Design, synthesis and antidiabetic evaluation of oxazolone derivatives

Article abstract of DOI:10.1007/s12039-011-0079-2

A series of ten novel (2a-j) 4-arylidine 2-[4-methoxy phenyl] oxazol-5-one derivatives were synthesized and assayed in vivo to investigate their antidiabetic activities by streptozotocin-induced model in rat. These derivatives showed considerable biological efficacy when compared to rosiglitazone, a potent and wellknown antidiabetic agent as a reference drug. All the compounds were effective, amongst them 2d shows more prominent activity at 50 mg/k.g.p.o. The experimental results are statistically significant at P < 0.01 level. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0079-2

c
J. Chem. Sci. Vol. 123, No. 3, May 2011, pp. 335–341. ꢀ Indian Academy of Sciences.
Design, synthesis and antidiabetic evaluation of oxazolone derivatives
G MARIAPPANa∗, B P SAHAa, SRIPARNA DATTAa, DEEPAK KUMARa and P K HALDARb
aDepartment of Medicinal Chemistry, bDepartment of Pharmacology, Himalayan Pharmacy Institute,
East Sikkim 737 136, India
e-mail: gmariappanhpi@yahoo.co.in
MS received 1 December 2010; revised 16 March 2011; accepted 18 March 2011
Abstract. A series of ten novel (2a–j) 4-arylidine 2-[4-methoxy phenyl] oxazol-5-one derivatives were syn-
thesized and assayed in vivo to investigate their antidiabetic activities by streptozotocin-induced model in rat.
These derivatives showed considerable biological efficacy when compared to rosiglitazone, a potent and well-
known antidiabetic agent as a reference drug. All the compounds were effective, amongst them 2d shows more
prominent activity at 50 mg/k.g.p.o. The experimental results are statistically significant at P < 0.01 level.
Keywords. Oxazolone scaffold; acetyl glycine; hypoglycemic activity; antiinflammatory.
1. Introduction
numerous reactive sites allowing for a diverse set of
possible modifications. This diverse reactivity makes
them excellent substrates for their use in diversity ori-
ented synthesis.18 The onset of insulin in body, which
causes an abnormal effect on glucose metabolism, is
related not only to the development of Type II diabetes
but also to cardiovascular disease.19 Sulfonylureas, the
first generation of antidiabetic agents such as chlor-
propamide, tolbutamide and tolazamide are still in use
but are less potent than the second generation drugs like
glibenclamide, glipizide and glimepiride. Sulfonylureas
are mostly subjected to hepatic metabolism, yielding
less active or inactive metabolites that are then elimi-
nated through the kidneys. Patients with impaired hep-
atic or renal function risk severe hypoglycemia because
of accumulation of active drug in circulation. From the
pioneering discovery of ciglitazone,20 a new class of
thiazolidinedione based compounds has been developed
to treat diabetic patients that can reverse the insulin
resistance in non-insulin dependent diabetes mellitus
(NIDDM). Amongst various substituted benzyl-2,4-
thiazolidinedione compounds, troglitazone,21 pioglita-
zone,22 and rosiglitazone,23 are potentially antidiabetic
compounds that have been clinically examined. The
first marketed thiazolidinedione, troglitazone,24 was
withdrawn because of increased risk of hepatotoxic-
ity.25,26 The potent side effect i.e., hepatotoxicity lim-
its the use of thiazolidine derivatives as safe drug can-
didates. In view of this, it was of considerable interest
to synthesize the title compound with a hope to obtain
potent biologically active and safe oral antidiabetic
agents (figure 1).
