Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines

Article abstract of DOI:10.1016/j.bmc.2003.12.026

A series of aryloxypropanolamines (5a-r) of different chalcones (3a-e) were synthesized and evaluated for antihyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them compounds 5a, g, m, o, p and r

Full text of DOI:10.1016/j.bmc.2003.12.026

Bioorganic & Medicinal Chemistry 12 (2004) 883–889
Synthesis and antihyperglycemic activity of chalcone based
aryloxypropanolamines§
M. Satyanarayana,a Priti Tiwari,b Brajendra K. Tripathi,b A. K. Srivastavab
and Ram Pratapa,*
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
Received 23 October 2003; revised 23 December 2003; accepted 24 December 2003
Abstract—A series of aryloxypropanolamines (5a–r) of different chalcones (3a–e) were synthesized and evaluated for anti-
hyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them com-
pounds 5a, g, m, o, p and r showed significant reduction in blood glucose levels in both SLM and STZ animal models.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lipolysis and thermogenesis respectively.6 BAT also
plays an important role in the maintenance of glucose
homeostasis; hence b3-AR agonists are useful for treat-
ing diabetes as well as obesity.7 The aryloxy-
propanolamines were first described as b3-AR agonists
in the mid 1980s.8 Later on several pharmaceutical
industries are engaged in developing potent selective b3-
AR agonists for treatment of type-II diabetes and obe-
sity. CL-3162439 has been reported for the treatment of
type-II diabetes as well as obesity and recently L-
75550710 as highly selective b3-AR agonist acting as
metabolic rate enhancer in rodents.
Non-insulin dependent diabetes mellitus (NIDDM,
type-II diabetes) is a chronic metabolic disease char-
acterized by insulin resistance, hyperglycemia and
hyperinsulinaemia. It represents 80–90% of the human
population with diabetes and approximately 215
million will be afflicted worldwide by 2010.1 The disease
is often associated with obesity, dyslipidemia and
hypertension leading to cardiovascular risks.2 Primary
therapy for type-II diabetes is caloric restriction and
aerobic exercise3 but only a small percentage of patients
adopt them with sufficient rigor to achieve a significant
improvement in hyperglycemic condition. Current
therapies for type-II diabetes have inherent problems
including non-compliance, ineffectiveness and hypogly-
cemic episodes with insulin and sulphonyl ureas.4 Gli-
tazone type therapeutic agents are in the market but
some of them have been reported to have hepatotoxi-
city.5 Therefore, here still remains a great need for more
effective orally administered agents.
b3-adrenergic receptors (b3-AR) are found on the cell
surface of both white adipose (WAT) and brown adi-
pose tissues (BAT) where their stimulation promotes
Keywords: Chalcones; Aryloxypropanolamines and antihyperglycemic
activity.
Chalcones either natural or synthetic are known to
exhibit various biological activities. They have been
reported as antioxidant,11ꢀ14 antimalarial,15 antil-
eishmanial,16 antiinflammatory17 and antitumor18
§C.D.R.I. Communication no. 6474.
* Corresponding author. Tel.: +91-522-2212411x4347; fax: +91-522-
2223405; e-mail: rpcdri@yahoo.com
0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.026

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M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
an indirect effect of measuring antihyperglycemic activ-
ity. The blood glucose levels of all animals were checked
after an overnight fasting (16 h) by Glucostrips (Boeh-
ringer Mannheim). Animals showing blood glucose
levels between 60–80 mg/dl (3.33–4.44 mM) were divi-
ded into groups of five to six animals in each. Animals
of experimental groups were administered the suspen-
sion of the synthetic compounds orally (made 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/vehicle. 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 tolerance of each
animal was calculated by Area Under Curve (AUC)
method. Comparing the AUC of experimental and
control groups was calculated the percentage anti-
hyperglycemic effect. Samples showing significant inhi-
bition (p<0.05) on postprandial hyperglycemia (AUC)
were considered as active samples.
Figure 1. General structure of synthesized aryloxypropanolamines.
agents. Chalcones with proper substitution have recently
been isolated from Broussonetia papyrifera known to
selectively inhibit enzymes like protein tyrosine phos-
19
phatase 1B (PTP1B)
and aldose reductase.20 Their
antioxidant property attracted us to explore hybrid
structures as antihyperglycemic agents, because oxida-
tive stress also plays an important role in diabetic
2,21
patients leading tovascular complications.
On this
background we designed and synthesized compounds
corresponding to general formula given in Figure 1 to
explore their potential for antihyperglycemic activity.
2. Results and discussion
The general synthetic route used to synthesize the
designated compounds is outlined in Scheme 1. The
target compounds (5a–r) as typified by general structure
(Fig. 1) were prepared by reacting different amines with
aryloxypropeneoxides in methanol at room temper-
ature. The structures and antihyperglycemic activities of
aryloxypropanolamines are summarized in Table 1.
