Synthesis of propiophenone derivatives as new class of antidiabetic agents reducing body weight in db/db mice

Article abstract of DOI:10.1016/j.bmc.2011.12.027

A series of propiophenone derivatives (6-23) have been synthesized and evaluated for their in vivo antihyperglycemic activities in sucrose loaded model (SLM), sucrose challenged streptozotocin (STZ-S) induced diabetic rat model and C57BL/KsJ db/db diabetic mice model. Compound 15 and 16 were emerged as potent antihyperglycemics and lipid lowering agents. These compounds (15, 16) further validate the potency by reducing body weight and food intake in db/db mice model. Possible mechanism of action for the propiophenone derivatives was established by the evaluation in various in vitro models. Interestingly some of the compounds were efficiently inhibiting PTP-1B.

Full text of DOI:10.1016/j.bmc.2011.12.027

Bioorganic & Medicinal Chemistry 20 (2012) 2172–2179
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of propiophenone derivatives as new class of antidiabetic agents
reducing body weight in db/db mice
Atul Kumar a, , Siddharth Sharma a, Lalit Prakash Gupta a, Pervez Ahmad a, Swayam Prakash Srivastava b,
⇑
Neha Rahuja b, A.K. Tamrakar b, Arvind K. Srivastava b
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226 001, India
b Biochemistry Division, Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of propiophenone derivatives (6–23) have been synthesized and evaluated for their in vivo anti-
hyperglycemic activities in sucrose loaded model (SLM), sucrose challenged streptozotocin (STZ-S)
induced diabetic rat model and C57BL/KsJ db/db diabetic mice model. Compound 15 and 16 were
emerged as potent antihyperglycemics and lipid lowering agents. These compounds (15, 16) further val-
idate the potency by reducing body weight and food intake in db/db mice model. Possible mechanism of
action for the propiophenone derivatives was established by the evaluation in various in vitro models.
Interestingly some of the compounds were efficiently inhibiting PTP-1B.
Received 31 October 2011
Revised 7 December 2011
Accepted 8 December 2011
Available online 24 December 2011
Keywords:
Propiophenone
Antidiabetic
PTP-1B
Ó 2012 Elsevier Ltd. All rights reserved.
db/db Mice
Body weight
1. Introduction
treatment.10 The activation of insulin receptor in PTP-1B takes
place via autophosphorylation on tyrosine part so the receptor is
Diabetes mellitus is a global burden as approximately 4–5% will
be affected all over the world by 2025.1 While the rise will be of the
order of 45% in developed countries and almost 200% in developing
countries makes the situation more threatening.2 Diabetes mellitus
may be categorized into two subclasses (1) type I, known as insulin
dependent diabetes mellitus (IDDM), (2) type II, noninsulin depen-
dent diabetes mellitus (NIDDM). Type-2 diabetes accounts for
approximately 80–90% of all diabetes cases and it is the fourth
leading cause of death in developed countries.3,4 Type-2 diabetes
mellitus is characterized by hyperglycemia, insulin resistance, pro-
gressive metabolic disorder of carbohydrate and lipid metabolism.5
Patients with type-2 diabetes often suffer from dyslipidemia in the
form of high triglycerides, cholesterol and phospholipids.6 Increase
in cholesterol is a common feature of atherosclerosis by the
involvement of arterial damage and lead to ischemic heart disease,
myocardial infarction, and cerebro-vascular accidents. These
conditions are responsible for one-third of deaths in industrialized
nations.7 Hence, in recent years several groups have focused their
attention towards the development of dual acting (blood glucose
as well as lipid lowering) drugs.8 Protein tyrosine phosphatases
(PTPases) plays a significant role in several diseases such as diabe-
tes, cancer, obesity, and inflammation.9 Recently PTP-1B has been
emerged as new target to combat type-2 diabetes and obesity
shut off by tyrosine phosphatase. Knockout mice of PTP-1B re-
sulted in increased insulin sensitivity and glucose tolerance in skel-
etal muscle without affecting insulin action in adipose tissue,
which resulted in decreased obesity.11
In continuation to our anti-diabetic drug discovery program,12
we have designed and synthesized new propiophenone derivatives
as antidiabetic agents. Rational behind the synthesis of propiophe-
none derivatives were based on previously reported propiophe-
none as well as acetophenone (I,13 II,14 III15 and IV16) derivatives
(Scheme 1). Benzofuran ring (heterocyclic) is attached to the proto-
type I at 3rd carbon of propiophenone scaffold, whereas benzene
ring is attached to the 2nd and 3rd carbon atom on prototype II.
Propiophenone derivatives (I and II) have better activity then ace-
tophenone derivative (III and IV), therefore our interest has been
developed towards the use of propiophenone scaffold instead of
acetophenone for the search of orally active antidiabetic agents
as well as potent inhibitor of PTP 1B. Herein, we have synthesized
novel propiophenone derivatives and evaluated against several
in vivo and in vitro models of diabetes.
2. Results and discussion
2.1. Chemistry
The synthetic strategy followed for the synthesis of novel propi-
ophenone derivatives is depicted in Scheme 2. Synthesis of key
⇑
Corresponding author. Tel.: +91 522 2621411; fax: +91 522 2623405.
E-mail address: dratulsax@gmail.com (A. Kumar).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.12.027

A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
2173
the alkylation of compound (5) using different chloroethyldialkyla-
mino hydrochloride and diethyl 2-(3-chloropropyl)malonate.
Disubstituted propiophenone derivative 11 was alkylated by
diethyl malonate, (CH3)3COK, and THF as a solvent.
OH
O
O
O
F
O
F
Br
PO3H2
HO
O
HO
2.2. Biological activity
I
II
OR'
O
Our previous experiences in antidiabetic drug discovery12 and
antidiabetic in vivo screening program of CDRI inspired us to de-
velop lead in vivo active compounds with the ability of glucose
as well as lipid lowering potential. In course of searching potent
compounds, all the synthesized compounds have been evaluated
against various in vivo antidiabetic models. Some of the synthes-
ised compounds 7(, 8, 9, 14, 15, 17, 18 and 22) significantly lowered
the blood glucose level in SLM model as compared to insulin sen-
sitizer (metformin) and insulin secreting drug (glybenclamide).