Diabetes mellitus (DM) is a major degenerative disease
in the world today.1 Several epidemiological and clini-
cal studies indicate a direct relationship between hyper-
glycemia and long-term complications such as retinopa-
thy, nephropathy, neuropathy and angiopathy, etc.2,3
India has today become the diabetic capital of the world
with over 20 million diabetics and this number is set to
increase to 57 million by 2025.4 DM is a multifacto-
rial disease which is characterized by hyperglycemia,5
lipoprotein abnormalities,6 raised basal metabolic rate,7
defect in reactive oxygen species scavenging enzymes8
and high oxidative stress-induced damage to pancre-
atic beta cells.9 It is ranked seventh among the lead-
ing causes of death and is considered third when
its fatal complications are taken into account.10 Sev-
eral drugs such as sulfonylureas and biguanides are
presently available to reduce hyperglycaemia in dia-
betes mellitus. These drugs have side effects and thus
searching for a new class of compounds is essential to
overcome this problems.11 Nevertheless, there is con-
tinuous search for alternative drugs; management of
diabetes without any side effects is still a challenge to
the medicinal chemist. Therefore, it is prudent to look
for options in novel drugs for diabetes as well. Oxazole
plays very vital role in the development of various bio-
logically active agents such as analgesic,12 antiinflam-
matory,13 antidepressant,14 anticancer,15 antimicrobial,
antidiabetic and antiobesity.16,17 Oxazol-5-ones contain
∗For correspondence
335

336
G Mariappan et al.
Thiazolidinedione analogs
O
O
CH3
N
CH3
N
O
O
N
N
S
O
N
S
O
Pioglitazone
Rosiglitazone
R
N
O
OCH3
O
Our designed prototype
Figure 1. Structural resemblance of thiazolidinedione and oxazolone derivatives.
The starting material 4-methoxy benzoyl glycine was 2. Experimental
prepared by the reaction of glycine and 4-methoxy ben-
zoyl chloride in the presence of sodium hydroxide.27
It was then reacted with substituted aromatic and het-
ero aldehyde in presence of acetic anhydride and glacial
acetic acid to obtain oxazolones. The chemistry used to
prepare these analogs is illustrated in scheme 1. Their
2.1 Material and methods
All the chemicals were of synthetic grade and commer-
cially procured from SD fine Chemicals Ltd. Mumbai,
India. Melting points were recorded on a Buchi cap-
illary melting point apparatus and are uncorrected.
IR spectra were recorded on FT-IR8400S, Fourier
Transform (SHIMADZU) Infrared spectrophotometer
1
structures have been elucidated from UV-Vis, IR, H
NMR, Mass spectral data and elemental analysis. Phys-
ical data of synthesized compounds are given in table 1.
CONHCH2COOH
R
R
CHO
NH2
N
H3CO
COCl
O
OCH3
O
CH2COOH
Glycine
Ac2O/AcONa
10% NaOH
2a−e & 2g−j
OCH3
4-Methoxy benzoyl glycine
(1)
Ac2O/AcONa
O
OHC
N
O
O
OCH3
O
2f
Scheme 1. Synthesis of oxazolone derivatives.

Design, synthesis and antidiabetic evaluation of oxazolone derivatives
Table 1. Physical data of synthesized compounds.
337
Compound
R
Mol. formula
Mol. weight
M.P(◦C)
Yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
-H
2-Cl
4-OMe
3-OMe
3-Cl
C17H13NO3
C17H12ClNO3
C18H15NO4
C18H15NO4
C17H12ClNO3
C15H11NO4
C17H13NO4
C18H14NO3
C17H12N2O5
C19H18N2O3
279
313
309
309
313
269
295
292
324
322
208–210
203–205
182–185
158–160
180–182
175–177
170–172
168–170
204–206
206–208
65
68
60
71
69
60
65
75
72
75
-
2-OH
phenyl ethenyl
3-NO2
4-N-(Me)2
2j
1
using KBr disc method. The H-NMR spectra were 2.3a 4-[Benzylidene]-2-(4-methoxy-phenyl) oxazol-5-
recorded in DMSO- δ6 on Perkin Elmer NMR one (2a): Pale yellow powder; IR (KBr): υ (cm−1),
Spectrophotometer-300 MHz. using TMS as an internal 1782 (C = O), 1651 (C = N), 1506 (C = C–Ar),
1
standard. Mass spectra were recorded on Micro mass 3064 (=C–H), 2914 (CH3), 2762 (Ar C–H); H NMR
Q-TOF and Shimadzu LCMS 2010A Mass spectrome- (300 MHz, CDCl3,δ ppm): 3.90 (s, 3H, −OCH3), 7.37
ter. Elemental analysis was performed at a Perkin Elmer (s, H, C = C–H), 7.56 (d, 2H, Ar–H), 7.19 (d, 2H, Ar–
Auto system XL Analyzer. Thin layer chromatography H), 8.09 (t,1H, Ar–H) 8.18 (d, 2H, Ar–H), 8.31 (d, 2H,
analyses were performed on pre-coated silica gel plates Ar–H); MS (EI): 302 m/z [M + Na+]+, 259, 227,60;
(G 350, Merck).
