Synthesis of new N-acryl-1-amino-2-phenylethanol and N-acyl-1-amino-3- aryloxypropanols and evaluation of their antihyperlipidemic, LDL-oxidation and antioxidant activity

Article abstract of DOI:10.1016/j.ejmech.2014.04.020

As a part of our drug discovery program, we identified an alkaloidal amide i.e. Aegeline (V) isolated from the leaves of Aegle marmelos as a dual acting agent (antihyperlipidemic and antihyperglycemic). In continuation of this program, we synthesized new N-acyl-1-amino-2-alcohols (N-acrylated-1-amino-2- phenylethanol and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction and screened for their in-vivo antihyperlipdemic activity in Triton induced hyperlipidemia model, LDL-oxidation and antioxidant activity. Compounds 3, 11 and 13 showed good antihyperlipidemic activity, LDL-oxidation as well as antioxidant activity and comparable activity with marketed antidyslipidemic drug.

Full text of DOI:10.1016/j.ejmech.2014.04.020

European Journal of Medicinal Chemistry 80 (2014) 135e144
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of new N-acryl-1-amino-2-phenylethanol and N-acyl-1-
amino-3-aryloxypropanols and evaluation of their antihyperlipidemic,
LDL-oxidation and antioxidant activity
,
Satinath Sarkar a, Ravi Sonkar b, Gitika Bhatia b, Narender Tadigoppula a
*
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 031, U.P., India
b Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 031, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of our drug discovery program, we identified an alkaloidal amide i.e. Aegeline (V) isolated from
the leaves of Aegle marmelos as a dual acting agent (antihyperlipidemic and antihyperglycemic). In
continuation of this program, we synthesized new N-acyl-1-amino-2-alcohols (N-acrylated-1-amino-2-
phenylethanol and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction and screened for their in-
vivo antihyperlipdemic activity in Triton induced hyperlipidemia model, LDL-oxidation and antioxidant
activity. Compounds 3, 11 and 13 showed good antihyperlipidemic activity, LDL-oxidation as well as
antioxidant activity and comparable activity with marketed antidyslipidemic drug.
Received 18 September 2013
Received in revised form
27 March 2014
Accepted 5 April 2014
Available online 8 April 2014
Keywords:
Aegeline
Ó 2014 Published by Elsevier Masson SAS.
N-Acyl-1-amino-2-alcohols
Antihyperlipidemic activity
LDL-oxidation anti-oxidant activity
Triton model
1. Introduction
synthesized on the basis of a natural product lead, that is, galegine
(II) [5]. The synthetic cholesterol lowering statins such as fluvas-
Hyperlipidemia is an elevation of lipids in the bloodstream and
these lipids include fats, fatty acids, cholesterol, cholesterol esters,
phospholipids, and triglycerides. An increase in plasma lipids,
particularly cholesterol, is a common feature of atherosclerosis, a
condition involving arterial damage, which may lead to ischaemic
heart disease, myocardial infarction, and cerebrovascular accidents.
These conditions are responsible for one-third of deaths in indus-
trialized nations [1]. In 1984, it was demonstrated for the first time
that there exists a link between serum cholesterol levels and risk to
coronary heart disease (CHD) [2]. CHD is caused by the narrowing
of the artery that supplies nutrients and oxygen to the heart. A 1%
drop in serum cholesterol reduces the risk for CHD by 2% [3]. In
addition to this, cholesterol lowering drugs treatments can signif-
icantly reduce morbidity from CHD, thus providing a causal role for
cholesterol in coronary events. The discovery of new drugs from
traditional medicine is not a new phenomenon (Fig. 1). Metformin
(I) is currently used as antidiabetic agent in the treatment of type 2
diabetes (Fig. 1). Metformin (I) and its analogues [4] were
tatin (III) [6], cerivastatin [7] were synthesized on the basis of
natural product lead, that is, mevastatin (IV) [8]. The plant derived
saponin derivative, pamaqueside (CP-148623) [9], has been re-
ported for cholesterol absorption up to 35e40% and the fish oils,
which contain fatty acids such as eicosapentaenoic acid and
docosahexenoic acids, have been reported for their lowering ac-
tivity on triglycerides and cholesterol [10]. Christophe et al. [11]
discovered glucose induced insulin secretion in vitro and ex vivo
of 4-hydroxyisoleucine. Furthermore, in type 2 diabetic rat model
the compound was active and partly corrected hyperglycemia and
glucose tolerance. Our group had reported the lipid lowering ac-
tivity in phytoconstituents such as 4-hydroxyisoleucine, [12]
amyrin derivatives [13], lupeol derivatives [14], calophyllic acid
and isocalophyllic acid [15], canophyllic acid [15], amentoflavone
[15], and furanoflavonoids [16] etc. On the other hand, interesting
lipid lowering activities of synthetic hybrid benzofuranebisindole
derivatives [17], 2,5,6-Trisubstituted imidazo[2,1-b][1,3,4]thiadia-
zoles [18], and 2-(4-[(2-hydroxybenzyl) amino]-phenyl amino-
methyl)-phenol [19] etc are also found in literature.
The plant Aegle marmelos is commonly known as ‘bael’ in India
[20], belongs to the family of Rutaceae, widely used in Indian Ay-
urvedic medicine for the treatment of diabetes mellitus. In addition
* Corresponding author.
E-mail
addresses:
tnarender@rediffmail.com,
t_narendra@cdri.res.in
(N. Tadigoppula).
http://dx.doi.org/10.1016/j.ejmech.2014.04.020
0223-5234/Ó 2014 Published by Elsevier Masson SAS.

136
S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
oxirane (7) were prepared in very good yields from 4-tert-Butyl-
phenol, 3-methoxyphenol, 4-chlorophenol and 3-methylphenol
respectively by refluxing with epichlorohydrin in dry acetone in
presence of potassium carbonate at 60 ꢀC for 4 h.
2-[(4-tert-Butylphenoxy)methyl]oxirane
(4),
2-[(3-
methoxyphenoxy)methyl]oxirane (5) and 2-[(4-chlorophenoxy)
methyl]oxirane (6) were treated respectively with BF3*OEt2 in nitriles
(acetonitrile, acrylonitrile, benzonitrile and 4-methoxybenzonitrile)
under similar reaction condition as shown in Scheme 1, which
provided N-[3-(4-tert-Butylphenoxy)-2-hydroxy-propyl]acetamide
(8), N-[3-(4-tert-Butylphenoxy)-2-hydroxypropyl]acrylamide (9),
N-[3-(4-tert-Butylphenoxy)-2-hydroxypropyl]benzamide (10) and
N-[3-(4-tert-Butylphenoxy)-2-hydroxypropyl]-4-methoxybenzamide
(11), N-[2-hydroxy-3-(3-methoxyphenoxy)-propyl]acetamide (12),
N-[2-hydroxy-3-(3-methoxyphenoxy)propyl]acrylamide (13), N-[2-
hydroxy-3-(3-methoxyphenoxy)propyl]benzamide (14) and N-[2-
hydroxy-3-(3-methoxyphenoxy)propyl]-4-methoxybenzamide (15),
N-[3-(4-chlorophenoxy)-2-hydroxypropyl]acetamide (16), N-[3-(4-
chlorophenoxy)-2-hydroxypropyl]acrylamide (17), N-[3-(4-chloro-
phenoxy)-2-hydroxypropyl]benzamide (18) and N-[3-(4-chloro-
phenoxy)-2-hydroxypropyl]-4-methoxybenzamide (19) with good
yields (Scheme 2).