Compounds were evaluated in STZ-S model on the basis of the
glucose lowering ability in SLM. Few of the compounds (7, 9, 15
and 16) significantly lowered the blood glucose area under curve
(AUC) at 0–5 h and 0–24 h. The most active compound (15)
showed 22.1 (0–5 h) and 22.8% (0–24 h) reduction in glucose
AUC in STZ-S model (Table 1). Compound 16 lowered the blood
glucose in STZ-S rat model (27.5% and 21.5%) but did not have
much effect on blood glucose in SLM model. No effect on the
hyperglycemia of normal rats may be the possible reason behind
the glucose lowering via compound 16 in SLM model. Inspired by
these findings, we were evaluated these compounds in anti-hyper-
glycemic and lipid lowering activity in db/db mice model (Fig. 1).
Compound 15 and 16 at the dose of 30 mg/kg were significant
reducing the postprandial hyperglycemia by 23.9% (p < 0.05) and
39.6% (p < 0.05), respectively, as compared rosiglitazone 51.3%
(p < 0.01).
RO
O
X
Cl
O
O
R''
Cl
O
IV
III
Scheme 1. Some propiophenone and acetophenone derivatives as PTP 1B
inhibitors.
intermediate 2,6-dihydroxy propiophenone (5) was achieved in
three steps by previously reported procedure.17 7-Hydroxy-4-
methylcoumarin (2) was synthesized by the reaction of resorcinol,
ethylacetoacetate and concentrated sulphuric acid. Compound (2)
was further propionated in refluxing propionic anhydride followed
by Fries rearrangement with AlCl3 as catalyst afforded 8-propyl-7-
hydroxy coumarin (4) via ortho migration of propyl group. Hydro-
lysis of compound 4 in 10% sodium hydroxide solution resulted
2,6-dihydroxy propiophenone 5. Plausible mechanism for the syn-
thesis of compound 5 via the hydrolysis of coumarin ring followed
by decarboxylation and elimination of 1-propyne. The alkylation of
2,6-dihydroxy propiophenone (5) was achieved using different
alkyl halide, and dihaloalkane in the presence of base for the syn-
thesis of compounds 6–23. Compounds 6–9 were synthesized via
Oral glucose tolerance in db/db mice was evaluated for their
anti-hyperglycemic potential. Figs. 2 and 3 represents the effect
Ethylacetoacetate
(b)
(c)
HO
(d)
OH
(a)
HO
OH
O
O
O
HO
O
O
HO
O
O
1
O
3
2
4
O
O
5
R1
COOEt
COOEt
O
O
(e)
R1
O
OH
20-23
COOEt
COOEt
O
Cl
6-9
O
O
(e)
(f)
HO
O
R1
(h)
5
HO
O
Cl
O
13-18
(g)
10
EtOOC
EtOOC
O
O
Cl
Cl
O
O
Cl
(i)
COOEt
12
O
O
11
NH2
(h)
O
O
N
12
H
COOEt
19
O
Scheme 2. Synthetic procedure for the synthesis of novel propiophenone derivatives. Reagent and conditions: (a) H2SO4, stirring at 0–8 °C; (b) Propionic anhydride, reflux; (c)
Anhydrous AlCl3, 170 °C; (d) Aqueous NaOH, reflux; (e) K2CO3, dry acetone, alkyl halides; (f) BrCH2CH2CH2Cl, K2CO3, acetone; (g) BrCH2CH2CH2Cl (excess), K2CO3, dry acetone;
(h) DMF, KI, amines; (i) (CH3)3COK, THF, diethyl malonate.

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A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
Table 1
In vivo anti hyperglycemic activity profile for the compounds 6–23a
Compound no.
R1
Antihyperglycemic activityb
SLM
STZ-S
0–5 h
0–24 h
6
7
8
9
13
14
15
16
Dimethylamine
Diethylamine
Pyrrolidine
Piperidine
n-butylamine
p-Toludine,
p-Anisidine
n-Butylmethylamine
Pyrrolidine
Piperidine
p-Toludine
19.45⁄
38.4⁄⁄
21.08⁄
40.4⁄⁄
11.0
12.1
23⁄
7.4
20.4
ND
19.7
ND
2.02
22.8⁄
21.5⁄
14.8
8.6
ND
29.2⁄
ND
28.7⁄
54.60⁄⁄
23.8⁄⁄
26.8
3.02
22.1⁄
27.5⁄
16.9
10.2
ND
17
18
19
Figure 3. Post prandial OGTT on day 10th.
33.2⁄⁄
8.49
ND
20
21
22
23
Dimethylamine
Diethylamine
Pyrrolidine
11.5
ND
ND
ND
ND
ND
ND
ND
ND
Compound 15 and 16 had significant improved dyslipidemia in
db/db mice (Figs. 4a, 4b, 4c). These compounds were lowering the
plasma triglycerides level (TG) by 22.0%, 23.8%, and plasma total
cholesterol (T-Chol) level by 14.8%, 20.4%, respectively. Slightly in-
creased level of HDL-cholesterol by 7.20%, 4.03% for 15 and 16 was
also observed at same dose enhance the potency of compound.
We were interested to study the effect of these compounds on
insulin level as hyperglycemia in db/db mice is due to insulin resis-
tance. Compound 15 and 16 showed 23.6% (p < 0.05), 27.7%
(p < 0.05) reduction in insulin level, respectively, as compare to
the level of control mice (Fig. 5). Excessive consumption of food in-
take and body weight is responsible for the development of obesity
and it can be directly linked with the type-2 diabetes. Further
observation on body weight during the antidiabetic activity in
db/db mice resulted decrease in body weight of mice during the
treatment (Fig. 6.) of compound 15 and 16. However, the calcu-
lated effect of compound 15 on body weight reduction was more
in compare to compound 16. We were pleased to find that com-
pounds also had the beneficial effect on body weight besides the
anti-hyperglycemic and lipid lowering activity. The reason behind
the consistent lowering in body weight of mice was due to the de-
creased intake of food in db/db mice. Significant reduction in food
intake was observed by the treatment of compound 15 and 16
starts from day 3rd and continues till day 10th (Fig. 7)
17.0
22.9⁄
16.4⁄
18.9
Piperidine
Metformin
Glybenclamide
19.1
32.3⁄⁄
a
Single dose = 100 mg/kg; ND = Not determine.
