Synthesis, hypoglycaemic, hypolipidemic and pparγ agonist activities of 5-(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene-1,3-thiazolidinediones

Article abstract of DOI:10.1111/cbdd.12140

A novel series of 5-(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene-1,3-thiazolidinediones were synthesized as possible PPARγ agonists. The structures of these target molecules were established by spectral and analytical data. All the n

Full text of DOI:10.1111/cbdd.12140

Chem Biol Drug Des 2013; 82: 147–155
Research Article
Synthesis, Hypoglycaemic, Hypolipidemic and PPARc
Agonist Activities of 5-(2-Alkyl/aryl-6-Arylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl)methylene-1,3-Thiazolidinediones
Mohammed Iqbal A. Khazi1, Ningaraddi S.
Pioglitazone (3,5) had high affinity for PPARc receptor and
have significantly improved the clinical situation of type 2
diabetics with serious side-effects of hepatotoxicity, weight
Belavagi1, Kwang R. Kim2, Young-Dae Gong3
and Imtiyaz Ahmed M. Khazi1,3,
*
gain and oedema. This situation leads to identify strategies
to develop new highly effective, safe and orally active anti-
diabetic agents that could retain the insulin-sensitizing
properties of TZDs through PPARc agonist activity with
minimum or no side-effects.
1Department of Chemistry, Karnatak University, Dharwad,
India
2Bio-Organic Science Division, Korea Research Institute of
Chemical Technology, Daejeon, Korea
3Center for Innovative Drug Library Research, Science
College, Dongguk University, Seoul, Korea
*Corresponding author: Imitiyaz A. M. Khazi,
drimkorgchem@gmail.com
Imidazo[2,1-b][1,3,4]thiadiazole derivatives have attracted
the interest of medicinal chemists for many years because
of their diverse pharmacological properties such as anti-
cancer (6), antitubercular (7), antibacterial (8), antifungal
(9), anticonvulsant, analgesic (10) and antisecretory (11)
activities. They have been reported to selectively inhibit
several therapeutic receptors and enzymes, extending their
applications in modern drug design. Further, there are
reports in the literature about the antidiabetic activity of the
derivatives containing thiadiazole ring system (12).
A
novel series of 5-(2-alkyl/aryl-6-arylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl)methylene-1,3-thiazolidinediones
were synthesized as possible PPARc agonists. The
structures of these target molecules were established
by spectral and analytical data. All the newly synthe-
sized compounds were screened for their in vivo hypo-
glycaemic and hypolipidemic activity in male Wistar
rats. Further, compounds with good activity were
screened for PPARc agonist activity. Among the
screened compounds, 5-{[2-Cyclohexyl-6-(4-methoxy
phenyl)imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]methylene}-
1,3-thiazolidine-2,4-dione (3i) exhibits promising hypo-
glycaemic and hypolipidemic activity via potential
PPARc agonist activity.
In view of the above facts, we herein report the synthesis
of novel prototype structures (Figure 1) having fused imi-
dazo[2,1-b][1,3,4]thiadiazoles ring linked with various alkyl/
aryl/heterocycle moieties at 2nd and 6th position with the
objective of exploring the pharmacologically important imi-
dazo[2,1-b][1,3,4]thiadiazoles ring system for developing
new TZDs to obtain drug candidates with better hypogly-
caemic, hypolipidemic and PPARc agonist activity.
Key words: 5-(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazol-
5-yl)methylene-1,3-thiazolidinediones, hypoglycaemic, hypolipi-
demic, PPARc agonist activity
Received 19 December 2012, revised 13 February 2013 and
accepted for publication 25 March 2013
Methods and Materials
Chemistry – general aspects
All reagents were of analytical grade and were used
directly. Thin-layer chromatography (TLC) was performed
on silica gel plates (60 F254; Merck). Column chromato-
graphy was performed using silica gel (100–200 and 60–
120 mesh size; Merck). Melting points were determined in
open capillaries and are uncorrected. The IR spectra were
recorded on Nicolet Impact 410 FT IR spectrophotometer
using KBr pellets. 1H and 13C NMR were recorded on
Bruker 300-MHz and 75-MHz FT NMR spectrometer in
CDCl3 and TFA with TMS as internal standard. Mass
spectra were recorded on Finnigan MAT (Model MAT8200)
spectrometer, Shimadzu GCMS-QP2010S, and elemental
The treatment of type 2 diabetes has been revolutionized
with the advent of thiazolidinedione (TZD) class of
molecules that ameliorate insulin resistance and thereby
normalize elevated blood glucose levels (1,2). Thiazolidin-
ediones are synthetic, high-affinity ligands of peroxisome
proliferator-activated receptor-gamma (PPARc), a member
of the nuclear receptor family that controls the expression
of genes in the target tissues of insulin action (3,4). The
peroxisome proliferator-activated receptors (PPARs) are
legitimate molecular targets for the development of the
antidiabetic agents. The reported synthetic ligands such as
ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12140
147

Khazi et al.
5-{[2-Ethyl-6-(4-methoxyphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3c)
central imidazo- Polar
alkyl/aryl/
hetrocycle
thiazolidinedione
thiadiazole ring
O
Yellow granules (DMF), yield 90%, m.p. 258–262 °C;IR
(KBr)/υcm: 3158, 2923, 1729, 1698, 1606, 1550, 1177;
1H NMR (300 MHz, CDCl3 + TFA) d: 1.59(t, J = 7.4 Hz,
3H, CH2CH3), 3.28(q, J = 7.5 Hz, 2H, CH2CH3), 3.86(s,
3H, OCH3), 7.13(d, J = 8.5 Hz, 2H, C3, C5-H, phenyl),
7.53 (d, J = 8.8 Hz, 2H, C2, C6-H phenyl), 7.96(s, 1H,
vinylic proton); 13C NMR (75 MHz, CDCl3 + TFA): 13.2,
25.9, 55.9, 115.8, 117.9, 118.2, 122.8, 125.7, 131.0,
131.4, 143.2, 162.7, 167.7, 168.3 and 171.0. MS m/z:
386 (M+). Anal. calcd. for C17H14N4O3S2: C, 52.84; H,
3.65; N, 14.50. Found: C, 52.97; H, 3.76; N, 14.35.
