Synthesis and oral hypoglycemic activity of 3-[5′-Methyl-2′- aryl-3′-(thiazol-2′-yl amino) thiazolidin-4'-one]coumarin Derivatives

Article abstract of DOI:10.1155/2011/258680

Number of heterocyclic compounds has been exploited to develop pharmaceutically important molecules, out of which biheterocyclic coumarins are clinically used potential drug candidates showing oral hypoglycemic and antidiabetic activities. A new series of

Full text of DOI:10.1155/2011/258680

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(1), 386-390
http://www.e-journals.net
Synthesis and Oral Hypoglycemic Activity of
3-[5'-Methyl-2'-aryl-3'-(thiazol-2''-yl amino)
thiazolidin-4'-one]coumarin Derivatives
DEEPTHI KINI and MANJUNATH GHATE*
Department of Pharmaceutical Chemistry
Karnataka College of Pharmacy, Bangalore, India
*Department of Pharmaceutical Chemistry
Institute of Pharmacy Nirma University, Ahmedabad-382 481, India
ghate72@gmail.com
Received 21 May 2009; Revised 21 January 2010; Accepted 15 March 2010
Abstract: Number of heterocyclic compounds has been exploited to develop
pharmaceutically important molecules, out of which biheterocyclic coumarins are
clinically used potential drug candidates showing oral hypoglycemic and
antidiabetic activities. A new series of 3-[5'-methyl-2'-aryl-3'-(thiazol-2''-yl
amino)thiazolidin-4'-one]coumarin derivatives were designed and synthesized.
The title compounds were synthesized from starting material 3- acetyl coumarin.
All the synthesized compounds were characterized and screened for
hypoglycemic activity. Some of the compounds exhibited promising activity.
Keywords: Oral hypoglycemic, Coumarins, Thiazilidinones.
Introduction
Diabetes mellitus is one of life threatening disorder found in most of the countries in the
world which is due to impaired carbohydrate, fat and protein metabolism1. A defective or
deficient insulin secretion, which translates into impaired carbohydrate (glucose) use, is a
characteristic feature of diabetes mellitus results in hyperglycemia in the blood2. Recent
survey showed that it is fourth leading cause of death in developed countries and worry
more than 5% of world’s population; suffer from diabetes. There are more than 125 million
persons with diabetes in the world today and by 2010, this number is expected to approach
220 million3. A standard treatment regimen has considered the use of Insulin and number of
other chemical classes of drugs which may increase the production of Insulin. The chemical
compounds like sulphonyl ureas, biguanides, thiazolidinediones that reduce the
hyperglycemia by inducing the βcells to release more insulin3. However, prolonged use of
sulphonylureas cause undesirable effects which include hypoglycemic episodes, ultimate

Synthesis and Oral Hypoglycemic Activity
387
exertion of β cell as well as long term angiogenic side effects that are results of chronic day
long exposure to increased insulin level4. From literature survey, it was found that
thiazolidine derivatives exhibited 10 fold more potent antidiabetic activity (ED25=0.05 mg/kg/d)
than pioglitazone (ED25=0.05 mg/kg/d) in Wistar fatty rats4. Even it was found that
3,5-dimethyl pyrazoles possess hypoglycemic activity as greater as 100 times that of
tolbutamide in glucose prime in rats5.
Coumarins are very important oxygen containing heterocycles having diverse biological
activities of natural and synthetic origin as anticoagulants and antithrombotics6. Some of the
coumarin derivatives are found to possess antimicrobial7, antitumour8, antiviral9 and other
activities10. Due to these importance of thiazolidinones and coumarin derivatives we have
planed to synthesize new series of 3-[5'-methyl-2'-aryl-3'-(thiazol-2''-yl amino)thiazolidin-4'-
one] coumarin derivatives and test for oral hypoglycemic activity.
Experimental
The synthetic pathway for the coumarins derivatives presented here is shown in Scheme 1. In the
first step the 3-bromoacetyl derivatives were prepared by bromination of 3-acetyl coumarin (1)
in acetic acid afforded 3-(2'-bromoacetyl)coumarins (2). The 3-[2'-(2''-arylidenehydrazinyl)
thiazolyl]coumarins (3) was prepared by the reaction of 3- bromoacetyl coumarin with
benzaldehyde thiosemicarbazones in ethanol under refluxing conditions. The reaction undergone
smoothly in ethanol as solvent. Further the reaction of 3 with thiolactic acid in the presence of
zinc chloride in dioxane under refluxing condition to afford 5-methyl-3-(4'-(2''-methyl-3-(4'-(2''-
oxo-2H-chromen-3'-yl)thiazol-2'-ylamino)-2-phenylthiazolidin-4-one (4a-4j) in moderate yields
(Scheme 1). All the synthesized compounds were characterized by spectroscopic and elemental
analysis. The physical data of title compounds is summarized in Table 1.
Table 1. Physical data of the compounds 4a-j
Compound code
R
MP OC
133-135
223-228
255-260
202-207
220-230
220-225
178-180
156-158
187-189
224-226
% Yield
69
68.6
63.21
60.46
56
Rf
H
0.5
0.6
0.6
0.6
0.6
0.6
0.5
0.5
0.5
0.5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-CH3
4-Cl
4-OH
5,6-benzo
4-F
4-NO2
2-Cl
2-Br
56
60
62
63
4-Br
58
4j
Melting points were determined in open capillary tubes on a Thomas Hoover apparatus
and were uncorrected. IR spectra were recorded on the Nicolet FT-IR spectrophotmeter
1
using KBr pressed pellet technique. H NMR were recorded on Bruker Model DRX-300
MHz NMR spectrophotometer in CDCl3 and DMSO-d6 using Tetramethylsilane (TMS) as
internal reference. MS spectra were obtained on Jeol SX 102/DA-6000 mass spectrometer.
Elemental analysis was performed on Carlo Erba 1108 analyzer.
Results and Discussion
As outlined in Scheme 1, 3-(2-bromoacetyl)coumarins 2 were prepared by bromination of
3-acetyl coumarins 1 in chloroform at room temperature. 3-bromoacetyl)coumarin 2 were

