Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.06.059

This study mainly focused on the modification of the X² position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X² position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC₅₀ values ranging from 0.21?μM to 26.13?μM. Among them, compound 1s (IC₅₀?=?0.21?μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X² position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study.

Full text of DOI:10.1016/j.bmcl.2017.06.059

Accepted Manuscript
Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid de-
rivatives as xanthine oxidase inhibitors
Ting-jian Zhang, Qing-xia Wu, Song-ye Li, Lin Wang, Qi Sun, Yi Zhang, Fan-
hao Meng, Hua Gao
PII:
S0960-894X(17)30661-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.059
BMCL 25093
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
5 April 2017
17 May 2017
22 June 2017
Please cite this article as: Zhang, T-j., Wu, Q-x., Li, S-y., Wang, L., Sun, Q., Zhang, Y., Meng, F-h., Gao, H.,
Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors,
Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.06.059
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Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as
xanthine oxidase inhibitors
Ting-jian Zhang a, Qing-xia Wua, Song-ye Lia, Lin Wanga, Qi Suna, Yi Zhanga, Fan-hao Meng a, *, Hua Gaoa, b,
a School of Pharmacy, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China
b Division of Pharmacology Laboratory, National Institutes for Food and Drug Control, Beijing 100050, China
* Corresponding authors.
*
E-mail addresses: fhmeng@cmu.edu.cn (F-h. Meng), huag55@163.com (H. Gao).
Abstract
This study mainly focused on the modification of the X2 position in febuxostat analogs. A
series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom
occupying the X2 position was designed and synthesized. Evaluation of their inhibitory
potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar
level potencies, with IC50 values ranging from 0.21 µM to 26.13 µM. Among them,
compound 1s (IC50 = 0.21 µM) showed the most promising inhibitory effects and was 36-fold
more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700,
which meant that a polar atom fused at the X2 position could be unfavorable for potency. The
Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase
inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic
ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency.
Molecular modeling provided a reasonable explanation for the structure–activity relationships
observed in this study.
Keywords: 1,2,3-Triazole; Xanthine oxidase inhibitor; Hyperuricemia.
Xanthine oxidase (XO) is an important enzyme that catalyzes the hydroxylation of both
hypoxanthine and xanthine in the last two steps of urate biosynthesis in humans.1 The
over-production of uric acid can lead to hyperuricemia, which is the key cause of gout. Thus,
XO is considered the most promising target for treating this pathological condition.2
1

During purine oxidation, XO delivers an electron to the molecular oxygen and generates
reactive oxygen species (ROS). An excess of ROS could evoke various pathological states
including inflammation, metabolic disorders, atherosclerosis, cancer and chronic obstructive
pulmonary disease.3 Thus, inhibiting XO could reduce the production of ROS and benefit the
treatment of these diseases.4
Allopurinol is a prototypical XO inhibitor and has been widely used in the treatment of
hyperuricemia and gout for several decades. However, in some cases, it has been reported
that allopurinol and its analogs, which possess a purine backbone, can lead to severe
life-threatening side effects.5 Therefore, searching for novel non-purine XO inhibitors with
more potent XO inhibitory potency but fewer side effects has always been a hotspot. Y-700 is
a classic non-purine XO inhibitor that was first reported by Ishibuchi S. et al.6 Although it has
not introduced into the market, the excellent activity of Y-700 has widely attracted
researchers. Febuxostat7 is another non-purine XO inhibitor that bears a thiazole moiety and
has an outstanding inhibitory potency as well as acceptable side effects and was approved by
the US Food and Drug Administration (FDA) in 2009. Thereafter, febuxostat analogs, which
are characterized by a five-member aromatic ring linking a benzonitrile moiety and a
carboxyl group, have been reported, such as selenazoles,8 imidazoles9 and isoxazoles10 (Fig.
1). Furthermore, other XO inhibitors with different structural classes have also been recently
12
reported, including topiroxostat (approved in Japan in 2013),11 isocytosines,3,
2-(indol-5-yl)thiazoles,13 N-(1,3-diaryl-3-oxo-propyl)amides,14 N-acetyl pyrazolines,15
hydroxylated
chalcones,16
9-deazaguanines,17
flavonoids,18
fraxamoside,19
pyrano[3,2-d]pyrimidine,20 2-arylbenzo[b]furan21 and benzaldehydes.22
2

