F. V. Singh et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2158–2161
2161
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ity, which is attributed to their highly lipophilic nature. For exam-
ple, the solubility of 3a in neat triple distilled water was 0.13 g/
mL. These active compounds are non-charged molecules and pos-
sess an amino group (H-bond donor) and hydrophobic phenyl res-
idues, which indicate the probability of a level of caco-2 flux
predictive for good oral absorption.
In summary, we have demonstrated synthesis, in vitro and
in vivo antihyperglycemic activity of a new class of 5,6-diarylan-
thranilo-1,3-dinitriles functionalized with donor–acceptor groups,
which demonstrated good sugar lowering activity. Among various
screened compounds, 4’-amino-4’’-methoxy-6’-methylsulfanyl-
[1,1’;2’,1’’]terphenyl-3’,5’-dicarbonitrile 3b showed 36.9% blood
sugar lowering at 100 mg/kg dose in STZ-S induced male Spra-
gue–Dawley diabetic rats. The compound was found to inhibit
the activity of PTP-1B to a significant level. This may be the under-
lying mechanism of antihyperglycemic activity of this compound.
Further investigations on 5,6-diarylanthranilo-1,3-dinitrile tem-
plate are currently in progress.
l
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Acknowledgment
Authors are thankful to CSIR (Grant NWP0032), and ICMR, New
Delhi, for financial support. F.V.S., S.C. and S.P.S. are grateful to
CSIR, New Delhi, for research fellowships. A.G. is thankful to Profes-
sor G. Bringmann for his support and to the Alexander von Hum-
boldt Foundation for research fellowship. We thank SAIF, CDRI,
for spectral analyses of the synthesized compounds.
19. Allen, C. F. H.; Barker, W. E.. In Deoxybenzoins: Organic Syntheses; Blatt, A. H.,
Ed.; John Wiley and Sons: New York, 1943; Vol. 2, p 156.
20. General procedure for the synthesis of 3a–f: A mixture of 4-methylsulfanyl-2-
oxo-5,6-diphenyl-2H-pyran-3-carbonitrile 1a–f (1 mmol), malononitrile
(1 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at
room temperature for 6–8 h. At the end reaction mixture was poured into ice
water with vigorous stirring and finally neutralized with dilute HCl. The solid
thus obtained was filtered and purified on a neutral alumina column using
chloroform–hexane (1:4) as eluent. Compound 3a: White solid; mp 198–
200 °C; 1H NMR (200 MHz, CDCl3) d 2.27 (s, 3H, SCH3), 5.31 (br s, 2H, NH2),
6.93–6.96 (m, 2H, ArH), 7.00–7.04 (m, 2H, ArH), 7.15–7.22 (m, 6H, ArH); 13C
NMR (50 MHz, CDCl3) d 19.67 (SCH3), 97.92, 100.83, 115.77 (CN), 115.9 (CN),
127.85, 128.21, 128.41, 128.87, 129.57, 131.31, 135.19, 137.18, 147.73, 150.03,
152.03; IR (KBr) 2219 (CN), 3353, 3468 cmÀ1 (NH2); MS (FAB) 342 (M++1).
21. General procedure for the synthesis of compounds 5a–f: A mixture of 5-aryl-3-
cyano-6-methyl-4-methylsulfanyl-2H-pyran-2-ones 4 (1 mmol), malononitrile
(1.2 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at
room temperature for 12–15 h. At the end the reaction mixture was poured
into ice water with vigorous stirring and finally neutralized with dilute HCl.
The solid thus obtained was filtered and purified on a neutral alumina column
using chloroform–hexane (1:3) as eluent. Compound 5a: White solid; mp 192–
194 °C; 1H NMR (200 MHz, CDCl3) d 2.20 (s, 3H, CH3), 2.30 (s, 3H, SCH3), 5.22
(br s, 2H, NH2), 7.04–7.19 (m, 4H, ArH); IR (KBr) 2220 (CN), 3352, 3413 (NH2)
cmÀ1; MS (FAB) 298 (M++1); Anal. Calcd for C16H12FN3S: C, 64.63; H, 4.07;
N,14.13. Found: C, 64.69; H, 4.10, N, 14.19.
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