A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.02.011

Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase. Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase. Structure-activity relationship studies indicated that 5-(p- toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities.

Full text of DOI:10.1016/j.bmcl.2013.02.011

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2022–2026
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A new series of N2-substituted-5-(p-toluenesulfonylamino)phthali-
mide analogues as a-glucosidase inhibitors
Xiaoli Bian a, Qian Wang b, Changhu Ke a, Guilan Zhao a, Yiping Li a,
⇑
a College of Pharmacy, Xi’an Jiaotong University, No. 76 Yanta West Road, Shaanxi Province, Xi’an 710061, People’s Republic of China
b Department of Pharmacy, College of Life Science & Engineering, Shaanxi University of Science & Technology, Xi’an 710021, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Several members of a new family of non-sugar-type
sulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and
their activities were investigated. The newly synthesized compounds displayed different inhibition
a-glycosidase inhibitors, bearing a 5-(p-toluene-
Received 29 December 2012
Revised 25 January 2013
Accepted 1 February 2013
Available online 13 February 2013
profile towards yeast
strong inhibitory activities against yeast
logs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal
maltase and lactase and nearly all compounds showed no inhibition against rat intestinal -amylase.
Structure–activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is
a favorable scaffold to exert the -glucosidase inhibitory activity and substituents at the N2 position have
considerable influence on the efficacy of the inhibition activities.
a
-glycosidase and rat intestinal
a-glycosidase. Almost all the compounds had
a
-glycosidase. Regarding rat intestinal
a
-glycosidase, only ana-
Keywords:
a
5-(p-Toluenesulfonylamino)phthalimide
a-Glucosidase inhibitors
a
Postprandial hyperglycemia
Diabetes
Ó 2013 Elsevier Ltd. All rights reserved.
Diabetes mellitus type 2 (T2DM), comprising 90% of all cases of
diabetes mellitus is increasing dramatically and affecting about 5%
of the world population. The burden of diabetes is driven by vascu-
lar complications such as cardiovascular disease, stroke, nephrop-
athy, retinopathy, renal failure, and amputations of the
extremities. With the admission of the fact that ‘diabetes is a car-
diovascular disease’ (CVD), rise in CVD is being cautioned due to
the worldwide increase in the prevalence of diabetes.1,2 It is now
generally accepted that these cardiovascular complications are re-
lated to prevailing hyperglycemia, particularly postprandial hyper-
glycemia (PPHG). Multiple works have convincingly demonstrated
that blood glucose variability is more deleterious than chronic sus-
tained hyperglycemia as a key player in contributing to diabetic
micro- and macro-vascular complications.3–5 In recent years,
importance of PPHG has been recognized as an important cardio-
vascular risk factor. A growing body of evidence suggests that there
is a strong association between PPHG and cardiovascular risk and
other diabetic complications. PPHG is also identified as one of
the earliest detectable abnormalities expressed in diabetes, better
predictor of progression of diabetes and has been implicated in
inducing oxidative stress that is recognized as a major pathophys-
iological link between CVD and diabetes.6–8
down of digestion and absorption of dietary starches either by
means of dietary manipulation with low glycemic-index food or
by inhibition of starch digesting enzyme a-glucosidase present at
the intestinal brush borders, have shown promise in reducing
PPHGE, hyperinsulinemia, burden of oxidative stress, and CVD.9–
11
a-Glucosidase inhibitors (AGIs) delay carbohydrate digestion
and prolong overall carbohydrate digestion time, causing a reduc-
tion in the rate of glucose absorption and consequently blunting
the postprandial plasma glucose rise.12,13
Several AGIs, including acarbose, voglibose, and miglitol, are
clinically used in the effective treatment of type 2 diabetes melli-
tus. AGIs appear better therapeutic in controlling PPHGE in Asian
people presumably because of their specific food habits. Only a
few AGIs are available commercially and they are all sugar deriva-
tives and require tedious multi-steps during preparation. Gastroin-
testinal side-effects, such as flatulence and diarrhea, are also
problems for
a-glucosidase inhibitors. Intense efforts have been
directed towards the development of effective non-saccharide
AGIs.14–19 For instance, Kavitha et al. explored the binding mode
of interaction of several sugar/non-sugar AGIs at the active site of
a-glucosidase and developed a pharmacophore model which
would represent the critical features responsible for
a-glucosidase
Therefore, agents that hold capacity of slowing down postpran-
dial hyperglycemic excursion (PPHGE) and resultant oxidative
stress may become therapeutics of colossal importance. Food
starches contribute to major postprandial blood glucose. Slowing
inhibitory activity, as illustrated in Figure 1a.15
These results encouraged us to explore a series of 5-(p-toluene-
sulfonylamino)phthalimide derivatives as a novel class of non-
sugar-type AGIs based on the pharmacophore model. In this series,
5-(p-toluenesulfonylamino)phthalimide moiety was designed as a
new scaffold possessing the similar structural characters as AGIs
pharmacophore model described, and a variety of alkyl or aromatic
⇑
Corresponding author. Tel./fax: +86 29 82657833.
