Reduction in post-prandial hyperglycemic excursion through α-glucosidase inhibition by β-acetamido carbonyl compounds

Article abstract of DOI:10.1016/j.bmcl.2008.05.088

A series of β-acetamido carbonyl compounds (S₁-S₇) were prepared using Dakin-West reaction from different substituted aldehyde and acetophenone in the presence of lanthanum triflate as a solid catalyst. All the compounds were tested for their α-glucosidase inhibitory potential against rat intestinal α-glucosidase. The most potent rat intestinal α-glucosidase inhibitors S₅ and S₇ were tested for their antihyperglycemic activity following carbohydrate tolerance test. Both the compounds displayed antihyperglycemic activity equivalent to the standard drug acarbose.

Full text of DOI:10.1016/j.bmcl.2008.05.088

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4130–4132
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Bioorganic & Medicinal Chemistry Letters
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Reduction in post-prandial hyperglycemic excursion through
a
-glucosidase
inhibition by b-acetamido carbonyl compounds
b
a
a
b
Ashok K. Tiwari a, , Ravindra M. Kumbhare , Sachin B. Agawane , Amtul Z. Ali , K. Vijay Kumar
*
a Pharmacology Division, Taranaka, Indian Institute of Chemical Technology, Hyderabad 500607, India
b Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of b-acetamido carbonyl compounds (S1–S7) were prepared using Dakin-West reaction from dif-
Received 31 March 2008
Revised 22 April 2008
Accepted 22 May 2008
Available online 27 May 2008
ferent substituted aldehyde and acetophenone in the presence of lanthanum triflate as a solid catalyst. All
the compounds were tested for their
dase. The most potent rat intestinal
a
-glucosidase inhibitory potential against rat intestinal
a-glucosi-
a
-glucosidase inhibitors S5 and S7 were tested for their antihypergly-
cemic activity following carbohydrate tolerance test. Both the compounds displayed antihyperglycemic
activity equivalent to the standard drug acarbose.
Keywords:
b-Acetamido carbonyls
Ó 2008 Elsevier Ltd. All rights reserved.
a
-Glucosidase inhibitors
Postprandial hyperglycemia and diabetes
Postprandial hyperglycemia (PPHG) has emerged as a promi-
nent and early defect in type II diabetes.1 Type II diabetes subjects
carry an excess risk for micro- and macrovascular diseases and
possess higher risk for cardiovascular morbidity and mortality.
Over the past two years several studies have identified PPHG as a
better predictor of cardiovascular or even of all cause mortality
as well as, an independent risk factor for atherosclerosis.2 Target-
ing PPHG, therefore, may prove to represent the ’sine qua non’ for
the ’return’ of postprandial glucose values at a ’non-deleterious
threshold’ for early stages of the disease and latter in the progres-
sion of diabetes.2
importance due to environmental and economic considerations.12
Among them, the application of lanthanum trifluoro methane sul-
phonate (lanthanum triflate) as a stable and solid acid catalyst in
organic synthesis has been widely studied.13 This catalyst is impor-
tant from an environmental point of view, because it produces lit-
tle waste, gives excellent activity and selectivity even on an
industrial scale.
As a part of our interest in systematic investigation of chemical
feature of b-acetamido-b-(4- nitrophenyl)-4-nitropropiophenone
(S5) in relation to
a-glucosidase inhibitory activity, we prepared
various derivatives of Dakin-West reaction of acetamido ketones
using Lanthanum triflate as a solid catalyst, from different substi-
tuted aldehyde and acetophenone (Scheme 1),14
Inhibition of a-glucosidase, an enzyme abundant in brush bor-
der of the small intestine, has been found to delay carbohydrate
digestion, absorption, and thereby diminish PPHG level.3–5 It has
also proved to be a promising therapeutics strategy for reducing in-
creased risk for diabetes, hypertension, dyslipidemia, obesity and
cardiovascular diseases in patients with metabolic syndrome.6 In
To find the optimal conditions for synthesis, a mixture of benz-
aldehyde (2 mmol), acetophenone (2 mmol), acetyl chloride
(3 mmol) and acetonitrile (5 ml) was stirred under various reaction
conditions. It was observed that in absence of the catalyst (solid
lanthanum triflate), product b-acetamido ketone was obtained
only with 14% yield after 24 hrs. However, addition of 10 mol %
of catalyst furnished b-acetamido carbonyl compound in excellent
yields. Structures of the resulting Dakin-West reaction derivatives
of acetamido ketone were confirmed by 1H NMR and Mass analy-
sis.15 This report gives a simple and new synthetic methodology
for the one-pot synthesis of b-acetamido ketone by coupling four
components aromatic aldehydes, acetophenones, acetylchloride
and acetonitrile in the presence of lanthanum triflate as a catalyst.
