Sulfonamide chalcone as a new class of α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.08.087

Chalcones 1-20, a new class of glycosidase inhibitors, were synthesized, and their glycosidase inhibitory activities were investigated. Non-aminochalcones 1-12 had no inhibitory activity, however, aminochalcones 13-20 had strong glycosidase (α-glucosidase, α-amylase, and β-amylase) inhibitory activities. In particular, sulfonamide chalcones 17-20 had more potent α-glucosidase inhibitory activity than aminated chalcone 13-16. 4′-(p-Toluenesulfonamide)-3,4-dihydroxy chalcone 20 (IC₅₀ = 0.4 μM) was the best inhibitor against α-glucosidase, and these sulfonamide chalcones showed non-competitive inhibition.

Full text of DOI:10.1016/j.bmcl.2005.08.087

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5514–5516
Sulfonamide chalcone as a new class of a-glucosidase inhibitors
Woo Duck Seo,a Jin Hyo Kim,a Jae Eun Kang,a Hyung Won Ryu,a
Marcus J. Curtis-Long,b Hyun Sun Lee,c Min Suk Yanga and Ki Hun Parka,*
aDivision of Applied Life Science (BK21 Program), Department of Agricultural Chemistry, Institute of Agriculture & Life Sciences,
Gyeongsang National University, Jinju 660-701, Republic of Korea
bTrout Beck, Wansford, Driffield, East Yorkshire YO25 8NX, UK
cLaboratory of Lipid Metabolism, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-333, Republic of Korea
Received 18 July 2005; revised 25 August 2005; accepted 26 August 2005
Available online 3 October 2005
Abstract—Chalcones 1–20, a new class of glycosidase inhibitors, were synthesized, and their glycosidase inhibitory activities were
investigated. Non-aminochalcones 1–12 had no inhibitory activity, however, aminochalcones 13–20 had strong glycosidase (a-glu-
cosidase, a-amylase, and b-amylase) inhibitory activities. In particular, sulfonamide chalcones 17–20 had more potent a-glucosidase
inhibitory activity than aminated chalcone 13–16. 40-(p-Toluenesulfonamide)-3,4-dihydroxy chalcone 20 (IC50 = 0.4 lM) was the
best inhibitor against a-glucosidase, and these sulfonamide chalcones showed non-competitive inhibition.
Ó 2005 Elsevier Ltd. All rights reserved.
Screening of glycosidase inhibitors is becoming increas-
ingly prevalent because glycosidases are responsible for
the processing and synthesis of complex carbohydrates,
which are essential in numerous biological recognition
processes.1 Inhibitors of these enzymes are important
molecular tools for glycobiology and can be used to
modulate cellular functions.2 Furthermore, in cases
where the control of oligosaccharide metabolism can
be linked to cellular dysfunction, they are potential
drugs.3 a-Glucosidases (EC 3.2.1.20) are exo-acting car-
bohydrases, catalyzing the release of a-D-glucopyranose
from the non-reducing ends of various substrates,4 and
also these enzymes are key enzymes in the processing
of glycoproteins and glycolipids.1 Inhibitors can retard
the uptake of dietary carbohydrates and suppress post-
prandial hyperglycemia, and may be useful to treat dia-
betic or obese patients.5 This enzyme is a target for
inhibition by antiviral agents that interfere with the for-
mation of essential glycoproteins required in viral
assembly, secretion, and infectivity.6 Consequently,
many efforts have been made to develop a-glucosidase
inhibitors for the treatment of diseases such as diabetes,5
viral diseases,6 and cancer.7 However, most of developed
glycosidase inhibitors are sugar mimics (aza sugars,8
isoxazoles,9 and aminosugars10) which require tedious
multi-steps from carbohydrate and non-carbohydrate
(Fig. 1).
Recently, we have found that aminated chalcones have
the potential to act as a new class of highly specific a-
glucosidase inhibitors, which can be obtained with the
simple steps economically.
Chalcones, considered as the precursor of flavonoids
and isoflavonoids, are abundant in edible plants,11 and
have also been shown to display a diverse array of phar-
macological activities, among which anti-protozoal,12
anti-inflammatory,13 immuno-modulatory,14 nitric
oxide inhibitory,15 anticancer,16 and anti-HIV activi-
ties,17 have been cited in the literature. But, to the best
of our knowledge there is, to date, no report that chal-
cone derivatives have any inhibitory activity against gly-
cosidase. Chalcone is a biosynthetic product of
shikimate pathway and can be easily obtained through
O
OH
OH
O
Keywords: Chalcone; Sulfonamide chalcone; a-Glucosidase inhibitor;
Amylase.
Me
S N
H
O
*
Corresponding author. Tel.: +82 55 751 5472; fax: +82 55 757
0178; e-mail: khpark@gsnu.ac.kr
Figure 1.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.087