NH
3
4
N
5
2
S
N
O
6
S
N
7
1
aryl
Figure 1: Representation of designed novel prototype structure.
analyses were carried out using Heraus CHN rapid
analyzer.
5-{[6-(4-Chlorophenyl)-2-propylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3d)
Bright yellow granules (DMF), yield 93%, m.p. 272–
276 °C; IR (KBr)/υcm: 3162, 2893, 1729, 1696, 1614,
1556; 1H NMR (300 MHz, C6D6 + TFA) d: 1.08(t,
General procedure for preparation of 5-(2-alkyl/
aryl-6-arylimidazo [2, 1-b][1,3,4]thiadiazol-5-yl)
methylene-1,3-thiazolidinediones (3a–r)
A mixture of 2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiaz-
ole-5-carbaldehyde 2 (0.001 mol) and 1,3-thiazolidine-2,4-
dione (0.11 g, 0.001 mol) was refluxed in toluene (25 mL)
with catalytic amount of piperidine acetate for 2 h. The yel-
low solid separated was collected by filtration, washed
with hot benzene and methanol. The products were
recrystallized from dimethylformamide.
J = 6.3 Hz, 3H, CH2CH2CH3), 1.88 (sextet, JCH2CH3
=
6.1 Hz, JCH2CH2 = 6.3 Hz, 2H, CH2CH2CH3), 3.10(t,
J = 6.6 Hz, 2H, CH2CH2CH3), 7.60(d, J = 8.4 Hz, 2H, C3,
C5-H, phenyl), 7.78(d, J = 8.9 Hz, 2H, C2, C6-H, phenyl),
7.98 (s, 1H, vinylic proton); 13C NMR (75 MHz,
C6D6 + TFA) d: 13.3, 22.3, 33.0, 55.2, 115.7, 117.6,
118.0, 124.2, 124.9, 126.5, 130.9, 133.0, 142.8, 162.9,
167.3 and 171.2.MS m/z: 406 (M + 2), 404 (M+). Anal.
calcd. for C17H13ClN4O2S2: C, 50.43; H, 3.24; N, 13.84.
Found: C, 50.76; H, 3.32; N, 13.64.
5-{[6-(4-Chlorophenyl)-2-ethylimidazo[2,1-b][1,3,4]
thiadiazol-5-yl]methylene}-1,3-thiazolidine-2,
4-dione (3a)
Yellow granules (DMF), yield 92%, m.p. 276–728 °C; IR
1
(KBr)/υcm: 3154, 2931, 1730, 1702, 1605, 1549; H NMR
(300 MHz, CDCl3 + TFA) d: 1.57(t, J = 3.3 Hz, 3H,
CH2CH3), 3.29(q, J = 3.5 Hz, 2H, CH2CH3), 7.47(d,
J = 8.9 Hz, 2H, C3, C5-H, phenyl), 7.81(d, J = 8.8 Hz,
2H, C2, C6-H, phenyl), 7.98 (s, 1H, vinylic proton), 13C
NMR (75 MHz, CDCl3 + TFA): 13.7, 21.8, 113.2, 117.1,
119.3, 124.8, 127.0, 130.5, 133.4, 141.5, 146.5, 167.5,
169.4 and 172.0. MS m/z: 392 (M + 2), 390 (M+). Anal.
calcd. for C16H11ClN4O2S2: C, 49.17; H, 2.84; N, 14.33.
Found: C, 49.35; H, 2.89; N, 14.16.
5-{[6-(4-Methylphenyl)-2-propylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3e)
Bright yellow granules (DMF), yield 88%, m.p. 262–
264 °C; IR (KBr)/υcm: 3153, 3042, 2927, 2854, 1733,
1702, 1616,1545; 1H NMR (300 MHz, C6D6 + TFA) d:
1.08(t, J = 6.3 Hz, 3H, CH2CH2CH3), 1.88(sextet,
JCH2CH3 = 6.1 Hz
and
JCH2CH2 = 6.1 Hz,
2H,
CH2CH2CH3), 2.44(s, 3H, CH3), 3.10(t, J = 6.0 Hz, 2H,
CH2CH2CH3), 7.32(d, J = 8.9 Hz, 2H, C3, C5-H, phenyl),
7.66(d, J = 8.9 Hz, 2H, C2, C6-H, phenyl), 7.98(s, 1H,
vinylic proton); 13C NMR (75 MHz, C6D6 + TFA) d: 13.3,
22.0, 22.6, 33.5, 55.2, 115.7, 117.6, 124.9, 125.2,
127.5, 128.0, 130.9, 131.0, 142.8, 162.9, 167.3 and
171.0. MS m/z: 384 (M+). Anal. calcd. for C18H16
N4O2S2: C, 56.23; H, 4.19; N, 14.57. Found: C, 56.48;
H, 4.27; N, 14.40.
5-{[2-Ethyl-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]
thiadiazol-5-yl]methylene}-1,3-thiazolidine-2,
4-dione (3b)
Yellow granules (DMF), yield 90%, m.p. 265–268 °C; IR
1
(KBr)/υcm: 3120, 2924, 1727, 1693, 1604, 1553; H NMR
(300 MHz, CDCl3 + TFA) d: 1.61 (t, J = 3.3 Hz, 3H,
CH2CH3), 2.46(s, 3H, CH3), 3.27(q, J = 3.1 Hz, 2H,
CH2CH3), 7.42(m, 4H, phenyl), 7.97(s, 1H, vinylic proton);
13C NMR (75 MHz, CDCl3 + TFA) d: 13.5, 21, 21.8, 113.2,
117.1, 119.0, 124.5, 126.8, 130.5, 132.4, 141.5, 146.5,
167.5, 169.4 and 172.2. MS m/z: 370 (M+). Anal. calcd.
for C17H14N4O2S2: C, 55.12; H, 3.81; N, 15.12. Found: C,
55.34; H, 3.88; N, 15.01.