After verifying the Ritter reaction with three different oxiranes,
2-(m-tolyloxymethyl)oxirane (7) was also treated with BF3*OEt2 in
nitriles (acetonitrile and acrylonitrile) under same experimental
condition as shown in Scheme 1, which gave N-[2-hydroxy-3-(m-
tolyloxy)propyl]acetamide (20) and N-[2-hydroxy-3-(m-tolyloxy)-
propyl]acrylamide (21) in good yields (Scheme 3).
The yields of N-acylated-1-amino-2-alcohols indicate that the
transformation seems to be general; thus the reaction can be car-
ried out easily on oxiranes with different nitriles such as aliphatic
and aromatic. The known compounds were identified by spectro-
scopic data and compared with those data reported in literatures.
Further structure elucidation of new compounds was performed by
different NMR spectroscopic and Mass spectrometry techniques.
Fig. 1. Naturally occurring and synthetic Antidiabetic and Antidyslipdemic agents.
to this our group has discovered the antidyslipidemic activity in the
leave’s of alcoholic extract and its chloroform fraction and
bioactivity-guided fractionation and isolation work led to discovery
of Aegeline (Fig. 1), as an antihyperglycemic and antidyslipidemic
principle [21].
Aegeline is a naturally occurring N-acylated-1-amino-2-alcohol.
Recently our group synthesized few N-acylated-1-amino-2-
alcohols, as Aegeline analogues, which showed antidyslipidemic
and antioxidant activity in Triton induced hyperlipidemia model
[22]. In continuation of this program, we synthesized new N-acyl-
ated-1-amino-2-alcohols (N-acrylated-1-amino-2-phenylethanol
and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction
to evaluate their antihyperlipidemic, LDL-oxidation and antioxi-
dant activity. Further we have studied the dose dependent lipid
lowering activity, lipoprotein triglycerides level, LPL activity, anti-
oxidant and LDL oxidation.
3. Pharmacology study
3.1. Animals used
2. Chemistry
Rats (Charles foster strain, male, adult, body weight 200e225 g)
were kept in a room with controlled temperature (25e26 ꢀC), hu-
midity (60e80%) and12/12 h light/dark cycle (light on from 8.00
A.M. to 8.00 P.M.) under hygienic conditions. Animals, which were
acclimatized for one week before starting the experiment, had free
access to the normal diet and water.
The synthesis of N-acylated-1-amino-2-alcohols via Ritter re-
action, was started with the ring opening reaction of commercially
available styrene oxide 1 in acetonitrile in the presence of
BF3*OEt2, which led to N-(2-hydroxy-2-phenylethyl)acetamide (2)
in good yield (Scheme 1). Encouraged by these results similar re-
action on styrene oxide 1 was performed using acrylonitrile and
obtained respective N-(2-hydroxy-2-phenyl-ethyl)acrylamide (3)
in good yield (Scheme 1). Compound 2 and 3 are close structural
analogues of aegeline (V).
3.2. Lipid lowering and post heparin lipolytic activity
Rats were divided into groups, control, triton-induced,
After the successful results with styrene oxide (1), oxiranes (4e
7) were used to generate N-acylated-1-amino-3-aryloxy-2-
propanols (N-acyl-1-amino-3-aryloxy-2-propanols) to extend the
scope and the generality of this reaction. 2-[(4-tert-Butylphenoxy)
methyl]oxirane (4), 2-[(3-methoxyphenoxy)methyl]oxirane (5), 2-
[(4-chlorophenoxy)methyl]oxirane (6) and 2-(m-tolyloxymethyl)
triton
þ
compound (2,3 and 8e21) and Gemfibrozil (Gem)
(100 mg/kg) treated groups containing six rats in each group. In this
experiment of 18 h, hyperlipidemia was developed by administra-
tion of triton WR-1339 (Sigma chemical company, St. Louis, MO,
USA) at a dose of 400 mg/kg b.w. intraperitoneally to animals of all
the groups except the control. These derivatives were macerated
with gum acacia (0.2% w/v), suspended in water and fed simulta-
neously with triton with a dose of 100 mg/kg, p.o. to the animals of
treated group and the diet being withdrawn. Animals of control and
triton group without treatment with compounds (2,3 and 8e21)
were given same amount of gum acacia suspension (vehicle). After
18 h of treatment the animals were anaesthetized with thiopentone
solution (50 mg/kg, b.w.) prepared in normal saline and then 1.0 ml
blood was withdrawn from retro-orbital sinus using glass capillary
in EDTA coated Eppendorf tube (3.0 mg/ml blood). The blood was
Scheme 1. Synthesis of N-acylated-1-amino-2-alcohols 2 and 3. Reagents and condi-
tions: (a) BF3*OEt2 (0.2 mmol), CH3CN (1 ml), 80 ꢀC, 12 h. (b) BF3*OEt2 (0.2 mmol),
CH2]CHCN (1 ml), 80 ꢀC, 12 h.

S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
137
Scheme 2. Synthesis of N-acylated-1-amino-3-aryloxy-2-propanols 8e19. Reagents and conditions: (a) BF3*OEt2 (0.2 mmol), CH3CN (1 ml), 80 ꢀC, 12 h. (b) BF3*OEt2 (0.2 mmol),
CH2]CHCN (1 ꢀml), 80 ꢀC, 12 h. (c) BF3*OEt2 (0.2 mmol), C6H5CN (1 ml), 80 ꢀC, 12 h. (d) BF3*OEt2 (0.2 mmol), 4-OCH3C6H5 (1 ml), 80 ꢀC, 12 h.

