C21H23ClN6O2:
C, 54.96; H, 4.81; N, 18.31. Found: C, 54.68; H, 5.13; N, 18.67.
Antifungal activity
The fungicidal activity of compounds (5a, 5d, 5f, 5h, 5i, 5l, 5m)
were tested with the growth inhibition in vitro against Fusarium
omysporum, Physalospora piricola, Alternaria solani, Cercospora
arachidicola and Gibberella zeae, and their relative inhibition ratio
(%) has been determined using the mycelium growth rate method
(16). Chlorothalonil was used as a positive control. After the myc-
elia grew completely, the diameters of the mycelia were measured,
and the inhibition rate was calculated according to the formula:
1-(2¢-Chloro-4¢-nitro)phenyl-4-[N-[4-(2¢-morpholi-
nothoxy)]phenyl]aminomethyl]-1H-1,2,3-
triazoles 5j
1H NMR (CDCl3, 400 MHz), d: 8.45 (s, 1H, triazolyl-H), 8.29 (m, 1H,
Ar-H), 8.04 (s, 1H, Ar-H), 7.89 (d, 1H, J = 8.8, Ar-H), 6.80 (d, 2H,
J = 8.9, 2 · Ar-H), 6.66 (d, 2H, J = 8.9, 2 · Ar-H), 4.53 (s, 2H,
CH2), 4.05 (t, 2H, O-CH2), 3.73(t, 4H, CH2-O-CH2), 2.81 (t, 2H, N-
CH2), 2.61 (t, 4H, CH2-N-CH2). Anal. Calcd for C21H23ClN6O2: C,
54.96; H, 4.81; N, 18.31. Found: C, 55.21; H, 4.88; N, 18.50.
I ¼ ðD1 ꢀ D2Þ=D1 ꢁ 100%
In the formula, I is the inhibition rate, D1 is the average diameter
of mycelia in the blank test and D2 is the average diameter of myc-
elia in the presence of those compounds. The inhibition ratios of
compounds (5a, 5d, 5f, 5h, 5i, 5l, 5m) at the dose of
50 lg ⁄ mL are summarized in Table 2.
1-(2¢,4¢,6¢-Trichloro)phenyl-4-[N-[4-(2¢-morpholin-
othoxy)]phenyl]aminomethyl]-1H-1,2,3-triazoles
5k
1H NMR (CDCl3, 400 MHz), d: 7.58 (s, 1H, triazolyl-H), 7.50 (s, 2H,
2 · Ar-H), 6.78 (d, 2H, J = 8.8, 2 · Ar-H), 6.64 (d, 2H, J = 8.8,
2 · Ar-H), 4.52 (s, 2H, CH2), 4.03 (t, 2H, O-CH2), 3.73 (t, 4H, CH2-O-
CH2), 2.76 (t, 2H, N-CH2), 2.60 (s, 4H, CH2-N-CH2). Anal. Calcd for
C21H22Cl3N5O2: C, 52.24; H, 4.59; N, 14.51. Found: C, 52.01; H, 4.77;
N, 14.26.
Results and Discussion
Chemistry
Compounds 2a–c were prepared from nitrophenol and (2-chloroeth-
yl)morpholine hydrochloride as shown in Scheme 1 (12). We did not
observe the reaction of nitrophenol with (2-chloroethyl) morpholine
hydrochloride within 18 h. However, the addition of an excess of potas-
sium carbonate into the reaction mixture as acid binding agent improved
this expected procedure with the completion of reaction within 6 h.
1-(2¢,4¢,6¢-Trichloro)phenyl-4-[N-[3-chloro-4-(2¢-
morpholinothoxy)]phenyl]aminomethyl]-1H-
1,2,3-triazoles 5l
1H NMR (CDCl3, 400 MHz), d: 7.58 (s, 1H, triazolyl-H), 7.51 (s, 2H,
2 · Ar-H), 6.82 (d, 1H, J = 8.7, 2 · Ar-H), 6.72 (d, 1H, J = 2.4,
2 · Ar-H), 6.54 (m, 1H, Ar-H), 4.52 (s, 2H, CH2), 4.07 (t, 2H, O-CH2),
3.73 (t, 4H, CH2-O-CH2), 2.80 (t, 2H, N-CH2), 2.61 (s, 4H, CH2-N-
CH2). Anal. Calcd for C21H21Cl4N5O2: C, 18.76; H, 4.09; N, 13.54.
Found: C, 48.98; H, 4.51; N, 13.23.
Compounds 3a–b were obtained in high yields by hydrogen with pal-
ladium on charcoal. However, during the synthesis of 3c with the
same method, dechlorination was found in the reduction. This com-
pound was successfully obtained via reflux in the presence of zinc
power in the acetic acid with ethanol and water (V:V, 3:2) as solvents.