⁄p < 0.05 and ⁄⁄p < 0.01 versus vehicle treated control and statistical analysis
b
was made by Dunnett’s test (Prism Software). Number of experiments was 3.
Synthesized compounds were evaluated against the glucose-6-
Figure 1. The blood glucose lowering activity of compound 15 and 16 till 10 day
treatment of 30 mg/kg dose.
phosphatase, glycogen phosphorylase,
a-glucosidase, DPP-IV, and
PTP-1B enzymes at 100 M concentrations to know the possible
l
mechanism of anti-hyperglycemic action (Table 2). All the synthe-
sized compounds were showing poor inhibitory activities against
of compound 15 and 16 on day 6th and day 10th, respectively. The
db/db mice were subjected to an oral glucose tolerance test post
3.0 g/kg oral glucose load. Significant improvement on oral glucose
tolerance by 28.4% (p < 0.05), 26.7% (p < 0.01) on day 6th and 29.9%
(p < 0.05) and 33.6% (p < 0.01) on day 10th were observed for the
compound 15 and 16 comparable to rosiglitazone (33.9%
(p < 0.01) on day 6th and 46.5% (p < 0.01) on day 10th).
the glucose-6-phosphatase, glycogen phosphorylase,
a-glucosi-
dase, and DPP IV enzymes. To our delight eight compounds (13,
14, 15, 17, 19, 20, 21 and 22) were inhibiting PTP-1B with more
than 40% inhibition (Table 2). It may be one of the possible reason
that PTP-1B inhibition plays significant role in the in vivo
anti-hyperglycemic activity of the compounds. SAR studies of
Figure 2. Post prandial OGTT on day 6th.
Figure 4a. Effect of compound 15 and 16 on plasma triglycerides level (TG).

A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
2175
Figure 4b. Effect of compound 15 and 16 on plasma total cholesterol.
Figure 7. Effect on food intake.
noteworthy that aromatic substitution (14 and 15) in place of ali-
phatic substitution highly modulate the PTP-1B inhibition.
3. Conclusion
In conclusion, newly synthesized propiophenone derivatives
emerged as potent antidiabetic as well as lipid lowering agents.
Propiophenone derivatives further signify the results by effectively
reducing body weight and food intake in db/db mice. PTP-1B may
be the potential target for the anti-hyperglycemic activity by the
in vitro evaluation of synthesized compound. Most active com-
pound of the series 15 has shown 83.6% inhibition with IC50 of
Figure 4c. Effect of compound 15 and 16 on HDL-cholesterol.
8.3 lM with promising in vivo activity.
4. Experimental
4.1. Chemistry
Unless otherwise specified all the reagents and catalysts were
purchased from Sigma–Aldrich and were used without further
any purification. The common solvents were purchased from
Ranbaxy. Organic solutions were concentrated under reduced pres-
sure on a Büchi rotary evaporator. Chromatographic purification of
products was accomplished using flash chromatography on
60–120 or 100–200 mesh silica gel. Reactions were monitored by
thin-layer chromatography (TLC) on 0.25 mm silica gel plates visu-
alized under UV light, iodine or KMnO4 staining. 1H NMR spectra
were recorded on a Brucker DRX-200 Spectrometer. Chemical
shifts (d) are given in ppm relative to TMS and coupling constants
(J) in Hz. IR spectra were recorded on a FT IR spectrophotometer
Shimadzu 8201 PC and are reported in terms of frequency of
absorption (cmÀ1). Mass spectra (ESIMS) were obtained by Micro-
mass Quattro II instrument.
Figure 5. Effect on insulin level.
4.1.1. Typical experimental procedure for the synthesis of 2-
alkoxy 1-(6-hydroxy-phenyl)-propane-1-ones derivatives (6–9)
A mixture of compound 5, (830 mg, 5 mmol) and chloroethyl-
dimethylamino hydrochloride (760 mg, 7 mmol) was taken in to
the 50 ml round bottom flask and dry potassium carbonate
(6.5 g, 50 mmol) in 30 ml dry acetone was added. Reaction mixture
was refluxed on oil bath for 8 h. Reaction mixture was filtered and
filtrate was concentrated to remove acetone. Reaction mixture was
extracted with ethyl acetate (100 ml) and washed with (50 Â 3 ml)
of distilled water. Purification was done on silica gel column using
hexane/chloroform solvent system to yield compound 6 in 85.23%.
Figure 6. Effect on body weight of compounds 15 and 16.
antidiabetic activity on synthesized compounds revealed that the
two carbon chain length containing compounds (6–9) were less ac-
tive against the PTP-1B in comparison to three carbon chain length
(13–18). SAR studies on the side chain substitution indicated that
the pyrrolidine ring containing compounds (7, 17 and 22) gave
more significant results than piperidine ring (9, 18 and 23). It is
4.1.1.1. 1-(2-(2-(Dimethylamino)ethoxy)-6-hydroxyphenyl)pro-
pan-1-one (6).
Yield (85.23%), mp 62 °C. ESIMS (m/z) 238

2176
A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
Table 2
In vitro enzyme inhibitory activity of compounds 6–23a
Compoundsa
Glucose-6-phosphatase
Glycogen phosphorylase
a-Glucosidase
DPP IV
PTP-1B
6
7
8
9
13
14
15
16
11.3
11.6
NI
21.3
18.3
18.9
NI
17.3
13.6
NI
NI
NI
13.7
NI
24.8
NI
23
NI
19.5
NI
18.4
19.3
28.9
NI
24.2
NI
NI
NI
17.4
NI
13.7
NI
25.6
NI
19.3
28.8
36.4
27.5
52.1(19.2)
79.8 (12.5)
83.6(8.3)
31.9
42.1
31.8
NI
18.9
19.3
NI
NI
NI
17
18
19
20
21
22
NI
NI
NI
13.9
NI
NI
NI
22.9
NI
NI
11.8
NI
NI
NI
NI
NI
NI
NI
18.3
NI
42.6
51.1(20.4)
40.4
58.6(18.6)
19.6
23
Na-orthovanadate
56.0(15.2)
a
Compounds were evaluated at 100
lM concentration; NI means no inhibition or <5%. For IC50 calculation against PTP inhibition, we have checked these compounds at
variable doses. IC50 M) values are given in parentheses. Number of experiments-3.
