Design and synthesis of N-hydroxytriazole-4-carboxamides as HIV integrase inhibitors

Article abstract of DOI:10.1007/s00044-014-1136-4

A series of N-hydroxytriazole-4-carboxamide derivatives were synthesized, and their potential HIV integrase inhibitory activities were evaluated.

Full text of DOI:10.1007/s00044-014-1136-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:423–429
DOI 10.1007/s00044-014-1136-4
ORIGINAL RESEARCH
Design and synthesis of N-hydroxytriazole-4-carboxamides as HIV
integrase inhibitors
•
Yue-Xia Bai Long-Ji Li Xiao-Li Wang
•
•
•
Cheng-Chu Zeng Li-Ming Hu
Received: 17 February 2014 / Accepted: 25 June 2014 / Published online: 15 July 2014
Ó Springer Science+Business Media New York 2014
Abstract A series of N-hydroxytriazole-4-carboxamide
derivatives were synthesized, and their potential HIV in-
tegrase inhibitory activities were evaluated.
are believed to bind Mg2? and Mn2? ions, which is
essential for the catalytic activity of IN (Engelman and
Craigie, 1992; Hazuda et al., 1997), it is commonly
anticipated that the pharmacophore of aryl b-diketo acid
type of HIV IN inhibitors binds competitively the two
Mg2? metal ions in the IN active site and thus to block the
access of a host DNA to the IN enzyme. On the other hand,
the hydrophobic subunit is identified to participate in a
specific interaction with an adjacent hydrophobic pocket or
surface (Bacchi et al., 2008; Sechui et al., 2006).
Keywords N-hydroxytriazole-4-carboxamides Á
HIV integrase inhibitors Á Diketo acids Á Metal binding
Introduction
Design and synthesis of HIV-1 integrase (IN) inhibitors
have emerged as the main interest for the treatment of
AIDS (Malet et al., 2012; Wainberg et al., 2012). During
the past decades, extensive efforts have been made, which
lead to the finding of a type of HIV IN inhibitors bearing an
aryl b-diketo acid scaffold (See Fig. 1 for its structure and
some typical inhibitors) (Hazuda et al., 2000, 2004; Gro-
bler et al., 2002; Johnson et al., 2004), and to the recent
approval of raltegravir (MK-0518) (Summa et al., 2008;
Anker and Corales, 2008) and phase II clinical trial of
elvitegravir (GS-9137) (Shimura et al., 2008) (Fig. 1). The
general structure of the aryl b-diketo acid type of HIV IN
inhibitors comprises a pharmacophore (such as diketo acid
scaffold) and a hydrophobic subunit (the aryl ring side
chain) with or without a linking unit (Fig. 1). Since the two
aspartate (Asp64, Asp116) and one glutamate (Glu152)
residues, situating at the catalytic core domain of HIV IN,
Given the above mentioned structural characteristics of
diketo acid type of HIV inhibitors, we have recently carried
out a project with an basic assumption that the development
of a new HIV inhibitor can be logically conducted by an
assembly of appropriate pharmacophore(s) and a hydro-
phobic subunit(s) linked by an 1,2,3-triazole ring through
‘‘click reaction’’ (Bock et al., 2006; Hou et al., 2012). We
speculate that, in this way, HIV IN inhibitors library can be
easily created, and thus the finding and modification of a lead
compound can be dramatically accelerated, due to the fact
that click reaction can be furnished under benign reaction
conditions, and thus most of the functional groups may tol-
erate. In addition, click reaction requires only fairly simple
workup and purification process. To this end, we have syn-
thesized 1,4-dihydro-4-oxo-1,5-napthyridine-3-carboxylic
acids as HIV IN inhibitors (Zeng et al., 2009). As a contin-
uation of our project, in this paper, we design and synthesize
N-hydroxy-triazole-4-carboxamides and evaluate their
potential HIV IN inhibitory activity.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-1136-4) contains supplementary
material, which is available to authorized users.