E-mail address: yipingli@mail.xjtu.edu.cn (Y. Li).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.011

X. Bian et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2022–2026
2023
HBA3
HBD
HBA1
HBA2
O
H
N
O
O
S
alkyl
5
2
N
or aryl
1
O
HBA3
(a)
(b)
Figure 1. (a) Mapping of pharmacophore model for a
-glucosidase inhibitory compounds.15 (b) The general structure of target compounds.
moieties were connected to N2 position of phthalimide, as
illustrated in Figure 1b. In the present study, a series of N2-
Compounds 17–18 were prepared via the synthetic route
shown in Scheme 2. 5-Nitro-phthalimide 2 was reacted with form-
aldehyde to form N-hydroxymethyl-5-nitro-phthalimide 16, fol-
lowed by coupling with the corresponding phenol compound to
provide N-substituted-5-nitro-phthalimide intermediates 17a–
18a, respectively. The intermediates 17a–18a were submitted to
the reduction and sulfonylation procedures after the phenolic hy-
droxy group was protected by acetyl to give 17c–18c. Then the
intermediates 17c–18c underwent deprotection in presence of
chlorhydric acid to obtain the target compounds 17–18.
The intermediate 16was treated with hydrochloric acidto gaveN-
chloromethyl-5-nitro-phthalimide 19 (Scheme 3), which underwent
amination with morpholine or piperazine to obtain the
N-substituted-5-nitro-phthalimide intermediates 20a–21a, respec-
tively. The intermediates 20a–21a were submitted to reduction and
sulfonylation procedures gave the target compounds 20–21.
The following strategy was adopted to prepare final compounds
22–25 (Scheme 4). The intermediate 22a was obtained by reaction
of N-(2-bromoethyl)-5-nitro-phthalimide 5a with 4-amino-ben-
zene-1,2-di-ol diacetate and the intermediates 23a–25a were pre-
pared by reaction of 5-nitro-phthalimide potassium salt 3 with
appropriate 2-bromoethyl phenyl ether. All the intermediates
substituted-5-(p-toluenesulfonylamino)phthalimide
(Table 1) was synthesized and their -glucosidase inhibitory activ-
ities were evaluated against yeast -glucosidase and rat intestinal
-glucosidase (maltase, lactase and amylase) and their structure–
activity relationships were discussed.
analogues
a
a
a
A generalised synthetic approach for the proposed compounds
was shown in Schemes 1–4. Synthesis of the title compounds
4–15 was completed as depicted in Scheme 1. 5-Nitro-phthalimide
potassium salt 3, which was conveniently prepared according to
the procedures described in literature,20 was reacted with corre-
sponding halogenated hydrocarbon to obtain the N-substituted-
5-nitro-phthalimide intermediates 4a–14a, respectively. These
intermediates 4a–14a were reduced with formamide and Pd/C to
obtain N2-substituted-5-amino-phthalimide intermediates 4b–
14b, respectively, which underwent sulfonylation upon treatment
with para-toluenesulfonic chloride in the presence of triethyl-
amine gave the target compounds 4–14. The intermediate 14a
was hydrolyzed to give intermediate 15a, which carried the reduc-
tion and sulfonylation procedure under the same condition as de-
scribed above to obtain compound 15.