Table 2: Inhibitory rate (%) of
compounds 5 against five fungi at
50 lg ⁄ mL
Compound
Fusarium
omysporum
Physalospora
piricola
Alternaria
solani
Cercospora
arachidicola
Gibberella
zeae
5a
5d
0.0
31.0
5.6
14.3
4.8
49.0
0.0
84.0
10.4
25.0
35.4
52.9
29.0
53.3
40.1
88.5
26.7
36.7
40.0
56.8
30.5
46.8
43.6
63.6
16.7
20.0
26.7
45.0
22.5
56.3
42.5
58.8
0.0
14.3
21.0
14.0
11.5
36.8
21.0
73.1
5f
5h
5i
5l
5m
Chlorothalonil
Chem Biol Drug Des 2011; 78: 695–699
697

Mao et al.
N
O
O
ii
NH2
N
OH
X
Cl
HCl
O
X
O
N
O
i
+
3a–3b
O
NO2
NO2
N
iii
1a–1c
2a–2c
Cl
O
a: p-NO2, X=H
b: o-NO2, X=H
c: p-NO2, X=Cl
NH2
3c
Scheme 1: Reagents and
conditions: (i) K2CO3, acetone,
reflux; (ii) H2, Pd ⁄ C, C2H5OH; (iii)
Zn, CH3COOH, C2H5OH ⁄ H2O, reflux;
(iv) propargyl bromide, THF, KOH,
microwave, 45 ꢀC; (v) azidoben-
zene, t-BuOH ⁄ H2O (1:1), sodium
ascorbate, CuSO4Æ5H2O, rt.
N
O
N
O
O
X
O
v
iv
R1
N
X
NH
N
N
NH
R3
R2
4a–4c
5a–5m
According to the literature (17,18), the synthesis of intermediates
4a–c gave consistently poor yields. It was difficult to separate the
by-products in the reaction mixture; 3-h prolonged reaction in a
water bath supersonic device did not help improving the reaction.
Interestingly, it is well known that microwave irradiation can cir-
cumvent the need for prolonged heating and generally accelerate
the rate of chemical reactions and in most cases with increased
yields (19–21). This technique was applied in this case. A reaction
with less by-products in milder reaction conditions with reasonable
yields was observed compared with the conventional methods when
microwave (1 h, 45 ꢀC) was utilized.
References
1. Beena Kumar N., Rohilla R.K., Roy N., Rawat D.S. (2009) Synthe-
sis and antibacterial activity evaluation of metronidazole–triazole
conjugates. Bioorg Med Chem Lett;19:1396–1398.
2. Jordao A.K., Afonso P.P., Ferreira V.F., Maria C.B.V., Souza
M.C.B.V., Maria C.B., Almeida M.C.B., Beltrame C.O., Paiva D.P.,
Wardell S.M.S.V., Wardell J.L., Tiekink E.R.T., Damaso C.R.,
Cunha A.C. (2009) Antiviral evaluation of N-amino-1,2,3-triazoles
against Cantagalo virus replication in cell culture. Eur J Med
Chem;44:3777–3783.
3. Genin M.J., Allwine D.A., Anderson D.J., Barbachyn M.R., Emm-
ert D.E., Garmon S.A., Graber D.R. et al. (2000) Substituent
effects on the antibacterial activity of nitrogen)carbon-linked
(azolylphenyl)oxazolidinones with expanded activity against the
fastidious gram-negative organisms haemophilus influenzae and
moraxella catarrhalis. J Med Chem;43:953–970.
Azidobenzene was prepared according to the literature (22). In the
presence of sodium ascorbate and copper sulphate in t-butanol and
water (V:V, 1:1), Huisgen cycloaddition between obtained terminal
alkynes 4a–c and azidobenzene provided target compound 5a–m
in good yields.
4. Sanghvi Y.S., Bhattacharya B.K., Kini G.D., Matsumoto S.S., Larso
S.B., Jolley W.B., Robins R.K., Revankar G.R. (1990) Growth inhi-
bition and induction of cellular differentiation of human myeloid
leukemia cells in culture by carbamoyl congeners of ribavirin. J
Med Chem;33:336–344.
5. Alvarez R., Vela¢zquez S., San-Fe¢lix A., Aquaro S., De Clercq E.,
Perno C.F., Karlsson A., Balzarini J., Camarasa M.J. (1994) 1,2,3-
Triazole-[2,5-bis-O-(tert-butyldimethylsilyl)-.beta.-D-ribofuranosyl]-
3¢-spiro-5¢¢-(4¢¢-amino-1¢¢,2¢¢-oxathiole 2¢¢,2¢¢-dioxide) (TSAO) ana-
logues:synthesis and anti-HIV-1 activity. J Med Chem;37:4185–
4194.
6. Al-Masoudi N.A., Al-Soud Y.A. (2002) Synthesis of 1-b-d-gluco-
pyranosyl-1,2,3-triazole-45-dimethanol-4,5-bis(isopropylcarbamate)
as potential antineoplastic agent. Tetrahedron Lett;43:4021–4022.