Results and discussion
Y.-X. Bai Á L.-J. Li Á X.-L. Wang Á C.-C. Zeng (&) Á L.-M. Hu
College of Life Science & Bioengineering, Beijing University
of Technology, Beijing 100124, China
Our inspiration comes from Plewe’s discovery. Recently,
Plewe et al. have found that azaindole carboxylic acid
e-mail: zengcc@bjut.edu.cn; zengcc138@gmail.com
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Med Chem Res (2015) 24:423–429
Fig. 1 The metal-binding
model of aryl diketo acid and
some typical HIV IN inhibitors
pharmacophore
hydrophobic subunit
O
OH
O
O
Mg2+
N
O
HN
O
F
N
O
Mg2+
Aryl
O
O
O
OH
S
O
O
OH
Basic scaffold of diketo
acid and metal binding model
L-870,810
L-708,906
O
F
O
O
F
HO
Cl
N
OH
N
N
H
H
N
N
N
O
O
O
O
OH
Raltegravir (MK-0518)
Elvitegravir (GS-9137)
Fig. 2 Metal binding of
picolinic acid (a), picoline
hydroxamic acid (b), and
N-hydroxy triazole-4-
carboxamide (c)
O
HN
O
O
O
Mg2+
N
HN
Mg2+
Mg2+
O
Mg2+
O
Mg2+
N
N
N
N
N
N
Ar
Ar
Ar
A
B
C
derivatives exhibit modest HIV IN inhibitory activity
(IC50: 0.95–7.35 lM) (Plewe et al., 2009) and good ligand
efficiencies (LE) (Dg [ 0.35 kcal/mol) (Hopkins et al.,
2004; Kuntz et al., 1999). However, improved inhibitory
activity was achieved when the carboxylic acid moiety was
replaced by a hydroxamic acid moiety. The authors pro-
posed that this results were stemmed from the one Mg2?
ion binding of the bidentate picolinic acid subunit (A,
Fig. 2), whereas a picoline hydroxamic acid moiety would
greatly facilitate binding of two Mg2? ions (B, Fig. 2)
(Plewe et al., 2009). Based on this observation, we believe
that the N-hydroxy carboxamide subunit appended by an
azo-heteroaromatic may be a suitable pharmocophore for
the design of HIV IN inhibitor. Moreover, if the azo-het-
eroaromatic is a triazole ring generated from a click reac-
tion, alike our previous report on design of HIV IN
inhibitors using click reaction (Zeng et al., 2009), the
desired N-hydroxy-triazole-4-carboxamide is thus sup-
posed to bind two metal ions in a pattern analogous to the
picoline hydroxamic acid (C, Fig. 2). It is worthy noting
that in the N-hydroxy-triazole-4-carboxamide structural
scaffold, the triazole cycle functions not only as one of the
component of the pharmacophore, but also as a linker for
efficient assembly of the pharmacophore and a hydropho-
bic unit through ‘‘click reaction’’. As a result, a library of
N-hydroxy-triazole-4-carboxamide derivatives may be
easily accessible.
a known procedure (Suzuki et al., 2010), the condensation
of propynoic acid (1) and NH2OTHP gives tetrahydropy-
ran-2-yloxy propynoic acid amide 3. After treatment using
TsOH, the key intermediate propynoic acid hydroxyamide
4 was produced. On the other hand, nucleophilic substitu-
tion of benzyl bromides 5 with sodium azide afforded
benzyl azides 6. Finally, the click reaction of 6 and 4
generated the desired benzyl-substituted N-hydroxy-tria-
zole-4-carboxamide 7 in good to excellent yields.
To investigate the influence of the rigidity of the linker
on the inhibitory activity, we also designed phenyl-
substituted N-hydroxytriazole-4-carboxamides. As shown
in Scheme 2, aniline derivatives 8 were initially converted
into corresponding aromatic azides 9 (Barral et al., 2007),
which underwent click reaction with 4 to give the desired
N-hydroxytriazole-4-carboxamides 10 in good yield. It is
worthy noting that compounds 10 could also be accessible
by a one pot, two-step procedure.
During the synthetic processes, the click reaction
between propynoic acid hydroxyamide 4 and various
azides was the key step. It was reported that the presence of
carbonylic acid could promote the fragmentation of tria-
zole-Cu adduct, an essential intermediate, to form the final
click reaction product (Shao et al., 2010). Then following a
modified procedure (Shao et al., 2010), we initially opti-
mized the click reaction conditions taking azidobenzene 9a
as a model compound. As shown in Table 1, when the
reaction of azidobenzene and propynoic acid hydroxya-
mide 4 was conducted in the presence of a ratio of
0.01:0.02:0.1 for CuSOÁ45H2O, NaAsc, and PhCO2H, the
As expected, the synthesis of N-hydroxytriazole-4-car-
boxamide is fairly straightforward, and the synthetic routes
are showed in Schemes 1 and 2. At the beginning, followed
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Med Chem Res (2015) 24:423–429
425
Scheme 1 Synthesis of benzyl-
substituted N-hydroxy-triazole-
4-carboxamide 7
O
H
N
O
O
OH
O
O
DCC
TsOH/MeOH
NH2
N
OH
H
CH2Cl2
O
O
3
2
1
4
H
N
OH
.
