Synthesis and biological activity of novel acridinylidene and benzylidene thiazolidinediones

Article abstract of DOI:10.1016/j.ejmech.2005.06.002

A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacrylates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglycer

Full text of DOI:10.1016/j.ejmech.2005.06.002

European Journal of Medicinal Chemistry 40 (2005) 1129–1133
www.elsevier.com/locate/ejmech
Original article
Synthesis and Biological Activity of Novel Acridinylidene
and Benzylidene thiazolidinediones
R.H. Mourão a, T.G. Silva a, A.L.M. Soares a, E.S. Vieira a, J.N. Santos a, M.C.A. Lima a,
V.L.M. Lima a, S.L. Galdino a, J. Barbe b, I.R. Pitta a,*
a Departamento de antibioticos, universidade federal de Pernambuco, centro de ciências biológicas, 50670-901 Recife, Brasil
b GERCTOP – UMR CNRS 6178, université de la Méditerranée, faculté de pharmacie, 13385 marseille cedex 5, France
Received 2 December 2004; received in revised form 30 May 2005; accepted 6 June 2005
Available online 29 August 2005
Abstract
A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacry-
lates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglyceride level in alloxan
diabetic mice.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Thiazolidinediones; hypoglycaemic agents
1. Introduction
synthesis and gives the structural characteristics of several
derivatives of the 5-benzylidene-3-(4-methyl-benzyl)-
thiazolidine-2,4-dione substituted on the benzylidene moiety
and those of the 3-benzyl-5-acridinylidene-thiazolidine-2,4-
dione substituted on the benzyl ring branched on the thiazo-
lidine moiety. Some of these compounds were evaluated in
after oral administration at doses of 10 mg/kg or 30 mg/kg in
alloxan diabetic mice. Plasma glucose (PG) and triglyceride
(TG) levels were measured and compared with rosiglitazone
(10 mg/kg p.o.) as the reference drug.
The thiazolidinediones (TZDs) or glitazones are oral
hypoglycaemic agents, which act mainly by increasing tissue
sensitivity especially adipose tissue, to insulin [1–4]. Various
studies report the effects of TZDs on the metabolism of lip-
ids, on cell differentiation and on some cardiovascular risk
factors [5,6]. The first compound described was ciglitazone,
which produced a dramatic decrease in the glycaemia level
in animal models but showed poor clinical effect. In 1997 tro-
glitazone was launched onto the market, but had to be with-
drawn in the USA in March 2000 because of idiosyncratic
liver failure. Since 1999, rosiglitazone and pioglitazone have
been available in Europe as second line drugs restricted to
combination therapy while in the United States, their use has
been allowed as first line agents in monotherapy or in com-
bination with other drugs [4]. It was demonstrated that the
molecular target of the TZDs is part of the nuclear receptor
called Peroxisome Proliferator-Activated Receptor-gamma
(PPAR-c) which controls the differentiation of adipocytes [3],
the metabolism of fatty acids and alters the expression of genes
that are also regulated by insulin [7]. This paper describes the
2. Chemistry
The 5-benzylidene-3-(4-methyl-benzyl)-thiazolidine-2,4-
diones, 3, were prepared by a nucleophilic addition of the
3-(4-methyl-benzyl)-thiazolidine-2,4-dione, 2, on selected
aryl-substituted ethyl-(2-cyano-3-phenyl)-acrylates [8]
according to Daboun et al. [9]. Synthetic pathways are por-
trayed in Fig. 1. Thiazolidine-2,4-dione, 1, was N-(3)-
alkylated in the presence of potassium hydroxide which leads
to the thiazolidine potassium salt which reacts with benzyl or
phenacyl halides in hot alcoholic medium [10]. The 3-benzyl
(or phenacyl)-thiazolidine-2,4-diones, 2 or 7, were obtained
in this way. The acridinylidene thiazolidinedione derivatives,
8a-8d, were synthesized by a nucleophilic addition of substi-
* Corresponding author.
E-mail address: IRPITTA@aol.com (I.R. Pitta).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.06.002

1130
R.H. Mourão et al. / European Journal of Medicinal Chemistry 40 (2005) 1129–1133
Fig. 1. Synthetic pathways of benzylidene-thiazolidinediones.