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S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
Scheme 3. Synthesis of N-[2-hydroxy-3-(m-tolyloxy)propyl]acetamide (20) and N-[2-hydroxy-3-(m-tolyloxy)-propyl]acrylamide (21). Reagents and conditions: (a) BF3*OEt2
(0.2 mmol), CH3CN (1 ml), 80 ꢀC, 12 h. (b) BF3*OEt2 (0.2 mmol), CH2]CHCN (1 ml), 80 ꢀC, 12 h.
centrifuged at 4 ꢀC for 10 min and plasma was separated. Plasma
was diluted with normal saline (ratio of 1:3) and used for analysis
of total cholesterol (TC), triglycerides (TG) and phospholipids (PL)
by standard enzymatic methods [23] and post-heparin lipolytic
activity (PHLA) were assayed using spectrophotometer and Beck-
mann auto-analyzer and standard kits purchased from Beckmann
Coulter International, USA [24].
on polyacrylamide gel electrophoresis. LDL (0.71 mg) and CuCl2$2H2O
(10 M) in the absence or presence of compound 2 in 50 mM phos-
m
phate buffer saline (pH 7.4) to a final volume of 1.5 ml, was incubated at
37 ꢀC for 16 h. The level of lipid peroxides in unoxidised LDL, oxidised
LDL with Cuþþ in the absence or presence of compounds was assayed
as thiobarbituric acid reactive substances (TBARS). Briefly the reaction
mixture contained 0.5 ml SDS (8% w/v), 0.5 ml glacial acetic acid,1.5 ml
TBA (0.8% w/v) was heated in a boiling water bath for one hour. After
cooling up to room temperature optical density of reaction mixture
was read at 532 nm with respective reagent blank. The level of lipid
peroxide as nmol of Malondialdehyde formed was calculated by taking
absorption coefficient of MDA as 1.78 ꢂ 105 cmꢁ1 Mꢁ1 mg protein.
3.3. Lipoprotein measurement in blood plasma of triton induced
hyperlipidemic rats
Plasma was fractionated into very low density lipoprotein (VLDL),
low density lipoprotein (LDL) and high density lipoprotein (HDL) by
poly anionic precipitation methods. Plasma and lipoproteins were
analyzed for their total cholesterol (TC), phospholipid (PL), and tri-
glyceride (TG) by standard procedures reported earlier [25].
4. Results and discussion
4.1. Effect of synthesized compounds on blood plasma lipids profile
in triton induced hyperlipidemic rat
3.4. Lipoprotein lipase activity in liver of triton induced
hyperlipidemic rats
All the synthesized compounds (2,3 and 8e21) were screened in
Triton-induced hyperlipidemic rats [17,30] at dose of 100 mg/kg
(Table 1). Compounds 3,11 and 13 showedgood lipidlowering activity
(Table 1). Compound 3 lowered the total cholesterol (TC) by 28%,
triglycerides (TG) by 28%, phospholipids (PL) by 26%, reactivation of
post heparin lipolytic activity (PHLA) by 17%, compound 11 lowered
the TC by 26%, TG by 25% PL by 27%, reactivation of PHLA by 15%,
compound 13 lowered the TC by 24%, TG by 23%, PL by 26%, reac-
tivation of PHLA by 6% (Table 1). Marketed drug Gemfibrozil (Gem)
lowered the TC by 33%, TG by 31% PL by 35%, reactivation of PHLA by
18% (Table 1). Whereas, compounds2,10,19, and20showedmoderate
antihyperlipidemic activity (Table 1). Compound 2 lowered the TC by
20%, TGby21%,PL by22%,andreactivationofPHLAby12%. Compound
10 lowered the TC by 17%, TG by 16%, PL by 15%, and reactivation of
PHLA by 10%. Compound 19 lowered the TC by 14%, TG by 14%, PL by
13%, and reactivation of PHLA by 8%. Compound 20 lowered the TC by
16%, TG by 14%, PL by 14%, and reactivation of PHLA by 6%.
Liver was homogenized (10%, w/v) in cold 100 mM phosphate
buffer pH 7.2 and used for the assay of total lipolytic activity of li-
poprotein lipase (LPL) [24].
3.5. Antioxidant activity (generation of free radicals)
Superoxide anions (Oꢁ2) were generated enzymatically by
xanthine (160 mM), xanthine oxidase (0.04 U) and nitroblue
tetrazolium (320
mM) in absence or presence of compounds
(200 g/ml) in 100 mM phosphate buffer (pH 8.2) [26]. Fractions
m
were sonicated well in phosphate buffer before use. The reaction
mixtures were incubated at 37 ꢀC and after 30 min the reaction was
stopped by adding 0.5 ml glacial acetic acid. The amount of for-
mazone formed was measured at 560 nm on a spectrophotom-
eter. Percentage inhibition was calculated taking absorption coef-
ficient of formazone as 7.2 ꢂ 103 M/cm. In another set of
experiment, an effect of compounds on generation of hydroxyl
radicals (OHꢃ) was also studied by non-enzymic reactants [27].
Briefly (OHꢃ) were generated in a non-enzymic system comprised
of deoxy ribose (2.8 mM), FeSO4$7H2O (2 mM), sodium ascorbate
4.2. Effect of compounds 3, 11 and 13 on lipid lowering at different
doses in triton induced hyperlipidemic rat
After the confirmation of most active compounds in primary
screening we further, evaluated the dose dependent efficacy of most
active compounds 3,11 and 13 in triton-induced hyperlipidemic rats
at different doses of 50, 100 and 150 mg/kg body weight. The dose
dependent activity results are shown in Table 2. Compound 3 low-
ered the TC by 21%e28%, PL by 22%e27% and TG by 20%e30% fol-
lowed by increase in PHLA level by 12%e18%. Compound 11 lowered
the TC by 18%e29%, PL by 16%e28%, and TG by 18%e27% followed by
increase in PHLA level by 11%e16% similarly compound 13 lowered
the TC by 14%e25%, PL by 17%e28%, and TG by 16%e26% followed by
increase in PHLA level by 10%e15% respectively.
(2.0 mM) and H2O2 (2.8 mM) in 50
final volume of 2.5 ml. The above reaction mixtures in the absence
or presence of compounds (200
g/ml) were incubated at 37 ꢀC for
mM KH2PO4 buffer, pH 7.4 to a
m
90 min. Reference samples and reagent blanks were also run
simultaneously. Malondialdehyde (MDA) content in both experi-
mental and reference samples were estimated spectrophotomet-
rically by thiobarbituric acid method as mentioned above [23,28].
3.6. LDL oxidation
Serum was separated from the blood of normolipemic donors who
were fasted overnight and fractionated into very low-density lipo-
protein (VLDL), low density lipoprotein (LDL) and high density lipo-
protein (HDL) by ultracentrifugation [29]. The lipoproteins
preparations were dialyzed against 150 mM NaCl containing EDTA
(0.02% w/v) inpresence of N2 gas in cold. The purity of LDL was checked
4.3. Effect of compounds 3, 11 and 13 on plasma lipoprotein lipids
in triton induced hyperlipidemic rats
The most active compounds 3,11 and 13 were also tested for their
effect on plasma lipoprotein lipids. As shown in Fig. 2, the analysis of

S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
139
Table 1
Percentage (%) change of plasma lipids with the treatment of compounds in Triton-induced hyperlipidemic rats at dose of 100 mg/kg body weight.