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02;
Found: C, 72.71; H, 4.19; N, 4.62.
2.2 Preparation of 4-methoxy benzoyl glycine
2.3b 4-[2-Chloro-benzylidene]-2-(4-methoxy-phenyl)-
(4H)-oxazol-5-one (2b): Yellow powder; IR (KBr)
υ (cm−1): 1788 (C = O), 1651 (C = N), 1506 (C =
C–Ar), 3074 (=CH), 2922 (CH3), 2833 (Ar–CH);
1H NMR (300 MHz, CDCl3,δ ppm): 3.81 (s, 3H,
OCH3), 7.40–7.65 (s, 1H, H–C=), 7.19 (d, 2H, Ar–
H), 7.31 (d, 2H, Ar–H), 7.44–7.56 (m, 4H, Ar–H);
MS (EI): 311 m/z [M-2]+, 283, 255; Anal. Calcd for
C17H12ClNO3: C, 65.08; H, 3.86; N, 4.46; Found: C,
65.50; H, 3.36; N, 4.86.
Glycine (0.1 mol) was dissolved in 30 ml sodium
hydroxide (2N) in a 500 ml conical flask. The mixture
was stirred vigorously with mechanical stirrer until the
solid almost completely dissolved. 4-methoxy benzoyl
chloride (0.1 mol) was added in five portions and stirred
vigorously for further 1 h. The crystallized 4-methoxy
benzoyl glycine was left in refrigerator overnight. The
crystals were filtered on a Buchner funnel, washed with
ice cold water and dried at 100◦C. The melting point
145–149◦C, yield 80%.
2.3c 4-[4-Methoxy-benzylidene]-2-(4-methoxy-phenyl)
oxazol-5-one (2c): Deep yellow powder; IR (KBr)
υ (cm−1): 1784 (C = O), 1651 (C = N), 1600 (C =
C–Ar), 3431 (=C–H), 2928 (CH3), 885, 825 (Ar–CH);
1H NMR (300 MHz, CDCl3,δ ppm): 3.32 (s, 6H, 2 ×
OCH3), 7.26 (s, 1H, H–C=), 7.23 (d, 2H, Ar–H), 7.30
(d, 2H, Ar–H), 7.56 (d, 2H, Ar–H), 8.38 (d, 2H, Ar–
H); MS (EI): 309 m/z [M]+, 310, 321, 331, 332[M +
Na+]+, 333; Anal. Calcd for C18H15NO4: C, 69.89; H,
4.89; N, 4.53; Found: C, 69.48; H,4.46; N, 4.91.
2.3 General method for the preparation of
4-substituted-[Benzylidene]-2-(4-methoxy phenyl)
oxazol-5-one28 (2a–j)
A mixture of 4-methoxy benzoyl glycine (0.01 mol),
substituted aromatic aldehyde (0.02 mol), anhydrous
sodium acetate (0.01 mol) and acetic anhydride
(0.04 mol) was refluxed for 1 h on a water bath with
occasional stirring. The resulting mixture was left in
refrigerator overnight. The solid thus obtained was fil-
tered, washed with cold water, dried in hot air oven
at 60◦C and recrystallized from ethanol. All the title
compounds were synthesized by adopting the same
procedure with variation in reaction time.