O
4
NaN3
Br
N
N3
R
O
R
R
CH3COCH3:H2O
= 3:1 (V:V)
N
NaAsc / CuSO4 5H2O
N
HN
OH
PhCOOH, t-BuOH in H2O
7a-7i
5a-5i
6a-6i
a: R = H; b: R = o-Me; c: R = m-Me;
d: R = p-Me; e: R = o-F; f: R = m-F;
g: R = p-F; h: R = o-Br; i: R = m-NO2
Scheme 2 Synthesis of phenyl-
substituted N-hydroxy-triazole-
4-carboxamide 10
H
N
OH
OH
HN
O
NH2
4
N
N
N3
t-BuONO,TMSN3
R
R
N
NaAsc / CuSO4 .5H2O
CH3CN
O
R
PhCOOH, t-BuOH in H2O
8a-8e
9a-9e
10a-10e
a: R = H; b: R = o-OMe
c: R = m-NO2; d: R = p-Cl
e: R = o-NO2-m-Cl
Table 1 Condition optimization of click reaction using 9a as model
starting material
Table 2 Inhibitory rate of synthesized N-hydroxytriazole-4-
carboxamides
Entry 1 CuSO4Á5H2O, NaAsc and Time Temperature Yield
Compound Inhabitory rate %
(0.39 lg/mL)
Compound Inhabitory rate %
(0.39 lg/mL)
PhCO2H (eq)
(h)
(oC)
(%)
1
2
3
4
5
0.01, 0.02, 0.1
0.01, 0.02, 0.1
0.01, 0.02, 0.1
0.02, 0.04, 0.2
0.02, 0.04, 0.2
2
5
5
5
5
rt
–
Raltegravir 94.09 (0.1 lg/mL)a Raltegravir 70.99 (0.01 lg/mL)a
rt
–
7a
7b
7c
7d
7e
7f
7g
a
37.77
21.93
0.00
7h
5.49
0.00
45
rt
–
7i
65
68
10a
10b
10c
10d
10e
31.57
16.88
19.17
4.25
45
0.00
13.11
0.00
Conditions: propynoic acid hydroxyamide 4 (1 mmol) and azido-
benzene (1.1 mmol) in 2 mL of t-butanol/water (V:V = 1:2) mixed
solvent
15.94
35.25
IC50 of Raltegravir is 0.00427 lg/mL under the same antiviral
assays conditions
desired 10a did not generate (Table 1, entry 1). Prolonging
to 5 h or raising temperature to 45 °C did not improve the
reaction (Table 1, entries 2 and 3). Delightly, the desired
10a was afforded in 65 % yield when the loading amount
of catalysts and benzoic acid was doubled while main-
taining same ratio of catalysts to benzoic acid. A slightly
increasing of yield could also achieve when the reaction
was conducted at 45 °C. With the optimized conditions in
hand, all products 7 and 10 were afforded in good to
excellent yields (see experimental section for the yields).
The possible HIV inhibitory activity of the title com-
pounds 7 and 10 was preliminarily tested using multinu-
clear activation of a galactosidase indicator (MAGI)
method (Vodicka et al., 1997; Hu et al., 2012). The
inhibitory rates of all samples at a concentration of
0.39 lg/mL are listed in Table 2. For comparison, the
known IN inhibitor, Raltegravir, was used as a positive
drug control, whose inhibitory rates were measured to be
94.09 % (at 0.1 lg/mL) and 70.99 % (0.01 lg/mL) under
the same biological testing conditions. Very lower inhibi-
tory efficiency was observed for most of the compounds 7,
wherein the triazole cycles are appended with benzyl
group, although 7a exhibited 37.77 % inhibitory rate.
When the benzyl group was replaced by a phenyl group, as
in the cases of compounds 10, a little higher inhibitory
activity was afforded, and 10e gave 35.24 % of inhibitory
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Med Chem Res (2015) 24:423–429
rate. These results indicate that a rigid hydrophobic side
chain may improve the inhibitory activity of the N-hydro-
xytriazole-4-carboxamides.
was then precipitated to give gray solid. Pure products
N-hydroxy-triazole-4-carboxamides 7 could be obtained
after recrystallization with ethyl acetate/petroleum ether or
flash chromatograph (Vethyl acetate/Vpetroleum ether = 1:10).