Table 1
IC50 values (
l
M) for the inhibition of
a
-glucosidase by the synthesized compoundsa
O
H
N
O
S
O
R
N
O
CH3
Compd
R
Yeast
>200
a
-glucosidase
Rat intestinal a-glucosidase
Maltase
Lactase
a-Amylase
4
5
6
7
8
9
CH3–
Br-CH2-CH2–
Br-CH2-CH2-CH2–
Br-CH2-(CH2)2-CH2–
C6H5-CH2–
4-F-C6H4-CH2–
2-F-C6H4-CH2–
4-Cl-C6H4-CH2–
3,4-Cl2-C6H4-CH2–
C6H5-NH-CH2CH2–
4-NC-C6H4-CH2–
4-H2NCO-C6H4-CH2–
3,4-(OH)2-C6H3-CH2–
3-HOOC-4-OH-C6H3-CH2–
4-Morpholinyl
>200
>200
>200
>200
>200
>200
>200
>200
>200
172.13 10.39
180.47 8.06
155.32 9.699
100.94 4.98
176.53 6.81
199.02 10.33
84.15 3.25
164.44 5.78
44.73 1.38
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
188.01 8.69
>200
>200
>200
94.22 4.36
88.43 2.87
69.71 3.65
54.16 2.91
42.70 0.86
40.77 1.32
32.63 0.67
28.74 0.45
58.45 1.52
66.50 2.48
60.32 2.38
72.62 2.21
79.46 2.09
52.13 1.52
46.57 1.35
44.48 0.75
28.72 0.71
25.53 0.39
47.26 1.08
235 3.89
>200
194.02 13.62
194.61 10.76
188.2 9.65
122.2 4.98
99.56 4.02
>200
61.37 1.88
154.40 6.12
101.15 3.69
>200
10
11
12
13
14
15
17
18
20
21
22
23
24
25
Acar
Piperazin-1-yl
>200
>200
3,4-(OH)2C6H3-NH-CH2CH2–
3-OH-C6H4-O-CH2CH2–
4-OH-C6H4-O-CH2CH2–
C6H5-O-CH2CH2–
28.82 1.02
55.60 1.51
47.70 1.85
51.13 1.52
25.52 0.78
66.64 2.08
110.53 4.21
100.46 2.42
170.20 3.62
166.85 6.65
>200
>200
>200
8.65 0.98
a
The results summarized are the mean values of n = 3 for IC50 values.

2024
X. Bian et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2022–2026
O
O
O
O
a
b
c
RX
N
R
NH
NH
NK
O2N
O2N
O2N
O
O
O
O
4a-14a
3
2
1
d
O
O
e
N
R
N
R
H2N
p Ts
N
H
O
O
4-14
4b-14b
CONH2
CN
CONH2
O
O
O
d, e
f
N
N
N
O2N
O2N
p Ts
N
H
O
O
O
15a
14a
15
Scheme 1. Synthetic pathway to compounds 4–15. Reagents and conditions: (a) HNO3, H2SO4, 5 °C to rt, 16 h, 75%; (b) KOH–MeOH, C2H5OH, rt, 3 h, 98%; (c) RX, K2CO3, DMF,
reflux 1 h, overnight, 80–88%; (d) Pd/C, ammonium formate, THF, rt, 12 h, 80–95%; (e) p-TsCl, Et3N, DMF, rt, 3 h, 62–75%; (f) Na2CO3, H2O–MeOH–H2O2, Na2MoO4, rt, 4 h, 78%.
R
O
O
O
R
a
OH
N
NH
N
b
OH
d, e
O2N
O2N
O2N
OH
O
O
O
2
16
17a: R=OH
18a: R=COOH
c
O
O
R
R
N
N
O
p
Ts
N
H
O2N
OAc
OAc
O
17c: R=OAc
17b: R=OAc
18c: R=COOH
18b: R=COOH
f
O
R
N
O
Ts
N
H
p
OH
17: R=OH
18: R=COOH
Scheme 2. Synthetic pathway to compounds 17–18. Reagents and conditions: (a) 38% formaldehyde–H2O, reflux 3 h, 77%; (b) HNO3/H2SO4 = 5:1, rt, 7 h, 70–76%; (c) Ac2O,
reflux 3 h, 88%; (d) Pd/C, ammonium formate, THF, rt, 12 h, 93–95%; (e) p-TsCl, Et3N, DMF, rt, 6 h, 65–69%; (f) 10% HCl, acetone, rt, 1 h, 85%.