2.3d 4-[3-Methoxy-benzylidene]-2-(4-methoxy-phenyl)
oxazol-5-one (2d): Pale yellow powder; IR (KBr) υ
(cm−1): 1784 (C = O), 1656 (C = N), 1604 (C = C–
Ar), 3074 (=CH), 2958 (CH3), 883,835,771,678,604

338
G Mariappan et al.
1
(Ar–CH); H NMR (300 MHz, CDCl3,δ ppm): 3.86, ton), 7.37 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 7.91 (d,
3.90 (s, 6H, 2 × OCH3), 7.45 (s, 1H, H–C=), 7.10 2H, Ar–H), 8.06 (d, 2H, Ar–H); 315 m/z [M + Na+]+,
(d, 2H, Ar–H), 7.49 (d, 2H, Ar–H), 7.52-8.09 (m, 4H, 300,256; Anal. Calcd for C18H14NO3: C, 73.96; H,
Ar–H); 310 m/z [M + 1]+, 331, 332[M + Na+]+, 333 4.83; N, 4.79; Found: C, 73.36; H, 4.33; N, 4.32.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53;
Found: C, 69.38; H,4.45; N, 4.94.
2.3i 4-[3-nitro-benzylidene]-2-(4-methoxy-phenyl)-
(4H)-oxazol-5-one (2i): Yellow powder; IR (KBr) υ
(cm−1): 1790 (C = O), 1654 (C = N), 1606 (C = C–
2.3e 4-[3-Chloro-benzylidene]-2-(4-methoxy-phenyl)
1
oxazol-5-one (2e): Pale yellow powder; IR (KBr)
Ar), 3103 (CH3), 3443 (=C–H), 2856 (C–H–Ar); H
υ (cm−1): 1791 (C = O), 1658 (C = N), 1556 (C =
NMR (300 MHz, CDCl3,δ ppm): 3.90 (s, H, OMe), 7.41
C–Ar), 2902 (CH3), 3502 (=C–H), 883, 785, 680,559
(s, 1H, H–C=), 7.20 (d, 2H, Ar–H ), 7.33 (d, 2H, Ar–
H), 7.80 (m, 4H, Ar–H); Anal. Calcd for C17H12N2O5:
C, 62.96; H, 3.73 ; N, 8.64; 347 m/z [M+Na]+ Found:
C, 62.45;H, 4.23 ; N, 9.06.
1
(Ar–CH); H NMR (300 MHz, CDCl3,δ ppm): 3.92 (s,
3H, −OCH3), 7.57 (s, 1H, H–C=),7.23 (d, 2H, Ar–H),
7.96 (d, 2H, Ar–H), 7.56 (d, 2H, Ar–H),8.01-8.38 (m,
4H, Ar–H); 313 m/z [M + Na+]+, 336 Anal. Calcd for
C17H12ClNO3: C, 65.08; H, 3.86; N, 4.46; Found: C,
65.51; H, 3.40; N, 4.96.
2.3j 4-[4-Dimethylamino-benzylidene]-2-(4-methoxy-
phenyl)-(4H)-oxazol-5-one (2j): Orange powder; IR
(KBr) υ (cm−1): 1780 (C = O), 1647 (C = N), 1604
(C = C–Ar), 2976 (CH3), 3443 (=C–H), 2810 (C–H–
2.3f 4-[Furan-3-ylmethylene]-2-(4-methoxy-phenyl)-
(4H)-oxazol-5-one (2f): Light green powder; IR
(KBr) υ (cm−1): 1790 (C = O), 1654 (C = N), 1556
(C = C–Ar), 3601 (=C–H), 3064 (CH3), 2362 [C-
1
Ar); H NMR (300 MHz, CDCl3,δ ppm): 3.88 (s, 3H,
−OCH3), 3.07 (s, 6H,N-CH3), 7.37 (1H, H–C=), 6.82
(d, 2H, Ar–H), 6.97 (d, 2H, Ar–H), 7.01-8.17 (m, 4H,
Ar–H); 323 m/z [M + 1]+, 345 [M + Na+]+ Anal.
Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.64;
Found: C, 70.38; H, 5.24; N, 8.22.
1
H(furan)], 941, 860, 758, 696 (Ar–CH); H NMR
(300 MHz, CDCl3,δ ppm): 3.89 (s, 3H, −OCH3), 7.57
(s, 1H, H–C=), 6.82 (d, 2H, Ar–H), 6.83 (s, H, Ar–
H), 7.13 (d, 2H, Ar–H), 8.08 (d, 2H, Ar–H); 269 m/z
[M]+, 292, [M + Na+]+, 227, 142; Anal. Calcd for
C15H11NO4: C, 66.91; H, 4.12; N, 5.20; Found: C,
67.41; H, 4.69; N, 5.57.
2.4 Pharmacological evaluation
2.4a Acute toxicity studies: Groups of six albino
mice, weighing 20–25 g were fasted overnight and
treated per orally with the test compounds.29,30 The
dosage was varied from 100 mg kg−1 body weights. The
animals were observed for 24 h for any signs of acute
toxicity such as increased or decreased motor activ-
ity, tremors, convulsion, sedation, lacrimation, etc. No
mortality of the animals was observed even after 24 h.
Hence the LD50 cut-off value of the test compounds was
fixed as 100 mg kg−1, so that 100 mg kg−1 i.e., 1/10 of
cut-off value was taken as screening dose for evalua-
tion of antidiabetic activity. All the animal experiments
were conducted by the approval of Institutional Animal
Ethics Committee, Himalayan Pharmacy Institute, East
2.3g 4-[2-Hydroxy-benzylidene]-2-(4-methoxy-phenyl)
oxazol-5-one (2g): Pale yellow crystal; IR (KBr) υ
(cm−1): 1712 (C = O), 1666 (C = N), 1539 (C =
C–Ar), 3065 (=C–H), 2837 (CH3), 3007 (C–H–Ar),
906, 848, 750, 601(Ar–CH); 1H NMR (300 MHz,
CDCl3,δ ppm): 3.85 (s, 3H, −OCH3), 7.07 (s, 1H, H–
C=), 7.94 (s, 1H, OH), 7.09 (d, 2H, Ar–H), 7.22 (d,
2H, Ar–H), 7.24–7.97 (m, 4H, Ar–H); 318 m/z [M +
Na+]+ Anal. Calcd for C17H13NO4: C, 69.15; H, 4.44;
N, 4.74; Found: C, 69.56; H, 4.98; N, 4.52.
2.3h 4-[3-phenyl-allylidene]-2-(4-Methoxy-phenyl)- Sikkim, India. During the study period, guidelines of
(4H)-oxazol-5-one (2h): Deep yellow powder; IR Committee for the Purpose of Control and Supervision
(KBr) υ (cm−1): 1778 (C = O), 1641 (C = N), 1506 of Experiments on Animals (CPCSEA), Institutional
(C = C–Ar), 3443 (=C–H), 3103 (CH3), 958,883,840, Animals Ethics Committee (IAEC) were followed for
1
742 (Ar–CH ); H NMR (300 MHz, CDCl3,δ ppm): the maintenance of animals. The research work was
3.88 (s, 3H, −OCH3), 7.14,7.18, 7.28 (3H,olefinic pro- approved by IAEC No: HPI/10/60/IAEC/0085.

Design, synthesis and antidiabetic evaluation of oxazolone derivatives
2.5 Antidiabetic activity31,32
339
3. Results and discussion
2.5a Streptozotocin induction of experimental dia- All the compounds were screened in vivo for their
betes: The rats were injected intraperitoneally with oral hypoglycemic activity by streptozotocin-induced
streptozotocin dissolved in sterile normal saline at a diabetic model in rat. All the compounds are hav-
dose of 60 mg kg−1 b.w. A blood glucose range of 200– ing remarkable hypoglycemic property, however with a
300 mg dL-1 was used for the experiment. Hyper- degree of variation. Blood glucose changes in treatment
glycemia was confirmed in animals after 72 h of strep- of diabetic rats with synthesized oxazolone deriva-
tozotocin injection.
tives were presented in (table 2). A significant increase
in blood glucose was observed in diabetic rats. All
the compounds 2a–2j had shown significant reduc-
tion in blood glucose as compared to control diabetic
rats at 50 mg/kg body weight for 5th and 10th days.