2.2. Streptozotocin-induced diabetic rats (STZ)
Sprague–Dawley strain male albinorats fo average
body weight 140ꢁ20 g were selected having blood glu-
cose profiles between 60–80 mg/dl. Streptozotocin
(Sigma, 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
(Boehringer 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 pro-
file was again checked on the day of experiment (Day 3).
Animals showing almost equal or similar blood glucose
profiles were divided into groups consisting of 5 to 6
animals in each group. Animals of experimental groups
were administered suspension of the test sample orally
(prepared 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 toeach animal orally exactly after 30 min
post administration of the test sample/vehicle. Blood
All the chalcones (3a–e) were prepared using the Clai-
sen-Schmidt condensation, which has been previously
reported.22 Yields ranged from 65% to quantitative but
were not optimized. The chalcones were always obtained
1
as trans-alkenes (E-form) as judged by H NMR spec-
troscopy. The chalcones thus obtained were alkylated at
hydroxyl groups with epichlorohydrin using NaH as base
in dry dimethyl formamide (DMF) at room temperature.
All the synthesized compounds (5a–r) were evaluated
for antihyperglycemic activity23 in sucrose-loaded model
(SLM) followed by streptozotocin (STZ) induced b-cell
damaged diabetic model of Sprague–Dawley strain male
albinorats.
2.1. Sucrose loaded rat model (SLM)
Compounds were tested for their effect on glucose tol-
erance curve in rats of average body weight 160ꢁ20 g,
Scheme 1. Reagents and conditions: (i) 50% aq NaOH, MeOH, rt; (ii) NaH, Epichlorohydrin, DMF, rt; (iii) Amine, MeOH, rt.

M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
885
Table 1. In vivo antihyperglycemic activity of aryloxypropanolamines (5a–r) in STZ and SLM rat models
S.No
Compd
Position
R0
R00
%Antihyperglycemic activity
STZ SLM
1
2
5a
5b
40
40
3, 4-OMe
3, 4-OMe
20.3
NIL
15.4
11.2
(CH3)3CNH—
3
5c
40
4-OMe
NIL
7.78
4
5
6
5d
5e
5f
40
40
40
(CH3)2CHCH2NH—
(CH3)3CNH—
(CH3)2CHNH—
4-OMe
4-OMe
4-OMe
ND
NIL
ND
5.67
11.8
Inactive
7
5g
40
4-OMe
6.18
10.8
8
5h
40
4-OMe
ND
Inactive
9
10
5i
5j
40
40
CH3NH—
CH3(CH2)3NH—
4-OMe
4-OMe
ND
NIL
Inactive
38.0
11
5k
30
4-OMe
ND
4.41
12
13
14
15
16
5l
5m
5n
5o
5p
30
30
20
20
40
(CH3)2CHNH—
(CH3)3CNH—
CH3(CH2)3NH—
(CH3)2CHNH—
(CH3)3CNH—
4-OMe
4-OMe
4-OMe
NIL
11.3
NIL
2.77
23.0
6.85
20.0
33.1
47.0
21.1
4-OMe
3, 4-Methylenedioxy
17
5q
40
40
3, 4-Methylenedioxy
3, 4-Methylenedioxy
ND
5.03
18
19
20
21
22
23
5r
3a
3b
3c
3d
(CH3)2CHCH2NH—
11.58
NIL
NIL
ND
23.8
NIL
NIL
NIL
ND
NIL
12.9
33.7
ND
3e
Metformin
Glybenclamide
NIL
19.1
29.0
ND, Not Determined; NIL, Insignificant activity.
glucose profile of each animal was determined at 30,
60, and 90, 120, 180, 240, 300 min and at 24 h post
administration of sucrose. Food but not water was
withheld from the cages during the experimentation.
The % fall in blood glucose by test sample was calcu-
lated according to the AUC method. The average fall
in AUC in experimental group compared to control
group provided % antihyperglycemic activity. Metfor-
min and glybenclamide acting with twodifferent
mechanisms were used as standard drugs tocompare
the activity of compounds reported here. Chalcones
(3a–e) without oxypropanolamine chain showed insig-
nificant activities.
compound 5a displayed significant antihyperglycemic
effect, 15.4% in SLM and 20.3% in STZ model. From
mono methoxy series 5g and m showed blood glucose
lowering activity 10.8% and 20% in SLM model and
moderate activity 6.18% and 11.3% in STZ model.
Another active compound 5o from the same series
reduced blood glucose level significantly to 47% in SLM
model but showed insignificant activity (2.77%) in STZ
model. Compounds 5f, h and i were found to be inactive
in SLM model, while compounds 5d, k and q showed
insignificant blood glucose lowering activity. Rest of the
compounds (5b, c, e, j, l and n) showed moderate to
significant antihyperglycemic effect in SLM model but
showed poor activity in STZ model. In conclusion
compounds (5a, b, p, q and r) vicinally dioxygenated as
dimethoxy and methylenedioxy substitution showed the
best antihyperglycemic activity when compared to the
corresponding monomethoxy compounds (5c, d and e).