Fig. 2. Synthetic pathways of acridinylidene-thiazolidinediones.
tuted thiazolidinediones, 7, on 9-[ethyl-(2′-cyano)-acrylate]-
acridine, 6. Direct condensation of 9-acridinaldehyde, 5, with
the substituted thiazolidinediones, 7, did not led to the
expected 3-benzyl-5-acridinylidene-thiazolidine-2,4-diones,
8a-8d. 9-Methyl-acridine, 4, was prepared from dipheny-
lamine treated with zinc dichloride in acetic acid medium
according to Tsuge et al. [11]. Subsequent oxidation of 4 with
pyridinium chlorochromate according to Mosher et al. [12],
gave 9-acridinaldehyde, 5. Condensation of 5 with ethyl
cyanoacetate in the presence of piperidine in hot anhydrous
benzene led to the 9-[ethyl-(2′-cyano)-acrylate]-acridine, 6.
Synthetic pathways are portrayed in Fig. 2. Benzylidene-
thiazolidinediones were isolated in a single isomeric form.
X-ray crystallographic studies and 13C NMR have demon-
strated the preferred Z configuration for 5-arylidene-
thiazolidinones [13]. In contrast, acridinylidene-
thiazolidinedione derivatives, 8a-8d, were isolated as isomeric
tested show a dose-dependent hypoglycaemic activity during
the 15 days treatment. The decrease in the level of plasma
glucose observed with these compounds was progressive
throughout the treatment, especially at a 30 mg/kg/day dose.
After 15 days of treatment with this dose, compound 3c
showed a better biological activity than other compounds do
in both parameters analysed, i.e. around 50% decrease in PG
and 59% decrease in TG. However, this compound was re-
cognized to be very toxic, with a 50% mortality rate during
Table 1
Effect of oral administration of benzylidene-thiazolidinedione derivatives
on the glucose (PG) and triglyceride (TG) levels in mice with alloxan-
induced hyperglycaemia with reference to rosiglitazone
Compound
Dose
(mg/kg/day
p.o.)
% of decreasea in
PGb at day
TGb at
day
15
1
3
10
15
19
23
19
43
21
51
22
35
15
41
9
3a
3b
3c
3d
3e
3f
10
30
10
30
10
30
10
30
10
30
10
30
4
12
7
17
22
1
mixtures. The isomers were readily identified by H NMR,
1.5
0.5
9
18.5
10
48
the ethylene proton being more deshielded in the isomer Z
than it is in the isomer E, owing to the cis-position of the
exocyclic carbonyl function. Chemical shifts listed in the
experimental part are those of the Z isomer, which is the preva-
lent isomer. MS data fully agree with the structure proposed.
10
15
12.5 24.5
26
4
1
24
29
17
30
23
23
11
14
38
16.5 21
59
NE
9
NE
40
17
NE
12
7
46.5
8
3
10
NE
8
44
3. Results and Discussion
22
NE
20
37
33
The glucose and triglyceride lowering effects after oral
administration of new thiazolidine analogues, 3a-3f, in alloxan
diabetic mice are summarized in Table 1. All the compounds
Rosiglitazone 10
23
24.5 22.5
43
a standard deviation is less than 0.05 in all cases.
b in mg/dL.

R.H. Mourão et al. / European Journal of Medicinal Chemistry 40 (2005) 1129–1133
1131
Table 2
Effect of oral administration of benzylidene-thiazolidinedione derivatives and rosiglitazone (10 mg/kg/day), on the change in body weight and mortality of
mice with alloxan-induced hyperglycaemia
Tested Group
Dose
Body weight (g) SD
(mg/kg p.o.)
Initial
Final (day 15)
28.5 1.7
22.4 2.6
23.3 1.4
24.9 1.1
26.2 0.8
21.1 0.6
21.7 1.6
% of corporal loss
% of mortality
Normoglycaemic
Diabetic + CMC
“ + 3a
-
27.0 1.0
25.2 0.8
25.3 0.6
28.0 0.8
26.4 0.4
25.0 0.9
21.3 0.7
26.4 1.2
-
0
10a
10
30
10
30
10
30
10
30
10
30
10
30
10
11
8
20
0
11
0.75
16
-
17
20
14
50
50
17
0
“ + 3b
“ + 3c
22.7 2.0
23.3 2.7
21.3 1.5
20.2 0.9
21.9 0.7
27.2 3.0
24.0 0.9
27.4 1.3
14
16
11
11
10
6.5
5
“ + 3d
27.9
2
24.0 0.8
22.7 1.5
24.4 0.7
29.1 3.4
25.3 0.4
26.5 0.4
“ + 3e
17
0
“ + 3f
0
0
“ + Rosiglitazone
a this value is given in mL/kg p.o.