5-{[6-(4-Methoxyphenyl)-2-propylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3f)
Yellow granules (DMF), yield 91%, m.p. 266–270 °C; IR
(KBr)/υcm: 3104, 3022, 2927, 1730, 1685, 1585, 1209;
148
Chem Biol Drug Des 2013; 82: 147–155

Imidazo[2,1-b][1,3,4]thiadiazoles and Thiazolidinediones
1H NMR (300 MHz, C6D6 + TFA) d: 1.10(t, J = 6.3 Hz,
3H, CH2CH2CH3), 1.89(sextet, JCH2CH3 = 6.0 Hz,
5-{[2-Benzyl-6-(4-chlorophenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
JCH2CH2 = 6.1 Hz, 2H, CH2CH2CH3), 3.10(t, J = 6.0 Hz,
2H, CH2CH2CH3), 3.82(s, 3H, OCH3), 6.98(d, J = 7.8 Hz,
2H, C3, C5-H, phenyl), 7.55(d, J = 7.8 Hz, 2H, C2, C6-H,
phenyl), 8.00(s, 1H, vinylic proton); 13C NMR (75 MHz,
C6D6 + TFA) d: 13.3, 22.3, 33.0, 55.2, 113.8, 115.7,
117.6, 117.8, 118.3, 124.9, 130.9, 142.8, 145.8, 162.9,
167.3 and 171.2. MS m/z: 400 (M+). Anal. cald. for
C18H16N4O3S2: C, 53.98; H, 4.03%; N, 13.99. Found: C,
54.16; H, 4.08; N, 13.75.
3-thiazolidine-2,4-dione (3j)
Yellow solid (DMF), yield: 86%, m.p. 290–292 °C; IR
(KBr)/υcm: 3154, 3043, 1732, 1699, 1604; 1H NMR
(300 MHz, CDCl3 + TFA) d: 4.02(s, 2H, CH2), 7.28–7.87
(m, 9H, Ar-H), 8.01(s, 1H, vinylic proton). MS m/z: 454
(M + 2), 452 (M+). Anal. calcd. for C21H13ClN4O2S2: C,
55.69; H, 2.89; N, 12.37, Found C, 55.88; H, 2.95; N,
12.21.
5-{[2-Benzyl-6-(4-methylphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3k)
Bright yellow granules (DMF), yield 86%, m.p. 286–
290 °C; IR (KBr)/υcm: 3162, 3048, 1733, 1701, 1598,
1561, 1184; 1H NMR (300 MHz, CDCl3 + TFA) d: 2.29(s,
3H, CH3), 3.96(s, 2H, CH2), 7.16–7.75(m, 9H, Ar-H), 7.92
(s, 1H, vinylic proton). MS m/z: 452 (M+). Anal. calcd. for
C22H16N4O2S2: C, 61.09; H, 3.73; N, 12.95. Found: C,
61.32; H, 3.78; N, 12.86.
5-{[6-(4-Chlorophenyl)-2-cyclohexylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3g)
Bright yellow granules (DMF), yield 94%, m.p. >300 °C; IR
(KBr)/υcm: 3158, 2943, 2887, 1735, 1702, 1616, 1547;
1H NMR (300 MHz, CDCl3 + TFA) d: 1.35–2.31(m, 10H,
cyclohexyl), 3.24(m, 1H, C1-H, cyclohexyl), 7.37(d,
J = 8.3 Hz, 2H, C3, C5-H, phenyl),7.63(d, J = 8.3 Hz, 2H,
C2, C6-H, phenyl), 7.93(s, 1H, vinylic proton); 13C NMR
(75 MHz, CDCl3 + TFA) d: 25.4, 25.7, 33.1, 41.7, 162.9,
130.9,142.8, 117.6, 124.9, 115.7, 171.0,167.2,128.0,
121.2,125.0,133.0. MS m/z: 446 (M + 2), 444 (M+). Anal.
calcd. for C20H17ClN4O2S2: C, 53.99; H, 3.85; N, 12.59.
Found: C, 53.78; H, 3.92; N, 12.44.
5-{[2-Benzyl-6-(4-methoxyphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3l)
Pale yellow solid (DMF), yield 90%, m.p.276–278 °C IR
1
(KBr)/υcm: 3167, 3054, 1729, 1705, 1602, 1561; H NMR
5-{[2-Cyclohexyl-6-(4-methylphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3h)
(300 MHz, CDCl3 + TFA) d: 3.94(s, 3H, OCH3), 4.06 (s,
2H, CH2), 7.07–7.76(m, 9H, Ar-H), 7.97(s, 1H, vinylic pro-
ton). MS m/z: 448 (M+). Anal. calcd. for C22H16N4O3S2: C,
58.91; H, 3.60; N,12.49. Found: C, 59.15; H, 3.74; N,
12.28.
Bright yellow granules (DMF), yield 91%, m.p. >300 °C; IR
(KBr)/υcm: 3154, 2933, 2889, 1736, 1704, 1608, 1563;
1H NMR (300 MHz, C6D6 + TFA) d: 1.14–1.98(m, 10H, cy-
clohexyl), 2.25(s, 3H, CH3), 2.70(m, 1H, C1-H, cyclohexyl),
7.24(d, J = 7.1 Hz, 2H, C3, C5-H, phenyl), 7.45(d,
J = 7.4 Hz, 2H, C2, C6-H, phenyl), 7.76(s, 1H, vinylic pro-
ton). MS m/z: 424 (M+). Anal. calcd. for C21H20N4O2S2: C,
59.41; H, 4.75; N, 13.20. Found: C, 59.70; H, 4.72; N,
13.08.