Conclusion
1-Benzyl-N-hydroxy-1H-1,2,3-triazole-4-carboxamide (7a)
In conclusion, based on the possible metal-binding mode of
picoline hydroxamic acid, we assumed that an N-hydro-
xytriazole-4-carboxamide scaffold may serve as a phar-
macophore for the design of HIV IN inhibitor. Therefore, a
series of N-hydroxy-triazole-4-carboxamide derivatives
appended by hydrophobic benzyl and phenyl side chain
were synthesized. The two subunits were efficiently
assembled by a click reaction between a terminal alkyne
and an azide compound. Their HIV inhibitory activity was
evaluated, and no satisfactory activities were observed.
Yield: 90 %; m.p.: 197–198 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.64 (s, 2H), 7.33–7.41 (m, 5H, Ar–H), 8.59
(s, 1H, triazole-H), 9.03 (s, 1H, OH), 11.25 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 53.5, 126.7, 128.5,
128.8, 129.3, 136.1, 141.9, 158.0; IR (KBr): m 3,290, 3,129,
2,894, 1,643, 1,577, 1,458, 1,432, 1,256, 1,051, 1,005, 881,
716, 696, 575 cm-1; ESI–MS: ESI–MS m/z 219.0 (M??1);
241.0 (M ? Na)?.
1-(2-Methylbenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7b)
Experimental
Yield: 88 %; m.p.: 191–193 °C; 1H NMR (400 MHz,
DMSO-d6): d 2.32 (s, 3H, CH3), 5.65 (s, 2H, CH2), 7.11 (d,
1H, J = 7.2 Hz, Ar–H), 7.18–7.28 (m, 3H, Ar–H), 8.47 (s,
1H, triazole-H), 9.04 (s, 1H, OH), 11.25 (s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6): d 19.1, 51.6, 126.7, 126.8,
128.9, 129.2, 130.9, 134.2, 136.8, 141.8, 158.0; IR (KBr): m
3,429, 3,316, 3,120, 2,921, 2,853, 1,644, 1,625, 1,578,
1,381, 1,239, 1,045, 880, 690 cm-1; ESI–MS m/z 233.0
(M??1); 254.9 (M ? Na)?.
All melting points (mp) were measured with an XT4A
electrothermal apparatus equipped with a microscope and
are uncorrected. Infrared spectra (IR) were recorded as thin
films on KBr plates on a Bruker IR spectrophotometer and
are expressed in v (cm-1). H and 13C NMR spectra were
1
recorded on an AV 400 M Bruker spectrometer (400 MHz
1
for H frequency, 100 MHz for 13C frequency) in solvent
(CDCl3 or DMSO-d6) with TMS as an internal reference.
MS data (ESI) were recorded on a Bruker esquire 6000
mass spectrometer. All solvents were of commercial
quality and were dried and purified by standard procedures.
Propynoic acid hydroxyamide 4 (Suzuki et al., 2010),
1-(3-Methylbenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7c)
Yield: 85 %; m.p.: 174.2–179 °C; 1H NMR (400 MHz,
DMSO-d6): d 2.29 (s, 3H, CH3), 5.58 (s, 2H, CH2),
7.12–7.29 (m, 4H, Ar–H), 8.58 (s, H, triazole-H), 9.03 (s,
1H, OH), 11.24 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6): d 21.4, 53.5, 125.6, 126.7, 129.1, 129.2, 129.4, 136.0,
138.6, 142.0, 158.1; IR (KBr): m 3,435, 3,348, 3,116, 2,856,
1,635, 1,574, 1,096, 880, 754 cm-1; ESI–MS m/z 233.0
(M??1); 254.9 (M ? Na)?.
´
benzyl azides 5 (Sa and Ramos, 2006), and aromatics
azides 9 (Barral et al., 2007) were synthesized following
known procedures and used directly.
General procedure for the synthesis of benzyl-
substituted N-hydroxy-triazole-4-carboxamides (7)
A 25-mL round flask was charged with CuSO4Á5H2O
(5.0 mg, 0.02 mmol), sodium ascorbate (7.9 mg,
0.04 mmol), benzoic acid (24.4 mg, 0.2 mmol), and 2 mL
of t-butanol/water (V:V = 1:2) mixed solvent. To the
solution was added azides 6 (1.1 mmol) and propynoic acid
hydroxyamide 4 (1 mmol), and the reaction was stirred at
room temperature. After stirring for about 50 min, TLC
monitoring showed that starting materials were consumed.