-
17
the treatment at the two doses tested. In contrast, the other
compounds, although they produced less reduction in PG and
TG rates, had a very low if not zero mortality rate (Tables 1,2).
The percentage for mortality observed in the case of a
10 mg/kg/day dose of 3a,3b,3d-3f was also very low. The
mortality observed with the 10 mg/kg/day dose could not be
due to the compounds under evaluation but to the hypergly-
caemia caused by alloxan, as the mortality rate for diabetic
animals treated with this vehicle (CMC 0.5%) is in the same
range. The presence of the two methoxy groups in position
2 and 4 of the benzylidene ring in 3d led to a reduction in
hypoglycaemia (35%) and hypolipidemia (46%) activity,
although this compound did not show toxicity and there were
no deaths at the 30 mg/kg/day dose as observed with 3c which
is only substituted by one methoxy group. The change in the
position of the chlorine atom on the phenyl ring led to a sig-
nificant hypoglycaemic activity (P< 0.05). This is clearly de-
monstrated by comparing the 4-chloro derivative 3a (PG
=23%; TG = 48%) with the 2-chloro substituted one 3b
(PG = 43%; TG = 26%). However, the opposite is seen for
the hypolipidemic activity which is greater with 3a than it is
with 3b.
5. Experimental protocols
5.1. Chemistry
Melting points were measured in a capillary tube on a
Buchi (or Quimis) apparatus. Thin Layer Chromatography
was performed on silicagel plates Merck 60F254. Infrared
spectra of 1% KBr pellets were recorded on a Bruker
IFS66 spectrometer (or Perkin Elmer 1310 spectrometer for
1
compounds 3a-3d). H NMR spectra were recorded on a
BrukerAC 300 P spectrophotometer in DMSO-d6 as solvent,
with tetramethylsilane as internal standard. Mass spectra were
recorded on Delsi-Nermag R 1010 C spectrometer (or HP
5897 for compounds 8a-8d). The published chemical data on
2,4,5,6 [14], are not reported here.
Analyses of all the compounds prepared were
within 0.4% of the theoretical values.
5-Benzylidene-3-(4-methyl-benzyl)-thiazolidine-2,4-
diones, 3a-3h: general procedure.
A mixture of 3-(4-methyl-benzyl)-thiazolidine-2,4-dione,
2, (0.59 g, 2.5 mmol) and ethyl-(2-cyano-3-phenyl)-acrylate
(2.7 mmol) is refluxed for 2-6 h in absolute ethanol (20 mL)
with piperidine (0.25 mL) added. After cooling, precipitates
are purified by column chromatography or crystallized in suit-
able solvents.
5-(4-Chloro-benzylidene)-3-(4-methyl-benzyl)-thiazoli-
dine-2,4-dione, 3a.
4. Conclusion
C18H14ClNO2S, yield: 0.427 g (89%). Mp: 184 °C. TLC
benzene: ethyl acetate (95:5) Rf: 0.8. IR cm−1 (KBr): t 1730,
1670, 1600, 1374, 1335, 1138, 820. 1H NMR (d ppm, DMSO-
d6): 2.27 (s, CH3), 4.79 (s, NCH2), 7.97 (s, CH), 7.17 (m, 4H
benzyl), 7.63 (m, 4H benzylidene). Ms, m/z (%) : 343(M+
100), 344(22.2), 345(24.6),105(96.9), 103(6).
The new 5-arylidene-3-(4-methyl-benzyl)-thiazolidine-
2,4-diones investigated have shown promising glucose low-
ering activity. Their activity on the triglyceride level is close
to that of the rosiglitazone when used at the same concentra-
tion but activity is much better at higher concentration
(30 mg/kg) which can be used safely because of the low tox-
icity of compounds evaluated. These results indicate the need
for additional investigations, chiefly about the agonistic effect
of these drugs on PPAR-c and PPAR-a.