From monomethoxy series also compounds (5e, g, j, m,
n and o) showed moderate to significant blood glucose
lowering activity in SLM model but only 5g, m showed
moderate activity in STZ model. Furthermore com-
pounds containing propanolamine chain at para posi-
In general all the screened compounds (except 5d, f, h, i
and k) showed moderate to potent antihyperglycemic
activity in SLM model but only 6 compounds (5a, g, m,
o, p and r) displayed blood glucose lowering activity at
100-mg/kg doses in STZ model.
3,4-Methylenedioxy compounds 5p and r lowered blood
glucose level to 23.0% and 11.58% in STZ and 21.1%
and 23.8% in SLM models respectively. 3,4-Dimethoxy

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M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
tion showed significant activity as compared to meta
and ortho substituted compounds
(s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz,
1H), 6.93 (d, J=8.5 Hz, 2H), 3.95 (s, 3H, OMe), 3.92 (s,
3H, OMe).
3.1.5. 40-Hydroxy-3,4-methylenedioxy-chalcone (3e).
3. Experimental
Yield 65%; mp 191–193 ꢂC; MS (FAB) 269 (M+ +1);
1
Melting points were determined on a capillary melting
point apparatus and are uncorrected. 1H NMR and
13C NMR spectra were recorded in the indicated sol-
vent on Bruker WM 200 MHz spectrometer with TMS
as internal standard. Infrared spectra were recorded in
KBr on Perkin–Elmer AC-1 spectrometer. FAB mass
spectra were recorded on JEOL SX 102/DA 6000 mass
spectrometer. Microanalyses were performed on Carlo
Erba EA-1108 element analyzer and were within
theꢁ0.5% of the theoretical values. Column chroma-
tography was performed on silica gel (Merck, 60–120
mesh).
IR (KBr) 3410 (OH), 1646 (CO); H NMR (200 MHz,
CDCl3) d 9.15 (s, 1H, OH), 7.98 (d, J=8.7 Hz, 2H),
7.72 (d, J=15.5 Hz, 1H), 7.37 (d, J=15.5 Hz, 1H), 7.16
(s, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.8 Hz,
2H), 6.82 (d, J=7.9 Hz, 1H), 6.02 (s, 2H).
3.2. (B) General procedure for the O-alkylation of
hydroxy chalcones (4a–e)
To a well stirred solution of chalcone (40 mmol) in dry
DMF (160 mL) was added NaH (40 mmol) at 0–5 ꢂC.
To the above reaction mixture excess of epichlorohydrin
(120 mmol) was added and stirred at room temper-
ature approximately for 8 h. The reaction mixture
was concentrated under reduced pressure, diluted with
water and extracted with chloroform. The combined
organic layers were dried (Na2SO4), filtered and
evaporated. The product was purified by column
chromatography.
3.1. (A) General procedure for the preparation of chal-
cones (3a–e)
To a well stirred solution of substituted acetophenone
(50 mmol) and appropriately substituted benzaldehyde
(50 mmol) in methanol (150 mL) was added a 50% w/v
aq NaOH solution (30 mL). The reaction mixture was
stirred overnight at room temperature. It was neu-
tralized with 1N HCl and filtered the product; in case of
the absence of precipitate it was extracted with chloro-
form. The combined organic layers were dried
(Na2SO4), filtered and evaporated. The product was
purified by column chromatography.
3.2.1. 40-(2,3-Epoxy-propoxy)-4-methoxy-chalcone (4a).
Yield 60%; mp 85–87 ꢂC; MS (FAB) 311 (M+ +1); IR
1
(KBr) 1655 (CO); H NMR (200 MHz, CDCl3) d 8.02
(d, J=8.8 Hz, 2H), 7.77 (d, J=15.6 Hz, 1H), 7.59 (d,
J=8.7 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H), 6.99 (d,
J=8.8 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.32 (dd,
J=11.1 Hz, 2.9 Hz, 1H), 4.01 (dd, J=11.1 Hz, 5.7 Hz,
1H), 3.84 (s, 3H, OMe), 3.40–3.35 (m, 1H), 2.92 (t,
J=4.5 Hz, 4.5 Hz, 1H), 2.77 (dd, J=4.8 Hz, 2.6 Hz,
1H).
3.1.1. 40-Hydroxy-4-methoxy-chalcone (3a). Yield 90%;
mp 184–185 ꢂC (lit. 188–190 ꢂC) 24; MS (EI) m/z 254
(M+, 100), 253 (34.7), 239 (32.3), 161 (36.8), 121 (79.5);
1
IR (KBr) 3371 (OH), 1654 (CO); H NMR (200 MHz,
CDCl3) d 7.99 (d, J=8.6 Hz, 2H), 7.78 (d, J=15.6 Hz,
1H), 7.60 (d, J=8.6 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H),
6.93 (d, J=7.2 Hz, 4H), 5.85 (broad s, 1H, OH), 3.86 (s,
3H, OMe).