5-{[6-(4-Chlorophenyl)-2-thien-2-ylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3m)
Orange yellow granules (DMF), yield 85%, m.p.290–
294 °C; IR (KBr)/υcm: 3146, 3036, 2985, 1732, 1699,
1611, 1561; 1H NMR (300 MHz, CDCl3 + TFA) d: 7.18
(dd, JH3H4 = 3.1 Hz, JH4H5 = 3.3 Hz, 1H, C4-H, thio-
phene), 7.20–7.91(m, 6H, C3, C5-H, thiophene and
phenyl protons), 8.02(s, 1H, vinylic proton); 13C NMR
(75 MHz, CDCl3 + TFA) d: 110.2, 113.3, 117.0, 117.9,
120.8, 121.0, 125.0, 128.0, 129.0, 129.3, 131.0, 133.0,
133.9, 161.5, 167.1 and 169.2. MS m/z: 445.9 (M + 2),
443.9 (M+), Anal. calcd. for C18H9ClN4O2S3: C,
48.59; H, 2.04; N, 12.59. Found: C, 48.59; H, 2.04; N,
12.59.
5-{[2-Cyclohexyl-6-(4-methoxyphenyl)imidazo
[2,1-b][1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3i)
Bright yellow granules (DMF), yield 94%, m.p. >300 °C; IR
(KBr)/υcm: 3172, 2952, 2865, 1734, 1698, 1611, 1575,
1184; 1H NMR (300 MHz, CDCl3 + TFA) d: 1.35–2.30(m,
10H, cyclohexyl), 3.24 (m, 1H, C1-H, cyclohexyl), 3.93(s,
3H, OCH3), 7.14(d, J = 8.6 Hz, 2H, C3, C5-H, phenyl),
7.52(d, J = 8.5 Hz, 2H, C2, C6-H, phenyl), 7.76(s, 1H,
vinylic proton); 13C NMR (75 MHz, CDCl3 + TFA) d: 25.4,
25.7, 33.1, 41.7, 55.4, 162.9, 130.9, 142.8, 117.6,
124.9, 115.7, 171.0, 167.2, 118.1, 118.4, 113.6, 145.0.
MS m/z: 440 (M+). Anal. calcd. for C21H20 N4O3S2: C,
57.25; H, 4.58; N, 12.72. Found: C, 57.38; H, 4.64; N,
12.65.
5-{[6-(4-Methylphenyl)-2-thien-2-ylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3n)
Bright yellow solid (DMF), yield 92%, m.p. 288–292 °C; IR
(KBr)/υcm: 3158, 1733, 1697, 1605; 1H NMR (300 MHz,
Chem Biol Drug Des 2013; 82: 147–155
149

Khazi et al.
C6D6 + TFA) d: 2.27(s, 3H, CH3), 6.74(t, J = 4.5 Hz, 1H,
C4-H, thiophene), 7.08(d, J = 4.7 Hz, 1H, C3-H, thio-
phene), 7.28(d, J = 6.0 Hz, 2H, C3, C5-H phenyl), 7.42–
7.46(m, 3H, C5-H, thiophene; C2, C6-H phenyl), 7.77(s,
1H, vinylic proton); 13C NMR (75 MHz, C6D6 + TFA) d:
21.0, 110.2, 113.3, 117.0, 117.9, 120.8, 125.3, 127.7,
128.3, 129.0, 129.3, 131.0, 132.9, 133.9, 161.5, 167.1
and 169.2. MS m/z: 424 (M+). Anal. calcd. for
5-{[2-(2-Furyl)-6-(4-methoxyphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,3-thiazolidine-
2,4-dione (3r)
Orange yellow granules (DMF), yield 82%, m.p. >300 °C;
IR (KBr)/υcm: 3213, 1730, 1698, 1604, 1564, 1176; 1H
NMR (300 MHz, CDCl3 + TFA) d: 3.82(s, 3H, OCH3), 6.76
(dd, JH3H4 = 3.4 Hz, JH4H5 = 3.3 Hz, 1H, C4-H, furan),
7.10(d, J = 7 Hz, 2H, C3, C5-H, phenyl), 7.51(d,
J = 4.1 Hz, 1H, C3-H, furan), 7.68(d, J = 6.8 Hz, 2H, C2,
C6-H, phenyl), 7.76(d, J = 3.3 Hz, 1H, C5-H, furan), 7.96
(s, 1H, vinylic). MS m/z: 424 (M+). Anal. calcd. for
C19H12NO4S2: C, 53.76, H, 2.85; N, 13.20. Found: C,
53.93; H, 2.78; N, 13.16.
C
19H12N4O2S3: C, 53.76; H, 2.85; N, 13.20. Found: C,
53.95; H, 2.94; N, 13.07.
5-{[6-(4-Methoxyphenyl)-2-thien-2-ylimidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3o)
Bright yellow solid (DMF), yield 84%, m.p. 276–278 °C;
IR (KBr)/υcm: 3216, 1736, 1704, 1610, 1560, 1174; 1H
NMR (300 MHz, CDCl3 + TFA) d: 3.95(s, 3H, OCH3),
7.16(dd, JH3H4 = 3.8 Hz, JH4H5 = 3.9 Hz, 1H, C4-H, thio-
phene), 7.32–7.38(m, 3H, C3-H, thiophene; C3, C5-H,
phenyl), 7.55(d, J = 7.4 Hz, C5-H, thiophene), 7.84 (d,
J = 7.4, 2H, C2, C6-H), 8.02(s, 1H, vinylic proton) 13C
NMR (75 MHz, CDCl3 + TFA) d: 21.0, 55.9, 110.2,
113.3, 117.0, 117.9, 120.8, 118.5, 114.2, 117.8, 129.0,
129.3, 131.0, 145.4, 133.9, 161.3, 167.1 and 169.4.
MS m/z: 440 (M+). Anal. calcd. for C19H12N4O3S3: C,
51.80; H, 2.75; N, 12.72. Found: C, 52.06; H, 2.78; N,
12.54.
Biological evaluation
Hypoglycaemic and hypolipidemic activity
Male Wistar rats weighing 150–200 g were used for this
study (13). All animals were maintained under 12 h light
and 12 h dark cycle at 25 Æ 1 °C. All animals were given
standard chow (National Institute of Nutrition, India) and
water ad libitum. The experiments were designed and con-
ducted in accordance with the guidelines of institutional
animal’s ethics committee. The acclimatized animals were
kept fasting for 24 h with water ad libitum and alloxan
monohydrate (120 mg/kg i.p.) in normal saline was then
administered. Serum glucose level was checked after 72 h.