W. D. Seo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5514–5516
5515
the Claisen–Schmidt condensation of hydroxy acetoph-
enone or carboxy acetophenone using either basic18 or
acidic catalysis.19 The chalcone products (1–8) described
were prepared from acetophenone and benzaldehyde
using catalytic amount of H2SO4 in MeOH and some
phenolic compounds (9–12) which were purchased from
Sigma Co. (Fig. 2).
rized in Table 2. The a-glucosidase inhibitory activities
of sulfonamide chalcones 17 (IC50 = 12.4 lM), 18
(IC50 = 15.6 lM), 19 (IC50 = 1.0 lM), and 20
(IC50 = 0.4 lM) have improved progressively compared
with aminated chalcones 15 (IC50 = 41.0 lM), 16
(IC50 = 62.1 lM), 13 (IC50 = >200 lM), and 14
(IC50 = >200 lM). Especially, sulfonamide chalcone 20
showed 150-fold stronger inhibitory activity than acar-
bose (IC50 = 60.8 lM) as well-known a-glucosidase
inhibitor.
The synthesized and purchased chalcones were tested for
their enzymatic inhibitory activities against three glyco-
sidases (a-glucosidase from bakerÕs yeast, a-amylase
from Bacillus licheniformis, and b-amylase from barley).
The glycosidases were assayed according to standard
procedures by following the hydrolysis of nitrophenyl
glycosides spectrophotometrically or by evaluating the
reducing sugar formed in amylase assays.8
The type of inhibition was analyzed by Lineweaver–
Burk plots (Fig. 3), which showed that compound 20
behaves as a non-competitive inhibitor because Vmax
Table 2. Inhibitory activities of chalcones
Chalcone derivatives 1–12 had no inhibitory activities at
200 lM concentration, but aminated chalcones 15 and
16 had strong inhibitory activities at 200 lM concentra-
tion for three glycosidases. Anti-diabetic sulfonylureas20
have encouraged us to design and synthesize sulfon-
amide chalcones to develop a more potent new class of
glycosidase inhibitors. All sulfonamide chalcone prod-
ucts 17–20 were obtained through sulfonylation of
aminoacetophenone with p-toluenesulfonylchloride and
the condensation of sulfonylated acetophenone and
benzaldehyde using a catalytic amount of H2SO4 in
MeOH (Table 1).21 The synthetic sulfonamide chalcones
17–20 were tested for a-glucosidase inhibitory activities,
and the results of their inhibitory activities are summa-
Compound
IC50 (lM)
a-Amylase
NIa
NI
b-Amylase
13
14
15
16
17
18
19
20
206.5
NI
NI
268.9
NI
126.8
201.4
24.8
247.3
65.0
37.3
16.8
87.8
193.7
a NI means no inhibition (less than 20% inhibition at 200 lM).
1.2
0.8
0.4
0
O
R1
O
R5
R6
R2
R3
HO
R4
R5 = OH, R6 = H
R5 = R6 = OH
7
8
R1 = R2 = OH, R3 = R4 = H
R1 = R3 = OH, R2 = R4 = H
R1 = R4 = OH, R2 = R3 = H
R2 = R3 = OH, R1 = R4 = H
R1 = OH, R2 = R3 = R4 = H
R3 = OH, R1 = R2 = R4 = H
1
2
3
4
-1
1
3
5
9
Myricetin
-0.4
10 Quercetin
1/[S, mM]
11 (+)-Catechin
12 (-)-Catechin
5
6
Figure 3. Lineweaver–Burk plot analysis of the inhibition kinetics of
a-glucosidase inhibitory effects by compound 20 [j, 0.5 lM inhibitor;
Ç control].
Figure 2. Target chalcones for glycosidase inhibition.
Table 1. Synthetic eight aminated chalcones
O
H
R1
N
R2
Compound
R1
R2
IC50, (Ki, lM) a-glucosidase
13
14
15
16
17
18
19
20
3-H
3-H
4-Hydroxy
3,4-Dihydroxy
4-Hydroxy
>200
>200
4-H
4-H
41.0
62.1
3,4-Dihydroxy
4-Hydroxy
3-p-Tosyl
3-p-Tosyl
4-p-Tosyl
4-p-Tosyl
12.4 (7.38), non-competitive
15.6 (9.25), non-competitive
0.98 (0.58), non-competitive
0.40 (0.24), non-competitive
3,4-Dihydroxy
4-Hydroxy
3,4-Dihydroxy

5516
W. D. Seo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5514–5516
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Compounds 1–12 did not have inhibitory activity
against a-amylase and b-amylase; however, sulfonamide
chalcones 17–20 were strong inhibitors against a-amy-
lase and b-amylase, and aminated chalcones (13, 16)
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This work was supported by the Korea Science and
Engineering Foundation (KOSEF) through the Region-
al Animal Industry Research Center at Jinju National
University, Jinju, Korea. We thank Brain Korea 21 pro-
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2005.08.087.
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