Chalcone based aryloxypropanolamines as potential antihyperglycemic agents

Article abstract of DOI:10.1016/j.bmcl.2006.10.068

A series of chalcone based aryloxypropanolamines were synthesized and evaluated for their antihyperglycemic activity in SLM and STZ rat models. Most of the compounds exhibited moderate to good activity ranging from 6.5% to 31.1% in SLM and 8.3% to 22.6% i

Full text of DOI:10.1016/j.bmcl.2006.10.068

Bioorganic & Medicinal Chemistry Letters 17 (2007) 799–802
Chalcone based aryloxypropanolamines as potential
antihyperglycemic agentsq
Poonam Shukla, Amar Bahadur Singh, Arvind Kumar Srivastava and Ram Pratap*
Central Drug Research Institute, Lucknow, India
Received 13 September 2006; revised 9 October 2006; accepted 24 October 2006
Available online 27 October 2006
Abstract—A series of chalcone based aryloxypropanolamines were synthesized and evaluated for their antihyperglycemic activity in
SLM and STZ rat models. Most of the compounds exhibited moderate to good activity ranging from 6.5% to 31.1% in SLM and
8.3% to 22.6% in STZ models, respectively. The most potent compound 5g exhibited glucose lowering of 26.7% in SLM and 22.6%
in STZ models. A definite structure–activity relationship was observed while varying the nature as well as the position of the amine
in ring B.
Ó 2006 Elsevier Ltd. All rights reserved.
Diabetes of type-II (non-insulin dependent diabetes
mellitus, NIDDM) is a chronic metabolic disease char-
acterized by insulin resistance, hyperglycemia and
hyperinsulinaemia. The disease is often associated with
obesity, dyslipidemia and hypertension leading to car-
diovascular risks.1 In such cases, restoration of normal
adipose tissue levels results in an alleviation of the insu-
lin resistant state.2 Given the link between obesity and
type-II diabetes, reduction in body fat mass via diet
and exercise is generally the first treatment for diabetes.
The majority of previous and current anti-obesity drug
based therapies are targeted at a reduction of energy in-
take or absorption (anorectic drugs) but pharmacologi-
cal approaches to an increase in energy expenditure
(thermogenic drugs) serve as an attractive alternative
option for the treatment of obesity and hence, diabetes.
There are approaches to induce thermogenesis either
through stimulation of nuclear receptor of PPAR fami-
ly3 or adrenergic receptor (AR) in membrane of adipose
tissue.4
simultaneously increase lipolysis, fat oxidation, energy
expenditure5 and insulin action leading to the belief that,
this receptor might serve as an attractive target for the
treatment of diabetes and obesity.6
Arylethanolamines and aryloxypropanolamines were
first reported as b3-AR agonists in the mid 1980s.7
CL-316,243 (I),8 the most selective b3-AR agonist tested
in humans, led to concentration-dependent increase of
lipolysis, fat oxidation and insulin activation.
Troglitazone is another antidiabetic drug of thiazolidin-
edione class. The unique structural feature of Troglitaz-
one,15 is the presence of the antioxidant moiety of
vitamin E together with a PPAR-c nuclear receptor
stimulating pharmacophore in a single molecule. Trog-
litazone, however failed due to its toxic metabolites
but provided a basis for further designing molecules
for multi-factorial diseases. Thus molecules with multi-
ple ligands are being designed for such diseases. Oxida-
tive stress plays a crucial role in diabetic patients leading
to macrovascular complications through Maillard reac-
tion.14 The chalcones are antioxidant molecules of plant
origin which being consumed daily through fruits and
vegetables have attracted our attention to explore
hybrid structures with them for antidiabetic activity.
Chalcones are also known to exhibit various biological
activities including antioxidant,9 antimalarial,10 antile-
ishmanial,11 antiinflammatory12 and antitumor.13 The
antioxidant property of chalcones may be one of the fac-
tors for various activities. In this ongoing programme,
An ‘atypical’ b3-adrenergic receptor was discovered in
early 1980s4 on the cell surface of both white and brown
adipose tissues. Agonists of the b3-AR were observed to
Keywords: Aryloxypropanolamines; Chalcone; Antihyperglycemic
agents.
q
CDRI Communication No. 7056, Fax: +91 522 2623405.
Corresponding author. Fax: +91 522 2623405; e-mail: rpcdri@
yahoo.com
*
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.068