(
l
(M+H)+. IR (KBr) 2966, 1599, 1097 cmÀ1. 1H NMR (CDCl3, 200 MHz)
d: 1.17 (t, J = 7.2 Hz, 3H), 2.33 (s, 6H), 2.78 (t, J = 6.0 Hz, 2H), 3.14 (q,
J = 7.2 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 6.37 (d, J = 8.2 Hz, 1H), 6.56
(d, J = 8.2 Hz, 1H), 7.28 (m, 1H), 8.23 (s, 1H). Analysis calcd for
refluxed on oil bath for 6 h. After completion of the reaction on
TLC, reaction mixture was filtered to remove K2CO3 and filtrate
was concentrated. Reaction mixture was extracted with ethyl ace-
tate (100 ml), washed with distilled water (50Â3 ml) and dried
over anhydrous sodium sulfate. Reaction mixture was concen-
trated and crystallized with benzene and hexane to yield com-
pound 10. Yield (76.03%). mp 70–72 °C. ESIMS (m/z) 243 (M+H)+.
C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.73; H, 8.32; N,
5.61.
4.1.1.2. 1-(2-(2-(Diethylamino)ethoxy)-6-hydroxyphenyl)pro-
IR (KBr): 2977, 1599, 1079 cmÀ1 1H NMR (CDCl3, 200 MHz) d:
.
pan-1-one (7).
Yield (85.28%), State semisolid. ESIMS (m/z)
1.17 (t, J = 7.2 Hz, 3H, COCH2CH3), 2.34 (m, 2H, ClCH2CH2CH2O),
3.06(q, J = 7.2 Hz, 2H, COCH2CH3), 3.74 (t, J = 6.2 Hz, 2H, ClCH2),
4.22 (t, J = 6.0 Hz, 2H, OCH2), 6.44 (d, J = 8.2 Hz, 1H, ArH), 6.57 (d,
J = 8.2 Hz, 1H, ArH), 7.33 (m, 1H, ArH), 10.48 (s, 1H, OH). Analysis
Calcd for C12H15ClO3: C, 59.39; H, 6.23. Found: C, 59.31; H, 6.21.
266 (M+H)+. IR (KBr): 2972, 1621, 1058 cmÀ1
.
1H NMR (CDCl3,
200 MHz) d: 1.14 (t, J = 7.0 Hz, 3H, COCH2CH3), 1.18 (t, J = 5.0 Hz,
6H, NCH2CH3), 2.65 (q, J = 6.0 Hz, 4H, NCH2CH3), 2.90 (t,
J = 6.4 Hz, 2H, OCH2CH2N), 3.14 (q, J = 7.0 Hz, 2H, COCH2CH3),
4.10 (t, J = 6.4 Hz, 2H, OCH2CH2N), 6.38 (d, J = 8.2 Hz, 1H, ArH),
6.55 (d, J = 8.2 Hz, 1H, ArH), 7.32 (m, 1H, ArH), 8.34 (s, 1H, –OH).
Analysis calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.84; H, 8.64; N 5.41.
4.1.3. 1-(2,6-Bis(3-chloropropoxy)phenyl)propan-1-one (11)
A mixture of compound 5 (1.66 g, 10 mmol), anhydrous potas-
sium carbonate (13.8 g, 100 mmol), dry acetone (50 ml) and bro-
mochloropropane (4 ml, excess) were taken in 50 ml round
bottom flask. The reaction mixture was refluxed on oil bath for
6 h. After completion of the reaction on TLC, reaction mixture
was filtered, concentrated to remove acetone and extracted with
ethyl acetate (100 ml) and dried over anhydrous sodium sulfate.
Reaction mixture was purified by column chromatography using
basic alumina as adsorbent, hexane and ethyl acetate as eluent to
yield compound 11. Yield (94.96%). Physical state. oily. ESIMS
4.1.1.3. 1-(2-Hydroxy-6-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pro-
pan-1-one (8).
Yield (78.46%). mp 156 °C (hydrochloride
salt). ESIMS (m/z) 264 (M+H)+. IR (KBr): 2976, 1621, 1091 cmÀ1
.
1H NMR (CDCl3, 200 MHz) d: 1.17 (t, J = 7.2 Hz, 3H, COCH2CH3),
1.81 (m, 4H, N(CH2)2(CH2)2), 2.59 (m, 4H, N(CH2)2(CH2)2), 2.96 (t,
J = 6.4 Hz, 2H, NCH2CH2O), 3.18 (q, J = 7.2 Hz, 2H COCH2CH3), 4.18
(t, J = 6.4 Hz, 2H, OCH2CH2N), 6.37 (d, J = 8.4 Hz, 1H, ArH), 6.56(d,
J = 8.2 Hz, 1H, ArH), 7.32(m, 1H, ArH), 8.69 (s, 1H, –OH). Analysis
calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.54;
H, 8.12; N, 5.44.
(m/z) 319 (M+H)+. IR (KBr): 2967, 1591, 1051 cmÀ1 1H NMR
.
(CDCl3, 200 MHz) d: 1.15 (t, J = 7.2 Hz, 3H, COCH2CH3), 2.17 (m,
4H, CH2CH2 CH2), 2.77 (q, J = 7.2 Hz, 2H, COCH2CH3), 3.66 (t,
J = 6.2 Hz, 4H, ClCH2CH2), 4.11 (t, J = 5.8 Hz, 4H, OCH2 CH2), 6.57
(d, J = 8.4 Hz, 2H, ArH), 7.25 (t, J = 8.4 Hz, 1H, ArH). Analysis Calcd
for C15H20Cl2O3: C, 56.44; H, 6.31. Found: C, 56.59; H, 6.16.