Animal groups
Lipids profile
PHLA (nmol of free fatty acids
formed/h/ml of plasma)
TC (mg/dl)
PL (mg/dl)
TG (mg/dl)
Control
Triton
78.53 ꢄ 5.13
82.64 ꢄ 4.71
79.43 ꢄ 6.08
18.86 ꢄ 1.37
244.27 ꢄ 16.84C
(þ3.110 Fold)
269.23 ꢄ 19.82C
(þ3.257 Fold)
239.38 ꢄ 16.38C
(þ3.013 Fold)
11.59 ꢄ 0.93C
(ꢁ38.54%)
Tritonþ
Tritonþ
Tritonþ
195.41 ꢄ 12.33** (ꢁ20%)
212.69 ꢄ 16.36** (ꢁ21%)
189.11 ꢄ 14.28** (ꢁ21%)
12.98 ꢄ 0.93* (þ12%)
175.87 ꢄ 10.56*** (ꢁ28%)
219.84 ꢄ 17.26* (ꢁ10%)
199.23 ꢄ 13.78*** (ꢁ26%)
239.61 ꢄ 13.67* (ꢁ11%)
172.35 ꢄ 11.99*** (ꢁ28%)
208.26 ꢄ 18.61* (ꢁ13)
13.56 ꢄ 1.18* (þ17%)
12.05 ꢄ 0.73NS (þ4%)
Tritonþ
Tritonþ
217.40 ꢄ 14.83* (ꢁ11%)
202.74 ꢄ 15.91* (ꢁ17%)
242.30 ꢄ 15.48* (ꢁ10%)
226.15 ꢄ 14.26* (ꢁ16%)
210.65 ꢄ 12.96* (ꢁ12)
203.47 ꢄ 18.21* (ꢁ15)
13.32 ꢄ 1.2NS (þ4%)
12.74 ꢄ 0.91* (þ10%)
Tritonþ
Tritonþ
180.75 ꢄ 13.49*** (ꢁ26%)
212.51 ꢄ 18.27* (ꢁ13%)
196.53 ꢄ 16.11*** (ꢁ27%)
242.30 ꢄ 17.91* (ꢁ10%)
179.53 ꢄ 13.73*** (ꢁ25)
210.65 ꢄ 14.52* (ꢁ12)
11.93 ꢄ 0.52* (þ15%)
12.28 ꢄ 0.88NS (þ6%)
Tritonþ
Tritonþ
185.64 ꢄ 11.63*** (ꢁ24%)
217.40 ꢄ 16.62* (ꢁ11%)
199.23 ꢄ 16.19*** (ꢁ26%)
242.30 ꢄ 21.68* (ꢁ10%)
184.32 ꢄ 11.85*** (ꢁ23)
215.44 ꢄ 17.33* (ꢁ10)
13.21 ꢄ 1.11* (þ14%)
12.16 ꢄ 0.63NS (þ5%)
Tritonþ
Tritonþ
222.28 ꢄ 29.35NS (ꢁ9%)
224.72 ꢄ 18.69NS (ꢁ8%)
247.69 ꢄ 15.82NS (ꢁ8%)
253.07 ꢄ 19.47NS (ꢁ6%)
217.83 ꢄ 13.29NS (ꢁ9)
11.93 ꢄ 0.71NS (þ3%)
220.22 ꢄ 18.46NS (ꢁ8)
12.63 ꢄ 0.66NS (þ3%)
(continued on next page)

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S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
Table 1 (continued )
Animal groups
Lipids profile
PHLA (nmol of free fatty acids
formed/h/ml of plasma)
TC (mg/dl)
PL (mg/dl)
TG (mg/dl)
Tritonþ
214.95 ꢄ 17.32* (ꢁ12%)
242.30 ꢄ 17.83* (ꢁ10%)
213.04 ꢄ 17.83* (ꢁ11)
11.93 ꢄ 0.79NS (þ9%)
Tritonþ
Tritonþ
Tritonþ
227.17 ꢄ 12.87NS (ꢁ7%)
210.07 ꢄ 14.63* (ꢁ14%)
205.18 ꢄ 13.81* (ꢁ16%)
255.76 ꢄ 22.31NS (ꢁ5%)
231.53 ꢄ 18.72* (ꢁ14%)
231.53 ꢄ 18.39* (ꢁ14%)
220.22 ꢄ 15.39NS (ꢁ8)
208.26 ꢄ 16.26* (ꢁ13)
205.86 ꢄ 17.38* (ꢁ14%)
12.51 ꢄ 0.96NS (þ3%)
13.67 ꢄ 0.51NS (þ8%)
12.28 ꢄ 0.82NS (þ6%)
Tritonþ
214.95 ꢄ 18.92* (ꢁ12%)
163.66 ꢄ 11.38*** (ꢁ33%)
242.30 ꢄ 12.79* (ꢁ10%)
185.76 ꢄ 11.66*** (ꢁ31%)
208.26 ꢄ 18.34* (ꢁ13%)
155.59 ꢄ 10.72*** (ꢁ35)
12.05 ꢄ 0.77NS (þ4%)
Triton þ Gemfibrozil
13.67 ꢄ 0.51* (þ18%)
Each parameter represents pooled data from 6 rats/group and values are expressed as mean ꢄ S.D. CP < 0.001, Triton treated group compared with control group and *P < 0.05;
NS
**P < 0.01; ***P < 0.001 Triton plus compounds groups compared with Triton treated group only. NOTE:
(non significant) and F (Fold change over control group).
hyperlipidemic plasma of triton administered rats showed marked
increase in the level of lipoprotein TG and these effects were pro-
nounced for VLDL-TG and LDL-TG followed by a decrease in HDL-TG
as compared to control rats. Interestingly, compounds 3, 11 and 13,
significantly reversed the levels of VLDL-TG, LDL-TG and HDL-TG, the
complete lipid profile results are shown in Fig. 2.
decreased the level of FFA followed by increase in LPL, complete
activity results are shown in Fig. 3.
4.5. Antioxidant activity
Recent studies have demonstrated that the generation of large
quantities of reactive oxygen species can cause activation of lipid
peroxidation, protein modification, which leads to cardiovascular
diseases (CVD) [31]. Therefore all the synthesized compounds (8e
21) were screened for their antioxidant activity (Table 3). The
compounds 3, 10, 11 and 13 exhibited antioxidant activity (Table 3),
among them 3, 11 and 13 are also active in hyperlipidemia studies.
