6750
O. Bozdag˘-Dündar et al. / Bioorg. Med. Chem. 16 (2008) 6747–6751
considered that the acidic hydrogen (imidic or acetic acid) instead
of lipophilic groups on N-3 position of the 2,4-TZD ring played a
noticeable role for increasing the ARI effect, whereas decreasing
insulinotropic effect.
CO); 1H NMR (CDCl3, 400 MHz, d, ppm): 1.32 (t, 3H, CH3), 4.27 (q,
2H, CH2), 4.52 (s, 2H, CH2CO), 6.88 (s, 1H, 3-H), 7.47 (td, 1H, 6-
H), 7.62 (d, 1H, j8,7 = 8.80 Hz, 8-H), 7.65–7.68 (m, 2H, 50, 60-H),
7.76 (td, 1H, 7-H), 7.97 (dd, 1H, jo = 8.40 Hz, jm = 1.60 Hz, 40-H),
8.01 (s, 1H, C@C–H), 8.11 (s, 1H, 2-H), 8.25 (dd, 1H, j5,6 = 8.00 Hz,
j5,7 = 1.60 Hz, 5-H); MS (ESI+) m/z (rel. intensity): 436 (M+H,
100%); Anal. Calcd for C23H17NO6S.0.2H2O C: 62.92, H: 3.97, N:
3.19, S: 7.29%; found: C: 62.91, H: 3.94, N: 3.36, S: 7.18%.
3. Conclusions
We report the synthesis and the in vitro insulin releasing and
aldose reductase inhibitory activity effects of the flavonyl-2,4-thia-
zolidinediones V–VI. Among newly synthesized compounds, acetic
4.1.3.2. Ethyl{2,4-dioxo-5-[4-(4-oxo-4H-chromen-2-yl)benzyl-
idene]-1,3-thiazolidine-3yl}acetate (Vb). Yield (%): 85.1, mp:
acids VIa, VIc with IC50 values lower than 1 lM for aldose reduc-
248 °C. Spectroscopic analysis: IR (KBr) t c pyrone
max/cmꢀ1: 1652 (
tase inhibitory activity were obtained. The importance of the acidic
hydrogen (imidic hydrogen or carboxylic acid) function on N-3 was
stressed by the findings. But, in this study, it can be concluded that
acetic acid as a pharmacophoric group caused an increase for only
aldose reductase inhibitory effect as shown for compound VIa.
CO); 1H NMR (CDCl3, 400 MHz, d, ppm): 1.32 (t, 3H, CH3), 4.27 (q,
2H, CH2), 4.51 (s, 2H, CH2CO), 6.90 (s, 1H, 3-H), 7.46 (td, 1H, 6-
H), 7.60 (d, 1H, j8,7 = 8.40 Hz, 8-H), 7.68 (d, 2H, jo = 8.40 Hz, 30,50-
H), 7.74 (td, 1H, 7-H), 7.97 (s, 1H, C@C–H), 8.06 (dd, 2H,
jo = 8.40 Hz, 20,60-H), 8.25 (dd, 1H, j5,6 = 8.40 Hz, j5,7 = 1.60 Hz, 5-
H); MS (ESI+) m/z (rel. intensity): 436 (M+H, 100%); Anal. Calcd
for C23H17NO6S C: 63.44, H: 3.94, N: 3.22, S: 7.36%; found: C:
63.07, H: 3.95, N: 3.30, S: 7.26%.
4. Experimental
4.1. Chemistry
Melting points were determined via a Büchi SMP-20 melting
point apparatus (Büchi, Flawil, Switzerland) and uncorrected.
All instrumental analyses were performed in Central Laboratory
of Pharmacy Faculty of Ankara University. IR spectra were re-
corded on a Jasco FT/IR-420 spectrometer (Jasco, Tokyo, Japan).
1H NMR and 13C NMR spectra were measured with a VARIAN
Mercury 400 FT-NMR spectrometer (Varian Inc., Palo Alto, CA,
USA) in DMSO-d6. All chemical shifts were reported as d (ppm)
values. Mass spectra were recorded on Waters Micromass ZQ
(Waters Corporation, Milford, MA, USA) by using ESI(+) method.
Elementary analyses were performed on a Leco CHNS 932 ana-
lyzer (Leco, St. Joseph, USA) and satisfactory results 0.4% of cal-
culated values (C, H, N) were obtained. For the chromatographic
analysis Merck Silica Gel 60 (230–400 mesh ASTM) was used.
The chemical reagents used in synthesis were purchased from
E. Merck (Darmstadt, Germany) and Aldrich (Milwaukee, MI,
USA).
4.1.3.3. Ethyl{2,4-dioxo-5-[(4-oxo-2-phenyl-4H-chromen-6-yl)-
methylene]-1,3-thiazolidine-3yl}acetate (Vc). Yield (%): 60.02,
mp: 223.5 °C. Spectroscopic analysis: IR (KBr) t c
max/cmꢀ1: 1658 (
pyrone CO); 1H NMR (DMSO-d6, 400 MHz, d, ppm): 1.22 (t, 3H,
CH3), 4.18 (q, 2H, CH2), 4.52 (s, 2H, CH2CO), 7.16 (s, 1H, 3-H),
7.60–7.64 (m, 3H, 30, 40, 50-H), 7.97 (d, 1H, j8,7 = 8.80 Hz, 8-H),
8.10–8.15 (m, 3H, 7, 20, 60-H), 8.17 (s, 1H, C@C–H), 8.27 (d, 1H,
j5,7 = 2.40 Hz, 5-H); MS (ESI+) m/z (rel. intensity): 436 (M+H,
100%); Anal. Calcd for C23H17NO6S C: 63.44, H: 3.94, N: 3.22, S:
7.36%; found: C: 63.32, H: 4.13, N: 3.32, S: 7.28%.