Animals with serum glucose levels >250 mg/dL were con-
sidered diabetic and were used for the study. The animals
were divided into two groups of six animals each. Group I
animals were termed as control or untreated and group II
animals were termed as treated. Group II animals were
administered with compounds to be screened for euglyce-
mic effect. The suspension of the compound was prepared
in water with 1% carboxy methyl cellulose as suspending
agent. All the test compounds were orally administered at
different doses (3, 10, 30, 100 mg/kg) for 15 days. Pioglit-
azone was used as standard drug. On the final day, the
blood samples were collected from the tail vein. Plasma
was separated from whole blood of each group by centrifu-
gation. Plasma glucose (PG) and triglyceride (TG) levels
were estimated using commercial kits (14–16).
5-{[6-(4-Chlorophenyl)-2-(2-furyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3p)
Bright orange yellow solid (DMF), yield 89%, m.p.
>300 °C; IR (KBr)/υcm: 3226, 3042, 1733, 1701, 1614,
1562; 1H NMR (300 MHz, CDCl3 + TFA) d: 6.78(dd,
JH3H4=3.0 Hz, JH4H5=3.5 Hz, 1H, C4-H, furan), 7.45(d,
J = 8.9 Hz, 2H, C3, C5-H, phenyl), 7.53(d, J = 3.0 Hz,
1H,C3-H, furan), 7.75 (d, J = 8.9 Hz, 2H, C2, C6-H, phe-
nyl), 7.79(d, J = 3.2 Hz, 1H, C5-H, furan), 7.97(s, 1H, viny-
lic proton). MS m/z: 430 (M + 2), 428 (M+). Anal. calcd. for
C
18H9ClN4O3S2: C, 50.41; H, 2.12; N, 13.06. Found: C,
50.65; H, 2.18; N, 12.93.
5-{[2-(2-Furyl)-6-(4-methylphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-5-yl]methylene}-1,
3-thiazolidine-2,4-dione (3q)
PPARc agonist activity
The ligand-binding domains (LBDs) of hPPARc (amino
acids 163–477) were generated by PCR amplification
using Pfu polymerase (Stratagene, La Jolla, CA, USA), and
gene-specific primers flanked with restriction enzymes
BamHI and XbaI. The LBDs were subcloned in-frame into
the pFA-CMV vector (Stratagene) to prepare pFA-Gal4-
PPARa-LBD, PPARd-LBD and -PPARg-LBD. At 75–90%
confluence, NIH3T3 cells were transiently cotransfected
with the expression vectors for pFA-Gal4-PPAR-LBDs
together with pFR-Luc and pRL-CMV (Promega) using
Lipofectamine PLUS reagent according to the instructions
of manufacturer (Invitrogen, Carlsbad, CA, USA). After 24-
Bright yellow solid (DMF), yield 89%, m.p. >300 °C; IR
(KBr)/υcm: 3164, 1735, 1702, 1607, 1558; 1H NMR
(300 MHz, CDCl3 + TFA) d: 2.26(s, 3H, CH3), 6.73 (dd,
JH3H4=3.4 Hz, JH4H5 = 3.5 Hz, 1H, C4-H, furan), 7.28(d,
J = 7.6 Hz, 2H, C3, C5-H, phenyl), 7.52(d, J = 3.9 Hz,
1H, C3-H, furan), 7.67(d, J = 7.8 Hz, 2H, C2, C6-H, phe-
nyl), 7.75(d, J = 3.1 Hz, 1H, C5-H, furan), 7.96(s, 1H, viny-
lic). MS m/z: 408 (M+). Anal. calcd. for C19H12N4O3S2: C,
55.87; H, 2.96; N, 13.72. Found: C, 55.98; H, 3.08; N,
13.56.
150
Chem Biol Drug Des 2013; 82: 147–155

Imidazo[2,1-b][1,3,4]thiadiazoles and Thiazolidinediones
h incubation, the cells were treated with various concen-
trations of compounds and pioglitazone as a positive con-
trol and incubated for 16 h. Luciferase assay was
performed using dual-luciferase reporter assay system
according to the instructions of the manufacturer (Pro-
mega, Madison, WI, USA), and the activity was determined
in Luminoskan (Thermo Fisher Scientific Co., Waltham,
MA, USA) by measuring light emission for 10 s. The results
were normalized to the activity of renilla expressed by
cotransfected Rluc gene under the control of a constitutive
promoter. The EC50 values of compounds were deter-
mined using Prism 4 software (GraphPad Software, Inc.,
La Jolla, CA, USA).
rigid and very stable structural framework. The formation
of 5-[(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)
methylene]-1,3-thiazolidine-2,4-diones 3a–r were con-
firmed by their IR spectra, which displayed the mC=O bands
around 1735 and 1700/cm. The mN-H is observed in the
region of 3226–3104/cm. Further, they are confirmed by
1H NMR spectra, where aldehydic proton disappeared
and the vinylic proton resonated in the region of d
7.70–7.90 as a singlet. These compounds were further
confirmed by their 13C NMR and mass spectral data.
The configuration of the title compounds were established
based on 1H NMR analysis (olefinic C-H around
d
7.70–8.0), (19,20) theoretical calculations (21–24) and ther-
modynamic stability (25,26). All these observation support
Results and Discussion
the Z configuration. Hence, the Z configuration was
confirmed for the TZD derivatives.
Chemistry
The reaction sequence employed for the synthesis of title
compounds is shown in Scheme 1. The fused imidazo
[2,1-b][1,3,4]thiadiazole nucleus 1a–r were prepared by
the condensation of 2-aminothiadiazole with a-haloaryl
ketones under reflux in dry ethanol. Further, Vilsmeier–Haack
formylation reaction of Imidazo[2,1-b][1,3,4]thiadiazoles
1a–r affords imidazo[2,1-b] [1,3,4]thiadiazole-5-carbalde-
hydes 2a–r (17,18).