A significant decrease in superoxide anions (26%, 27%, 33% and 25%)
and hydroxyl radicals (23%, 29%, 35% and 23%) were observed
4.4. Effect of compounds 3, 11 and 13 on hepatic-LPL activity in
triton induced hyperlipidemic rats
Further the compounds 3, 11 and 13 were studied for hepatic-
LPL activity in triton induced hyperlipidemic rats. Administration
of triton in rats markedly decreased LPL activity in liver as shown in
Fig. 3. After treatment with compounds 3, 11 and 13 significantly
Table 2
Percentage (%) change of plasma lipids with the treatment of compounds 3, 11 and 13 in triton-induced hyperlipidemic rats at different doses.
Animal groups
Lipids profile
PHLA (nmol of free fatty
acids formed/h/ml of plasma)
TC (mg/dl)
PL (mg/dl)
TG (mg/dl)
Control
Triton
83.26 ꢄ 5.82
80.19 ꢄ 6.31
79.68 ꢄ 4.83
20.03 ꢄ 1.61
263.33 ꢄ 20.08c (þ3.16 Fold)
251.69 ꢄ 16.59c (þ3.13Fold)
248.92 ꢄ 18.23c (þ3.12Fold)
13.11 ꢄ 1.22c (ꢁ34.54%)
Triton D 3
50 mg/kg
100 mg/kg
150 mg/kg
Triton D 11
50 mg/kg
100 mg/kg
150 mg/kg
Triton D 13
50 mg/kg
100 mg/kg
150 mg/kg
208.03 ꢄ 13.36** (ꢁ21%)
189.59 ꢄ 11.23*** (ꢁ28%)
189.03 ꢄ 15.44***,# (ꢁ28%)
196.31 ꢄ 11.83** (ꢁ22%)
186.25 ꢄ 13.66*** (ꢁ26%)
183.73 ꢄ 15.73***,# (ꢁ27%)
199.13 ꢄ 13.61** (ꢁ20%)
179.22 ꢄ 11.76*** (ꢁ28%)
174.24 ꢄ 14.59***,# (ꢁ30%)
14.68 ꢄ 1.08* (þ12%)
15.33 ꢄ 1.14* (þ17%)
15.46 ꢄ 1.12*,# (þ18%)
215.93 ꢄ 16.22* (ꢁ18%)
194.86 ꢄ 14.31*** (ꢁ26%)
186.96 ꢄ 11.86***,# (ꢁ29%)
211.41 ꢄ 13.38* (ꢁ16%)
183.73 ꢄ 12.49*** (ꢁ27%)
181.21 ꢄ 13.92***,# (ꢁ28%)
204.11 ꢄ 14.16* (ꢁ18%)
186.69 ꢄ 12.27*** (ꢁ25%)
181.71 ꢄ 13.28***,# (ꢁ27%)
14.55 ꢄ 1.26* (þ11%)
15.05 ꢄ 1.20* (þ15%)
15.20 ꢄ 1.09*,# (þ16%)
226.46 ꢄ 15.88* (ꢁ14%)
200.13 ꢄ 16.19*** (ꢁ24%)
197.49 ꢄ 13.21***,# (ꢁ25%)
208.90 ꢄ 15.64* (ꢁ17%)
186.25 ꢄ 14.38*** (ꢁ26%)
181.16 ꢄ 15.18***,# (ꢁ28%)
209.09 ꢄ 12.82* (ꢁ16%)
191.66 ꢄ 15.22*** (ꢁ23%)
184.20 ꢄ 14.46***,# (ꢁ26%)
14.42 ꢄ 1.28* (þ10%)
14.94 ꢄ 1.21* (þ14%)
15.07 ꢄ 1.33*,# (þ15%)
Each parameter represents pooled data from 6 rats/group and values are expressed as mean ꢄ S.D. cP < 0.001, Triton treated group compared with control group and *P < 0.05;
**P < 0.01; ***P < 0.001 Triton plus compounds groups compared with Triton treated group only. NOTE: # non significant between 100 and 150 mg/kg doses in treated groups
of compounds; F (Fold change over control group).

S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
141
Fig. 2. Effect of compounds 3, 11 and 13 on lipoprotein metabolism in triton induced hyperlipidemic rats. Blood was drawn after 18 h of hyperlipidemia was developed by
administration of triton WR-1339 with and without compounds 3, 11 and 13 and gemfibrozil (100 mg/kg). Compounds 3, 11 and 13 and gemfibrozil (Gem) improve lipoprotein TG
level in triton induced hyperlipidemic rats. Values are expressed as the mean ꢄ SD (n ¼ 6). *P < 0.05; **P < 0.01; ***P < 0.001; NS (non significant) compared to triton treated only
and uP < 0.01; jP < 0.001 comparison triton and triton plus compound treated groups.
respectively by compounds 3, 10, 11 and 13. Furthermore, com-
pounds 3, 10, 11 and 13 at 200 g/ml reduced 25%, 26%, 34% and 23%
of the microsomal lipid per-oxidation respectively.
were recorded on PerkineElmer AC-1 spectrometer. 1H NMR and
13C spectra were run on Bruker Advance DPX 300 MHz spectrom-
eter in CDCl3 and TMS was used as internal standard. ESI mass
spectra were recorded on JEOL SX 102/DA-6000. Silica gel 60e120
mesh was used as stationary phase to isolate the compounds.
Melting points were uncorrected and were recorded on a Buchi B-
54 melting point apparatus.
m
4.6. Effect of compounds 3, 10, 11 and 13 on LDL oxidation
Aerobic oxidation of LDL even in the absence of metal ions
caused formation of TBARS (nmol MDA/mg protein), which were
increased by 10e15 folds in presence of Cuþ2. Compounds 3, 10, 11
6.2. Synthesis
and 13 at 200
mg/ml concentrations in above reaction mixture
protected LDL against oxidative changes (Fig. 4).
6.2.1. General procedure for the preparation of N-acyl-1-amino-2-
alcohols (2e3 & 8e21)
To a stirred solution of the corresponding epoxide 1 or oxiranes
4e7 (0.2 mmol) in the corresponding nitrile (1 ml) was added
BF3*OEt2 (0.025 ml, 0.2 mmol) at room temperature. After that the
mixture was stirred at 80 ꢀC for 12 h. An aqueous saturated solution
of sodium bicarbonate (5 ml) was added and the mixture was
stirred at room temperature for 5 min. Then, the aqueous phase
was extracted with ethyl acetate (3 ꢂ 5 ml), and the combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum. Column chromatography on silica gel
(60e120 mesh) using chloroform/methanol (10:1) as eluent pro-
vided the desired compounds 2e3 and 8e21.
5. Conclusion
In conclusion a new series of N-acyl-1-amino-2-alcohols (N-
acrylated-1-amino-2-phenylethanol, 3 and N-acylated-1-amino-3-
aryloxypropanols, 8e21) have been synthesized in one step via
Ritter reaction on the basis of natural product lead i.e. aegeline and
evaluated their antihyperlipidemic, LDL-oxidation and antioxidant
activity. From this series, compounds 3, 11 and 13 are turned out to
be active in antihyperlipidemic studies and also exhibited LDL-
oxidation and antioxidant activity. Further work is in progress in
our laboratory for lead optimization to develop a potent anti-
hyperlipidemic agent.