4.1.4. General synthesis of compounds VIa–c
A mixture of acetate Va–c (10 mmol), glacial acetic acid (40 ml),
and HCl 12 N (10 ml) was refluxed for 2 h. After evaporation in va-
cuo, the residue was refluxed again with glacial acetic acid (40 ml)
and HCl 12 N (10 ml) for 2 h. After evaporation to dryness in vacuo,
the crude solid was washed with water and recrystallized from
DMF–ethanol providing pure carboxylic acids VIa–c.
4.1.1. Synthesis of 30 (IIa)-40 (IIb)-6 (IIc)-bromomethyl flavone
A mixture of N-bromosuccinimide (1.2 g, 6.72 mmol) and 30
(Ia)/40 (Ib)/6-methyl flavone (Ic) (1.0 g, 4.2 mmol) was dissolved
in 70 ml of carbon tetrachloride and benzoyl peroxide (0.1 g) was
added. The reaction mixture was refluxed for 7 h and filtered while
still hot. The crude product was crystallized from toluene. IIa mp:
137 °C (mp: 137 °C34), IIb mp: 139 °C (mp: 139 °C34), IIc mp:
174 °C (mp: 175 °C35).
4.1.4.1. {2,4-Dioxo-5-[3-(4-oxo-4H-chromen-2-yl)benzylidene]-
1,3-thiazolidine-3yl}acetic acid (VIa). Yield (%): 82.9, mp: 286 °C.
Spectroscopic analysis: IR (KBr) t c
max/cmꢀ1: 1645 ( pyrone CO); 1H
NMR (DMSO-d6, 400 MHz, d, ppm): 4.40 (s, 2H, CH2CO), 7.16 (s, 1H,
3-H), 7.54 (td, 1H, 6-H), 7.76–7.88 (m, 4H, 7, 8, 50, 60-H), 8.07 (d, 1H,
jo = 8.00 Hz, 40-H), 8.14 (s, 1H, C@C–H), 8.25 (d, 1H, j5,6 = 8.00 Hz, 5-
H), 8.44 (s, 1H, 2-H); MS (ESI+) m/z (rel. intensity): 408 (M+H,
100%); Anal. Calcd for C21H13NO6S. H2O C: 59.29, H: 3.53, N:
3.29, S: 7.53%; found: C: 59.31, H: 3.65, N: 3.44, S: 7.38%.
4.1.2. Synthesis of 30 (IIIa)-40 (IIIb)-6 (IIIc)-flavonecarboxaldehyde
A mixture of bromomethylflavone (1.0 g, 3.17 mmol) and hexa-
methylenetetramine (4 g, 28.0 mmol) in 20 ml acetic acid (50%, v/
v) was refluxed for 4 h. HCl:H2O (1:1, 10 ml) was added and re-
fluxed for another 30 min. The product was crystallized from eth-
ylacetate:n-hexane. IIIa mp: 168 °C (mp: 168 °C34), IIIb mp: 165 °C
(mp: 165 °C34), IIIc mp: 186 °C (mp: 186 °C35).
4.1.4.2. {2,4-Dioxo-5-[4-(4-oxo-4H-chromen-2-yl)benzylidene]-
1,3-thiazolidine-3yl}acetic acid (VIb). Yield (%): 85.5, mp:
335.5 °C. Spectroscopic analysis: IR (KBr) t c pyr-
max/cmꢀ1: 1611 (
one CO); 1H NMR (DMSO-d6, 400 MHz, d, ppm): 4.39 (s, 2H,
CH2CO), 7.19 (s, 1H, 3-H), 7.53 (td, 1H, 6-H), 7.81–7.89 (m, 4H, 7,
8, 30, 50-H), 8.07 (d, 1H, j5,6 = 8.40 Hz, j5,7 = 1.20 Hz, 5-H), 8.09 (s,
1H, C@C–H), 8.30 (dd, 2H, jo = 8.40 Hz, 20, 60-H); MS (ESIꢀ) m/z
(rel. intensity): 408 (M+H, 100%); Anal. Calcd for C21H13NO6S.0.
3H2O C: 61.11, H: 3.29, N: 3.39, S: 7.76%; found: C: 60.93, H:
3.19, N: 3.53, S: 7.60%.
4.1.3. General synthesis of compounds Va–c
A
mixture of ethyl 2,4-dioxothiazolidine-3-ylacetate IV
(0.001 mol) and flavone carboxaldehydes IIIa–c (0.001 mol) was
heated at 100 °C in the presence of 1 ml glacial acetic acid and so-
dium acetate (0.001 mol) for 10 h. The residue was crystallized
from DMF–ethanol.
4.1.4.3. {2,4-Dioxo-5-[(4-oxo-2-phenyl-4H-chromen-6-yl)-
methylene]-1,3-thiazolidine-3yl}acetic acid (VIc). Yield (%):
t :
max/cmꢀ1
4.1.3.1. Ethyl{2,4-dioxo-5-[3-(4-oxo-4H-chromen-2-yl)benzyl-
93.1, mp: 350 °C. Spectroscopic analysis: IR (KBr)
1614 (
pyrone CO); 1H NMR (DMSO-d6, 400 MHz, d, ppm): 4.41
(s, 2H, CH2CO), 7.17 (s, 1H, 3-H), 7.60–7.65 (m, 3H, 30, 40, 50-H),
idene]-1,3-thiazolidine-3yl}acetate (Va). Yield (%): 62.3, mp:
c
203 °C. Spectroscopic analysis: IR (KBr) t c pyrone
max/cmꢀ1: 1640 (