22a–25a underwent the similar procedure of reduction, sulfonyla-
tion and deprotection to give the target compounds 22–25.
The structures of the target compounds were verified by 1H
NMR and mass spectrometry, while their purities were estimated
by HPLC analysis.
against yeast a-glucosidase with IC50 values <100 lM, except the
compound 4. The efficacy of the inhibition activity was influenced
by the variation of N2-substituents. Regarding structures of
N2-substituents, the target compounds include three series.
r
N2-Alkyl analogues, the compounds 4–7, having small alkyl or
s
a
-Glucosidase of divers source has been used for screening and
evaluation of -glucosidase inhibitors. Yeast -glucosidase has
been mostly used because of its simple and convenient method.21
In the present study, the -glucosidase inhibitory activity of the
newly synthesized compounds (Table 1) was firstly evaluated with
yeast -glucosidase. The inhibitory activity was determined as de-
scribed in the literature,19,22 and was expressed as the inhibitor
concentration required for 50% inhibition of the -glucosidase
bromoalkyl at the N2 position.
N2-saturated heterocycles deriv-
a
a
atives, the compounds 20 and 21, having morpholine or piperazine
t
ring in N2-substituent moiety.
N2-aromatic substituted ana-
a
logues, including N2-benzyl analogues 8–12, 14, 15, 17, 18 and
compounds 13, 22–25 having an aryl moiety connected to N2
through a chain of three atoms. The IC50 values in Table 1 indicate
that most of the N2-aromatic substituted analogues were more po-
tent than N2-alkyl derivatives. Among N2-alkyl derivatives 4–7,
compound 4 had no activity while the inhibition potency of the
other compounds increased with the length of the alkyl chain.
Concerning the N2-aromatic substituted compounds, their
a
a
activity (IC50) which is reported in Table 1. The results document
that the synthesized N2-substituted-5-(p-toluene sulfonylami-
no)phthalimide derivatives exhibited obvious inhibitory activity

X. Bian et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2022–2026
2025
O
O
O
OH
Cl
R
b
a
N
N
N
O2N
O2N
O2N
O
O
O
16
20a: R= 4- morpholinyl
19
21a: R= 4-benzyl-piperazin-1-yl
c, d
O
R
N
p
Ts
N
H
O
20: R= 4- morpholiny
21b: R= 4-benzyl-piperazin-1-yl
21: R= piperazin-1-yl
e
Scheme 3. Synthetic pathway to compounds 20–21. Reagents and conditions: (a) concd hydrochloric acid, toluene, 65 °C, 48 h, 71%; (b) morpholine or 1-benzylpiperazine,
K2CO3, acetone, 40 °C, 4.5 h, 91% and 89%; (c) Pd/C, ammonium formate, THF, rt, 2 h, 94–95%; (d) p-TsCl, Et3N, DMF, rt, 3 h, 55–60%; (e) Pd/C, HCOOH, THF, rt, 8 h, 81%.
R
R
O
O
X
X
c, d
N
N
p
Ts
N
H
O2N
O
O
a
22b: X=N, 3,4-di-OAc
23b: X=O, 3-OAc
24b: X=O, 4-OAc
25: X=O, H
5a
22a: X=N, 3,4-di-OAc
e
22: X=N, 3,4-di-OH
23: X=O, 3-OH
23a: X=O, 3-OAc
24a: X=O, 4-OAc
25a: X=O, H
b
24: X=O, 4-OH
3
Scheme 4. Synthetic pathway to compounds 22–25. Reagents and conditions: (a) 4-amino-benzene-1,2-di-ol diacetate, K2CO3, acetone, rt, 24 h; (b) corresponding 2-Br-
ethyl-phenolic ether, DMF, 60 °C, 3 h, 55%; (c) Pd/C, H2, 40 °C, 4 h, 98%; (d) p-TsCl, Et3N, DMF, rt, 4 h, 65%; (d)10% HCl, acetone, rt, 1 h, 88%.