Fig. 1. The chemical structures of some XO inhibitors and designed compounds 1a-s.
In our previous report, we drew attention to febuxostat analogs of imidazoles9 and
changes in their inhibitory effects due to isosteric replacement at the X1 position. In this study,
we mainly focused on modifications and structure activity relationships (SARs) at the X2
position. According to the co-crystal structure of XO in complex with Y-700,23 X2 is the
closest point on the ligand from the molybdenum-pterin, which is the catalytic center of XO.
Between them, W498 was observed as a water bridge linked by the H-bonds to the
molybdenum-pterin hydroxyl and the Glu1261 carboxyl group.23 These interactions inspired
us and suggest that a polar N atom fixed at the X2 position may promote some interactions
with molybdenum-pterin (e.g., link the molybdenum-pterin by a water bridge) and contribute
to the inhibitory potency. Therefore, we designed and synthesized a series of XO inhibitors
(1a-s) based on 1,2,3-triazole and investigated the effects of a fixed nitrogen atom at the X2
position in the lead compound Y-700.
The synthesis strategy of target compounds 1 was performed as outlined in Scheme 1.
Commercially available 2-hydroxybenzonitrile was nitrated in a conc. HNO3/AcOH system
to provide 2-hydroxy-5-nitrobenzonitrile (2). The reaction was triggered at 50°C by the
addition of a small amount of HNO3 and maintained by the continuous addition of the
remaining HNO3. During the nitration process, it was essential to carefully control the HNO3
dropping rate such that the reactive temperature was no higher than 70°C to prevent the
3

generation of oxidative by-products. In this reaction, a nitro group could also be introduced at
the 3-position and generate the by-product 2-hydroxy-3-nitrobenzonitrile. This by-product
was difficult to separate out due to its similar polarity, so we employed the mixture directly. A
continuous three-step procedure of alkylation with the corresponding alkyl bromide or alkyl
chloride followed by reduction using iron powder and isolation with column chromatography
effortlessly provided pure 2-alkoxy-5-aminobenzonitriles (4). The diazotization of 4 was
performed by treatment with sodium azide, which yielded the key intermediate
2-alkoxy-5-azidobenzonitriles (5). Cyclization of 5 with ethyl propiolate in the presence of
copper sulfate and vitamin C via the Husigen reaction under microwave conditions produced
ethyl 1-(4-alkoxy-3-cyanophenyl)-1H-1,2,3-triazole-4-carboxylates (6), which were
hydrolyzed with sodium hydroxide and then acidified to give 1. The structures of the
synthesized compounds were elucidated by 1H NMR, 13C NMR and MS. All the spectral data
were in accordance with the assumed structures.
NO2
NO2
NH2
ⅲ
ⅰ
ⅱ
HO
HO
RO
RO
CN
CN
CN
CN
2
4
3
O
N
O
OEt
OH
N3
ⅴ
N
N
ⅳ
ⅵ
N
N
N
RO
R
R
CN
O
O
6
1
5
CN
CN
Scheme 1. Reagents and conditions: (i) HNO3 and AcOH at 50°C for 4 h; (ii) RCl or RBr,
K2CO3, KI, and DMF at 60°C overnight; (iii) 1) Fe, NH4Cl, EtOH and H2O reflux for 3 h
followed by 2) isolation by column chromatography (ethyl acetate:petroleum ether = 1:5 to
1:1); (iv) 1) NaNO2, AcOH, and H2O at -10°C for 30 min followed by 2) NaN3 at 0°C for 3 h;
(v) Ethyl propiolate, CuSO4, and vitamin C at 50°C under microwave conditions for 8 min;
and (vi) NaOH, MeOH, and H2O at 50°C for 1.5 h, followed by the addition of 1 M HCl.
Bovine XO in vitro inhibitory potencies by target compounds 1a–s were determined by
4

