Synthesis and antihyperglycemic activity of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines

Article abstract of DOI:10.1016/j.bmcl.2008.03.003

A series of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines were synthesized and evaluated for their antihyperglycemic activity. Compounds 3g and 6d exhibited lowering of postprandial plasma glucose by 30.7%, 23.3% in SLM and 25.6%, 25.4% in STZ models respectively which is significant compared to metformin and glybenclamide. Other compounds exhibited moderate to good activity ranging from 19.5% to 32.8% in SLM and 3.26% to 25.4% in STZ models.

Full text of DOI:10.1016/j.bmcl.2008.03.003

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2301–2305
Synthesis and antihyperglycemic activity of novel
N-acyl-2-arylethylamines and N-acyl-3-coumarylaminesq
Atma P. Dwivedi,a Shailesh Kumar,a Vandana Varshney,a
Amar B. Singh,b Arvind K. Srivastavab and Devi P. Sahua,*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, M.G. Marg, P B No. 173, Lucknow 226001, India
bBiochemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 2 January 2008; revised 27 February 2008; accepted 1 March 2008
Available online 6 March 2008
Abstract—A series of novel N-acyl-2-arylethylamines and N-acyl-3-coumarylamines were synthesized and evaluated for their anti-
hyperglycemic activity. Compounds 3g and 6d exhibited lowering of postprandial plasma glucose by 30.7%, 23.3% in SLM and
25.6%, 25.4% in STZ models respectively which is significant compared to metformin and glybenclamide. Other compounds exhib-
ited moderate to good activity ranging from 19.5% to 32.8% in SLM and 3.26% to 25.4% in STZ models.
Ó 2008 Elsevier Ltd. All rights reserved.
Diabetes mellitus (type-II diabetes, T2D) is an acquired
syndrome of elevated blood glucose and develops due to
the effect of sedentary lifestyle, dietary changes and ge-
netic factors. T2D is closely associated with obesity
and other metabolic syndromes, and is characterized
by initial phase progressive insulin resistance and subse-
quent phase exhaustion of b cells in the pancreas. It is
estimated that over 330 million people worldwide would
be affected by T2D by 2030.1 The current treatment of
T2D includes efficient oral antidiabetic agents such as
Metformin, sulfonyl ureas, glinides, and glitazones.
Metformin though safe and well tolerated poses a risk
of inducing lactic acidolysis and is contraindicated in
the setting of renal failure. Both sulfonyl ureas and gli-
nides induce weight gain and have adverse effect in obese
patients. The glitazones pose a risk of oedema, weight
gain, and is contraindicated in the setting of congestive
heart failure. A number of candidates based upon action
on different molecular targets such as DPP4 inhibitors,
GLP1 analogues, SGL2 inhibitors are at various stages
of clinical trials and soon may replace existing drugs.2
Despite the remarkable progress in the management of
diabetes mellitus there has been a resurgence of phyto-
therapeutical approach for the generation of new leads
from active principle of medicinal plants traditionally
used worldwide for the treatment of T2D and related
metabolic disorders.3 The active compounds isolated
from some of the plants such as Scoparone from
Artemesia Capillaris,4 3-hydroxyumbelliferone deriva-
tives from Bahia ambrosioides,5 Glycyrin from Glycyr-
rhiza uralensis6 and Marmesin and Umbelliferone ether
isolated from Aegle marmelos7 used traditionally for
the management of diabetes and related metabolic disor-
ders contain 7-hydoxycoumarin motif. An alkaloid,
Aegeline (N-cinnamoyl-4-methoxyphenylethanolamine)
isolated from the same plant Aegle marmelos reported
to exhibit both antihyperglycemic and antidyslipidemic
activities.8 The active constituent isolated from the
plants Actaea dahurica, Cinnamomum aromaticum Nees,
Ipomoea batatas, Scrophularia buergeriana are derivative
of either mono or polyhydroxylated cinnamic acids.3
Based upon these phytochemical leads it was envisaged
that a library of N-acyl 2-arylethylamines and N-acyl-
3-coumarylamines of type A (Chart 1) should possess
antihyperglycemic activity. The synthesis and our
preliminary study on antihyperglycemic activity of N-
acyl-2-arylethylamines and N-acyl-3-coumarylamines
are presented in this letter.
Keywords: N-Acyl 2-arylethylammines; N-Acyl-3-coumarylamines;
SLM; STZ.
q
N-Cinnamoyl-3,4-dimethoxyphenylethylamines 3 were
synthesized by the acylation of 2 with substituted cin-
namic acid 1 (Scheme 1). Thus, the acid chloride ob-
tained on treatment of cinnamic acid 1 with either
CDRI Communication No.7440.
*
Corresponding author. Tel.: +91 522 2612415x4378; fax: +91 522
2623405; e-mail addresses: dpsahuin@yahoo.com; dp_sahu@cdri.
res.in
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.003