4.1.1.4. 1-(2-Hydroxy-6-(2-(piperidin-1-yl)ethoxy)phenyl)pro-
pan-1-one (9).
Yield (80.57%). mp 72 °C. ESIMS (m/z) 278
(M+H)+. IR (KBr): 2938, 1621, 1090 cmÀ1
.
1H NMR (CDCl3,
200 MHz) d: 1.21 (t, J = 8.0 Hz, 3H, COCH2CH3), 1.30 (m, 2H,
N(CH2)2(CH2)2CH2), 1.55 (m, 4H, N(CH2)2(CH2)2CH2), 2.48 (m, 4H,
N(CH2)2(CH2)2CH2), 2.80 (t, J = 6.4 Hz, 2H, OCH2CH2N), 3.16 (q,
J = 8.0 Hz, 2H COCH2CH3), 4.16 (t, J = 6.4 Hz, 2H, OCH2CH2 N), 6.37
(d, J = 8.4 Hz, 1H, ArH), 6.56 (d, J = 8.4 Hz, 1H, ArH),7.32 (m, 1H,
ArH), 8.56 (s, 1H, –OH). Analysis calcd for C16H23NO3: C, 69.29; H,
8.36; N, 5.05. Found: C, 69.34; H, 8.24; N, 5.14.
4.1.4. Diethyl 2-(3-(3-(3-chloropropoxy)-2-propionylphenoxy)
propyl)malonate (12)
In a 50 ml of round bottom flask potassium tertiary butoxide
(0.6 g, 5 mmol) and THF (30 ml) was stirred for five minute and
diethyl malonate (0.8 g, 5 mmol) was slowly added in to the reac-
tion mixture. Reaction mixture was stirred for 3 h. 2,6-dichloropro-
pyl propiophenone (1.58 g) was dissolved in THF and added drop
wise to the reaction mixture and stirred for 26 h at 80–90 °C. After
completion of the reaction on TLC reaction mixture was concen-
trated, extracted with ethyl acetate (50 ml), washed with water
and dried over anhydrous sodium sulfate. Solvent was removed
and purified by column chromatography with hexane and ethyl
acetate to yield compound 12. Yield (61.12%). ESIMS (m/z) 443
4.1.2. 1-(2-(3-chloropropoxy)-6-hydroxyphenyl)propan-1-one
(10)
A mixture of compound 5 (830 mg, 5 mmol), anhydrous potas-
sium carbonate (6.6 g), dry acetone (30 ml) and 1-bromo-3-chloro-
propane (5 mmol) were taken in 50 ml round bottom flask, and

A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
2177
(M+H)+. IR (KBr): 2967, 1591, 1051 cmÀ1
.
1H NMR (CDCl3,
4.1.5.5.
propan-1-one (17).
278 (M+H)+. IR (KBr): 2959, 1604, 1083 cmÀ1
200 MHz) d: 1.17 (t, J = 6.0 Hz, 3H, COCH2CH3), 1.82 (m, 4H, CH2
of pyrrolidine), 2.11(m, 2H, OCH2CH2CH2N), 2.56 (m, 4H, CH2 of
pyrrolidine), 2.62 (m, 2H, NCH2CH2CH2O), 3.11 (q, J = 6.0 Hz, 2H,
COCH2CH3), 4.12 (t, J = 6.4 Hz, 2H, OCH2CH2CH2N), 6.38 (d,
J = 8.2 Hz, 1H, ArH,), 6.55 (d, J = 8.2 Hz, 1H, ArH), 7.32 (m, 1H,
ArH), 10.45 (s, 1H, –OH). Analysis calcd for C16H23NO3: C, 69.29;
H, 8.36; N, 5.05. Found: C, 69.38; H, 8.43; N, 4.86.
1-(2-Hydroxy-6-(3-(pyrrolidin-1-yl)propoxy)phenyl)
Yield (91.95%). mp 154 °C. ESIMS (m/z)
1H NMR (CDCl3,
200 MHz) d: 1.14 (t, J = 7.2 Hz, 3H, COCH2CH3), 1.26 (t, J = 7.0 Hz,
6H, COOCH2CH3), 1.9 (m, 2H, OCH2CH2CH2CH), 2.02 (m, 2H,
OCH2CH2CH2CH), 2.12 (m, 2H, OCH2CH2CH2Cl), 2.75 (q, J = 7.2 Hz,
2H, COCH2CH3), 3.35 (m, 1H,CH), 3.66 (t, J = 6.2 Hz, 2H, ClCH2,),
4.10 (t, J = 6.0 Hz, 4H, PhOCH2CH2), 4.19 (q, J=7.0 Hz, 4H,
COOCH2CH3), 6.51 (m, 2H, ArH), 7.19 (m, 1H, ArH). Analysis calcd
for C22H31ClO7: C, 59.66; H, 7.05. Found: C, 59.65; H, 7.19.
.
4.1.5. Typical experimental procedure for the synthesis of
compounds 13–18
4.1.5.6. 1-(2-Hydroxy-6-(3-(piperidin-1-yl)propoxy)phenyl)pro-
A mixture of compound 10 (726 mg, 3 mmol), potassium iodide
(1.66 g, 10 mmol), dry DMF (10 ml) and n-butyl amine (1.5 ml, ex-
cess) were taken in 50 ml round bottom flask. Reaction mixture
was heated at 80 °C for 4 h. After completion of the reaction on
TLC, reaction mixture was poured in distilled water (100 ml), ex-
tracted with ethyl acetate (50Â4 ml) and dried over sodium sul-
fate. Compound was purified with silica gel column using
chloroform and methanol to yield compound 13.
pan-1-one (18).
Yield (91.95%). ESIMS (m/z) 292 (M+H)+. IR
(KBr): 2929, 1619, 1088 cmÀ1
.