Biological evaluation
All the newly synthesized 5-(2-alkyl/aryl-6-arylimidazo
[2,1-b][1,3,4]thiadiazol-5-yl)methylene-1,3-thiazolidnedione
derivatives were screened for their in vivo hypoglycaemic
and hypolipidemic activities in alloxan-induced male Wistar
rats through oral treatment for 15 days. Acute toxicity
studies were performed and doses were fixed. Hypogly-
caemic and hypolipidemic activities summarized in terms
of percentage reduction in PG and TG levels. Pioglitazone
was used as a standard (Tables 1 and 2).
The imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehydes 2a–r
were exploited successfully for the preparation of target
molecules by Knoevenagel condensation with thiazolidine-
2,4-dione in the presence of piperidinium acetate in reflux-
ing toluene. This series of compounds are characterized
by the presence of one carbon atom spacer between
thiazolidine-2, 4-dione moiety and fused heterocyclic ring.
Compounds 3h, 3i and 3o (Figure 2) displayed promising
in vivo hypoglycaemic and hypolipidemic activities. Further,
the mode of action for hypoglycaemic activity of these
compounds was determined by performing PPARc agonist
activity (PPARc transactivation (Figure 3 and Table 3).
Compound 3i showed significant PPARc agonist activity
with receptor activation potential of 64% (compared with
All the TZD derivatives 3a–r are having high melting points
compared with their starting materials due to formation of
O
CHO
N
N
Br
N
S
N
S
ii
i
N
N
R
R
R1
R
R1
NH2
S
N
N
R1
1(a-r)
2(a-r)
iii
O
NH
O
S
N
S
N
R
R1
N
3(a-r)
Scheme 1: Synthesis of 5-(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene-1,3-thiazolidinedione. Reagents and conditions:
(i) dry ethanol, reflux, Na2CO3 (ii) DMF, POCl3 (iii) 1, 3-thiazolidinedione, piperidine acetate, toluene, reflux. R = Ethyl, Propyl, cyclohexyl,
benzyl, 2-furyl, 2-thienyl. R1 = p-Cl-Phenyl, p-CH3–phenyl, p-OCH3–phenyl.
Chem Biol Drug Des 2013; 82: 147–155
151

Khazi et al.
Table 1: Plasma glucose (PG) level of 3a–r at various drug doses
% Decrease in plasma glucose (PG) level at various drug doses (mg/kg body weight)
Compound
3 mg
10 mg
30 mg
100 mg
Pioglitazone
41.60 Æ 2.25
27.56 Æ 0.96
22.55 Æ 1.08
24.58 Æ 0.66
25.70 Æ 0.89
18.28 Æ 1.42
26.36 Æ 1.85
30.58 Æ 0.088
39.68 Æ 2.92
40.08 Æ 1.92
28.56 Æ 1.27
20.62 Æ 0.62
16.82 Æ 0.67
31.20 Æ 1.58
19.68 Æ 0.13
40.01 Æ 1.69
31.08 Æ 1.54
27.33 Æ 0.92
21.82 Æ 1.84
47.25 Æ 5.50
31.47 Æ 1.72
25.86 Æ 1.08
27.58 Æ 1.84
29.20 Æ 1.70
22.80 Æ 1.98
31.89 Æ 2.38
34.86 Æ 1.38
41.86 Æ 3.21
44.16 Æ 1.72
31.08 Æ 1.92
21.20 Æ 1.81
20.87 Æ 1.01
34.64 Æ 2.11
22.08 Æ 1.21
43.74 Æ 1.62
35.08 Æ 2.22
24.69 Æ 1.55
23.85 Æ 2.45
64.59 Æ 5.42
35.77 Æ 1.68
26.40 Æ 1.26
29.68 Æ 2.08
29.61 Æ 1.10
25.81 Æ 2.08
33.84 Æ 1.08
36.08 Æ 1.87
55.63 Æ 3.25
59.20 Æ 1.25
30.73 Æ 2.85
28.40 Æ 2.18
23.68 Æ 3.05
37.85 Æ 2.72
24.48 Æ 1.86
57.54 Æ 2.42
36.84 Æ 3.05
37.44 Æ 1.46
26.82 Æ 2.97
75.43 Æ 3.40
49.34 Æ 1.25
34.12 Æ 1.86
36.19 Æ 2.08
44.24 Æ 1.14
35.82 Æ 2.48
40.58 Æ 2.08
40.89 Æ 2.08
70.49 Æ 1.53
73.08 Æ 1.23
34.85 Æ 3.08
40.52 Æ 1.38
29.54 Æ 2.56
41.85 Æ 3.12
31.82 Æ 1.54
71.78 Æ 3.68
41.08 Æ 2.82
42.83 Æ 1.22
31.92 Æ 3.08
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Each value represents the mean Æ SEM (n = 6). Percentage reduction was calculated according to the formula: [(PG in control – PG in
treated)/PG in control]9100; [(TG in control – TG in treated)/TG in control]9100.
Table 2: Triglyceride (TG) level of 3a–r at various drug doses.