3.2.2. 30-(2,3-Epoxy-propoxy)-4-methoxy-chalcone (4b).
Yield 75%; mp 64–65 ꢂC; MS (FAB) 311 (M+ +1); IR
1
(KBr) 1658 (CO); H NMR (200 MHz, CDCl3) d 7.79
(d, J=15.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.60 (d,
J=8.7 Hz, 2H), 7.56 (d, J=1.3 Hz, 1H), 7.41 (t, J=7.9
Hz, 1H), 7.39 (d, J=15.5 Hz, 1H), 7.15 (dd, J=8.1 Hz,
1.4 Hz, 1H), 6.94 (d, J=8.6 Hz, 2H), 4.34 (dd, J=11.0
Hz, 2.8 Hz, 1H), 4.01 (dd, J=11.0 Hz, 5.8 Hz, 1H), 3.86
(s, 3H, OMe), 3.40–3.38 (m, 1H), 2.93 (t, J=4.5 Hz, 4.4
Hz, 1H), 2.79 (dd, J=4.7 Hz, 2.6 Hz, 1H).
3.1.2. 30-Hydroxy-4-methoxy-chalcone (3b). Yield 98%;
mp 93–94 ꢂC; MS (FAB) 255 (M+ +1); IR (KBr) 3366
1
(OH), 1649 (CO); H NMR (200 MHz, CDCl3) d 7.80
(d, J=15.6 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.58 (d,
J=8.7 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.38 (d,
J=15.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.9
Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 3.85 (s, 3H, OMe).
3.2.3. 20-(2,3-Epoxy-propoxy)-4-methoxy-chalcone (4c).
Yield 42%; mp 57–58 ꢂC; MS (FAB) 311 (M+ +1); IR
3.1.3. 20-Hydroxy-4-methoxy-chalcone (3c). Yield 92%;
(KBr) 1644 (CO); H NMR (200 MHz, CDCl3) d 7.64
1
mp 81–83 ꢂC (lit. 93–94) 25; MS (FAB) 255 (M+ +1);
(dd, J=8.5 Hz, 1.8 Hz, 1H), 7.63 (d, J=15.8 Hz, 1H),
7.60 (d, J=8.6 Hz, 2H), 7.45 (t, J=7.5 Hz, 1H), 7.34 (d,
J=15.8 Hz, 1H), 7.10–6.95 (m, 2H), 6.92 (d, J=8.8 Hz,
2H), 4.36 (dd, J=11.0 Hz, 2.6 Hz, 1H), 4.08 (dd,
J=11.0 Hz, 5.1 Hz, 1H), 3.84 (s, 3H, OMe), 3.34–3.31
(m, 1H), 2.85–2.77 (m, 2H).
1
IR (KBr) 3450 (OH), 1639 (CO); H NMR (200 MHz,
CDCl3) d 7.92 (dd, J=8.7 Hz, 1.4 Hz, 1H), 7.90 (d,
J=15.4 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.53 (d,
J=15.5 Hz, 1H), 7.49 (t, J=7.4 Hz, 1H), 6.95 (d, J=8.6
Hz, 2H), 7.03–6.89 (m, 2H), 3.86 (s, 3H, OMe).
3.1.4. 3,4-Dimethoxy-40-hydroxy-chalcone (3d). Yield
69%; mp 193–195 ꢂC; MS (FAB) 285 (M+ +1); IR
(KBr) 3443 (OH), 1643 (CO); 1H NMR (200 MHz,
CDCl3) d 10.45 (s, 1H, OH), 8.10 (d, J=8.5 Hz, 2H),
7.81 (d, J=15.5 Hz, 1H), 7.66 (d, J=15.5 Hz, 1H), 7.52
3.2.4.
3,4-Dimethoxy-40-(2,3-epoxy-propoxy)-chalcone
(4d). Yield 41%; mp 95–96 ꢂC; MS (FAB) 341 (M+
+1); IR (KBr) 1655 (CO); 1H NMR (200 MHz, CDCl3)
d 8.03 (d, J=8.8 Hz, 2H), 7.75 (d, J=15.5 Hz, 1H), 7.39
(d, J=15.5 Hz, 1H), 7.23 (dd, J=8.3 Hz, 1.5 Hz, 1H),

M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
887
7.16 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.3 Hz,
1H), 4.32 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.01 (dd,
J=11.1 Hz, 5.8 Hz, 1H), 3.95 (s, 3H, OMe), 3.93 (s, 3H,
OMe), 3.40–3.36 (m, 1H), 2.93 (t, J=4.5 Hz, 4.6 Hz,
1H), 2.79 (dd, J=4.8 Hz, 2.6 Hz, 1H).
(m, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz,
2H), 6.96–6.84 (m, 3H), 4.19–4.09 (m, 3H), 3.86 (s,
3H, OMe), 3.24 (t, J=4.9 Hz, 4H), 2.89–2.84 (m, 2H),
2.74–2.64 (m, 4H). Anal. calcd for C29H32N2O4: C,
73.70; H, 6.83; N, 5.93. Found: C, 73.32; H, 6.41; N,
5.69.