5-(2-Chloro-benzylidene)-3-(4-methyl-benzyl)-thiazoli-
dine-2,4-dione, 3b.
C18H14ClNO2S, yield: 0.087 g (30%). Mp: 116 °C. TLC
benzene: ethyl acetate (95:5) Rf: 0.74. IR cm−1 (KBr): t 1738,

1132
R.H. Mourão et al. / European Journal of Medicinal Chemistry 40 (2005) 1129–1133
1682, 1598, 1370, 1310, 755. 1H NMR (d ppm, DMSO-d6):
2.28 (s, CH3), 4.8 (s, NCH2), 8.06 (s, CH), 7.16 (d, 2H ben-
zyl, J = 8.1 Hz), 7.23 (d, 2H benzyl, J = 8.1 Hz), 7.51-7.54
(m, 2H benzylidene), 7.59-7.62 (m, 1H benzylidene), 7.64-
7.67 (m, 1H benzylidene). Ms, m/z (%): 343(M+ 45.1),
344(5.7), 345(8), 308(52.8), 280(5.2), 105(100), 94(7.8).
5-(4-Methoxy-benzylidene)-3-(4-methyl-benzyl)-thiazoli-
dine-2,4-dione, 3c.
C19H17NO3S, yield: 0.354 g (77%). Mp: 135 °C. TLC ben-
zene: ethyl acetate (95:5) Rf: 0.83. IR cm−1 (KBr): t 1738,
1672, 1588, 1503, 1365, 1260, 820. 1H NMR (d ppm, DMSO-
d6): 2.28 (s, CH3), 3.84 (s, OCH3), 4.79 (s, NCH2), 7.93 (s,
CH), 7.16 (d, 2H benzyl, J = 8.4 Hz), 7.21 (d, 2H benzyl,
J = 8.1 Hz), 7.12 (d, 2H benzylidene, J = 9 Hz), 7.61 (d, 2H
benzylidene, J = 9 Hz). Ms, m/z (%): 339(M+ 58.3), 340(15),
341(4),105(100).
5-(5-Bromo-2-methoxy-benzylidene)-3-(4-methyl-benzyl)-
thiazolidine-2,4-dione, 3h.
C19H16BrNO3S, yield: 0.352 g (62%). Mp: 147 °C. TLC
n-hexane: ethyl acetate (70:30) Rf: 0.78. IR cm−1 (KBr): t
1733, 1684, 1604, 1339, 1283, 808. 1H NMR (d ppm, DMSO-
d6): 2.27 (s, CH3), 3.89 (s, OCH3), 4.78 (s, NCH2), 7.96 (s,
CH), 7.15 (d, 2H benzyl, J = 8.1 Hz), 7.2 (d, 2H benzyl,
J = 8.4 Hz), 7.14 (d, 1H benzylidene, J = 9.3 Hz), 7.53 (d, 1H
benzylidene, J = 2.4 Hz), 7.65 (dd 1H benzylidene,
J = 9,3 Hz). Ms, m/z (%): 417(M+ 60), 386(7.1), 227(13),
199(11), 105(100), 91(31), 77(23.5).
3-Benzyl (or phenacyl)-5-acridinylidene-thiazolidine-
2,4-diones, 8a-8d : general procedure.
Benzyl (or phenacyl) thiazolidine, 7 (0.9 mmol) and
9-[ethyl-(2′-cyano)-acrylate]-acridine, 6, (0.9 mmol) are dis-
solved in absolute ethanol (8 mL). The solution is refluxed
for 4 h in the presence of a small amount of piperidine as
catalyst. The precipitate obtained is filtered and washed with
water. Compounds isolated are of acceptable purity and were
analysed without further recrystallization.
5-(2,4-Dimethoxy-benzylidene)-3-(4-methyl-benzyl)-
thiazolidine-2,4-dione, 3d.