388
M. GHATE et al.
allowed to react with substituted benzaldehyde thiosemicarbazones under reflux in ethanol
for 8 h to afford 3-[2'-(2''-arylidenehydrazinyl)thiazolyl]coumarin 3 derivatives in good
yields. The structures of compounds 3 were substantiated from analytical and spectral data.
Thus, the IR spectral data showed the presence NH, C=O and C=N stretching vibrations. In
1
addition the H NMR spectra showed signals corresponding to hydrazinyl, aromatic and NH
protons. Further the formation of the compound 3 is also confirmed by mass spectral data. The
compound 3 was treated with thiolactic acid in the presence of ZnCl2 under refluxing conditions
in dioxane gave 3-[5'-methyl-2'-aryl-3'-(thiazol-2''-ylamino)thiazolidin-4'-one]coumarins 4 in
moderate to good yields. We have tried with many reaction conditions for the preparation of the
titled compounds such as DMF and dichloro methane. The dioxane with zinc chloride under
reflux was found to undergo the reaction smoothly. The structure of the titled compound was
assigned by IR, 1H NMR and Mass spectra accordance with the structure.
S
O
O
C
NNHCNH2
H
Br
R
Br2
CH3
CH3COOH
Ethanol
O
O
O
O
1
2
SH
R
S
N
S
OH
NH
N
NHN=CH
H3C
N
R
O
S
O
O
O
O
O
ZnCl2/Dioxane
H3C
3
4
Scheme 1.
Synthesis of 3-[2'-(2''-arylidenehydrazinyl) thiazolyl] coumarin (3)
Equal molar (0.01 mole) of 2 and substituted benzaldehyde thiosemicarbazones were
dissolved in 25 mL of ethanol in a 100 mL round bottom flask. The reaction mixture was
refluxed for 8 h. After completion of the reaction, monitored by TLC the reaction mixture
was cooled to room temperature. The solvent was removed by rotary evaporator and the
o
solid was washed with water, dried and recrystallized from ethanol. M.P.: 155-160 C; Rf
Value (T:E:F; 5:4:1): 0.74; % Yield : 65; IR (KBr) cm-1: 3264 (N-H), 1622 (C=N), 1543
(C=C), 1515, 1455 and 1040 (characteristic of thiazole nucleus); 1H NMR (CDCl3, DMSO-
d6) δ ppm: 7.19 (s, 1H, Ar-H), 7.55 (m, 2H, Ar-H), 7.64 (t, J=8Hz, 2H, Ar-H), 7.83 (dd, 2H,
Ar-H), 7.98 (d, J=12Hz, 1H, Ar-H), 8.10 (d, J=12Hz, 1H, Ar-H), 8.24 (m, 4H, Ar-H, -
N=CH), 11.78 (s, 1H, NH); Elemental Analysis (C20H14N4O2S), Found % (Calculated %): C,
64.15 (64.16); H, 3.77 (3.77); N, 14.95 (14.96).
Synthesis of 3-[5-methyl-2-aryl-3-(thiazol-2-ylamino)thiazolidin-4-one]coumarin (4)
-General Procedure (c.f. Table 1)
To the solution of compound 3 (0.01 moles) and thiolactic acid (0.015 mol) in dioxane, a
pinch of ZnCl2 was added at room temperature. The reaction mixture was heated under
reflux for 8-10 h. After the completion of the reaction, which is monitored by TLC, the
reaction mixture was concentrated. It was then poured on crushed ice and solid so obtained
was filtered, washed with water, dried and recrystallized from dioxane.
3-[5-Methyl-2-(4-nitrophenyl)-3 (thiazol-2-ylamino)thiazolidin-4-one]coumarin (4a)
o
M.P.:133-135 C; Rf Value (T:E:F; 5:4:1): 0.79; % Yield : 55: IR (KBr) cm-1: 3241 (N-H),
1687 (C=O), 1614 (C=N), 1543 (C=C), 1512, 1444 and 1046 (characteristic of thiazole
nucleus); 1H NMR (CDCl3, DMSO-d6) δ ppm: 1.34 (d, J=8Hz, 3H, CH3), 4.79 (q, 1H, -CH-