inhibitory potential changed with substituents on phenyl of N2
moieties. Among the N2-benzyl analogues, inhibitory effect in-
creased with introduction of halogen atom at the benzyl moiety
as compare with 8 and the strongest inhibition was found for com-
that aromatic structure may be favorable for rat intestinal
-glucosidase inhibitory activity. This observation is in agreement
with the pharmacophore model described in Figure 1. Among the
a
active compounds, 22 emerged as the strongest rat intestinal
pound 12 which bearing
a
3,4-dichloro benzyl with an
a-glucosidase inhibitor with IC50 values 28.82 and 66.64 lM for
IC50 = 28.74 M. In contrast with the expectation, introduction of
l
maltase and lactase, respectively. Other analogues 23–25 also
hydroxy or other polar group to benzyl (14–15, 17–18) decreased
the activity. These may indicate that the hydrophobic group in this
region may be favorable for the binding interaction. As the connec-
tion chain between N2-aryl and phthalimide scaffold increased to
three atoms (13, 22–25), introduction of a hydroxy group intends
to increase the inhibitory potencies. Compound 24 displayed the
strongest inhibition in all of the synthesized compounds with an
showed obvious inhibitory activity against rat intestinal maltase
with IC50 values within 47.70–51.13
against rat intestinal lactase with IC50 values within 100.46–
170.20 M. Only one of the nine N2-benzyl analogues, compound
15, displayed strong activity against rat intestinal maltase and lac-
tase (IC50 = 61.37 and 84.15 M, respectively) and other analogues
behaved as moderate inhibitors against rat intestinal maltase and
lactase with the IC50 values more than 100 M. It appears therefore
that 3-atom connection chain between N2-aryl and phthalimide
scaffold has added advantage in improving rat intestinal -glucosi-
lM and moderate activity
l
l
IC50 = 25.53
l
M. In N2-saturated heterocycles series, compounds
l
20, 21 resemble aromatic substituted compounds in inhibitory po-
tential. These results may suggest that 5-(p-toluenesulfonylami-
no)phthalimide is a favorable scaffold and the substitutes at the
a
dase inhibitory activity than N2-benzyl analogues. Introduction of
hydroxy groups to N2-aryl of compound 13 yielding compound 22
significantly enhanced inhibitory potency. Introduction of one
hydroxy substitution on N2-aryl, as in compound 23 and 24,
displayed no advantage when compared to compound 25. These
reflect that catechol structure of N2-aryl moiety may be important
for improving the inhibitory potency.
N2 position may be various structures to exert yeast
inhibitory activity.
a-glucosidase
The inhibition potencies and selectivity of the target com-
pounds for several selected sugar hydrolases (maltase, lactase
and a-amylase) were further evaluated with rat intestinal a-gluco-
sidase.23–26 Results are summarized in Table 1. The IC50 values data
indicates that the inhibition profile of the target compounds to-
The IC50 data (Table 1) also demonstrates that the target com-
wards rat intestinal
yeast -glucosidase. No compound of the N2-alkyl derivatives and
N2-saturated heterocycles derivatives had activity against rat
intestinal -glucosidase. No compounds displayed activity towards
rat intestinal -amylase except compounds 18 which showed only
weaker inhibition (IC50 = 188.01 M). Compounds having activities
on rat intestinal -glucosidase (maltase and/or lactase) generally
have aromatic moieties in the N2-substituent regions, suggesting
a
-glucosidase are different from that towards
pounds behaved more selective inhibition of yeast
since the IC50 values against yeast -glucosidase are generally
lower than the corresponding IC50 values against rat intestinal
a-glucosidase,
a
a
a
a-glucosidas.
a
In order to clarify the important role of p-toluenesulfonylamino
l
group at the C5 position of phthalimide scaffold, several intermedi-
ates of compound 13 were tested and evaluated likewise. These
intermediates, compounds 13a, 13b and 26, have the same
a

2026
X. Bian et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2022–2026
Table 2
IC50 values (
26a
evidences in support of the rational design of the target com-
pounds based on the pharmacophore model.15 Although it seems
that the present series derivatives being more selective for yeast
l
M) for the inhibition of
a-glucosidase by compounds 13, 13a, 13b and
a-glucosidase over rat intestinal a-glucosidase, compound 22–25
proved to be promising inhibitors for rat intestinal maltase and
lactase. Molecular recognition in the target binding site in yeast
O
NH
N
a-glucosidase and rat intestinal a-glucosidase may be the reason
R
for different inhibition profile of these compounds.