7. Hager C., Miethchen R., Reinke H. (2000) Azide–alkyne 1,3-dipo-
lar cycloadditions: a valuable tool in carbohydrate chemistry. J
Fluor Chem;4:35–142.
Biological activity and structure–activity
relationship
To analyse the biological activity of 5a–m, antifungal activities
were tested. The bioassay results are shown in Table 2. All the
compounds did not exhibit significant fungicidal activity against
F. omysporum and G. zease. The bioassay data indicated that the
antifungal activity was affected by the change of the substituent at
phenyl ring. When the benzene ring is substituted by halogen, the
target compounds generally have higher antifungal activity against
P. piricola, A. solani and C. arachidicola. Especially, the inhibitory
rate of 5h towards A. solani was 56.8% (the control was 63.6%),
5l towards C. arachidicola was 56.3% (the control was 58.3%).
Hence, 1,2,3-triazoles could be useful for further optimization in
finding the potential antifungal agents.
8. Calderone V., Giorgi I., Martinotti E., Mantuano E., Martelli A.,
Nardi A. (2005) Benzoyl and ⁄ or benzyl substituted 1,2,3-triazoles
as potassium channel activators (VIII). Eur J Med Chem;40:21–
528.
Acknowledgments
This work was supported by Tianjin Natural Science Foundation
(NO. 09JCZDJC21300) and NNSFC (No. 31000861).
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Chem Biol Drug Des 2011; 78: 695–699

Synthesis and Biological Activity of Novel 1,2,3-Triazoles
9. Maurya S.K., Gollapalli D.R., Kirubakaran S., Zhang M.J., John-
son C.R., Benjamin N.N., Hedstrom L., Cuny G.D. (2009) Triazole
inhibitors of Cryptosporidium parvum Inosine 5¢-monophosphate
dehydrogenase. J Med Chem;2:4623–4630.
15. Rostovtsev V.V., Green L.G., Fokin V.V., Sharpless K.B. (2002) A
stepwise huisgen cycloaddition process: copper(I)-catalyzed regio-
selective ``ligation'' of azides and terminal alkynes. Angew Chem
Int Ed;41:2596–2599.
10. Wang M.Z., Xu H., Feng Q., Wang L.Z., Wang S.H., Li Z.M.
(2009) Design, synthesis, and fungicidal activity of novel ana-
logues of pyrrolnitrin. J Agric Food Chem;57:7912–7918.
11. Tripathi R.P., Yadav A.K., Ajay A., Bisht S.S., Chaturvedi V., Sinha
S.K. (2010) Application of Huisgen (3 + 2) cycloaddition reaction:
synthesis of 1-(2,3-dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles
and their antitubercular evaluations. Eur J Med Chem;45:142–
148.
12. Muller G.W., Chen R.S.C., Man H.W., Ruchelman A.L. (2007)
Preparation of dioxopiperidinyl-isoindolone and -isoindolediones
derivatives as antitumor agents. US patent 2007049618.
13. Maegawa T., Takahashi T., Yoshimur M., Suzuk H., Monguchi Y.,
Sajikia H. (2009) Development of molecular sieves-supported pal-
ladium catalyst and chemoselective hydrogenation of unsatu-
rated bonds in the presence of nitro groups. Adv Synth
Catal;351:2091–2095.
16. Chen N.C. (1991) Bioassay of Pesticides. Beijing, China: Beijing
Agricultural University Press; p. 161–162.
17. Gonzꢀlez-Gꢁmez ꢂ., AÇorbe L., Poblador A., Domꢃnguez G.,
Pꢄrez-Castells J. (2008) Intermolecular and Intramolecular Pau-
son–Khand reactions of functionalized allenes. Eur
Chem;8:1370–1377.
J Org
18. Mazitschek R., Patel V., Wirth D.F., Clardy J. (2008) Development
of a fluorescence polarization based assay for histone deacety-
lase ligand discovery. Bioorg Med Chem Lett;18:2809–2812.
19. Hamilton S.K., Wilkinson D.E., Hamilton G.S., Wu Y.Q. (2005)
Microwave-assisted synthesis of N,N-Diaryl Cyanoguanidines.
Org Lett;12:2429–2431.
20. Xu G., Wang Y.G. (2004) Microwave-assisted amination from aryl
triflates without base and catalyst. Org Lett;6:985–987.
21. Hayes B.L. (2002) Microwave Synthesis, Chemistry at the Speed
of Light. Matthews, North Carolina: CEM Publishing; p. 16.
22. Hu M.Y., Li J.Q., Yao S.Q. (2008) In situ ''click'' assembly of
small molecule matrix metalloprotease inhibitors containing zinc-
chelating groups. Org Lett;10:5529–5531.
14. Wang D.T., Wang Y.P. (2005) Study on preparing 2,5-dimethoxy -
4-chloro-aniline with zinc powder as reductant. Mater Sci Tech-
nol;13:662–664. (in Chinese).
Chem Biol Drug Des 2011; 78: 695–699
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