The biological significance of derivatives of b-acetamido car-
bonyl compounds (S1–S7) was established by screening them
the course of our search for potent
a
-glucosidase inhibitors from
various sources,7 we observed potent rat intestinal
a-glucosidase
inhibitory activity in b-acetamido carbonyl compounds. b-acetam-
ido carbonyl compounds have gained considerable attention in or-
ganic synthesis owing to their importance as valuable building
blocks for preparation of 1,3 amino alcohol,8 b-amino acids9 as well
as for synthesis of various antibiotics.10
b-acetamido carbonyl compounds have been synthesized previ-
ously using several catalysts such as Iron (III) chloride, CeCl3Á7H2O,
montmorillonite K-10 clay.11 Recently, solid catalysts have gained
in vitro against rat intestinal
a-glucosidase enzyme using p-nitro-
* Corresponding author. Tel./fax: +91 040 27193753.
E-mail addresses: astiwari@yahoo.com, tiwari@iict.res.in (A.K. Tiwari).
phenyl-a-D
-glucopyranoside as substrate.7 At initial screening
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.088

A. K. Tiwari et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4130–4132
4131
R1
R1
R2
R2
Lanthanum Triflate
+
CHO
+
CH3COCl
H3C
CH3CN, reflux
O
CH3CONH
O
1
2
3
Where,
R1 R2
F
R1 R2
CH3
( C17H15BrFNO2)
S1
Br
:
S5
( C18H18N2O4)
NO2
:
:
( C17 H15 F2NO2)
( C17H16N2O4)
(C12H16FNO3)
S2
S3
S4
:
F
H
F
F
(C17H15N3O6)
NO2 NO2
S6
S7
NO2
:
(C18H18BrNO2)
Br
CH3
:
OH
:
Scheme 1.
concentration (50 lg) from 5 mg/mL DMSO solution, enzyme
100
75
50
25
0
Control
S-5
Acarbose
S-7
inhibitory potential of compounds (in triplicate, means SD) was
observed as follows. S1 (2.7 0.3%); S2 (55.09 13.18%); S3
(72.23 1.52%); S4 (60.11 0.27%); S5 (85.03 7.97%); S6
(52.71 0.00%) and S7 (95.12 0.16%). Compounds displaying
more than 60% enzyme inhibition were further analyzed for
dose-response curve (Fig. 1). In this study, compound S7 emerged
**
as most potent
5.53 followed by S5 (9.07
(72.82 M). In our test system we included standard
inhibitor drug acarbose as reference that displayed IC50 value of
6.38 M.
a
-glucosidase inhibitor with IC50 value of
M), S3 (25.64 M) and S4
-glucosidase
***
lM
l
l
a
*
*
*
*
*
l
*
*
*
*
l
For compounds S5 and S7 displayed enzyme inhibitory potential
close to acarbose, they were selected for in vivo evaluation of their
potential in mitigating postprandial blood glucose rise following
carbohydrate tolerance test in rats.16 Slama et al.17 argued that
postprandial glycemic excursion plays an important role in total
hyperglycemia reflected by an increase in glycated haemoglobin
and advocates delta-postprandial glycemia (the difference be-
tween postprandial and preprandial blood glucose level) as a more
useful tool than conventional examination of absolute postprandial
rise in blood glucose level. Analysis of postprandial delta-glycemia
in our animal experiment (Fig. 2) revealed that compounds S5, S7
and drug acarbose were able to mitigate significantly the rise in
30min
60 min
90 min
120 min
Figure 2. Postprandial delta-glycemia after carbohydrate feeding. Acarbose as well
as test compounds S-5 and S-7 was able to check significantly the rise in plasma
glucose values. ANOVA analysis was used to study the changes produced after
carbohydrate feeding using Bonferroni’s Multiple Comparison test to compare the
differences between the groups. *p < 0.001, **p < 0.05, ***p < 0.01 when compared
with control. Data represents mean SD, N = 6.
100
postprandial glycemic excursion when compared with control,
though compound S7 could not show degree of significance at
30th minute. The antihyperglycemic potential of compounds S5,
S7 and acarbose was not significantly different.
