A. Goel et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1089–1092
1091
sugar level was measured after 48 h by glucometer.
Animals showing 200–400 mg/dl were selected for anti-
diabetic screening. The diabetic animals were divided
into groups of six animals each. Rats of experimental
group were administered a suspension of the desired test
sample (prepared in 1% gum acacia) orally (100 mg/kg
body weight). Controlled group animals were also fed
with 1% gum acacia. The blood glucose levels were
measured at 1-, 2-, 3-, 4-, 5-, 6-, 7- and 24-h intervals.
The % fall in blood glucose from 1 to 24 h by test
sample was calculated according to the area under curve
(AUC) method. The average fall in AUC in experi-
mental group compared to control group provided %
antihyperglycemic activity.
tate (1.5 g) in glacial acetic acid (5 mL) was refluxed for
2 h under nitrogen atmosphere. After completion of the
reaction, mixture was allowed to cool to room temper-
ature and thereafter poured into hot water with stirring.
Precipitate obtained was filtered, washed two times with
hot water and finally purified on silica gel column using
chloroform/hexane (1:4) as eluent. Yield 71%; mp 215–
216 ꢀC; MS (FAB) m/z 370 (M++1); IR(KBr) 3344
1
cmÀ1 (NH); H NMR(200 MHz, CDCl ) d 2.40 (s, 3H,
3
CH3), 3.52 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 6.47 (s,
1H, ArH), 6.70–6.83 (m, 2H, ArH), 7.04–7.25 (m, 10H,
ArH), 8.08 (brs, 1H, NH). Anal. calcd for C25H23NO2: C,
81.27; H, 6.27; N, 3.79. Found: C, 81.45; H, 6.26; N, 3.80.
Acknowledgements
3.2. Sucrose-loaded (SLM) model
Overnight fasted male Sprague–Dawley rats were used
for sucrose-loaded experiment. Blood was collected
initially and thereafter test compounds were given to the
test group consisting of five rats by oral gavage at a dose
of 100 mg/kg body weight. After half an hour post test
treatment, a sucrose-load of 10 gm/kg body weight was
given to each rat. Blood was collected at 30, 60, 90 and
120 min post sucrose-load. The % fall in blood glucose
level was calculated according to the AUC method.
Authors are thankful to Mr. P. K. Agarwal for his
technical support and RSIC, CDRI for spectral ana-
lyses of the synthesized compounds. N. Agarwal and A.
Sharon are grateful to CSIR, New Delhi for providing
financial assistance.
References and notes
1. Turner, N. C.; Clapham, J. C. Progress in Drug Research
1998, 51, 35.
The antihyperglycemic activity of the screened com-
pounds revealed that unsubstituted-phenyl ring at posi-
tions 4 and 5 of the pyrroles (3a–i) reduced elevated
blood sugar levels in the range of 20–50% in SLM
model except for compound 3a. Substitution at posi-
tions 3 or 4 of above phenyl ring (3e–g) resulted in
either reduction or a complete loss of antihyperglycemic
activity. The nature of substituent in aryl ring at posi-
tion 3 of the pyrroles (3a–i) revealed that the presence of
fluoro group at position 2 of the aryl ring produced
compounds without antihyperglycemic activity. A com-
pound with trifluoromethyl group at position 3 of the
aryl ring (3c) displayed good antidiabetic activity in
both SLM (40.8%) and STZ (25.1%) models. Two com-
pounds, 3-(3,4-dimethoxyphenyl)-2-methyl-4,5-diphenyl-
1H-pyrrole (3h) and 3-(2,4-dimethoxy-phenyl)-2-methyl-
4,5-diphenyl-1H-pyrrole (3i) reduced blood glucose
levels by 27.8% and 20.3%, respectively in SLM model
while 3h also displayed 28.6% reduction in blood glu-
cose level in streptozotocin-induced diabetic rats. A
byproduct, 2,3,5,6-tetraphenylpyrazine (4) also dis-
played 22% blood glucose lowering in SLM model.
2. (a) Astrup, A.; Breum, L.; Toubo, S. Obesity 1995, 3 (Suppl
4), 537S. (b) Kelley, D. E. Diabetes Rev. 1995, 3, 366.
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Rev. Physiol. 1998, 60, 667. (b) Aguilar-Bryan, L.; Clem-
ent, J. P., II; Gonzalez, G.; Kunjilwar, K.; Babenko, A.;
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574. (b) Dunn, C. J.; Peters, D. H. Drugs 1995, 49, 721. (c)
Cusi, K.; DeFronzo, R. A. Diabetes Rev. 1998, 6, 89.
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Diamant, M.; Heine, R. J. Drugs 2003, 63, 1373.
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In conclusion, 3,4,5-triaryl-1H-pyrroles showed good in
vivo antihyperglycemic activity in SLM and STZ mod-
els and hold potential to explore further this class of
compounds.
13. Crystal data for 3h: C25H23NO2, M=369.44, monoclinic,
P2 1/n, a=11.317(1), b=11.268(1), c=16.536(2) A,
V=2033.3 A3, Z=4, Dc=1.207 g cmÀ1, m (Mo-Ka)=
0.07 mm-1, F(000)=784.0, colorless rectangular crystal,
size 0.325Â0.20Â0.15 mm, 4583 reflections measured
(3549 unique), Rw=0.27, conventional R=0.0722 on F
values of 1524 reflections with I>2s(I), S=1.046 for all
data and 257 parameters. Crystal data of Unit cell deter-
mination and intensity data collection (2ꢀ=50ꢀ) was per-
4. Typical example
4.1. Synthesis of 3-(3,4-dimethoxy-phenyl)-2-methyl-4,5-
diphenyl-1H-pyrrole (3h)
A mixture of benzoin (0.21 g, 1 mmol), dimethox-
yphenyl acetone (0.194 g, 1 mmol) and ammonium ace-