C20H19NO4S, yield: 0.197 g (77%). Mp: 161 °C. TLC ben-
zene: ethyl acetate (95:5) Rf: 0.76. IR cm−1 (KBr): t 1720,
1675, 1575, 1367, 1267, 1147, 830. 1H NMR (d ppm, DMSO-
d6): 2.27 (s, CH3), 3.85 (s, OCH3), 3.9 (s, OCH3), 4.77 (s,
NCH2), 8.06 (s, CH), 6.7 (s, 1H benzylidene), 6.71 (d, 1H
benzylidene, J = 8.4 Hz), 7.39 (d, 1H benzylidene, J = 8.4 Hz),
7.15 (d, 2H benzyl, J = 8.1 Hz), 7.19 (d, 2H benzyl,
J = 8.1 Hz). Ms, m/z (%): 369(M+ 100), 370(12.7), 371(14.1),
264(29.2), 105(14.5).
5-Acridin-9-yl-methylene-3-benzyl-thiazolidine-2,4-
dione, 8a.
C24H16N2O2S, yield: 0.124 g (88%). Mp: 150-152 °C. TLC
n-hexane: ethyl acetate (7:3) Rf: 0.41. IR cm−1 (KBr): t 1750,
1694, 1623, 1381, 1339, 1149, 761. 1H NMR (d ppm, DMSO-
d6): 4.89 (s, NCH2), 7.41-7.4 (m, 4H benzyl), 7.39-7.34 (m,
1H benzyl), 7.72-7.66 (m, 2H acridine), 7.94-7.89 (2H acri-
dine), 8.14 (d, 2H acridine, J = 8.4 Hz), 8.24 (d, 2H acridine,
J = 8.4 Hz), 8.79 (s, 1H, CH). Ms, m/z (%): 396(M+ 4.2),
397(1.9), 305(8), 235(100), 232(26.6), 231(20.4), 91(10.1).
5-Acridin-9-yl-methylene-3-(4-fluoro-benzyl)-thiazoli-
dine-2,4-dione, 8b.
5-(4-Dimethylamino-benzylidene)-3-(4-methyl-benzyl)-
thiazolidine-2,4-dione, 3e.
C20H20N2O2S, yield: 0.215 g (47%). Mp: 180 °C. TLC
benzene: ethyl acetate (95:5) Rf: 0.75. IR cm−1 (KBr): t 1726,
1
1673, 1593, 1380, 811. H NMR (d ppm, DMSO-d6): 2.27
(s, CH3), 3.02 (s, N(CH3)2), 4.77 (s, NCH2), 8.06 (s, CH),
6.82 (d, 2H benzylidene, J = 9 Hz), 7.46 (d, 2H benzylidene,
J = 9 Hz), 7.14 (d, 2H benzyl, J = 8.1 Hz), 7.19 (d, 2H ben-
zyl, J = 8.4 Hz). Ms, m/z (%): 352(M+ 41.7), 353(2.1),
177(46.6), 176(34.6), 161(12), 105(100), 89(23.3), 77(37.2).
5-(4-Benzyloxy-benzylidene)-3-(4-methyl-benzyl)-thiazoli-
dine-2,4-dione, 3f.
C24H15FN2O2S, yield: 0.095 (56%). Mp: 200-202 °C. TLC
n-hexane: ethyl acetate (7:3) Rf: 0.58. IR cm−1 (KBr): t 1749,
1693, 1604, 1382, 1337, 1152, 763. 1H NMR (d ppm, DMSO-
d6): 4.88 (s, NCH2), 7.23 (t, 2H benzyl, J = 9 Hz), 7.45-7.5
(m, 2H benzyl), 7.71-7.66 (m, 2H acridine), 7.94-7.89 (m,
2H acridine), 8.14 (d, 2H acridine, J = 8.7 Hz), 8.24 (d, 2H
acridine, J = 8.7 Hz), 8.78 (s, 1H, CH). Ms, m/z (%): 414(M+
12.9), 415(4), 305(34.3), 261(19.9), 235(100), 234(44.1),
231(68.8), 191(16.9), 109(32.6).
C25H21NO3S, yield: 0.323 g (58%). Mp: 157 °C. TLC ben-
zene: ethyl acetate (95:5) Rf: 0.86. IR cm−1 (KBr): t 1736,
1
5-Acridin-9-yl-methylene-3[2-(4-nitro-phenyl)-2-oxo-
ethyl]-thiazolidine-2,4-dione, 8c.
1677, 1593, 1263, 826. H NMR (d ppm, DMSO-d6): 2.28
(s, CH3), 4.79 (s, NCH2), 5.21 (s, OCH2), 7.93 (s, CH), 7.15-
7.21 (m, 4H benzyl, 2H benzylidene), 7.35-7.46 (m, 5H ben-
zyloxy), 7.61 (d, 2H benzylidene, J = 9 Hz). Ms, m/z (%):
415(M+ 17.3), 416(2.5), 91(100), 77(6.9).