2302
A. P. Dwivedi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2301–2305
NH
NH
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. By comparing the AUC of experimental
and control groups the percentage of antihyperglycemic
effect was calculated. Samples showing significant inhi-
bition (p < 0.05) on postprandial hyperglycemia
(AUC) were considered as active samples. Streptozoto-
cin-induced diabetic mice model (STZ): Sprague–Daw-
ley strain male albino rats of average body weight
140 20 g were selected having blood glucose profiles
between 60 and 80 mg/dl. Streptozotocin (Sigma,
USA) was dissolved in 100 mM citrate buffer (pH 4.5)
and a 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 and 270 mg/dl were considered suit-
able for the experiment. These diabetic animals were
again divided into groups and their blood glucose pro-
files were again checked on the day of experiment (day
3). Animals showing almost equal or similar blood glu-
cose profiles were divided into groups consisting of 5–6
animals in each group. Animals of experimental group
were administered the suspension of the test sample or-
ally (in 1% gum acacia) at 100 mg/kg-body weight. Ani-
mals of control group were given an equal amount of 1%
gum acacia. A sucrose-load (2.5 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, 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 % antihyperglycemic
activity.
OH
H
N
N
H
N
NH2
O
O
Aegeline
Metformin
H
N
Ar
O
O
O
O
R
A
O
C10H21O2
Umbelliferone ether
O
Chart 1.
O
O
H2N
OCH3
i or ii or iii
NH
Ar
OCH3
OCH3
+
OH
Ar
OCH3
3
2
1
Scheme 1. Reagents and conditions: (i) 1 + SOCl2 (excess), reflux,
evaporation; the addition of 2, Et3N, DCM, 0 °C, rt, 2 h. (ii) 1 + oxalyl
chloride in DCM, stirring at rt evaporate; the addition of 2, Et3N,
dichloromethane, 0 °C, rt, 2 h. (iii) EDCÆHCl, Et3N, 0 °C, rt.
oxalyl chloride or thionyl chloride was reacted with 2 in
the presence of triethylamine at low temperature to fur-
nish 39 (Scheme 1).
Alternatively condensation of 1 with 2 mediated by 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDC. HCl) at 0 °C afforded 3g.10
The N-acyl-3-coumaryl amines 6 were synthesized11 in
moderate to good yield by modified Pechmann conden-
sation of N-acylglycine 5 with substituted salicyladehyde
4 in the presence of acetic anhydride and sodium acetate
as shown in Scheme 2.
All the compounds were tested for their effect on glucose
tolerance curve in mice of average body weight
160 20 g, an indirect effect of measuring antihypergly-
cemic activity. The blood glucose levels of all animals
were checked after an overnight fasting (16 h) by Gluco-
strips (Boehringer–Mannheim). Animals showing blood
glucose levels between 60 and 80 mg/dl (3.33–4.44 mM)
were divided into groups of 5–6 animals in each. Ani-
mals of experimental group were administered the sus-
pension of the synthetic compounds orally (in 1.0%
gum acacia) at a dosage of 100 mg/kg-body weight. Ani-
mals 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 adminis-
tration 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
The antihyperglycemic activity evaluated in the above
two models were compared with standard drugs metfor-
min and glybenclamide (Table 1). The most active com-
pound 3g (N-feruloyl-3,4-dimethoxy phenethyl amine),
lowered blood glucose level up to 30.7% in SLM and
25.6% (5 h) in STZ models. N-feruloyl-4-hydroxyphe-
nylethyl amine, an analog of 3g, isolated from Tinospora
tuberculata was reported to exhibit antibacterial activ-
ity.12 Ferulic acid amides were reported13 to exhibit their
stimulatory abilities on insulin secretion in rat pancre-
atic RIN-5F cells. Compounds 3f, 3g and 3h having
both electron donating or withdrawing substitution at
meta position of the cinnamoyl component showed an
appreciable increase in activity, whereas groups (elec-
tron donating or electron withdrawing) at para position
as in 3b, 3d, 3e sustain the activity in SLM model but
were found inferior in STZ models. Surprisingly, 3,4,5-
trimethoxycinnamic acid amide 3a has low antihypergly-
cemic activity.
O
H
N
CHO
+
OH
R2
i
R2
N
H
R1
O
OH
R1
O
O
O
5
4
6
In general, as compared to the compounds 3a–h, 3-
coumaryl amides 6a–c have uniformly higher effect in
the reduction of plasma glucose both in sucrose loaded
Scheme 2. Reagents and condition: (i) Acetic anhydride, sodium
acetate, reflux.