3.2.5. 40-(2,3-Epoxy-propoxy)-3,4-methylenedioxy-chalcone
(4e). Yield 80%; mp 83–84 ꢂC; MS (FAB) 325 (M+
+1); IR (KBr) 1650 (CO); 1H NMR (200 MHz, CDCl3)
d 7.98 (d, J=8.8 Hz, 2H), 7.72 (d, J=15.5 Hz, 1H), 7.36
(d, J=15.5 Hz, 1H), 7.16 (s, 1H), 7.12 (d, J=8.1 Hz,
1H), 6.99 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.9 Hz, 1H),
6.02 (s, 2H), 4.32 (dd, J=11.1 Hz, 3.0 Hz, 1H), 4.02 (dd,
J=11.1 Hz, 5.7 Hz, 1H), 3.38–3.36 (m, 1H), 2.93 (t,
J=4.4 Hz, 4.3 Hz, 1H), 2.78 (dd, J=4.8 Hz, 2.6 Hz,
1H).
3.3.4. 40-[3-iso-Butylamino-2-hydroxy-propoxy]-4-meth-
oxy-chalcone (5d). Yield 74%; mp 76–77 ꢂC; MS (FAB)
384 (M+ +1); IR (KBr) 3423 (broad, OH, NH), 1653
(CO); 1H NMR (200 MHz, CDCl3) d 8.02 (d, J=8.6 Hz,
2H), 7.78 (d, J=15.6 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H),
7.42 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.93
(d, J=8.6 Hz, 2H), 4.21–3.97 (m, 3H), 3.85 (s, 3H,
OMe), 2.91–2.72 (m, 2H), 2.48 (d, J=6.7 Hz, 2H), 1.83–
1.66 (m, 1H), 0.93 (d, J=6.6 Hz, 6H). Anal. calcd for
C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C,
72.12; H, 7.43; N, 3.52.
3.3. General procedure for the opening of epoxides with
amines (5a–r)
3.3.5. 40-[3-tert-Butylamino-2-hydroxy-propoxy]-4-meth-
oxy-chalcone (5e). Yield 85%; mp 70–71 ꢂC; MS (FAB)
384 (M+ +1); IR (KBr) 3391 (broad, OH, NH), 1640
(CO); 1H NMR (200 MHz, CDCl3) d 8.02 (d, J=8.7 Hz,
2H), 7.78 (d, J=15.7 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H),
7.41 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.9 Hz, 2H), 6.93
(d, J=8.7 Hz, 2H), 4.13–4.05 (m, 3H), 3.86 (s, 3H,
OMe), 2.95–2.73 (m, 2H), 1.21 (s, 9H). Anal. calcd for
C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C,
72.09; H, 7.13; N, 3.72.
To a solution of epoxide (5 mmol) in methanol (80 mL)
was added required amount of amine (5 mmol, excess of
amine required in case of primary amine ꢃ4 times) and
stirred at room temperature approximately for 6 h.
Methanol was removed under vaccum and product
purified by column chromatography.
3.3.1. 3,4-Dimethoxy-40-[2-hydroxy-3-(4-phenylpiperazin-
1-yl)-propoxy]-chalcone (5a). Yield 85%; mp 126–
127 ꢂC; MS (FAB) 503 (M+ +1); IR (KBr) 3426 (OH),
1652 (CO); 1H NMR (200 MHz, CDCl3) d 8.03 (d,
J=8.8 Hz, 2H), 7.76 (d, J=15.5 Hz, 1H), 7.39 (d,
J=15.5 Hz, 1H), 7.31–7.20 (m, 3H), 7.16 (d, J=1.3 Hz,
1H), 7.01 (d, J=8.8 Hz, 2H), 6.93 (d, J=7.8 Hz, 1H),
6.95–6.87 (m, 3H), 4.19–4.08 (m, 3H), 3.95 (s, 3H,
OMe), 3.92 (s, 3H, OMe), 3.23 (t, J=4.7 Hz, 4H), 2.90–
2.85 (m, 2H), 2.69–2.61 (m, 1H); 13C NMR d 189.2
(CO), 162.8, 151.8, 151.6, 149.7, 144.6, 132.1, 131.1,
129.6, 128.5, 123.4, 120.3, 116.6, 114.8, 111.7, 110.7,
70.9 (OCH2), 65.9 (CH), 60.8 (CH2N), 56.5 (2*OMe)
53.8 (NCH2,CH2), 49.7 (NCH2,CH2). Anal. calcd for
C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C,
71.18; H, 6.93; N, 5.32.
3.3.6.