5-(4-Fluoro-benzylidene)-3-(4-methyl-benzyl)-thiazoli-
dine-2,4-dione, 3g.
C18H14FNO2S, yield: 0.387 g (87%). Mp: 124 °C. TLC
benzene: ethyl acetate (95:5) Rf: 0.81. IR cm−1 (KBr): t 1736,
1685, 1613, 1376, 1291, 680. 1H NMR (d ppm, DMSO-d6):
2.27 (s, CH3), 4.8 (s, NCH2), 7.96 (s, CH), 7.15 (d, 2H ben-
zyl, J = 8.1 Hz), 7.21 (d, 2H benzyl, J = 8.4 Hz), 7.33-7.38
(m, 1H benzylidene), 7.45-7.5 (m, 2H benzylidene), 7.56-
7.64 (m, 1H benzylidene). Ms, m/z (%): 327(M+ 100),
328(16.4), 329(6.6), 105(91.8), 91(4.2).
C25H15N3O5S yield: 0.136 g (70%). Mp: 229-230 °C. TLC
n-hexane: ethyl acetate (7:3) Rf: 0.3. IR cm−1 (KBr): t 1747,
1699, 1629, 1603, 1530, 1346, 1222, 855, 761. 1H NMR (d
ppm, DMSO-d6): 5.49 (s, NCH2), 7.77-7.71 (m, 2H acri-
dine), 7.97-7.92 (m, 2H acridine), 8.13 (d, 2H acridine,
J = 8.7 Hz), 8.26 (d, 2H acridine, J = 9 Hz), 8.88 (s, 1H, CH).
Ms, m/z (%): 469(M+ 50), 470(16.2), 235(93.1), 234(30.8),
230(79.2), 150(100), 120(35.5), 104(40).
5-Acridin-9-yl-methylene-3[2-(4-fluoro-phenyl)-2-oxo-
ethyl]-thiazolidine-2,4-dione, 8d.
C25H15FN2O3S, yield: 0.084 g (48%). Mp: 213-214 °C.
TLC n-hexane: ethyl acetate (7:3) Rf: 0.41. IR cm−1 (KBr): t
1754, 1701, 1596, 1411, 1381, 1229, 1154, 759. 1H NMR (d

R.H. Mourão et al. / European Journal of Medicinal Chemistry 40 (2005) 1129–1133
1133
ppm, DMSO-d6): 5.39 (s, NCH2), 7.46 (t, 2H benzyl,
J = 8.7 Hz), 7.76-7.71 (m, 2H acridine), 7.97-7.91 (m, 2H
acridine), 8.12 (d, 2H acridine, J = 8.7 Hz), 8.26 (d, 2H acri-
dine, J = 8.4 Hz), 8.26-8.21 (m, 2H benzyl), 8.87 (s, 1H, CH).
Ms, m/z (%): 442(M+ 20.2), 443(5.8), 235(31.5), 234(14.1),
230(40.5), 191(9.5), 123(100), 113(12.2).
using the formula 1-[(TT/OT)/(TC/OC)] x 100, where
TT = treated test on the day; OT = treated test at day zero;
TC = control test on the day; OC = control at day zero, accord-
ing to Gurram et al. [16]. The diabetic animals treated with
0.5% CMC were used as controls in the above formula.
Acknowledgments
5.2. Animals and treatment
The CAPES/COFECUB (Coordenação de Aperfeiçoa-
mento de Pessoal do Ensino Superior/Comité Français
d’Evaluation et de Coopération Universitaire avec le Brésil)
and CNPq (Conselho Nacional de Desenvolvimento Cientí-
fico e Tecnológico) are gratefully acknowledged for their sup-
port to the join research programme.