Rosiglitazone was taken as standard drug which showed
69.33% blood glucose lowering activity at the dose of
100 mg/kg.p.o. Among all the derivatives, compound
2d (64.36%) was found to be better hypoglycemic agent
like the standard drug rosiglitazone (100 mg/kg b.w) in
reducing the blood glucose level. It is interesting to note
that Compounds 2c (61.2%), 2d (64.36%), 2j (61.80%),
2i (62.01%), and 2e (62.20%), having both electron
donating or withdrawing substituent at meta and para
position of the Oxazolone ring showed an appreciable
increase in hypoglycemic activity at 50 mg/kg, whereas
electron withdrawing groups at ortho position as in 2b
and 2g sustain the activity in STZ model but were found
inferior. Surprisingly 2f (61.60%) has shown significant
antihyperglycemic activity. Compound 2h (55.68%),
comparatively had shown poor hypoglycemic activity
followed by compound 2a (62.80%).
2.5b Experimental design: Animals were divided
into 12 groups of 6 animals (n = 6): Group 1 diabetic
animals (vehicle) received 0.5% CMC (1 ml); Group
2 diabetic animals received rosiglitazone 100 mg/kg.
Groups (3–12) diabetic animals received compounds
2a–2j in a single dose of 50 mg/kg body weight per oral
respectively for 7 days continuously.
2.5c Blood glucose measurement: Blood was with-
drawn from the tail vain each time. Blood glucose was
measured at 0, 5th and 10th days interval. At the end of
0, 5th and 10th day, blood sample was withdrawn from a
tail vein by snipping the tip of the tail and the blood glu-
cose level was measured by Accu Sure Blood Glucose
Monitoring System (Dr. Gene Health & Wellness).
2.5d Statistical analysis: Values are represented as
mean
SEM. Data were analysed using analysis of
variance and group means were compared with Tukey–
Kramer Post ANOVA test. The values were considered
when P < 0.01.
Those compounds having electron donating substit-
uent 2c, 2d and 2j have shown 61.2%, 64.36%
and 61.8% antihyperglycemic properties respectively,
Table 2. Hypoglycemic effects of synthesized test compounds of oxazolone derivatives.
Treatment (mg/kg b.w p.o)
blood glucose level (mg/dl)
0-day
5-day
10-day
% anti hyperglycemic
activity
Control (0.5%CMC)
Rosiglitazone100
338.8 6.5 381.6 7.0∗∗
339.5 4.4 138.3 3.7∗∗
343.6 5.8 210.3 3.2∗∗
342.1 4.2 236.3 2.7∗∗
338.3 4.8 243.1 4.2∗∗
406.6 3.9∗∗
104.1 2.8∗∗
147.5 3.3∗∗
149.6 3.5∗∗
131 2.6∗∗
69.30
62.80
56.27
61.20
64.36
62.20
61.60
58.90
55.68
62.01
61.80
2a
2b
2c
2d
2e
2f
2g
2h
2i
325 6.0
195.5 2.2∗∗
115.8 2.1∗∗
133 4.3∗∗
352.3 5.1 260.6 4.4∗∗
350.6 5.4 256.5 6.8∗∗
356.6 6.1 252.3 5.1∗∗
353.5 6.1 259.3 5.1∗∗
354.1 5.8 249.5 4.1∗∗
353.5 5.9 257.1 5.4∗∗
134.67 3.0∗∗
146.5 3.9∗∗
156.67 5.7∗∗
134.5 4.8∗∗
134.83 4.2∗∗
2j
Values are expressed as mean SEM; (n = 6), **P < 0.01.