A. P. Dwivedi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2301–2305
2303
Table 1. In-vivo antihyperglycemic evaluation of N-acyl-2-arylethyl-amines and N-acyl-3-coumarylamines in SLM and STZ-s model
Compound
Structure
% Antihyperglycemic activity
STZ/5 h
SLM
2.41
STZ/24 h
O
O
O
O
O
N
H
3a
3b
3c
3d
3e
3f
ND
7.17
6.7
ND
4.44
3.26
4.19
3.17
9.21
O
O
O
O
19.5
20.1
23.4
21.5
25.2
N
H
O
O
O
O
N
H
O
O
O
8.56
8.94
13.4
N
H
F
O
O
N
H
O
Cl
O
O
O
N
H
O
O
O
N
H
O
3g
3h
6a
6b
30.7
32.8
22.3
21.1
25.6
21.5
19.8
21.1
23.8
19.8
23.0
19.8
HO
O
O
O
O
N
H
CF3
O
O
O
O
O
N
H
O
N
H
CF3
O
O
O
O
O
6c
6d
10.7
23.3
ND
23.0
ND
25.4
N
H
O
N
H
(continued on next page)

2304
A. P. Dwivedi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2301–2305
Table 1 (continued)
Compound
Structure
% Antihyperglycemic activity
SLM
8.89
STZ/5 h
STZ/24 h
ND
O
O
O
6e
ND
N
H
Standard
Standard
Metformin
Glybenclamide
12.9
33.7
19.1
29.0
20.5
25.5
ND, not done.
and streptozotocin induced models. Amongst the series,
6d 6,8-bis tert-butylcoumarin derivative lowered post-
pand- ial plasma glucose by 23.0 and 25.4% at 5 and
24 h, respectively, in steptozotocin induced mice. In con-
trast, 6e corresponding N-cinnamoyl analog has lower
effect in the reduction of plasma glucose. The reverse
trend was observed in series 6a–c. The benzamide 6c
had low antihyperglycemic activity compared to cin-
namic acid amides 6a and 6b. The variation of blood
glucose at different interval of time after the administra-
tion of most active compounds 3g, 3h and 6d has been
shown in Figure 1.
study on lead optimization and mechanism of action is
in progress.
Acknowledgments
We are thankful to the Director, CDRI, Lucknow, India
for constant encouragement of the drug development
programme. We also acknowledge the SAIF division,
CDRI for providing spectroscopic data.
Supplementary data
In conclusion, the N-acyl-2-arylethylamines 3 and N-
acyl-3-coumarylamines 6 exhibited moderate to excel-
lent in vivo antihyperglycemic activity ranging from
19.5% to 32.8% in SLM and 3.26% to 25.4% in STZ
models respectively. Compounds 3g and 6d were low-
ered of postprandial plasma glucose at 30.7%, 23.3%
in SLM and 23.8%, 25.4% after 24 h in STZ models,
respectively, which is significant compared to metformin
and glybenclamide. The activity of 3g was found to be
statistically overlapping with that of 3h and 6d in the
range of animals in both SLM and STZ models. Further
The physical and spectral data of all synthesized com-
pounds are presented as pdf file. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2008.03.003.
References and notes
1. (a) Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H.
Diabetes Care 2004, 27, 1047; (b) American Diabetes
Association (ADA) National Dibetes Fact sheet, ADA
web site (on line), http://www.cdc.gov/diabetes/pubs/pdf/
ndfs_2005.pdf.
control
comp. 6d
2. Ashiya, M.; Smith, R. E. T. Nat. Rev. Drug Discov. 2007,
6, 777.
comp. 3h
comp. 3g
32
28
3. Zareba, G.; Serradell, N.; Castan˜er, R.; Davies, S. L.;
Prous, J.; Mealy, N. Drug Future 2005, 30, 1253.
4. Okada, Y.; Miyauchi, N.; Suzuki, K.; Kobayashi, T.;
Tsutsui, C.; Mayuzumi, K.; Nishibe, S.; Okuyama, T.
Chem. Pharm. Bull. 1995, 43, 1385.
5. Zdero, C.; Bohmann, F.; Niemeyer, H. M. Phytochemistry
1990, 29, 205.
6. Wakasugi, M.; Noguchi, T.; Inoue, M.; Tawata, M.;
Shindo, H.; Onaya, T. Prostaglandins Leukot. Essent.
Fatty Acids 1991, 44, 233.
24
20
16
12
8
7. Chatterjee, A.; Bhattacharya, A. J. Chem. Soc. 1959, 1922.
8. Narender, T.; Shweta, S.; Tiwari, P.; Reddy, P. K.;
Khaliq, T.; Prathipati, P.; Puri, A.; Srivastava, A. K.;
Chander, R.; Agarwal, S. C.; Raj, K. Bioorg. Med. Chem.
Lett. 2007, 17, 1808.
9. Typical procedure. To a stirred solution of 3-trifluorom-
ethylcinnamic acid (10 mmol) in DCM (20 mL), oxalyl
chloride (12 mmol) was added at rt. After stirring for 2 h,
the solvent was stripped off. The residual liquid was
4
0
-30
0
30 60 90 120 150 180 210 240 270 300 24h
Time (min)
Figure 1. Blood glucose levels in sucrose challenged streptozotocin-
induced diabetic rats before, and up to 24 h after administration of
vehicle and test samples.