Dichloromethane (30 mL) was added, the organic layer
was washed with brine and then water, and finally dried by
anhydrous MgSO4. After filtration, most of the solvents
were evaporated under reduced pressure, and the product
1-(4-Methylbenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7d)
Yield: 86 %; m.p.: 192–194 °C; 1H NMR (400 MHz,
DMSO-d6): d 2.28 (s, 3H, CH3), 5.58 (s, 2H, CH2), 7.19 (d,
2H, J = 7.6 Hz, Ar–H), 7.25 (d, 2H, J = 7.6 Hz, Ar–H),
8.55 (s, 1H, triazole-H), 9.03 (s, 1H, OH), 11.24 (s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 21.2, 53.3, 126.6,
128.6, 129.8, 133.1, 138.1, 142.3, 158.0; IR (KBr): m 3,316,
3,114, 2,922, 2,854, 1,625, 1,578, 1,449, 1,252, 1,045, 882,
761 cm-1; ESI–MS m/z 232.9 (M??1); 254.9 (M ? Na)?.
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Med Chem Res (2015) 24:423–429
427
1-(2-Fluorobenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
1-(3-Nitrobenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7e)
carboxamide (7i)
Yield: 85 %; m.p.: 189–192 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.71 (s, 2H, CH2), 7.25–7.29 (m, 2H, Ar–
H), 7.36–7.46 (m, 2H, Ar–H), 8.55 (s, 1H, triazole-H),
9.04 (s, 1H, OH), 11.25 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 47.63 (d), 116.1 (d), 123.0 (d),
125.3 (d), 126.8, 131.2 (d), 131.3 (d), 141.8, 158.0, 161.8
(d); IR (KBr): m 3,291, 3,125, 2,919, 1,641, 1,577, 1,493,
1,239, 1,049, 881, 756 cm-1; ESI–MS m/z 237.0 (M??1);
259.1 (M ? Na)?.
Yield: 82 %; m.p.: 178–181 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.82 (s, 2H, CH2), 7.70 (t, 1H, J = 8.0 Hz,
Ar–H), 7.80 (d, 1H, J = 7.6 Hz, Ar–H), 8.21 (t, 2H,
J = 8.4 Hz, Ar–H), 8.26 (s, 1H, Ar–H), 8.69 (s, 1H, tria-
zole-H), 9.06 (s, 1H, OH), 11.29 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 52.5, 123.4, 123.7, 127.1, 130.9,
135.3, 138.1, 142.1, 148.4, 157.9; IR (KBr): m 3,427, 3,313,
3,131, 3,070, 1,630, 1,581, 1,538, 1,350, 1,048, 880,
810 cm-1; ESI–MS m/z 264.0 (M??1).
General procedure for the synthesis of phenyl-
1-(3-Fluorobenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
substituted N-hydroxy-triazole-4-carboxamides (10)
carboxamide (7f)
Similar to the synthesis of benzyl-substituted N-hydroxy-
triazole-4-carboxamides 7, but the reaction mixture was
stirred at 45 °C for about 4 h.
Yield: 87 %; m.p.: 193–194 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.67 (s, 2H, CH2), 7.16–7.22 (m, 3H, Ar–
H), 7.41–7. 47 (m, 1H, Ar–H), 8.63 (s, 1H, triazole-H),
9.04 (s, 1H, OH), 11.25 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 52.8, 115.3 (d), 115.5 (d), 124.6
(d), 126.9, 131.3 (d), 138.7 (d), 142.0, 158.0, 162.6 (d); IR
(KBr): m 3,289, 3,132, 2,893, 1,642, 1,580, 1,488, 1,454,
1,006, 881, 742, 593 cm-1; ESI–MS m/z 237.0 (M??1);
258.9 (M ? Na)?.