1H NMR (CDCl3, 200 MHz) d: 1.21
(t, J = 7.9 Hz, 3H, COCH2CH3), 1.30 (m, 2H, CH2 of piperidine),
1.55 (m, 4H, CH2 of piperidine), 2.17 (m, 2H, NCH2CH2CH2O),
2.48 (m, 4H, N(CH2)2 of piperidine), 2.80 (t, J = 6.4 Hz, 2H,
OCH2CH2CH2N), 3.16 (q, J = 7.9 Hz, 2H COCH2CH3), 4.16 (t,
J = 5.8 Hz, 2H, OCH2CH2CH2N), 6.37 (d, J = 8.4 Hz, 1H, ArH), 6.56
(d, J = 8.4 Hz, 1H, ArH), 7.32 (m, 1H, ArH), 8.42 (s, 1H, –OH). Anal-
ysis calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C,
70.18; H, 8.69; N, 4.69.
4.1.5.1.
pan-1-one (13).
(M+H)+. IR (KBr): 2945, 1599, 1017 cmÀ1
1-(2-(3-(Butylamino)propoxy)-6-hydroxyphenyl)pro-
Yield (83.27%). mp 154 °C. ESIMS (m/z) 280
1H NMR (CDCl3,
.
4.1.6. Diethyl 2-(3-(2-propionyl-3-(3-(p-tolylamino)propoxy)
phenoxy)propyl)malonate (19)
200 MHz) d: 0.92 -1.40 (m, 13H,), 2.67 (t, J = 6.0 Hz, 2H, NCH2),
2.83 (t, J = 7.2 Hz, 2H, NCH2), 3.10 (q, J = 7.2 Hz, 2H, COCH2CH3),
4.10 (t, J = 6.2 Hz, 2H, OCH2), 6.38 (d, J = 8.4 Hz, 1H, ArH), 6.55(d,
J = 8.4 Hz, 1H, ArH), 7.28 (m, 1H, ArH), 9.55(s, 1H, –OH). Analysis
calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.43;
H, 8.73; N, 4.89.
A mixture of compound 12 (726 mg, 3 mmol), potassium iodide
(1.66 g, 10 mmol) and p-toludine (1.20 g) were taken in dry DMF
(10 ml). Reaction mixture was heated at 80 °C for 4 h. After com-
pletion of the reaction on TLC, reaction mixture was poured into
distilled water (100 ml), which was extracted with ethyl acetate
(50Â4 ml) and dried over sodium sulfate. The organic layer was
concentrated to remove excess ethyl acetate. Compound was puri-
fied on basic alumina column using hexane and ethyl acetate as a
elutent to yield compound 19. Yield (86.27%). Physical state: semi-
solid. ESIMS (m/z) 514 (M+H)+. IR (KBr): 2950, 1731, 1067 cmÀ1. 1H
NMR (CDCl3, 200 MHz) d: 1.16 (t, J = 7.2 Hz, 3H, COCH2CH3), 1.26 (t,
J = 7.0 Hz, 6H, COOCH2CH3), 1.99–2.34 (m, 6H,), 2.2 (s, 3H, PhCH3),
2.70 (q, J = 7.2 Hz, 2H, COCH2 CH3), 3.10 (m, 1H, CH), 3.97 (t,
J = 6.0 Hz, 2H, NCH2), 4.01–4.08 (m, 4H, OCH2CH2), 4.20 (q,
J = 7.0 Hz, 4H, COOCH2CH3), 4.44 (s, 1H, –NH), 6.55–6.92 (m, 4H,
ArH), 6.97 (d, J = 8.2 Hz, 2H, ArH), 7.17 (m, 1H, ArH). Analysis calcd
for C29H39NO7: C, 67.81; H, 7.65; N, 2.73. Found: C, 67.88; H, 7.58;
N, 2.62.
4.1.5.2. 1-(2-Hydroxy-6-(3-(p-tolylamino)propoxy)phenyl)pro-
pan-1-one (14).
Yield (84.66%). mp 96 °C. ESIMS (m/z) 314
(M+H)+. IR (KBr): 3413, 1592, 1087 cmÀ1
.
1HNMR (CDCl3,
200 MHz) d: 1.18 (t, J = 7.2 Hz, 3H, COCH2CH3), 2.17(m, 2H,
PhOCH2CH2 CH2N), 3.12 (q, J = 7.2 Hz, 2H, COCH2CH3), 3.33 (t,
J = 6.8 Hz, 2H, NCH2), 3.76(s, 3H, PhCH3), 4.17 (t, J = 6.0 Hz, 2H,
OCH2), 4.69(s, 1H, –NH), 6.38 (d, J = 8.4 Hz, 1H, ArH), 6.56 (m, 3H,
ArH), 7.00 (d, J = 8.3 Hz, 2H, ArH), 7.32 (m, 1H, ArH), 8.29(s, 1H, –
OH). Analysis calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47.
Found: C, 72.61; H, 7.53; N, 4.49.
4.1.5.3. 1-(2-Hydroxy-6-(3-(4-methoxyphenylamino)propoxy)
phenyl)propan-1-one (15).
Yield (85.16%). mp 59 °C. ESIMS
(m/z) 330 (M+H)+. IR (KBr): 3317, 1615, 1033 cmÀ1. 1H NMR (CDCl3,
200 MHz) d: 1.18 (t, J = 7.2 Hz, 3H, COCH2CH3), 2.17 (m, 2H,
NCH2CH2CH2O), 3.12 (q, J = 7.2 Hz, 2H, COCH2CH3), 3.33 (t,
J = 6.8 Hz, 2H, NCH2), 3.76 (s, 3H, PhOCH3), 4.17 (t, J = 6.0 Hz, 2H,
OCH2), 4.94 (s, 1H, –NH), 6.38 (d, J = 8.4 Hz, 1H, ArH), 6.55 (m,
3H, ArH), 7.32 (d, J = 8.3 Hz, 2H, ArH), 7.59 (m, 1H, ArH), 8.37(s,
1H, –OH). Analysis calcd for C19H23NO4: C, 69.28; H, 7.04; N,
4.25. Found: C, 69.15; H, 7.22; N, 4.29.
4.1.7. Typical experimental procedure for the synthesis of
compounds 20–23
A mixture of compound 6–9, (5 mmol) and diethyl 2-(3-chloro-
propyl)malonate (6 mmol) was taken in to the 50 ml round bottom
flask and dry potassium carbonate (20 mmol) in 30 ml dry acetone
was added. Reaction mixture was refluxed on oil bath for 8 h. Reac-
tion mixture was filtered and filtrate was concentrated to remove
acetone. Reaction mixture was extracted with ethyl acetate
(100 ml) and washed with (50Â3 ml) of distilled water. Purifica-
tion was done on silica gel column using hexane/chloroform sol-
vent system to yield compound 20–23.