% Decrease in triglyceride (TG) level at various drug doses (mg/kg body weight)
Compound
3 mg
10 mg
30 mg
100 mg
Pioglitazone
47.02 Æ 14.39
16.84 Æ 1.85
20.16 Æ 0.05
18.64 Æ 1.65
11.75 Æ 2.14
22.46 Æ 2.02
17.26 Æ 0.65
14.12 Æ 2.38
30.68 Æ 1.08
36.24 Æ 1.25
23.46 Æ 1.14
12.42 Æ 2.85
19.86 Æ 2.02
20.82 Æ 1.35
12.28 Æ 0.32
27.62 Æ 1.14
15.52 Æ 0.48
16.87 Æ 1.01
18.25 Æ 1.48
35.25 Æ 20.42
27.02 Æ 2.28
28.62 Æ 1.18
26.12 Æ 2.08
19.67 Æ 1.92
28.12 Æ 1.52
24.62 Æ 2.16
20.62 Æ 2.16
33.09 Æ 3.28
35.84 Æ 1.65
28.62 Æ 1.25
14.09 Æ 1.49
23.42 Æ 2.36
29.63 Æ 1.80
19.81 Æ 1.52
31.42 Æ 1.53
20.28 Æ 1.80
20.36 Æ 1.20
23.92 Æ 2.05
40.96 Æ 17.59
30.352 Æ 1.74
33.44 Æ 2.86
32.28 Æ 1.56
18.82 Æ 1.90
31.01 Æ 1.72
40.00 Æ 1.86
26.00 Æ 2.24
37.83 Æ 3.18
38.16 Æ 2.36
31.55 Æ 1.56
17.16 Æ 3.07
25.08 Æ 1.27
31.68 Æ 2.06
23.65 Æ 1.71
37.16 Æ 1.11
19.48 Æ 1.01
22.64 Æ 4.05
25.29 Æ 2.86
45.89 Æ 2.24
40.1 Æ 1.58
36.12 Æ 1.05
36.42 Æ 1.38
27.44 Æ 1.11
36.42 Æ 2.10
34.12 Æ 1.86
31.04 Æ 2.26
42.25 Æ 1.55
44.52 Æ 1.64
34.48 Æ 1.07
25.20 Æ 2.03
29.28 Æ 2.04
35.61 Æ 2.86
29.05 Æ 2.03
42.46 Æ 0.98
24.69 Æ 1.22
29.73 Æ 1.39
31.95 Æ 3.08
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Each value represents the mean Æ SEM (n = 6). Percentage reduction was calculated according to the formula: [(PG in control – PG in
treated)/PG in control]9100; [(TG in control – TG in treated)/TG in control]9100.
relative maximum efficacy to the percentage of the stan-
dard). The promising activity of compound 3i is attributed
to the presence of cyclohexyl group at 2nd position and
p-methoxy phenyl group at 6th position of imidazo[2,1-b]
[1,3,4]thiadiazole ring system.
Conclusions
In conclusion, we have designed and synthesized a novel
series
of
5-(2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thia-
diazol-5-yl)methylene-1,3-thiazolidinedione derivatives. The
152
Chem Biol Drug Des 2013; 82: 147–155

Imidazo[2,1-b][1,3,4]thiadiazoles and Thiazolidinediones
O
O
O
NH
NH
NH
O
O
O
S
S
S
N
S
N
S
S
N
S
N
N
N
CH3
OCH3
OCH3
N
N
N
3h
3o
3i
Figure 2: Structures of compounds exhibiting good results.
Figure 3: In vitro PPARc agonist activity.
Table 3: In vitro PPARc agonist activity data.
activity comparable with Pioglitazone. Further to know the
mode of action for hypoglycaemic activity, these three
compounds were screened for PPARc agonist activity.
From the results of these studies, we have demonstrated
that a novel imidazo[2,1-b][1,3,4]thiadiazoles containing
TZD 3i with a cyclohexyl group substituted at 2nd position
and p-methoxy phenyl group substituted at 6th position
exhibit promising hypoglycaemic and hypolipidemic activity
via potential PPARc agonist activity.
O
NH
O
S
N
S
N
R1
R
N
Compound
R
R1
EC50 (nM)
% Maxa
3h
Cyclohexyl
Cyclohexyl
2-Thienyl
–
p-CH3-ph
p-OCH3-ph
p-OCH3-ph
–
794
280
829
59
47
64
40
3i
3o
Acknowledgments
Pioglitazone
100
The authors thank the Karnatak University, Dharwad and
University Grants Commission (UGC), New Delhi, India,
for financial support [F.No: 36-138/2009 (SR)] and
thankful to the University Science Instruments Centre,
Karnatak University, Dharwad, for providing the spectral
data.
aThe relative maximum efficacy to the percentage of standard.
newly synthesized compounds were screened for their in
vivo hypoglycaemic and hypolipidemic activity in male Wi-
star rats. Compounds 3h, 3i and 3o displayed interesting
Chem Biol Drug Des 2013; 82: 147–155
153

Khazi et al.
12. Avetisyan A.Kh., Ovsepyan T.R., Stepanyan N.O., Sa-
pondzhyan L.G. (1981) Synthesis and hypoglycemic
activity of sulfonamido-1,3,4-thiadiazoles. Pharm Chem
J;15:416–418.
13. Murugan R., Anbazhagan S., Narayanan S.S. (2009)
Synthesis and in vivo antidiabetic activity of novel
dispiropyrrolidines through [3 + 2] cycloaddition reac-
tions with thiazolidinedione and rhodanine derivatives.
Eur J Med Chem;44:3272–3279.
References
1. Saltiel A.R., Olefsky J.M. (1996) Thiazolidinediones in
the treatment of insulin resistance and type II diabetes.
Diabetes;45:1661–1669.
2. Prashantha Kumar B.R., Nanjan M.J. (2010) Novel
glitazones: design, synthesis, glucose uptake and
structure–activity relationships. Bioorg Med Chem
Lett;20:1953–1956.
14. Hugget A., Nixon D.A. (1957) Use of glucose oxi-
dase, peroxidase, and O-dianisidine in determination
of blood and urinary glucose. The Lancet;270:368–
370.
3. Lehman J.M., Moore L.B., Smith Oliver T.A., Wilkison
W.O., Willson T.M., Kliewer S.A. (1995) An antidiabetic
thiazolidinedione is a high affinity ligand for peroxisome
proliferator-activated receptor
c
(PPARc).
J
Biol
15. Annino J.S., Giese R.W. (1976) Determination of Total
Proteins and Albumins in Serum. Clinical Chemistry,
Principles and Procedures, 4th edn. Boston: Little
Brown & Co; 184–188 p.
Chem;270:12953–12956.
4. Kliewer S.A., Lenhard J.M., Willson T.M., Patel I., Mor-
ris D.C., Lehmann J.M. (1995) A prostaglandin J2
metabolite binds peroxisome proliferator-activated
16. Frings C.S., Fendley T.W., Dunn R.T., Queen C.A.
(1972) Improved determination of total serum lipids by
the sulfo-phospho-vanillin reaction. Clin Chem;
18:673–674.