800
P. Shukla et al. / Bioorg. Med. Chem. Lett. 17 (2007) 799–802
we have earlier synthesized hybrid chalcones with aryl-
oxypropanol amine pharmacophore in ring A (Fig. 1)
and few compounds of type-II in the series have exhib-
ited potent antidiabetic activity in db/db mice with good
bioavailability profile.16 This led us to synthesize anoth-
er structural motif III for structure–activity relationship
study in order to optimize the activity in respect of
ADME profile.
5–6 animals in each. Animals of experimental group
were administered the suspension of the synthetic com-
pounds orally (in 1.0% gum acacia) at a dosage of
100 mg/kg-body weight. Animals of control group were
given an equal amount of 1.0% gum acacia. A sucrose-
load (10.0 g/kg) was given to each animal orally exactly
after 30 min post administration of the test sample/vehi-
cle. Blood glucose profile of each animal was determined
at 30, 60, 90 and 120 min post administration of sucrose.
Food but not water was removed from the cages during
the course of experimentation. Quantitative glucose tol-
erance of each animal was calculated by area under
curve (AUC) method. Comparing the AUC of experi-
mental and control groups was calculated the percent-
age anti-hyperglycemic effect. Samples showing
significant inhibition (p < 0.05) on postprandial hyper-
glycemia (AUC) were considered as active samples.
The general synthetic plan employed to prepare the dif-
ferent chalcones is by Claisen–Schmidt17 condensation.
Hydroxy chalcones 3 on reaction with epichlorohydrin
in presence of sodium hydride yielded compound 4
which on reaction with appropriate amine provided
the desired product 5 (Scheme 1).18
Antihyperglycemic activity: The compounds (5a–n) were
evaluated for their anti-hyperglycemic activity in su-
crose-loaded model (SLM) and in streptozotocin
(STZ) induced b-cell damaged diabetic model of Spra-
gue–Dawley strain male albino rats.
Streptozotocin-induced diabetic rat model (STZ): Spra-
gue–Dawley strain male albino rats of average body
weight 140 20 g were selected having blood glucose
profiles between 60 and 80 mg/dl. Streptozotocin (Sig-
ma, USA) was dissolved in 100 mM citrate buffer (pH
4.5) and calculated amount of freshly prepared solution
was injected to overnight fasted animals at a dose of
60 mg/kg-body weight intraperitoneally. Blood glucose
profile was checked after 48 h using Glucostrips (Boeh-
ringer–Mannheim) and animals showing blood glucose
profiles between 180–270 mg/dl were considered suitable
for the experiment. These diabetic animals were again
divided into groups and their blood glucose profiles were
again checked on the day of experiment (day 3). Ani-
mals showing almost equal or similar blood glucose pro-
files were divided into groups consisting of 5–6 animals
in each group. Animals of experimental group were
administered the suspension of the test sample orally
(in 1% gum acacia) at 100 mg/kg-body weight. Animals
of control group were given an equal amount of 1% gum
acacia. A sucrose-load (2.5 g/kg) was given to each ani-
mal orally exactly after 30 min post administration of
the test sample/vehicle. Blood glucose profile of each
animal was determined at 30, 60, 90, 120, 180, 240,
300 min and at 24 h post administration of sucrose.
Food but not water was removed from the cages during
the experimentation. The % fall in blood glucose by test
sample was calculated according to the AUC method.
The average fall in AUC in experimental group com-
pared to control group provided % anti-hyperglycemic
activity.
Sucrose-loaded rat model (SLM): compounds were test-
ed for their effect on glucose tolerance curve in rats of
average body weight 160 20 g, an indirect effect of
measuring anti-hyperglycemic activity. The blood glu-
cose levels of all animals were checked after an overnight
fasting (16 h) by Glucostrips (Boehringer–Mannheim).
Animals showing blood glucose levels between 60 and
80 mg/dl (3.33–4.44 mM) were divided into groups of
O
C
OH
H
N
O
O
ONa
ONa
C
O
CL-316, 243 (I)
Cl
O
B
A
R
N
O
II
OH
O
OH
O
N
III
Figure 1.
O
O
O
(i)
H
CH3
+
3
OH
O
2
OH
OH
1
(ii)
O
O
(iii)
O
R
O
5
4
Scheme 1. Reagents and conditions: (i) 50% aq NaOH, MeOH, rt; (ii) NaH, epichlorohydrin, DMF, rt; (iii) amine, MeOH, rt.