340
G Mariappan et al.
where as the compounds attached with electron with- metabolic regulators. The regulators increase expres-
drawing substituent like 2b, 2e and 2i show 56.27%, sion of a number of insulin responsive genes involved
62.2% and 62.01% hypoglycemic property respectively. in the regulation of glucose and lipid metabolism. Stud-
The compounds derived from cinnamaldehyde such ies have shown that there is a good correlation between
as compounds 2h exhibited less 55.68% antidiabetic PPAR γ -affinity and antihyperglycemic effects.35,36 It
property and the compound 2f derived from furfural may increase glucose transport into muscles and adi-
aldehyde exhibited 61.6% activity.
pose tissue by enhancing the synthesis and translocation
Amongst the compounds having electron donating of specific forms of the glucose transporter. However,
groups, the meta substituted compound 2d has more it is expected that the synthesized compounds can act
activity than the para substituted compounds 2c and 2j indirectly by stimulating the release of insulin into the
comparing both para substituted compounds 2c and 2j bloodstream. From the observed result it is concluded
are showing almost same activity. The electron with- that almost all the compounds 2a–2j reduced glucose
drawing groups substituted at meta position 2e, 2i are level in diabetic rats. However, the effect of 2d is more
showing nearly same activity whereas ortho position 2b pronounced in streptozotocin diabetic rats. Further tox-
showing less activity. Interestingly, the compounds sub- icity studies and mode of action of hypoglycemic activ-
stituted with furan ring are also showing more activity ity can provide an effective drug candidate for diabetes
which lies within the range of compounds 2c, 2e, 2i mellitus.
and 2j.
The compound 2a that is unsubstituted by neither
electron donating nor with electron withdrawing group
4. Conclusion
shows significant activity (62.8%). Amongst all the
This study reports the synthesis and antidiabetic activ-
compounds, compound 2h exhibits very less activity.
ity of novel oxazolones derivatives. The divergence
A conclusion can be arrived from these results that
in the antidiabetic activity of these compounds val-
as compared to electron withdrawing groups; electron
idates the significance of this study. The results of
donating group enhanced the activity. The substituted
the study revealed that most of the compounds tested
electron donor and acceptor groups at ortho position
showed moderate to good antidiabetic activity. Struc-
decrease the activity. The compounds derived from
ture and biological activity relationship of the title com-
aromatic and hetero aromatic aldehyde almost having
pounds showed the electron donating group enhanced
equal activity. All the compounds activity is lower than
the activity.
the standard. Interestingly, compound 2d at 50 mg/kg
lowers the blood glucose level almost equal to standard
rosiglitazone.
Acknowledgements
Streptozotocin causes diabetes by the rapid deple-
tion of β-cells and thereby brings about a reduction of
insulin release. In our study, an increase in blood glu-
cose level in diabetic rats confirmed the induction of
diabetes mellitus.33 The oral administration of a sin-
gle dose of synthesized compounds caused a significant
reduction in blood glucose in diabetic rats. These results
revealed that oxazolone derivatives may be effective
in insulin-independent diabetes mellitus. The signif-
icant hypoglycemic effects of oxazolone derivatives
in diabetic rats indicate that it can be mediated by
stimulation of glucose utilization by peripheral tissues.
Since the oxazolone derivatives are having structural
resemblance with thiazolidinone with minor modifica-
tion, it can be expected that the mode of action of
the oxazolone derivatives may be similar to thiazolidi-
none derivatives.34 Hence oxazolone derivatives may
act as agonist upon binding to peroxisome proliferator-
activated receptor (PPAR γ ) which preferentially binds
to DNA activating transcription of a wide variety of
The authors are thankful to the Director Dr. H P
Chhetri, Himalayan Pharmacy Institute, Majhitar, East
Sikkim, India for providing the facilities to carry out
the research work. The authors are also grateful to
Dr. P K Kar, Department of Pharmacology, Himalayan
Pharmacy Institute, who helped us to carry out the
antidiabetic studies.
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