N-Hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide
(10a)
Yield: 68 %; m.p.: 195–196 °C; 1H NMR (400 MHz,
DMSO-d6): d 7.53 (t, 1H, J = 7.2 Hz, Ar–H), 7.62 (t,
2H, J = 7.6 Hz, Ar–H), 7.96 (d, 2H, J = 8.0 Hz, Ar–H),
9.16 (s, 1H, OH), 9.26 (s, 1H, triazole-H), 11.42 (s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 120.9, 124.9,
129.6, 130.4, 136.7, 142.7, 157.8; IR (KBr): m 3,427,
1-(4-Fluorobenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7g)
3,328, 3,141, 1,632, 1,570, 1,498, 878, 762, 685 cm-1
;
Yield: 80 %; m.p.: 178–189 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.63 (s, 2H, CH2), 7.22 (t, 2H, J = 8.8 Hz,
Ar–H), 7.41–7.45 (m, 2H, Ar–H), 8.60 (s, 1H, triazole-H),
9.04 (s, 1H, OH), 11.25 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): d 52.7, 116.1 (d), 126.7, 130.9 (d),
132.3 (d), 142.0, 158.0, 162.4 (d); IR (KBr): m 3,322,
3,126, 2,993, 2,919, 1,902, 1,640, 1,514, 1,235, 1,015,
880, 858 cm-1; ESI–MS m/z 237.0 (M??1); 259.0
(M ? Na)?.
ESI–MS: m/z 203.1 (M?_1); 205.1 (M??1); 227.1
(M ? Na)?.
N-Hydroxy-1-(2-methoxyphenyl)-1H-1,2,3-triazole-4-
carboxamide (10b)
Yield: 71 %; m.p.: 194–195 °C; 1H NMR (400 MHz,
DMSO-d6): d 3.87 (s, 3H, OCH3), 7.16 (t, 1H, J = 7.6 Hz,
Ar–H), 7.11 (d, 1H, J = 8.4 Hz, Ar–H). 7.57 (t, 1H,
J = 7.6 Hz, Ar–H), 7.66 (d, 1H, J = 7.6 Hz, Ar–H), 8.82
(s, 1H, triazole-H), 9.12 (s, 1H, OH), 11.36 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 56.7, 113.5, 121.3,
125.7, 126.4, 128.3, 131.6, 141.5, 152.2, 158.0; IR (KBr): m
3,231, 3,172, 2,919, 2,849, 1,658, 1,603, 1,513 cm-1; ESI–
MS m/z 235.1 (M??1); 257.0 (M ? Na)?.
1-(2-Bromobenzyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (7h)
Yield: 79 %; m.p.: 200–205 °C; 1H NMR (400 MHz,
DMSO-d6): d 5.73 (s, 2H, CH2), 7.21 (d, 1H, J = 7.2 Hz,
Ar–H), 7.33 (t, 1H, J = 7.6 Hz, Ar–H), 7.42 (t, 1H,
J = 7.6 Hz, Ar–H), 7.70 (d, 1H, J = 8.0 Hz, Ar–H), 8.53
(s, 1H, triazole-H), 9.06 (s, 1H, OH), 11.28 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 53.7, 123.4, 127.1,
128.8, 131.0, 131.1, 133.4, 134.9, 141.7, 157.9; IR (KBr): m
3,425, 3329, 3,131, 2,920, 2,851, 1,623, 1,579, 1,445,
1,046, 746 cm-1; ESI–MS: m/z 296.9 (M??1); 318.9
(M ? Na)?.
N-Hydroxy-1-(3-nitrophenyl)-1H-1,2,3-triazole-4-
carboxamide (10c)
Yield: 70 %; m.p.: 199-201 °C; 1H NMR (400 MHz,
DMSO-d6): d 7.93 (t, 1H, J = 8.0 Hz, Ar–H), 8.36–8.47
(m, 2H, Ar–H), 8.80 (s, 1H, Ar–H), 9.22 (s, 1H, OH), 9.51
(s, 1H, triazole-H), 11.52 (s, 1H, NH); 13C NMR
123

428
Med Chem Res (2015) 24:423–429
Acknowledgments This work was supported by Grants from Bei-
jing Natural Science Foundation (No. 7112008), National Basic
Research Program of China (No. 2009CB930200), and Beijing City
Education Committee (KM201010005009).
(100 MHz, DMSO-d6): d 115.8, 124.0, 125.7, 127.0, 132.0,
137.3, 143.1, 149.0, 157.5; IR (KBr): m 3,449, 3,249, 3,113,
2,920, 2,851, 1,671, 1,630, 1,535, 1,351, 1,017, 778 cm-1
;
ESI–MS: m/z 250.0 (M??1), 272.0 (M ? Na)?.
1-(4-Chlorophenyl)-N-hydroxy-1H-1,2,3-triazole-4-
carboxamide (10d)
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