spectrophotometrically measuring uric acid levels at 294 nm.11, 24 Allopurinol and Y-700 were
included as reference compounds. The results are shown in Table 1.
Table 1. In vitro XO inhibitory potency of compounds 1a-s.
Compound
R group
n-propyl
IC50 (µM)
＞30
6.24
5.03
3.27
3.96
2.85
1.62
1.08
26.13
1.50
1.47
0.63
2.40
0.94
0.85
0.72
0.76
3.35
0.21
1a
1b
1c
1d
1e
1f
isopropyl
n-butyl
isobutyl
sec-butyl
n-pentyl
isopentyl
1g
1h
1i
cyclopentyl
methoxyethyl
n-hexyl
1j
1k
1l
n-heptyl
n-octyl
benzyl
1m
1n
10
1p
1q
1r
1s
para-chlorobenzyl
para-cyanobenzyl
para-methoxybenzyl
ortho-methoxybenzyl
meta-cyanobenzyl
meta-methoxybenzyl
5

Allopurinol
Y-700
/
/
7.56
0.016
According to the literature, an ether side chain containing 3-5 carbons at the 4′-position
of febuxostat analogs has been proven to be welcome. Therefore, we initially synthesized a
set of compounds bearing an ether chain with 3-5 carbons (1a-g) to examine the influence of
the various R groups on XO inhibitory potency. Despite having potencies below Y-700 (IC50
= 0.016 µM), most of these compounds (except 1a, IC50 ＞30 µM) showed higher activities
compared to allopurinol (IC50 = 7.56 µM), which encouraged us to carefully investigate the
SAR to identify more effective compounds with potencies comparable to Y-700. Among
these compounds, 1g (IC50 = 1.62 µM), which bears an iso-pentyl R group, displayed a higher
inhibitory effect. Moreover, a cycloalkyl derivative was involved in the series, and
transitioning from the iso-pentyl to cyclopentyl group (1h, IC50 = 1.08 µM) resulted in a
1.5-fold increase in potency.
Surprisingly, a slight tendency was observed in the 1a-g subseries that XO inhibitory
potency may be gradually improved with increasing R group size. To verify this tendency, a
few larger carbon chain derivatives were synthesized, including R = n-hexyl (1j, IC50 = 1.50
µM), R = n-heptyl (1k, IC50 = 1.47 µM) and R = n-octyl (1l, IC50 = 0.63 µM). The results
confirmed the existence of this tendency when the R group was prolonged to an n-octyl group.
This tendency was distinguished from the Y-700 analogs.6
A long carbon chain may lead to the following two effects: (1) increase the bulk and (2)
enhance the lipophilicity of the molecule. Due to the flexibility of the R groups and the fact
that the febuxostat analog R groups are usually located on the outer region of the XO
functional site,7, 23 which shows less bulk, the lipophilicity may be the primary factor
affecting the potency. Therefore, we calculated the log P values of some of the target
compounds with the linear R tails (Fig. 2) using the Ligand Properties Tools in the MOE
(Molecular Operating Environment, version 2015.1001) software, and found a negative
correlation between the log P and the IC50 when the R groups were elongated from n-butyl to
n-octyl. Hence, it can be observed that a lipophilic ether tail could benefit the inhibitory
6

activity of this series; in contrast, a less lipophilic tail may weaken the activity (1c versus 1i).
Fig. 2. The log P and IC50 values for compounds 1c, 1f, 1j, 1k and 1l.
However, a long carbon chain empirically appears to cause some pharmacokinetic
issues.25 Therefore, we alternately attempted to adopt some benzyl groups to play the role of
lipophilic tails. Installation of a benzyl as the R group led to 1m (IC50 = 2.40 µM), which
exhibited moderate potency. Introduction of some para-substituents, such as para-chloro (1n,
IC50 = 0.94 µM), para-cyano (1o, IC50 = 0.85 µM) and para-methoxy (1p, IC50 = 0.72 µM),
led to 1-3-fold increase in potency. Among these compounds, 1p showed comparable effects
to 1l. To investigate the influence of the substituent positions, ortho- (1q, IC50 = 0.76 µM)
and meta- (1s, IC50 = 0.21 µM) derivatives of 1p were synthesized. The meta-methoxy (1s)
position was more promising than either the para-methoxy (1p) or ortho-methoxy (1q)
positions, as the latter two showed almost equal activities. Specifically, 1s presented an
outstanding effect, which was 11-fold enhanced compared to 1m (R = benzyl) and 3-fold
higher than 1l (R = n-octyl). However, shifting the para-cyano (1o) to the meta-position (1t)
resulted in a 3.9-fold decrease in potency.
In summary, the most potent compound, 1s, bears a meta-methoxybenzoxy substituent at
the 4′-position and displayed an IC50 value of 0.21 µM, which was 36-fold more potent than
allopurinol, but still 13-fold less potent than Y-700. A steady-state kinetic analysis was
7

