Bioorganic & Medicinal Chemistry Letters
Discovery and biological evaluation of some (1H-1,2,3-triazol-4-yl)
methoxybenzaldehyde derivatives containing an anthraquinone moiety
as potent xanthine oxidase inhibitors
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Ting-jian Zhang, Song-ye Li , Wei-yan Yuan , Qing-xia Wu, Lin Wang, Su Yang, Qi Sun, Fan-hao Meng
School of Pharmacy, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety
Received 14 September 2016
Revised 28 December 2016
Accepted 14 January 2017
Available online 16 January 2017
were synthesized and identified as novel xanthine oxidase inhibitors. Among them, the most promising
compounds 1h and 1k were obtained with IC50 values of 0.6 lM and 0.8 lM, respectively, which were
more than 10-fold potent compared with allopurinol. The Lineweaver-Burk plot revealed that compound
1h acted as a mixed-type xanthine oxidase inhibitor. SAR analysis showed that the benzaldehyde moiety
played a more important role than the anthraquinone moiety for inhibition potency. The basis of signif-
icant inhibition of xanthine oxidase by 1h was rationalized by molecular modeling studies.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Anthraquinone
Xanthine oxidase
Hyperuricemia
Xanthine oxidase (XO) is a well-known target for the treatment
of hyperuricemia and gout. Inhibition of XO could block the
hydroxylation of both hypoxanthine and xanthine in the last two
steps of uric acid biosynthesis in humans.1 Indeed, the over-
production of uric acid is the key cause of hyperuricemia and gout.2
Therefore, inhibitors of XO could decrease the generation of uric
acid and benefit these pathological conditions.3 Reactive oxygen
species (ROS) are generated in concert with the oxidation process.
An excess of ROS could induce various pathological states such as
inflammation, metabolic disorders, atherosclerosis, cancer and
chronic obstructive pulmonary disease.4 Thus, inhibition of XO is
a potential treatment of diseases caused by the XO-derived ROS
as well.5
Reported XO inhibitors can be simply divided into two cate-
gories: purine analogs and non-purine XO inhibitors. Allopurinol
(Fig. 1), a prototypical inhibitor of XO with a recognizable purine
backbone, has been widely prescribed in the treatment of hyper-
uricemia and gout for several decades. However, in some cases,
severe life-threatening side effects of allopurinol have been
reported due to the purine backbone, such as fulminant hepatitis,
renal failure, and Stevens–Johnson syndrome.6 Given these limita-
tions, research has focused on the development of novel non-pur-
ine XO inhibitors with potent XO inhibitory potency, but with
fewer side effects. In recent decades, a great amount of non-purine
XO inhibitors of various chemotypes have been reported, such as
Febuxostat (approved in USA, 2009),7 Y-700,8 Topiroxostat
(approved in Japan, 2013),9 isoxazoles,10 schiff bases of benzalde-
hydes,11 N-(1,3-diaryl-3-oxo-propyl)amides,12 N-acetyl pyrazoli-
nes,13 isocytosines,14 selenazoles,15 imidazoles,16 2-(indol-5-yl)
thiazoles,17 chalcones,18 and 9-deazaguanines.19
In our previous studies on anthraquinone compounds as anti-
tumor agents, we unexpectedly found a compound (1a), which
contained a benzaldehyde moiety and an anthraquinone moiety
linked by a 1,2,3-triazole (Fig. 1), presented poor anti-tumor activ-
ity, but remarkable inhibitory potency in vitro against XO. Since
both benzaldehyde and anthraquinone have appeared as scaffolds
of XO inhibitors in recent studies,20 we investigated the activities
and the structure–activity relationship (SAR) around 1a.
The synthesis of compounds 1a-q is shown in the Scheme 1.
Commercially available phthalic anhydride reacted with toluene
via a Friedel-Craft reaction to provide 2-(4-methylbenzoyl)benzoic
acid 2, which underwent a intramolecular cyclization in acid-cat-
alyzed conditions, leading to 2-methylanthracene-9,10-dione 3.
The bromination of 3 with NBS obtained 2-(bromomethyl)an-
thracene-9,10-dione 4, which was then treated with sodium azide
to yield 2-(azidomethyl)anthracene-9,10-dione 5. The cyclization
of 5 with various alkyne analogs in the presence of copper sulfate
and vitamin C in a microwave condition resulted in compounds 1a-
o with good yields. Hydrolysis of compound 1o with sodium
hydroxide resulted in 1p, which was acetylated to yield 1q. The
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Corresponding author.
These authors contributed equally.
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0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.