40-[2-Hydroxy-3-iso-propylamino-propoxy]-4-
methoxy-chalcone (5f). Yield 59%; mp 105–106 ꢂC; MS
(FAB) 370 (M+ +1); IR (KBr) 3420 (OH), 3289 (NH),
1654 (CO); 1H NMR (200 MHz, CDCl3) d 8.02 (d,
J=8.6 Hz, 2H), 7.78 (d, J=15.7 Hz, 1H), 7.60 (d,
J=8.5 Hz, 2H), 7.42 (d, J=15.6 Hz, 1H), 6.99 (d,
J=8.9 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.23–4.09 (m,
3H), 3.85 (s, 3H, OMe), 2.96–2.74 (m, 3H), 1.11 (d,
J=6.2 Hz, 6H). Anal. calcd for C22H27NO4: C, 71.52;
H, 7.37; N, 3.79. Found: C, 71.33; H, 7.42; N, 3.63.
3.3.7. 40-[2-Hydroxy-3-{4-(2-methoxyphenyl)-piperazin-
1-yl}-propoxy]-4-methoxy-chalcone (5g). Yield 66%; mp
97–98 ꢂC; MS (FAB) 503 (M+ +1); IR (KBr) 3451
40-[3-tert-Butylamino-2-hydroxy-propoxy]-3,4-
(OH), 1652 (CO); H NMR (200 MHz, CDCl3) d 8.03
1
3.3.2.
dimethoxy-chalcone (5b). Yield 87%; mp 62–64 ꢂC; MS
(FAB) 414 (M+ +1); IR (KBr) 3450 (broad, OH,
NH), 1650 (CO); 1H NMR (200 MHz, CDCl3) d 8.03
(d, J=8.8 Hz, 2H), 7.76 (d, J=15.5 Hz, 1H), 7.40 (d,
J=15.5 Hz, 1H), 7.26 (s, 1H), 7.17 (dd, J=8.2 Hz, 1.6
Hz, 1H), 7.0 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.3 Hz,
1H), 4.07–4.05 (m, 3H), 3.95 (s, 3H, OMe), 3.93 (s, 3H,
OMe), 2.88 (dd, J=11.9 Hz, 4.0 Hz, 1H), 2.68 (dd,
J=11.9 Hz, 7.5 Hz, 2H), 1.13 (s, 9H). Anal. calcd for
C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found: C,
69.82; H, 7.41; N, 3.16.
(d, J=8.3 Hz, 2H), 7.78 (d, J=15.5 Hz, 1H), 7.60 (d,
J=8.1 Hz, 2H), 7.43 (d, J=15.4 Hz, 1H), 7.03–6.85 (m,
8H), 4.13–4.09 (m, 3H), 3.87 (s, 3H, OMe), 3.86 (s, 3H,
OMe), 3.14–3.10 (m, 4H), 2.90–2.88 (m, 2H), 2.67–2.63
(m, 4H). Anal. calcd for C30H34N2O5: C, 71.69; H, 6.82;
N, 5.57. Found: C, 71.62; H, 6.91; N, 5.42.
3.3.8.
40-[3-{2-(3,4-Dimethoxyphenyl)-ethylamino}-2-
hydroxy-propoxy]-4-methoxy-chalcone (5h). Yield 59%;
mp 120–121 ꢂC; MS (FAB) 492 (M+ +1); IR (KBr)
3431 (broad, OH, NH), 1654 (CO); 1H NMR
(200 MHz, CDCl3) d 8.01 (d, J=8.8 Hz, 2H), 7.78 (d,
J=15.6 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.42 (d,
J=15.5 Hz, 1H), 6.97 (d, J=8.6 Hz, 2H), 6.93 (d,
J=9.1 Hz, 2H), 6.78–6.73 (m, 3H), 4.09–4.01 (m, 3H),
3.87 (s, 3H, OMe), 3.85 (s, 6H, 2*OMe), 2.91–2.77 (m,
6H). Anal. calcd for C29H33NO6: C, 70.86; H, 6.77; N,
2.85. Found: C, 70.81; H, 6.72; N, 2.91.
3.3.3.
40-[2-Hydroxy-3-(4-phenylpiperazin-1-yl)-prop-
oxy]-4-methoxy-chalcone (5c). Yield 70%; mp 165–
167 ꢂC; MS (FAB) 473 (M+ +1); IR (KBr) 3392 (OH),
1652 (CO); 1H NMR (200 MHz, CDCl3) d 8.03 (d,
J=8.8 Hz, 2H), 7.78 (d, J=15.6 Hz, 1H), 7.60
(d, J=8.6 Hz, 2H), 7.42 (d, J=15.5 Hz, 1H), 7.31–7.24

888
M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
3.3.9.