performed to explore the inhibition behaviors of 1s using the method reported by Matsumoto
et al.11 The Lineweaver-Burk plot analysis revealed that 1s acts as a mixed-type XO inhibitor
(Fig. 3), and had similar actions to febuxostat7 and Y-700.23 This inhibition type could be
explained by the potent inhibition of both the oxidized and reduced forms of XO.26
Fig. 3. Lineweaver-Burk plot analysis of xanthine oxidase inhibition by compound 1s.
Compared with febuxostat,7 topiroxostat11 and especially Y-700 (IC50 = 0.016 µM), the
potency of the 1,2,3-triazoles were obviously lower. This result could be attributed to the
replacement of the X2 carbon atom with the nitrogen atom. The N-3 atom would locally
enhance the hydrophilicity and polarity around the X2 position, which may be the direct cause
for the decrease in potency. Similar effects were observed for the isoxazole series.10 Thus, it
can be concluded that a polar atom fused at the X2 position would be unfavorable for
enhancing the potency; inversely, a lipophilic fragment fixed around the X2 position would
benefit the potency. This implies a positive role for the 4-methyl groups in both imidazoles9
and febuxostat for XO inhibition.
8

To rationalize the observed SARs, docking simulations of 1s in the XO binding pocket
were performed. The crystal structure of the bovine milk XO/Y-700 complex (PDB code
1VDV) was used as the protein template.23 A molecular modeling study was undertaken
with Autodock 4.27 An 80 × 80 × 80 Å grid box with a grid spacing of 0.375 Å was generated
to define the binding pocket. The Lamarckian genetic algorithm was used as the search
parameters. The 1s carboxyl group was calculated in its dissociated form. The docking model
(Fig. 4) showed that the 1s scaffold overlapped with the original ligand very closely. A set of
similar binding features were observed, including the carboxylate group interacting with
Arg880 and Thr1010, the five-member ring sandwiched between Phe914 and Phe10097, 23
and the phenyl moiety cyano group accepting a hydrogen bond from the Asn768 amino group.
Moreover, we found that the meta-methoxybenzoxy tail was surrounded by several
hydrophobic amino acid residues, including Leu648, Phe649, Val1011 and Phe1013, at the
entrance to the active site channel. This strong hydrophobic interaction may help anchor 1s in
the XO active site tightly. However, the desired interaction between N-3 and the
molybdenum-pterin was not observed; in contrast, the polar N-3 atom, which was located
near the center of the Phe914 and Phe1009 sandwich structure, may not be accommodated as
well as the corresponding carbon atoms in either febuxostat or Y-700.7, 23 This suggests that
the polar N-3 atom would not enhance the inhibitory potency of the compound. These
interactions may provide a reasonable explanation for the gain or loss of the potency at the
molecular level.
9

Fig. 4. Docking pose of compound 1s (cyan) within the protein binding pocket and overlaid
with the reference ligand Y-700 (pink).
In summary, a series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s)
was designed and synthesized as XO inhibitors. Among them, 1s was the most promising
compound, with IC50 value of 0.21 µM and was 36-fold more potent than allopurinol, but
13-fold less potent than Y-700. The Lineweaver-Burk plot revealed that compound 1s acts as
a mixed-type XO inhibitor. The SAR analysis demonstrated that a polar atom fused at the X2
position would be unfavorable for potency and that a more lipophilic ether tail (e.g.,
meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency of these
1,2,3-triazoles. Molecular modeling rationalized the SARs observed in this study. The further
detailed investigation on compound 1s is under progress.
Acknowledgments
This work was supported by the Chinese National Science Foundation (Grant Nos.
81274182 and 81573687) and the project of the Liaoning distinguished professor.
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