75
It can be envisaged from these results that in acetamido car-
bonyl compounds, the aldehyde ring plays important role in a-glu-
cosidase inhibition and CH3-substitution (S5 and S7) over this ring
imparts better enzyme inhibitory activity than NO2-substitution
(S3 and S6). Furthermore, addition of different functional group
over acetophenone ring may influence activity level of the com-
pound. However, more number of compounds strategically synthe-
sized using this approach is required to better explain the structure
activity relationship.
50
S3
S4
25
S5
Glucosidase inhibitors have proved their usefulness in reducing
postprandial hyperglycemic excursion both in type I and type II dia-
betes and are drugs of choice for first-line treatment.17 Amongst
various types of glucosidase inhibitors, disaccharides, iminosugars,
carbasugars, thiosugars and non-sugar derivatives like polyhydroxy
compounds isolated from plants or microorganisms have provided
significant therapeutic insights.18 Compounds like b-acetamido
S7
0
0
10
20
30
40
50
60
Concentration (ug/mL)
Figure 1. Concentration dependent rat intestinal
of test compounds. Data represents mean SD, N = 3.
a-glucosidase inhibitory activity

4132
A. K. Tiwari et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4130–4132
and 15.62 Hz, 1H), 6.90 (d, J = 8.59 Hz, 2H), 7.25–7.32 (m, 2H), 7.45 (d, J = 6.25
and J = 8.59, 2H), 7.90–8.00 (m, 2H); FABMS: 364 (M++1); IR (KBr, cmÀ1): 3286,
1690, 1641, 1542, 1395, 1370, 1088, 892, 816, 759.Compound (S2). b-acetamido-
b-(4-fluorophenyl)-4-fluoropropiophenone. Mp 94 °C, yield 84%. 1H NMR
(DMSO-d6, 200 MHz): d 1.94 (s, 3H), 3.30 (dd, J = 6.25 and 16.40 Hz, 1H), 3.60
(dd, J = 7.81 and 17.19 Hz, 1H), 5.40 (dd, J = 7.03 and 14.06 Hz, 1H), 6.90 (d,
J = 8.59 Hz, 2H), 7.10 (d, J = 8.59, 2H), 7.30–7.40 (m, 2H), 7.95–8.03 (m, 2H);
FABMS: 304.1 (M++1); IR (KBr, cmÀ1): 3270, 3075, 1687, 1640, 1508, 1409,
1354, 1214, 1158, 1098, 993, 831, 751, 599. Compound (S3). b-acetamido-b-(4-
nitrophenyl)-propiophenone. Mp 150 °C, yield 80%, 1H NMR (DMSO-d6,
carbonyls in our report with no obvious structural similarity to both
a carbohydrate skeleton and the polyhydroxy nature, therefore,
present a novel class of
a-glucosidase inhibitors and hence may
add new insights in the search for better therapeutic agents than
the existing drugs.
Acknowledgments
200 MHz):
d 1.91 (s, 3H), 3.40 (dd, J = 5.82 and 17.55 Hz, 1H), 3.65 (dd,
Authors thank Dr. J.S. Yadav, Director IICT for his constant
encouragement. This work was supported in part from the Grant
No. SR/FTP/CS-93/2006 to R.M.K. from Department of Science and
Technology, Government of India under the Fast Track Scheme
for Young Scientists.
J = 8.04 and 17.55 Hz, 1H), 5.50 (dd, J = 6.58 and 13.16 Hz, 1H), 7.40–7.60 (m,
5H), 7.85 (d, J = 6.58, 2H), 8.15 (d, J = 8.7, 2H); FABMS: 313.1 (M++1); IR (KBr,
cmÀ1): 3310, 3046, 1686, 1649, 1582, 1513,1352, 1285, 1077,751, 658.