17. Hegde V.S., Kolavi G.D., Lamani R.S., Khazi I.M.
(2006) Mannich bases and novel benzothiazole deriva-
tives of imidazo[2,1-b][1,3,4]thiadiazoles and their bio-
logical evaluation. J Sulfur Chem;27:553–569.
18. Kolavi G., Hegde V., Khazi I.M., Gadad P. (2006) Syn-
thesis and evaluation of antitubercular activity of imi-
dazo[2,1-b][1,3,4]thiadiazole derivatives. Bioorg Med
Chem;14:3069–3080.
19. Patil V., Tilekar K., Mehendale-Munj S., Mohan R.,
Ramaa C.S. (2010) Synthesis and primary cytotoxicity
evaluation of new 5-benzylidene-2,4-thiazolidinedione
derivatives. Eur J Med Chem;45:4539–4544.
20. Momose Y., Meguro K., Ikeda H., Hatanaka C., Oi
S., Sohda T. (1991) Studies on antidiabetic agents.
X. Synthesis and biological activities of pioglitazone
and related compounds. Chem Pharm Bull;39:1440–
1445.
receptor
Cell;83:813–819.
c and promotes adipocyte differentiation.
5. Willson T.M., Cobb J.E., Cowan D.J., Wiethe R.W.,
Correa I.D., Prakash S.R., Beck K.D., Moore L.B.,
Kliewer S.A., Lehmann J.M. (1996) The structure-
activity relationship between peroxisome pro-
liferator-activated receptor c agonism and the anti-
hyperglycemic activity of thiazolidinediones.
Chem;39:665–668.
J Med
6. Terzioglu N., Gursoy A. (2003) Synthesis and antican-
cer evaluation of some new hydrazone derivatives of
2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5- carbo-
hydrazide. Eur J Med Chem;38:781–786.
7. Gadad A.K., Noolvi M.N., Karpoormath R.V. (2004)
Synthesis and antitubercular activity of a series of 2-
sulfonamido/trifluoromethyl- 6-substituted imidazo[2,1-
b]-1,3,4-
Chem;12:5651–5659.
8. Gadad A.K., Mahajanshetti C.S., Nimbalkar S., Rai-
churkar A. (2000) Synthesis and antibacterial activity of
some
thiadiazole
derivatives.
Bioorg
Med
5-guanylhydrazone/thiocyanato-6-arylimidazo
21. Costa Leite L.F.C., Veras Moura R.H., Alves de Lima
M.C., Galdino S.L., Hernandes M.Z., Rocha Neves
F.A., Vidal S., Barbe J., Pitta I.R. (2007) Synthesis, bio-
logical evaluation and molecular modeling studies of
arylidene-thiazolidinediones with potential hypoglyce-
mic and hypolipidemic activities. Eur J Med Chem;
42:1263–1271.
[2,1-b]- 1,3,4-thiadiazole-2-sulfonamide derivatives. Eur
J Med Chem;35:853–857.
9. Andotra C.S., Langer T.C., Kotha A. (1997) Synthesis
and antifungal activity of some substituted 1,3,4-thi-
adiazolo[3,2-a]-s-triazin-5-phenyl-7-thiones and imi-
dazo-[2,1-b]- 1,3,4-thiadiazol-5-ones. J Indian Chem
Soc;74:125–127.
22. Guarda V.L.M., Pereira M.A., De Simone C.A., Albu-
querque J.C., Galdino S.L., Chantegrel J., Perrissin
M., Beney C., Thomasson F., Pitta I.R., Luu-Duc C.
(2003) Synthesis and structural study of arylidene
thiazolidine and benzothiazine compounds. Sulfur
Lett;26:17–27.
10. Khazi I.A.M., Mahajanshetti C.S., Gadad A.K., Tarnalli
A.D., Sultanpur C.M. (1996) Synthesis, anticonvulsant
and analgesic activities of some 6-substituted imidazo
[2,1- b][1,3,4]thiadiazole-2-sulfonamides and their 5-
bromo
derivatives.
Arzneimittel-Forschung/Drug
Res;46:949–952.
23. Tan S.F., Ang K.P., Fong Y.F. (1986) (Z) - and (E)-5-A-
rylmethylenehydantoins: spectroscopic properties and
configuration assignment. J Chem Soc Perkin Trans;
II:1941–1944.
24. Albuquerque J.F.C., Albuquerque A., Azevedo C.C.,
Thomasson F., Galdino S.L., Chantegrel J., Catanho
11. Andreani A., Leonia A., Locatelli A., Morigi R., Rambal-
di M., Simon W.A., Senn-Bilfinger J. (2000) Synthesis
and antisecretory activity of 6-substituted 5- cyanome-
thylimidazo[2,1-b]thiazoles and 2,6-dimethyl-5-hydrox-
ymethylimidazo[2,1- b][1,3,4]thiadiazole. Arzneimittel/
Drug Res;50:550–553.
154
Chem Biol Drug Des 2013; 82: 147–155

Imidazo[2,1-b][1,3,4]thiadiazoles and Thiazolidinediones
M.T.J., Pitta I.R., Luu-Duc C. (1995) Substituted thia-
zolidinediones and thio-imidazolidinones: synthesis,
structural study and pharmacological activity. Pharma-
zie;50:387–389.
nine and thiazolidinedione scaffolds. Bioorg Med
Chem;19:7453–7463.
26. Ishida T., In Y., Inoue M., Ueno Y., Tanaka C., Hama-
naka N. (1989) Structural elucidation of epalrestat
(ONO-2235), a potent aldose reductase inhibitor, and
isomerization of its double bonds. Tetrahedron
Lett;30:959–962.
25. Heng S., Tieu W., Hautmann S., Kuan K., Pedersen
€
D.S., Pietsch M., Gutschow M., Abell A.D. (2011)
New cholesterol esterase inhibitors based on rhoda-
Chem Biol Drug Des 2013; 82: 147–155
155