O
Acknowledgment
Compd
R
Yeast
Rat intestinal
Maltase Lactase
184.14 7.16 >200
a-glucosidase
a
-glucosidase
a-Amylase
This work was supported by the National Natural Science Foun-
dation of China (Grant Nos. 21172177 and 81272448).
26
–H
–NO2
–NH2
>200
>200
>200
>200
13a
13b
13
68.91 1.29 111.44 5.81 >200
137.93 3.68 144.27 8.72 >200
References and notes
p-Ts-NH2– 58.45 1.52 99.56 4.22 176.53 11.34 >200
a
The results summarized are the mean values of n = 3 for IC50 values.
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intestinal and yeast a-glucosidase, as evidenced by the IC50 values
of 13a and 13b. Absence of substition at the C5 position, compound
26, lead to nearly disappearance of activity. This may be due to
favourable interactions of the p-toluenesulfonylamino group
which could interact with the binding subsite through H-bonds
by providing H-bond donors and H-bond receptors. But –NO2
group could only provide H-bond receptors and –NH2 group could
mainly provide H-bond donors. From these results, it is fair to con-
clude that both of H-bond donors and H-bond receptors are essen-
tial structural features for the inhibitory activity. In our research,
we also found that replacement of the tolylene of p-toluenesulfo-
nylamino moiety to methyl also decreases the inhibition strength
(data is not given here). This indicates the useful role of the aro-
matic ring of p-toluenesulfonylamin moiety which may interact
with the binding subsite through hydrophobic interaction or
22. Sahu, S. K.; Azam, M.; Afzal, B. M. J. Indian Chem. Soc. 2007, 84, 1011.
23. Zhiyun, D.; Rongrong, L.; Weiyan, S. Eur. J. Med. Chem. 2006, 41, 213.
24. Inhibitory activities assay with yeast
a
-glucosidase (Canada Bio Basic Inc.) was
-glucopyranoside as substrate
performed at 37 °C by using 4-nitro-phenyl-
a-D
in pH 7.28 buffer containing 10 mM sodium phsophate. Eight inhibitor
concentrations around the IC50 values, approximately estimated in previous
experiments, were employed. In each set of experiments the assay was
performed in triplicate and acarbose (acar) was used as reference drug. The
increased absorbance at 400 nm was compared with that of the control
containing DMSO in the place of the test solution. IC50 values were measured
graphically by a plot of percent activity versus log of the test compound
concentration.
p–p/p-cation interaction. These results verify the decisive role of
p-toluenesulfonylamino group for the inhibitory activity that
attributes to both sulfonylamino and aromatic moieties.
In conclusion, we have described the synthesis and evaluation
of a series of N2-substituted-5-p-toluenesulfonylamino phthali-
mide derivatives as novel
compounds appeared to be strong inhibitors towards yeast
-glucosidase but only analogues with N2-aromatic substituents
a-glucosidase inhibitors. Almost all
25. Kessler, M.; Acuto, O.; Strelli, C.; Murer, H.; Semenza, G. A. Biochem. Biophys.
Acta 1978, 6, 136.
26. Brush border membranes prepared from rat small intestine according to the
a
method of Kessler et al.23 were used as the enzyme source of rat intestinal
displayed varying degrees of inhibitory effects against rat intestinal
maltase, lactase and
a-amylase. Inhibitory activities of testes compounds
maltase and/or lactase and nearly no compounds showed inhibi-
against rat intestinal glucosidases were determined using an appropriate
disaccharide as substrate and acarbose was used as reference drug. The
tory activity against rat intestinal
a-amylase. The toluenesulfo-
released
D-glucose was determined colorimetrically using Glucose-B Test Kit
nylamino group was demonstrated to be an essential structural
moiety for this series and substituents at the N2 position had sig-
nificant influence on inhibitory potencies. These results produce
(Wako Pure Chem. Co., Osaka, Japan).