P. Shukla et al. / Bioorg. Med. Chem. Lett. 17 (2007) 799–802
Table 1. In vivo anti-hyperglycemic activity in rat models
801
Compound
Position
R
% anti-hyperglycemic activity
SLM STZ
5a
5b
3
3
(CH3)2–CH2NH–
t-ButNH–
14.5
21.7
NIL
10.6
5c
5d
3
3
22.9
11.3
10.4
9.4
N
N
N
Cl
5e
3
19.0
8.3
N
N
N
N
5f
4
3
3
31.1
26.7
20.4
3.0
22.6
20.1
5g
5h
[(CH3)2–CH]2N–
H3C
t-ButNH–
N
N
5i
4
3
4
29.0
20.8
7.9
10.3
8.3
5j
5k
Et2N(CH2)3NH–
[(CH3)2–CH]2N–
ND
5l
4
22.3
19.3
ND
N
5m
3
4
Inactive
NH
5n
Metformin
Glybenclamide
(CH3)2CH2NH–
6.5
12.9
33.7
ND
19.1
29.0
ND, not determined; NIL, insignificant activity.
The synthesized compounds were evaluated for their
anti-hyperglycemic activity in above two models and
compared with standard drugs Metformin and Glyben-
clamide. The most active compound 5g, in the series
having di-isopropyl amine in the chain, lowered blood
glucose level up to 26.7% in SLM and 22.6% in STZ
models. Besides, compounds 5h and 5l exhibited signifi-
cant anti-hyperglycemic activity, 20.4% and 22.3% in
SLM and 20.1% and 19.3% in STZ, models, respective-
ly. On contrary to di-isopropylamine, the compounds 5i
and 5b with tert-butylamine chain exhibited inferior
activity whereas compounds 5a and 5n with isopropyl-
amine chain have lost the activity. Compound 5l with
piperidine in the chain, a cyclic analogue is also exhibit-
ing good activity. Compounds having aromatic residue
at nitrogen atom as in phenylpiperazine exhibited insig-
nificant activity in STZ model.
Thus, the compounds with propoxypropanolamine
pharmacophore at either 3- or 4-position in ring B of
chalcone exhibit anti-hyperglycemic activity comparable
to Metformin and Glybenclamide. The compounds with
acyclic amine in the chain are specifically more active as
compared to their cyclic congeners. Further work is in
progress to improve the potency of these compounds.
Acknowledgments
Authors are grateful to Director, CDRI, Lucknow,
India, for constant encouragement of the drug develop-
ment program for metabolic diseases and Sophisticated
Analytical Instrumentation Facility (SAIF) group for
spectral data. Poonam is grateful to CSIR, New Delhi,
for awarding Diamond Jubilee year fellowship.
However, the substitution of propoxypropanol amine
moiety at two different positions either at 3- or 4- did
not exhibit much striking difference in activity profile.
Compound 5i, showed marked activity (29%) than the
meta substituted 5b (21.7%) in SLM model. Compound
5f with phenylpiperazine in chain at para position exhib-
ited better activity (31.1%) than its meta regiomer 5c
(22.9%) in SLM model. Similarly, piperidine compound
5l showed a higher activity (22.3% and 19.3%) than its
meta regiomer 5d (11.3% and 9.4%) in SLM and STZ
models, respectively Table 1.
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18. General procedure for the preparation of aryloxypropa-
nolamines (Scheme 1): To a stirred solution of chalcone
(8.9 mmol) in dry DMF (50 mL) was added NaH
(22.3 mmol) at 0–5 °C followed by epichlorohydrin
(30 mmol) and stirring was continued for another 10 h.
The solvent removed under reduced pressure, and reaction
mixture taken in water, extracted with chloroform. The
organic layer dried (Na2SO4), filtered, solvent removed to
yield crude product 4 which was purified on silica gel
column. The compound 4 (5.20 mmol) was further treated
with appropriate amine (6.5 mmol/excess) in methanol at
room temperature for ꢀ6 h. The solvent was removed and
the product purified by column chromatography. Spectral
1
data of the potent compounds: Compound 5g: H NMR
(CDCl3, 300 MHz): d 7.79 (d, J = 15.7 Hz, 1H, b-H), 8.03
(d, J = 7.0 Hz, 2H, 20, 60-H), 7.55-7.50 (m, 3H, 30, 40, 50-
H), 4.12-4.00 (m, 3H, –OCH2–CHOH), 3.19 (d,
J = 6.6 Hz, 2H, CH2–N), 2.83–2.60 (m, 2H, CH), 1.12 (s,
1
12H, CH3). Compound 5h: H NMR (CDCl3, 300 MHz):
d 7.63 (d, J = 15.7 Hz, 1H, b-H), 7.88 (d, J = 7.2 Hz, 2H,
20, 60-H), 7.40–7.34 (m, 3H, 30, 40, 50-H), 6.80 (s, 1H, 2-H),
6.72 (d, J = 7.2 Hz, 1H, 4-H), 7.09 (d, J = 10.4 Hz, 1H, 5-
H), 6.86 (d, J = 7.9 Hz, 1H, 6-H), 4.12–3.96 (m, 3H,
–OCH2–CHOH), 2.52 (d, J = 8.8 Hz, 2H, CH2–N), 2.73
(m, 8H, 200, 300, 500, 600-H), 2.40 (s, 3H, N–CH3). Compound
5l: 1H NMR (CDCl3, 200 MHz): d 7.78 (d, J = 15.8 Hz,
1H, b-H), 7.41 (d, J = 15.6 Hz, 1H, a-H), 8.01(d,
J = 6.4 Hz, 2H, 20, 60-H), 7.62–7.53 (m, 3H, 30, 40, 50-H),
6.97 (d, J = 8.6 Hz, 2H, 3, 5-H), 7.51 (d, J = 7.3 Hz, 2H, 2,
6-H), 4.14–4.02 (m, 3H, OCH2–CHOH), 2.53 (d,
J = 6.1 Hz, 2H, CH2–N), 1.50 (m, 4H, 200, 600-H), 1.21
(m, 6H, 300, 400, 500-H).