The experiment used 8 to 9 week-old Swiss albino mice of
both sexes, with weight between 22 and 30 g. Animals were
provided by the Bioterium of the Antibiotics Department of
the Federal University of Pernambuco (UFPE) ; they were
kept in a small colony in the animal house at a temperature of
25 3 °C, with 12 hour cycles of light and darkness, receiv-
ing standard feed (Purina®) and water as required. The experi-
mental procedure was approved by the Local Committee for
Animal Ethics. (CCB – UFPE). Drugs 3a-3f, were sus-
pended at a concentration of 10 and 30 mg/kg/day, in a solu-
tion of 0.5% carboxymethylcelulose (CMC) and they were
administered orally for 15 days to groups of hyperglycaemic
Swiss mice (N = 6, three males and three females). Hyperg-
lycaemia was induced by alloxan monohydrate at a 80 mg/kg
p.o. dose. After a 10 days treatment, mice with a 200-
350 mg/dL PG level and a 100-250 mg/dL TG level were
selected for further experiments. By comparison, the stan-
dard level was then around 100-130 mg/dL. Blood samples
were regularly collected from the animals after they had been
fed between 8 h and 10 h in the morning, the blood being
taken from the retro-orbital plexus under a light anaesthetic
(ethyl ether) one hour after the administration of the com-
pounds on different days throughout the treatment (1, 3,
10 and 15 days). Levels of plasma glucose and triglycerides
were analysed using commercially available kits (LABTEST-
Brazil), based on enzymatic methods [15]. Control groups of
diabetic and normoglycaemic animals were treated with the
vehicle solution (CMC 0.5% 10mL/kg). Rosiglitazone
10 mg/kg/day was used as standard drug. Effects on the glu-
cose and triglyceride levels of the compounds, vehicle and
rosiglitazone were calculated as a percentage of reduction,
References
[1] A.R. Saltiel, J.M. Olefsky, Diabetes 45 (1996) 1661–1669.
[2] R.J. Jha, Clin. Exp. Hypertens. 21 (1999) 157–166.
[3] J.M. Lehmann, L.B. Moore, T.A. Smith-Oliver, W.O. Wilkison,
T.M. Wilson, S.A. Kliewer, J. Biol. Chem. 270 (1995) 12953–12956.
[4] A.L. Peters, Am. J. Manag. Care 7 (2001) 587–595.
[5] R.E. Law, W.P. Meehan, K. Graf, D.A. Wuthric, W. Coats, J. Clin.
Invest. 98 (1996) 1897–1905.
[6] A.R. Collions, W.P. Meehan, U. Kintscher, S. Jackson, S. Wakino,
G. Noh, et al., Arterioscl, Throm. Vasc. Biol. 21 (2001) 365–371.
[7] A.C. Li, K.K. Brown, M.J. Silvestre, T.M. Wilson, W. Palinski,
C.K. Glass, J. Clin. Invest. 106 (2000) 523–531.
[8] W.M. Phillips, D.J. Currie, Can. J. Chem. 47 (1969) 3137–3141.
[9] H.A.F. Daboun, S.E. Abdou, M.M. Hussein, M.H. Enalgdi, Synthesis
(1982) 502–504.
[10] O.P. Shvaika, N.I. Korotkikh, A.Y. Chervinskii, N. Artemov, Zh. Org.
Khim. 39 (1983) 1533–1542.
[11] O. Tsuge, M. Nishinohara, M. Tashiro, Bull. Chem. Soc. Jpn. 36
(1963) 1477–1485.
[12] M.D. Mosher, N.R. Natale, J. Heterocyclic Chem. 32 (1995) 779–781.
[13] V.L.M. Guarda, M.A. Pereira, C.A. De Simone, J.C. Albuquerque,
S.L. Galdino, J. Chantegrel, M. Perrissin, C. Beney, F. Thomasson,
I.R. Pitta, C. Luu-Duc, Sulfur Letters 26 (2003) 17–27.
[14] T.G. Silva, F.S.V. Barbosa, S.S.F. Brandão, M.C.A. Lima, S.L. Gal-
dino, I.R. Pitta, J. Barbe, Heterocycl. Comm. 7 (2001) 523–528.
[15] D. Braham, P. Trinder, Analyst 97 (1972) 142–145.
[16] R.M.
Gurram,
R.
Chakrabarti,
R.K. Vikramadithyan,
R.N.V.S. Mamidi, V. Balraju, B.M. Rajesh, P. Misra, S.K.B. Kumar,
B.B. Lohray, V.B. Lohray, R. Rajagopalan, Bioorg. Med. Chem. 10
(2002) 2671–2680.