6.2.1.1. N-(2-Hydroxy-2-phenylethyl)acetamide (2). White solid;
m.p.: 125e127 ꢀC (lit. [32] m.p. 125e126 ꢀC); IR (KBr): nmax 3301,
6. Experimental protocols
3082, 1650, 1548, 1296 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d
7.43e
7.33 (m, 5H), 5.29 (t, J ¼ 4.1 Hz, 1H), 3.89e3.85 (m, 1H), 3.56e3.52
(m, 1H), 1.88 (s, 3H); 13C NMR (75 MHz):
173.2 (C), 143.1 (C), 128.6
6.1. General materials and instrumentations
d
All reagents were purchased from commercial suppliers and
used without further purification. IR spectra of the compounds
(2CH), 127.2 (2CH), 126.5 (CH), 72.3 (CH), 46.1 (CH2), 23.7 (CH3); MS
(ESI): m/z ¼ 180.1 (MþH)þ, 162.1 (M-H2OþH)þ.

142
S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
Fig. 4. Compounds 3, 10, 11 and 13 reduced the LDL-oxidation at dose of 200 mg/ml in
normal donor blood sample. Data expressed as mean ꢄ S.D. ***P < 0.001compared to
treated values with Control.
6.2.1.4. N-[3-(4-t-Butylphenoxy)-2-hydroxypropyl]acrylamide
Yellow oil; IR (Neat): nmax 3325, 3077, 2970, 2940, 1652, 1590, 1450,
1380 cmꢁ1 1H NMR (CDCl3, 300 MHz):
(9).
;
d
7.37 (d, J ¼ 8.8 Hz, 2H),
6.93 (d, J ¼ 8.6 Hz, 2H), 6.17e5.99 (m, 2H), 5.66e5.56 (m, 1H), 4.36e
4.22 (m, 2H), 4.01e3.95 (m, 1H), 3.38e3.35 (m, 1H), 3.35e3.23 (m,
1H), 1.37 (s, 9H); 13C NMR (75 MHz):
d 170.2 (C), 157.6 (C), 144.5 (C),
Fig. 3. Compounds 3, 11 and 13 at dose of 100 mg/kg, re-activate hepatic LPL activity
by 36%, 28% and 24% in triton induced hyperlipidemic rats. Each parameter represents
pooled data from 6 rats/group and values are expressed as mean ꢄ S.D. ***P < 0.001
between control and triton, triton plus compound treated rats groups gemfibrozil
(100 mg/kg) taken as standard drug. jP < 0.001 between triton and triton plus com-
pound treated rats groups gemfibrozil (Gem).
131.7 (CH), 127.9 (CH2), 126.1 (2CH), 114.5 (2CH), 72.9 (CH2), 67.2
(CH), 43.3 (CH2), 34.6 (C), 31.5 (3CH3); MS (ESI): m/z ¼ 278.2
(MþH)þ, 260.2 (M-H2OþH)þ.
6.2.1.5. N-[3-(4-t-Butylphenoxy)-2-hydroxypropyl]benzamide (10).
Yellow oil; IR (Neat): nmax 3322, 3065, 2960, 2915, 2845, 1651, 1610,
1510, 1385 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
d
8.01e7.99 (m, 2H),
7.53e7.28 (m, 2H), 5.12e5.03 (m, 1H), 4.35e3.89 (m, 4H), 1.34 (s,
9H); 13C NMR (75 MHz):
164.1 (C), 156.3 (C), 144.1 (C), 131.4 (CH),
6.2.1.2. N-(2-Hydroxy-2-phenylethyl)acrylamide (3). Pale yellow
oil; IR (Neat): nmax 3310, 3090,1648,1615,1448,1298 cmꢁ1; 1H NMR
d
(CDCl3, 300 MHz):
5.60 (m, 1H), 5.26e5.22 (m, 1H), 3.57e3.55 (m, 1H), 3.33e3.31 (m,
1H); 13C NMR (75 MHz):
168.0 (C), 143.3 (C), 128.6 (CH), 127.7
d 7.41e7.32 (m, 5H), 6.24e6.18 (m, 2H), 5.68e
128.3 (2CH), 128.3 (2CH), 127.6 (C), 126.3 (2CH), 114.2 (2CH), 76.5
(CH2), 69.4 (CH), 57.4 (CH2), 34.1 (C), 31.5 (3CH3); MS (ESI): m/
z ¼ 328.2 (MþH)þ, 310.2 (M-H2OþH)þ.
d
(2CH), 127.3 (2CH), 126.7 (CH), 126.3 (CH2), 72.1 (CH), 44.2 (CH2);
MS (ESI): m/z ¼ 192.1 (MþH)þ, 174.1 (M-H2OþH)þ.
6.2.1.6. N-[3-(4-t-Butylphenoxy)-2-hydroxypropyl]-4-
methoxybenzamide (11). Yellow oil; IR (Neat): nmax 3320, 3070,
6.2.1.3. N-[3-(4-t-Butylphenoxy)-2-hydroxypropyl]acetamide
Yellow oil; IR (Neat): nmax 3315, 2955, 1658, 1550, 1480, 1395,
1268 cmꢁ1 1H NMR (CDCl3, 300 MHz):
(8).
2965, 2925, 2855, 2830, 1650, 1605, 1515, 1395 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz):
7.12 (d, J ¼ 8.5 Hz, 2H), 6.84 (d, J ¼ 8.7 Hz, 2H), 4.48e4.20 (m, 2H),
4.05e3.98 (m, 1H), 3.79 (s, 3H), 3.53e3.51 (m, 2H), 1.35 (s, 9H); 13
NMR (75 MHz): 168.4 (C),159.7 (C), 155.5 (C),143.5 (C),130.6 (CH),
d
7.90 (d, J ¼ 8.7 Hz, 2H), 7.44 (d, J ¼ 8.7 Hz, 2H),
;
d
7.35 (d, J ¼ 8.7 Hz, 2H),
6.92 (d, J ¼ 8.7 Hz, 2H), 4.35e3.98 (m, 2H), 3.85e3.84 (m,1H), 3.36e
C
3.33 (m, 1H), 3.29e3.26 (m, 1H), 1.86 (s, 3H), 1.35 (s, 9H); 13C NMR
d
(75 MHz):
d
166.0 (C), 156.3 (C), 144.2 (C), 126.5 (2CH), 114.3 (2CH),
128.3 (2CH), 126.7 (2CH), 114.4 (2CH), 113.3 (2CH), 72.3 (CH2), 68.5
(CH), 56.5 (CH3), 44.4 (CH2), 34.3 (C), 31.5 (3CH3); MS (ESI): m/
z ¼ 358.2 (MþH)þ, 340.2 (M-H2OþH)þ.