4.1.5.4. 1-(2-(3-(Butyl(methyl)amino)propoxy)-6-hydroxyphen
yl)propan-1-one (16).
Yield (91.95%). mp 106 °C. ESIMS (m/
z) 294 (M+H)+. IR (KBr): 2985, 1625, 1083 cmÀ1
.
1H NMR (CDCl3,
200 MHz) d: 0.91 (t, J = 7.2 Hz, 3H, N(CH2)3CH3), 1.17 (t, J = 7.2 Hz,
3H, COCH2CH3), 1.30–1.41 (m, 4H, NCH2CH2CH2CH3), 2.06 (m, 2H,
OCH2CH2CH2N), 2.29 (s, 3H, NCH3), 2.41 (t, J = 7.0 Hz, 2H,
NCH2CH2CH2CH3), 2.58 (t, J = 7.0 Hz, 2H OCH2CH2CH2N), 3.11 (q,
J = 7.2 Hz, 2H, COCH2CH3), 4.10 (t, J = 6.4 Hz, 2H, OCH2CH2CH2N),
6.38 (d, J = 8.2 Hz, 1H, ArH), 6.55 (d, J = 8.2 Hz, 1H, ArH), 6.94 (s,
1H, –OH), 7.32 (m, 1H, ArH). Analysis calcd for C17H27NO3: C,
69.59; H, 9.28; N, 4.77. Found: C, 69.78; H, 9.43; N, 4.61.
4.1.7.1. Diethyl 2-(3-(3-(2-(dimethylamino)ethoxy)-2-propio-
nylphenoxy)propyl)malonate (20).
state: semisolid. ESIMS (m/z) 438 (M+H)+. IR (KBr): 2974, 1729,
1529, 758 cmÀ1 1H NMR (CDCl3, 200 MHz) d: 1.20 (t, J = 5.8 Hz,
Yield (64.22%). Physical
.
3H, COCH2CH3), 1.30–2.16 (m, 10H), 2.31 (s, 6H, N(CH3)2), 2.70
(q, J = 5.8 Hz, 2H, COCH2CH3), 2.76 (m, 2H, NCH2), 3.10 (m, 1H,
CH), 3.96(m, 2H, OCH2CH2CH2), 4.10 (m, 2H, OCH2CH2), 4.16 (t,
J = 7.2 Hz, 4H, OCH2), 6.50 (d, J = 4.2 Hz, 1H, ArH), 6.54 (d,

2178
A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
J = 4.2 Hz, 1H, ArH), 7.18 (m, 1H, ArH). Analysis calcd for
23H35NO7: C, 63.14; H, 8.06; N, 3.20. Found: C, 63.21; H, 8.15;
N, 2.83.
later by glucostrips and animals showing blood glucose values be-
tween 144 and 270 mg/dl (8–15 mM) were included in the exper-
iment and considered as diabetic. The diabetic animals were
divided into groups consisting of five to six animals in each group.
Animals of experimental groups were administered suspension of
the desired test samples orally (made in 1.0% gum acacia) at a sin-
gle dose of 100 mg/kg body weight. Animals of control group were
given an equal amount of 1.0% gum acacia. A sucrose load of 2.5 g/
kg body weight was given after 30 min of compound administra-
tion. After 30 min of post sucrose load blood glucose level was
again checked by glucostrips at 30, 60, 90, 120, 180, 240,
300 min and at 24 h, respectively. Animals not found diabetic after
24 h post treatment of the test sample were not considered and
omitted from the calculations and termed as non-responders. The
animals, which did not show any fall in blood glucose profile in a
group while the others in that group, showed fall in blood glucose
profile were also considered as nonresponders. Food but not water
was withheld from the cages during the experimentation. Compar-
ing the AUC of experimental and control groups determined the
percent antihyperglycemic activity.
C
4.1.7.2. Diethyl 2-(3-(3-(2-(diethylamino)ethoxy)-2-propionyl-
phenoxy)propyl)malonate (21).
state: semisolid. ESIMS (m/z) 466 (M+H)+. IR (KBr): 2976, 1723,
1324 cmÀ1 1H NMR (CDCl3, 200 MHz) d: 1.20 (t, J = 5.8 Hz, 3H,
Yield (61.05%). Physical
.
COCH2CH3), 1.32–2.23 (m, 10H), 2.31 (t, J = 6.8 Hz, 6H, N(CH2CH3)2),
2.72 (q, J = 5.8 Hz, 2H, COCH2CH3), 2.76 (m, 6H, NCH2), 3.10 (m,
1H, CH), 3.96(m, 2H, OCH2CH2CH2), 4.10 (m, 2H, OCH2CH2), 4.16
(t, J = 6.4 Hz, 4H, OCH2), 6.51 (d, J = 8.2 Hz, 1H, ArH), 6.55 (d,
J = 8.2 Hz, 1H, ArH), 7.18 (m, 1H, ArH). Analysis calcd for
C25H39NO7: C, 64.49; H, 8.44; N, 3.01. Found: C, 64.35; H, 8.47; N,
2.82.
4.1.7.3. Diethyl 2-(3-(2-propionyl-3-(2-(pyrrolidin-1-yl)eth-
oxy)phenoxy)propyl)malonate (22).
state: semisolid. ESIMS (m/z) 464 (M+H)+. IR (KBr): 2966, 1721,
752 cmÀ1 1H NMR (CDCl3, 200 MHz) d: 1.17–1.81(m, 17H), 2.61
Yield (66.92%). Physical
.
(m, 4H, NCH2 of pyrrolidine), 2.72 (q, J = 6.2 Hz, 2H, COCH2CH3),
2.98 (t, J = 6.3 Hz, 2H, OCH2), 3.10 (m, 1H, CH), 3.96–4.18 (m, 8H),
6.34 (d, J = 8.3 Hz, 1H, ArH), 6.56 (d, J = 8.3 Hz, 1H, ArH), 7.32(m,
1H, ArH). Analysis calcd for C25H37NO7: C, 64.77; H, 8.05; N, 3.02.