40-[2-Hydroxy-3-methylamino-propoxy]-4-meth-
1644 (CO); 1H NMR (200 MHz, CDCl3) d 7.60 (d,
J=8.9 Hz, 1H), 7.58 (d, J=15.8 Hz, 1H), 7.56
(d, J=8.4 Hz, 2H), 7.45 (t, J=7.1 Hz, 1H), 7.28 (d,
J=15.8 Hz, 1H), 7.08–7.01 (m, 2H), 6.91 (d, J=8.6 Hz,
2H), 4.15–4.04 (m, 3H), 3.84 (s, 3H, OMe), 2.84–2.68
(m, 2H), 2.52 (t, J=5.9 Hz, 2H), 1.40–1.25 (m, 4H), 0.87
(t, J=6.9 Hz, 3H). Anal. calcd for C23H29NO4: C,
72.04; H, 7.62; N, 3.65. Found: C, 71.96; H, 7.57; N,
3.61.
oxy-chalcone (5i). Yield 43%; mp 114–115 ꢂC; MS
(FAB) 342 (M+ +1); IR (KBr) 3487 (OH), 3344 (NH),
1652 (CO); 1H NMR (200 MHz, CDCl3) d 8.01 (d,
J=8.6 Hz, 2H), 7.77 (d, J=15.6 Hz, 1H), 7.59 (d,
J=8.5 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H), 6.98 (d,
J=8.9 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.07–4.05 (m,
3H), 3.85 (s, 3H, OMe), 2.93–2.82 (m, 2H), 2.50 (s, 3H).
Anal. calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10.
Found: C, 70.40; H, 6.72; N, 4.13.
3.3.15.
20-[2-Hydroxy-3-iso-propylamino-propoxy]-4-
3.3.10. 40-[3-n-Butylamino-2-hydroxy-propoxy]-4-meth-
oxy-chalcone (5j). Yield 72%; mp 163–164 ꢂC; MS
(FAB) 384 (M+ +1); IR (KBr) 3367 (broad, OH, NH),
1629 (CO); 1H NMR (200 MHz, CDCl3) d 8.02 (d,
J=8.7 Hz, 2H), 7.77 (d, J=15.3 Hz, 1H), 7.59 (d,
J=8.7 Hz, 2H), 7.41 (d, J=15.5 Hz, 1H), 6.99 (d,
J=8.9 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.20–3.95 (m,
3H), 3.86 (s, 3H, OMe), 2.93–2.55 (m, 2H), 2.55 (t,
J=5.9 Hz, 2H), 1.57–1.39 (m, 4H), 0.93 (t, J=6.9 Hz,
3H). Anal. calcd for C23H29NO4: C, 72.04; H, 7.62; N,
3.65. Found: C, 71.97; H, 7.58; N, 3.61.
methoxy-chalcone (5o). Yield 73%; mp 88–89 ꢂC; MS
(FAB) 370 (M+ +1); IR (KBr) 3450 (OH), 3284 (NH),
1645 (CO); 1H NMR (200 MHz, CDCl3) d 7.60 (d,
J=8.9 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.55 (d,
J=8.4 Hz, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.28 (d, J=15.8
Hz, 1H), 7.08–6.97 (m, 2H), 6.91 (d, J=8.6 Hz, 2H),
4.14–3.95 (m, 3H), 3.84 (s, 3H, OMe), 2.83–2.61 (m,
3H), 0.97 (d, J=6.0 Hz, 6H). Anal. calcd for
C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C,
71.48; H, 7.41; N, 3.71.
3.3.16.
40-[3-tert-Butylamino-2-hydroxy-propoxy]-3,4-
3.3.11.
30-[2-Hydroxy-3-(4-phenylpiperazin-1-yl)-prop-
methylenedioxy-chalcone (5p). Yield 89%; mp 122–
124 ꢂC; MS (FAB) 398 (M+ +1); IR (KBr) 3401
(broad, OH, NH), 1660 (CO); 1H NMR (200 MHz,
CDCl3) d 8.00 (d, J=8.7 Hz, 2H), 7.71 (d, J=15.5 Hz,
1H), 7.36 (d, J=15.5 Hz, 1H), 7.15 (s, 1H), 7.10 (d,
J=8.1 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 6.82 (d, J=7.9
Hz, 1H), 6.00 (s, 2H), 4.12–3.99 (m, 3H), 2.87 (dd,
J=11.8 Hz, 3.6 Hz, 1H), 2.68 (dd, J=11.6 Hz, 6.7 Hz,
1H), 1.13 (s, 9H); 13C NMR d 188.9 (CO), 162.9, 150.1,
148.8, 144.8, 131.9, 131.1, 129.9, 125.4, 120.3, 114.8,
109.0, 107.1, 101.9 (OCH2O), 71.2 (OCH2), 68.9 (CH),
45.0 (CH2N), 29.4 (3*CH3). Anal. calcd for C23H27NO5:
C, 69.50; H, 6.85; N, 3.52. Found: C, 68.84; H, 6.94; N,
3.42.
oxy]-4-methoxy-chalcone (5k). Yield 82%; mp 153–
154 ꢂC; MS (FAB) 473 (M++1); IR (KBr) 3485 (OH),
1652 (CO); 1H NMR (200 MHz, CDCl3) d 7.79 (d,
J=15.6 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8
Hz, 2H), 7.58 (d, J=2.9 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H),
7.39 (d, J=15.6 Hz, 1H), 7.31–7.23 (m, 2H), 7.16 (dd,
J=8.1 Hz, 1.9 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.96–
6.83 (m, 2H), 4.19–4.08 (m, 3H), 3.86 (s, 3H, OMe), 3.23
(t, J=4.9 Hz, 4H), 2.89–2.81 (m, 2H), 2.70–2.62 (m,
4H). Anal. calcd for C29H32N2O4: C, 73.70; H, 6.83; N,
5.93. Found: C, 71.63; H, 6.54; N, 5.91.
3.3.12.