A. P. Dwivedi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2301–2305
2305
dissolved in DCM (20 mL) and to the resulting solution
was added dropwise a mixture of triethyl amine (12 mmol)
and 2-(3,4-dimethoxy-phenyl)-ethylamine (11 mmol) at
0 °C with stirring, and the stirring was continued for next
2 h at rt. After the completion of the reaction saturated
solution of sodium bicarbonate (10 mL) was added to the
reaction mixture and the organic layer was separated,
washed successively with 3% aqueous hydrochloric acid
solution (10 mL), 5% NaHCO3 solution. It was dried over
sodium sulfate and evoporated to furnish the desired
product, N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(3-trifluoro-
methyl-phenyl) acrylamide (3h).
then at rt for 5 h. Aqueous workup followed by silica gel
chromatography afforded N-[2(3,4-dimethoxyphenyl)
ethyl]-3-(4-hydroxy-3-met-hoxyphenyl) acrylamide (3g).
11. Typical procedure. The mixture of salicylaldehyde
(10 mmol), hippuric acid (11 mmol), acetic anhydride
(20 mmol) sodium acetate (12 mmol) was allowed to reflux
with continous stirring for 2–4 h. The reaction mixture
was brought to rt and cooled at 0 °C. The solid obtained
was crystallized with alcohol and was filtered, dried in air
to get the pure N-(2-oxo-2H-chromen-3-yl)-3-phenyl-
acrylamide (6a).
12. Naomichi, F.; Michiko, Y.; Takeatsu, K. Chem. Pharm.
Bull. 1983, 31, 156.
13. Nomura, E.; Kashiwada, A.; Hosoda, A.; Nakamura, K.;
Morishita, H.; Tsunod, T.; Taniguchia, H. Bioorg. Med.
Chem. 2003, 11, 3807.
10. Typical procedure. A mixture of 3-(4-hydroxy-3-methoxy-
phenyl)-acrylic acid (10 mmol), 2-(3,4-dimethoxy-phenyl)-
ethylamine (11 mmol), EDCÆHCl (12 mmol) triethylamine
(12 mmol) in DCM (15 mL) was stirred at 0 °C for 1 h and