Found: C, 64.68; H, 8.21; N, 3.08.
4.2.3. Anti-hyperglycemic activity in db/db mice19
The background for the db/db mouse is the C57BL/Ks strain. The
major deficiency of the C57BL/KsBom-db mouse (db/db) is lack of a
functional leptin receptor. This leads to defective leptin signaling
and a complete lack of feedback from leptin. Both hypothalamic
Neuropeptide Y (NPY) content and secretion are consequently ele-
vated, and this result in hyperphagia and decreased energy expen-
4.1.7.4. Diethyl 2-(3-(3-(2-(piperidin-1-yl)ethoxy)-2-propionyl-
phenoxy)propyl)malonate (23).
state: semisolid. ESIMS (m/z) 478 (M+H)+. IR (KBr): 2964, 1725,
1352, 757 cmÀ1 1H NMR (CDCl3, 200 MHz) d: 1.14–1.84(m, 17H),
Yield (79.65%). Physical
diture,
obesity,
insulin-resistance,
hyperinsulinemia,
.
hyperglycaemia and dyslipidemia. The db/db mouse develops non
insulin dependent diabetes mellitus (NIDDM) from around week
10. The disease is stable until week 20, where destruction of pan-
creatic b-cells can be recognized clinically as decreasing levels of
plasma insulin and very severe hyperglycaemia. The db/db mouse
has a maximal life span of 9 -12 months. The male mice are more
diabetic than, and will normally die earlier than the females. The
advantage of using male mice for experimental purposes is that
the fluctuations in plasma parameters are less than in the females
where the oestrogen cycle affects the clinical diabetes. The C57BL/
KsBom-db mice 12–18 weeks, 40–50 g bred in the animal house of
CDRI, Lucknow. The mice were housed in groups of 5 (same sex) in
a room controlled for temperature (23 2.0 °C) and 12/12 h light/
dark cycle (lights on at 6.00 am). Animal of experimental groups
were dosed 30 mg/kg body weight for 10 days and control groups
were given 1% gum acacia at the same volume. Body weight was
measured daily from day 1 to day 10. All animals had free access
to fresh water and to normal chow except on the days of the post-
prandial protocol day 6 and during the overnight fast before the
OGTT on day 10. The animals always had access to water during
experimental periods. Blood glucose was checked every morning
up till day 5. On day 6 postprandial protocol was employed, in this
method blood glucose was checked at À0.5 h and 0 h Test drugs
were given to the treatment group whereas vehicle received only
gum acacia (1.0%); the blood glucose was again checked at 1, 2,
3, 4 and 6 h post test drug treatment. On day 10 an oral glucose tol-
erance test (OGTT) was performed after an overnight fasting. Blood
glucose was measured at À30.0 min and test drugs were adminis-
tered. The blood glucose was again measured at 0.0 min post treat-
ment and at this juncture glucose solution was given at a dose of
3 g/kg to all the groups including vehicle. The blood glucose levels
were checked at 30 min, 60 min, 90 min and 120 min post glucose
administration. At the end of the experiment blood has been with-
drawn from the retro-orbital plexus of mice for the estimation of
serum insulin and lipid profile. Quantitative glucose tolerance of
each animal was calculated by area under curve (AUC) method
(Prism software). Comparing the AUC of experimental and control
2.60 (m, 6H, NCH2 of piperidine), 2.73 (q, J = 6.0 Hz, 2H, COCH2CH3),
2.98 (t, J = 6.3 Hz, 2H, OCH2), 3.10 (m, 1H,, 3.92–4.16 (m, 8H), 6.35
(d, J = 8.1 Hz, 1H, ArH), 6.52 (d, J = 8.1 Hz, 1H, ArH), 7.31(m, 1H,
ArH). Analysis calcd for C26H39NO7: C, 65.39; H, 8.23; N, 2.93.
Found: C, 65.31; H, 8.27; N, 2.98.
4.2. Pharmacology
4.2.1. Sucrose loaded rat model (SLM)12d
Male albino rats of Charles Foster/Wistar strain of average body
weight 160 20 g were selected for this study. The blood glucose
level of each animal was checked by glucometer using glucostrips
(Boehringer Mannheim) after 16 h starvation. Animals showing
blood glucose levels between 3.33 and 4.44 mM (60–80 mg/dl)
were divided into groups of five to six animals in each. Animals
of experimental group were administered suspension of the de-
sired synthetic compound orally (made in 1.0% gum acacia) at a
single dose 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 pro-
file of each rat was again determined at 30, 60, 90 and 120 min
post administration of sucrose by glucometer Food but not water
was withheld from the cages during the course of experimentation.
Quantitative glucose tolerance of each animal was calculated by
Area Under Curve (AUC) method (Prism Software). Comparing
the AUC of experimental and control groups determined the per-
centage anti-hyperglycemic activity.
4.2.2. Sucrose-challenged streptozotocin-induced diabetic rat
model (STZ-S)18
Male albino rats of Sprague Dawley strain of body weight
160 20 g were selected for this study. Streptozotocin (Sigma,
USA) was dissolved in 100 mM citrate buffer pH 4.5 and calculated
amount of the fresh solution was injected to overnight fasted rats
(60 mg/kg) intraperitoneally. Blood glucose level was checked 48 h

A. Kumar et al. / Bioorg. Med. Chem. 20 (2012) 2172–2179
2179
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comparison was made by Dunnett’s test.
4.2.4. In vitro enzyme inhibition
For the enzyme inhibition essay of synthesized compounds
against glucose-6-phosphatase, glycogen phosphorylase,
a-gluco-
sidase, DPP-IV and PTP-1B, according to our previously reported
procedure.12d
Acknowledgments
SS, LPG, SPS, PA, and NR are thankful to CSIR New Delhi for the
award of research fellowship. The authors also thankful to SAIF
division for providing the spectral data.
9. Combs, A. P. J. Med. Chem. 2010, 53, 2333.
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