30-[2-Hydroxy-3-iso-propylamino-propoxy]-4-
methoxy-chalcone (5l). Yield 76%; mp 102–103 ꢂC; MS
(FAB) 370 (M+ +1); IR (KBr) 3391 (OH), 3131 (NH)
1650 (CO); 1H NMR (200 MHz, CDCl3) d 7.79 (d,
J=15.7 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.60 (d,
J=8.6 Hz, 2H), 7.55 (d, J=1.9 Hz, 1H), 7.40 (t, J=7.9
Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 7.14 (dd, J=7.6 Hz,
1.6 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 4.09–4.01 (m, 3H),
3.86 (s, 3H, OMe), 2.92–2.74 (m, 3H), 1.10 (d, J=6.2
Hz, 6H). Anal. calcd for C22H27NO4: C, 71.52; H, 7.37;
N, 3.79. Found: C, 71.13; H, 7.29; N, 3.81.
3.3.17.
40-[2-Hydroxy-3-(4-phenylpiperazin-1-yl)-prop-
oxy]-3,4-methylenedioxy-chalcone (5q). Yield 68%; mp
153–154 ꢂC; MS (FAB) 487 (M+ +1); IR (KBr) 3396
(OH), 1651 (CO); H NMR (200 MHz, CDCl3) d 8.02
1
(d, J=8.8 Hz, 2H), 7.71 (d, J=15.5 Hz, 1H), 7.38 (d,
J=15.5 Hz, 1H), 7.27 (t, J=7.9 Hz, 2H), 7.16 (s, 1H),
7.12 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.97
(d, J=7.2 Hz, 1H), 6.91–6.82 (m, 3H), 6.02 (s, 2H),
4.17–4.09 (m, 3H), 3.23 (t, J=4.8 Hz, 4H), 2.89–2.81
(m, 2H), 2.69–2.62 (m, 4H). Anal. calcd for
C29H30N2O5: C, 71.59; H, 6.21; N, 5.76. Found: C,
71.62; H, 6.30; N, 5.81.
3.3.13.
30-[3-tert-Butylamino-2-hydroxy-propoxy]-4-
methoxy-chalcone (5m). Yield 69%; mp 83–84 ꢂC; MS
(FAB) 384 (M+ +1); IR (KBr) 3387 (broad, OH, NH),
1653 (CO); 1H NMR (200 MHz, CDCl3) d 7.78 (d,
J=15.6 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.60 (d,
J=8.7 Hz, 2H), 7.56 (d, J=2.5 Hz, 1H), 7.40 (t, J=7.9
Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 7.14 (dd, J=7.6 Hz,
1.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 4.09–4.01 (m, 3H),
3.86 (s, 3H, OMe), 2.92–2.81 (m, 3H), 1.14 (s, 9H). Anal.
calcd for C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found:
C, 72.08; H, 7.57; N, 3.58.
3.3.18.
40-[3-iso-Butylamino-2-hydroxy-propoxy]-3,4-
methylenedioxy-chalcone (5r). Yield 80%; mp 122–
123 ꢂC; MS (FAB) 398 (M++1); IR (KBr) 3325 (broad,
OH, NH), 1657 (CO); 1H NMR (200 MHz, CDCl3)
d 8.00 (d, J=8.8 Hz, 2H), 7.72 (d, J=15.5 Hz, 1H),
7.36 (d, J=15.5 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J=8.7
Hz, 1.3 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.9
Hz, 1H), 6.01 (s, 2H), 4.09–4.03 (m, 3H), 2.85–2.76
(m, 2H), 2.47 (d, J=6.5 Hz, 2H), 1.78–1.72 (m, 1H),
0.93 (d, J=6.6 Hz, 6H). Anal. calcd for C23H27NO5: C,
69.50; H, 6.85; N, 3.52. Found: C, 69.53; H, 6. 71; N,
3.14.
3.3.14. 20-[3-n-Butylamino-2-hydroxy-propoxy]-4-meth-
oxy-chalcone (5n). Yield 86%; mp 106–107 ꢂC; MS
(FAB) 384 (M+ +1); IR (KBr) 3430 (OH), 3295 (NH),

M. Satyanarayana et al. / Bioorg. Med. Chem. 12 (2004) 883–889
889
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One of the authors, M.S is thankful to CSIR, New
Delhi for financial support and RSIC, CDRI, Lucknow
for providing spectroscopic data and elemental analyses.
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