71.7 (CH2), 69.5 (CH), 44.8 (CH2), 34.3 (C), 31.7 (3CH3), 23.3 (CH3);
MS (ESI): m/z ¼ 266.1 (MþH)þ, 248.1 (M-H2OþH)þ.
Table 3
Effect of compounds on generation of superoxide anions, hydroxyl radicals and lipid-peroxidation.
Series of compounds
Dose
g/ml)
Superoxide anions (%)
(nmol formazone formed/minute)
Hydroxyl radicals (%) (nmol MDA
formed/h/mg protein)
Lipid-peroxidation (%)
(nmol MDA formed/h/mg protein)
(
m
2
3
8
9
10
11
12
13
14
15
16
17
18
19
20
21
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
ꢁ17*
ꢁ14*
ꢁ18*
ꢁ26***
ꢁ11*
ꢁ23***
ꢁ13*
ꢁ25***
ꢁ14*
ꢁ14*
ꢁ12*
ꢁ13*
ꢁ27***
ꢁ33***
ꢁ17*
ꢁ29***
ꢁ35***
ꢁ15*
ꢁ26***
ꢁ34***
ꢁ19*
ꢁ25***
ꢁ14*
ꢁ23***
ꢁ17*
ꢁ23***
ꢁ15*
ꢁ17*
ꢁ19*
ꢁ19*
ꢁ11*
ꢁ10*
ꢁ12*
ꢁ21**
ꢁ16*
ꢁ20***
ꢁ18*
ꢁ21**
ꢁ15*
ꢁ20**
ꢁ13*
ꢁ20**
ꢁ10*
ꢁ22**
ꢁ15*
ꢁ16*
ꢁ12*
ꢁ17*
Standards
ꢁ43*** (Allopurinol)
ꢁ47*** (Mannitol)
ꢁ50*** (
a-tocopherol)
NS
Each value is mean ꢄ SD of six values, *P < 0.05; **P < 0.01; ***P < 0.001 experimental values compared with control values. NOTE:
(non significant).

S. Sarkar et al. / European Journal of Medicinal Chemistry 80 (2014) 135e144
143
6.2.1.7. N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]acetamide (12).
Yellow oil; IR (Neat): nmax 3365, 3230, 2815, 1648, 1600, 1570,
(C), 134.6 (2CH), 131.3 (2CH), 130.6 (2CH), 129.3 (2CH), 128.3 (2CH),
125.6 (C), 117.9 (2CH), 72.4 (CH2), 68.1 (CH), 57.4 (CH2); MS (ESI): m/
z ¼ 306.1 (MþH)þ, 288.1 (M-H2OþH)þ.
1280 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d
7.14e7.09 (m, 1H), 6.48e
6.43 (m, 3H), 4.05e3.87 (m, 3H), 3.71 (s, 3H), 3.55e3.51 (m, 1H),
3.33e3.29 (m,1H), 1.95 (s, 3H); 13C NMR (75 MHz):
172.1 (C), 160.7
d
6.2.1.14. N-[3-(4-Chlorophenoxy)-2-hydroxypropyl]-4-
methoxybenzamide (19). Yellow oil; IR (Neat): nmax 3344, 3090,
2988, 2930, 2855, 2845, 1640, 1605, 1525, 1395, 780 cmꢁ1; 1H NMR
(C), 159.6 (C), 129.9 (CH), 106.7 (CH), 106.5 (CH), 101.1 (CH), 69.6
(CH2), 69.2 (CH), 55.2 (CH3), 42.9 (CH2), 22.9 (CH3); MS (ESI): m/
z ¼ 240.1 (MþH)þ, 222.1 (M-H2OþH)þ.
(CDCl3, 300 MHz):
(d, J ¼ 8.2 Hz, 2H), 4.04e3.99 (m, 1H), 3.86e3.82 (m, 2H), 3.78 (s,
3H), 3.53 (s, 2H), 3.45e3.33 (m, 1H); 13C NMR (75 MHz):
173.3 (C),
d
7.22e7.14 (m, 4H), 6.84 (d, J ¼ 8.3 Hz, 2H), 6.74
6.2.1.8. N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]acrylamide
d
(13). Yellow oil; IR (Neat): nmax 3335, 3080, 2977, 2945, 2830, 1645,
158.8 (C), 157.6 (C), 130.4 (2CH), 129.3 (2CH), 126.6 (C), 125.9 (C),
115.8 (2CH), 114.3 (2CH), 69.9 (CH2), 69.1 (CH), 55.2 (CH3), 43.0
(CH2); MS (ESI): m/z ¼ 336.1 (MþH)þ, 318.1 (M-H2OþH)þ.
1595, 1450, 1382 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 7.20e7.14 (m,
1H), 6.55e6.49 (m, 3H), 6.18e6.00 (m, 2H), 5.67e5.57 (m, 1H),
4.10e3.93 (m, 3H), 3.77 (s, 3H), 3.67e3.62 (m, 1H), 3.39e3.34 (m,
1H); 13C NMR (75 MHz):
d 172.3 (C), 160.9 (C), 159.8 (C), 130.1 (CH),
6.2.1.15. N-[2-Hydroxy-3-(m-tolyloxy)propyl]acetamide
Yellow oil; IR (Neat): nmax 3325, 2950, 2855, 1656, 1550, 1483, 1395,
1266 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
7.25e7.19 (m, 1H), 6.86e
(20).
127.5 (CH), 121.3 (CH2), 106.8 (2CH), 101.3 (CH), 69.8 (CH2), 69.4
(CH), 55.4 (CH3), 43.1 (CH2); MS (ESI): m/z ¼ 252.1 (MþH)þ, 234.1
(M-H2OþH)þ.
d
6.67 (m, 3H), 4.33e4.16 (m, 2H), 3.95e3.88 (m, 1H), 3.25e3.24 (m,
1H), 3.18e3.14 (m, 1H), 2.39 (s, 3H), 1.93 (s, 3H); 13C NMR (75 MHz):
6.2.1.9. N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]benzamide
d
172.1 (C), 159.6 (C), 139.5 (C), 130.0 (CH), 122.1 (CH), 117.5 (CH),
(14). Yellow oil; IR (Neat): nmax 3342, 3085, 2960, 2915, 2845, 2830,
113.5 (CH), 73.2 (CH2), 69.3 (CH), 43.0 (CH2), 22.8 (CH3), 21.3 (CH3);
1642, 1612, 1512, 1386 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 7.99e
MS (ESI): m/z 224.1 (MþH)þ, 206.1 (M-H2OþH)þ.