Synthesis and Oral Hypoglycemic Activity
389
S-), 6.45 (s, 1H, -N-CH-), 7.35 (s, 1H, Ar-H), 7.42 (d, J=12Hz, 2H, Ar-H), 7.56 (m, 2H, Ar-
H), 7.67 (m, 4H, Ar-H), 7.97 (d, J=12Hz, 1H, Ar-H), 8.07 (d, J=12Hz, 1H, Ar-H), 8.21
(d, J=12Hz, 1H, Ar-H), 8.92 (s, 1H, NH); Elemental Analysis (C23H18N4O3S2), Found %
(Calculated %): C, 59.69 (59.72); H, 3.90 (3.92); N, 12.09 (12.11); Mass(m/z): 474
(M+, C24H18N4O3S2), 181 (100%, C7H5N2O2S), 154 (C11H8N), 70(C3H4NO), 57 (C3H5O).
Pharmacological activity (Oral hypoglycemic activity)
Three months old Wistar strain Albino rats of either sex, weighing 200-250 g were used. The
animals were allowed food and water ad libitum. They were housed in room temperature at
25 2˚ for 24 h. The animals were randomly allocated into 12 groups, each group contained 6
animals. The blood glucose level was induced by Streptozocin Model 16. All the test
compounds and standard drug were suspended in Tween- 80 and were administered orally.
This study was carried out in twelve different groups. The standard used is rosiglutazone.
Determination of LD50
There was no mortality in control group of rats up to a dose of 5000 mg/kg body weight; all the
coumarino thaizolo thiazolidinones derivatives up to a dose of 1000 mcg/kg body weight did not
produce mortality. Hence 1/5th dose of LD50 i.e. 200 mcg/kg body weight of the title compounds
were used for screening oral hypoglycemic activity111. The results are shown in the Table 2.
Table 2. Hypoglycemic activity of the test compounds (4a-j) were compared with respect to
control
Mean glucose concentration
mg/d SEM
Mean % change in
hypoglycemic activity SEM
-
S. No Compound No.
1
2
3
Control
103.55 2.23
Standard
4a
4b
68.51 1.331**
74.33 1.156**
82.53 1.019**
99.18 1.575ns
87.88 2.462**
83.53 1.493**
95.55 1.455*
44.089 1.233
23.845 2.134
20.764 2.592
4.880 2.653
15.569 3.919
19.885 1.862
6.88 1.598
27.567 1.708
27.394 2.564
4.880 2.653
4
5
6
4c
4d
7
4e
8
9
4f
4g
75.58 1.375**
75.63 1.197**
99.18 1.575ns
105.8 1.535ns
10
11
12
4h
4i
-1.495 3.021
4j
Data were analyzed by one way ANOVA followed by Tukey-Kramer's Multiple Comparisons Test n = 6,
** P<0.001, * P<0.01, ns P>0.05
Hypoglycemic activity
The test group of animal were treated with different derivatives of coumarino thaizolo
thaizolidinones (4a-4j) with defined dose (200 mcg/kg) orally. Control and standard groups of
animals were treated with normal saline and rosiglitazone (200 mcg/kg) respectively. After 2 h
blood samples were collected via retro orbital plexus. Estimated the blood glucose level by Semi-
auto analyzer (Qualigens AR 601, GSK), using commercially available glucose estimation kit
(Span diagnostics), as per manufacturers brochure. The statistical analysis of data was carried out
by one way ANOVA followed by Tukey-Kramer's Multiple Comparisons Test12-14. All the
values are expressed as mean blood glucose level (mg/dl) S.E.M, (n=6).

390
M. GHATE et al.
Conclusion
Several Coumarino Thaizolo thaizolidinones were synthesized from 3-acetyl coumarin as
starting material. Among the synthesized compounds 4a, 4b, 4d, 4e, 4f, 4g and 4h were
significantly active, where as others were inactive derivatives. The lipophilicity of the side
chains and their electronegativity seemed to be responsible for variation of the
hypoglycemic activity.
Acknowledgment
We are thankful to Chairman and Secretary of Krupanidhi Education Trust, Bangalore for
providing facilities.
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