Compound (S4). b-acetamido-b-(4-hydroxyphenyl)-4-fluoropropiophenone. Mp
132 °C, yield 85%, 1H NMR (DMSO-d6, 200 MHz): d 1.90 (s, 3H), 3.35 (dd,
J = 6.25 and 16.40 Hz, 1H), 3.65 (dd, J = 7.03 and 16.40 Hz, 1H), 5.40 (dd, J = 7.03
and 14.06 Hz, 1H), 6.95 (d, J = 8.59, 2H), 7.35 (d, J = 5.46 2H) 8.00–8.30 (m, 2H);
FABMS: 302 (M++1); IR (KBr, cmÀ1): 3260, 3030, 2850, 1658, 1629, 1515, 1459,
1350, 1278, 860, 745. Compound (S5). acetamido-b-(4-methylphenyl)-4-
nitropropiophenone. Mp 85 °C, yield 78%, 1H NMR (DMSO-d6, 200 MHz): d
1.90 (s, 3H), 2.15 (s, 3H), 3.25 (dd,J = 6.23 and 16.99 Hz, 1H), 3.60 (dd, J = 6.90
and 16.99 Hz, 1H), 5.35 (dd, J = 6.79 and 13.97 Hz, 1H), 6.90–7.07 (m, 4H), 7.90
(d, J = 8.68, 2H), 8.15 (d, J = 8.68 2H); FABMS: 327 (M++1); IR (KBr, cmÀ1): 3256,
3034, 2276, 1660, 1601, 1515, 1372, 1241, 970, 828, 670. Compound (S6). b-
acetamido-b-(4-nitrophenyl)-4-nitropropiophenone. Mp 152 °C, yield 82%, 1H
NMR (DMSO-d6, 200 MHz): d 1.90 (s, 3H), 3.44 (dd, J = 6.58 and 17.8 Hz, 1H),
3.80 (dd, J = 8.04 and 17.55 Hz, 1H), 5.55 (dd, J = 7.3 and 13.8 Hz, 1H), 7.62 (d,
J = 8.10 Hz, 1H), 8.10-8.20 (m, 4H), 8.24–8.40 (m, 4H); FABMS: 358(M++1); IR
(KBr, cmÀ1): 3280, 3072, 1690, 1646, 1590, 1530, 1358, 1073, 995, 816, 759.
Compound (S7). acetamido-b-(4-methylphenyl)-4-bromopropiophenone. Mp
116 °C, yield 80%, 1H NMR (DMSO-d6, 200 MHz): d 1.88 (s, 3H), 2.30 (s, 3H),
3.25 (dd, J = 6.57 and 15.77 Hz, 1H), 3.55 (dd, J = 6.57 and 15.77 Hz, 1H), 5.40
(dd, J = 7.88 and 14.46 Hz, 1H), 7.00–7.25 (m, 5H), 7.60 (d, J = 7.88, 2H), 7.85 (d,
J = 7.88, 2H); FABMS: 360 (M++1); IR (KBr, cmÀ1): 3301, 2928, 1680, 1642,
1545, 1374,1220, 1032, 755.
References and notes
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16. Animal experiment. Male Wistar rats weighing between 195 and 215 g were
obtained from National Institute of Nutrition (CPCSEA Reg. No. 154, registered
by Government of India dated 22 October 1999) Hyderabad. The animals were
housed in standard polyvinyl cages. The room temperature was maintained at
22 1 °C with an alternating 12 h light-dark cycle. Food and water were
provided ad libitum. Experiments were performed as per the Institutional
Animal Ethical Committee norms. The rats were divided into four groups viz
control, standard, S-5 and S-7, containing six rats in each group. All the animals
were kept for overnight fasting. Next day forenoon blood was collected from
retro orbital plexus in EDTA containing tubes, and plasma glucose levels for
basal (‘0’-h) value were measured by glucose-oxidase test method using auto
blood analyzer instrument (Bayer EXPRESS PLUS). Standard drug acarbose and
the test samples S5 and S7 were suspended in normal saline and were
administered orally in the dose of 100-mg/kg-body weight. The control group
of animals were given only normal saline. Fifteen minutes after acarbose and
test sample treatment, animals were fed with soluble-starch dissolved in
normal saline at a dose of 2-g/kg-body weight. Thereafter, blood was collected
at the intervals of 30, 60, 90 and 120th minutes post starch feeding. Plasma
was separated out for glucose measurement as described above.
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14. General procedure for the preparation of b-acetamido ketones or keto esters. To a
stirred solution of benzaldehyde (2 mmol) and acetophenone (2 mmol) in
acetonitrile (5 ml) were added acetyl chloride (3 mmol) and lanthanum triflate
(10%). The mixture was refluxed for 3–5 h following the progress of the reaction
by TLC. After completion of the reaction, the mixture was poured into crushed ice
(50 ml) and extracted with dichloromethane. The organic layer was dried over
anhy. Na2SO4 and concentrated under vacuum. The crude product was purified
by normal column chromatography to obtain of b-acetamido ketones.
15. NMR data: Compound (S1). b-acetamido-b-(4-fluorophenyl)-4-bromopropiophenone.
Mp 221 °C, yield 87%. 1H NMR (DMSO-d6, 200 MHz): d 1.90 (s, 3H), 3.25 (dd,
J = 7.03 and 14.06 Hz, 1H), 3.70 (dd, J = 7.81 and 14.85 Hz, 1H), 5.05 (dd, J = 7.80
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