7.96 (m, 2H), 7.48e7.38 (m, 3H), 7.20e7.15 (m, 1H), 6.55e6.51 (m,
3H), 5.06e5.01 (m, 1H), 4.24e3.93 (m, 4H), 3.76 (s, 3H), 3.67e3.54
6.2.1.16. N-[2-Hydroxy-3-(m-tolyloxy)propyl]acrylamide
Yellow oil; IR (Neat): nmax 3335, 3078, 2970, 2945, 2862, 1652, 1590,
1450, 1380 cmꢁ1 1H NMR (CDCl3, 300 MHz):
7.20e7.15 (m, 1H),
(21).
(m, 1H); 13C NMR (75 MHz):
d 164.1 (C), 160.8 (C), 159.7 (C), 131.1
(CH), 131.3 (CH), 129.9 (CH), 128.3 (CH), 128.2 (CH), 127.4 (CH), 126.8
(CH), 107.0 (CH), 106.6 (CH), 101.2 (CH), 76.8 (CH2), 69.2 (CH), 57.1
(CH2), 55.2 (CH3); MS (ESI): m/z ¼ 302.1 (MþH)þ, 284.1 (M-
H2OþH)þ.
;
d
6.83e6.76 (m, 3H), 6.24e6.06 (m, 2H), 5.61e5.57 (m, 1H), 4.42e
4.37 (m, 1H), 4.36e4.07 (m, 1H), 3.78e3.71 (m, 1H), 3.25e3.21 (m,
1H), 3.00e2.95 (m, 1H), 2.25 (s, 3H); 13C NMR (75 MHz):
d 166.3 (C),
158.6 (C), 139.3 (C), 131.2 (CH), 129.9 (CH), 126.5 (CH2), 121.1 (CH),
115.6 (CH), 113.7 (CH), 72.3 (CH2), 67.4 (CH), 44.3 (CH2), 22.1 (CH3);
MS (ESI): m/z 236.1 (MþH)þ, 218.1 (M-H2OþH)þ.
6.2.1.10. N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]-4-
methoxybenzamide (15). Yellow oil; IR (Neat): nmax 3342, 3090,
2985, 2935, 2855, 2835, 1640, 1605, 1515, 1395 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz):
7.04e6.85 (m, 2H), 6.55e6.43 (m, 2H), 4.07e4.02 (m, 1H), 3.88 (s,
2H), 3.78 (s, 3H), 3.55 (s, 2H); 13C NMR (75 MHz):
173.4 (C), 163.7
(C), 160.8 (C), 159.5 (C), 132.1 (CH), 130.5 (CH), 129.9 (CH), 126.4 (C),
114.4 (CH), 113.6 (CH), 106.8 (CH), 106.6 (CH), 101.1 (CH), 74.2 (CH2),
69.5 (CH), 55.3 (2CH3), 42.6 (CH2); MS (ESI): m/z ¼ 332.2 (MþH)þ,
314.2 (M-H2OþH)þ.
d
8.04 (d, J ¼ 8.6 Hz, 2H), 7.34e7.17 (m, 3H),
6.3. Statistical evaluation
d
Data were analyzed using student’s t-test and one way ANOVA
(NewmaneKeuls Multiple Comparison test). The hyperlipidemic
groups were compared with control drug treated groups. P < 0.05
was considered to be significant.
Acknowledgements
6.2.1.11. N-[3-(4-Chlorophenoxy)-2-hydroxypropyl]acetamide (16).
Yellow oil; IR (Neat): nmax 3355, 3080, 2945, 2870, 2810, 1655, 1600,
Authors are thankful to Dr. T. K. Chakrobarty, Director CDRI for
constant encouragement for the program on the synthesis of nat-
ural product analogues of biological importance, SAIF for spectral
data and ICMR, New Delhi for financial support in the form Ad-hoc
project (59/6/2010/BMS/TRM) (CDRI communication no. 8655).
1580, 1280, 777 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 7.22 (d,
J ¼ 7.3 Hz, 2H), 6.84 (d, J ¼ 7.1 Hz, 2H), 4.32e4.18 (m, 2H), 3.90e3.84
(m, 1H), 3.34e3.29 (m, 1H), 3.15e3.11 (m, 1H), 1.89 (s, 3H); 13C NMR
(75 MHz): d 170.6 (C), 157.8 (C), 129.4 (2CH), 125.8 (C), 115.7 (2CH2),
72.3 (CH2), 68.3 (CH), 42.1 (CH2), 23.1 (CH3); MS (ESI): m/z ¼ 244.1
(MþH)þ, 226.1 (M-H2OþH)þ.
Appendix A. Supplementary data
6.2.1.12. N-[3-(4-Chlorophenoxy)-2-hydroxypropyl]acrylamide (17).
Yellow oil; IR (Neat): nmax 3335, 3085, 2978, 2940, 2830, 1649, 1598,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.04.020.
1450, 1382, 1280, 776 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 7.23 (d,
J ¼ 7.5 Hz, 2H), 6.79 (d, J ¼ 7.4 Hz, 2H), 6.22e6.07 (m, 2H), 5.62e5.58
References
(m, 1H), 4.41e4.32 (m, 1H), 4.17e4.11 (m, 1H), 3.92e3.86 (m, 1H),
3.28e3.21 (m, 1H), 3.02e2.96 (m, 1H); 13C NMR (75 MHz):
d 167.8
[1] E. Eghdamian, K. Ghose, Drugs of Today 34 (1998) 943e956.
[2] H.C. McGill Jr., Geographical Pathology of Atheroslclerosis, Williams and
Wiken Co, Baltimore, 1985.
[3] (a) A.M. Gotto, S.M. Grundy, Circulation 99 (1999) e1ee7;
(b) J.E. Rossouw, B.M. Rifkind, Endocrinology and Metabolism Clinics of North
America 19 (1990) 279e297.
(C), 157.6 (C), 131.1 (CH), 129.4 (2CH), 127.2 (CH2), 125.3 (C), 115.4
(2CH), 72.3 (CH2), 68.5 (CH), 43.6 (CH2); MS (ESI): m/z ¼ 256.1
(MþH)þ, 238.1 (M-H2OþH)þ.
[4] (a) E.A. Werner, J. Bell, Journal of the Chemical Society, Transactions 121
(1922) 1790e1794;
6.2.1.13. N-[3-(4-Chlorophenoxy)-2-hydroxypropyl]benzamide (18).
Yellow oil; IR (Neat): nmax 3362, 3095, 2965, 2915, 2855, 2830, 1642,
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d
7.94 (d,
J ¼ 7.5 Hz, 2H), 7.47e7.27 (m, 2H), 6.85 (d, J ¼ 7.5 Hz, 2H), 5.06e4.97
(m, 1H), 4.22e3.91 (m, 4H); 13C NMR (75 MHz):
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144
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