Synthesis and in vivo antihyperglycemic activity of nature-mimicking furanyl-2-pyranones in STZ-S model

Article abstract of DOI:10.1016/j.bmcl.2007.02.036

Various nature-mimicking pyranones such as 6-(2,5-dimethylfuran-3-yl)-pyran-2-one and 6-(furan-2-yl)-pyran-2-one derivatives were synthesized and evaluated for their in vivo antihyperglycemic activity in sucrose-loaded streptozotocin-induced diabetic rat

Full text of DOI:10.1016/j.bmcl.2007.02.036

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2425–2429
Synthesis and in vivo antihyperglycemic activity of
nature-mimicking furanyl-2-pyranones in STZ-S modelq
Fateh V. Singh,a Sumit Chaurasia,a Maya D. Joshi,b
Arvind K. Srivastavab and Atul Goela,*
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
Received 3 October 2006; revised 15 January 2007; accepted 15 February 2007
Available online 17 February 2007
Abstract—Various nature-mimicking pyranones such as 6-(2,5-dimethylfuran-3-yl)-pyran-2-one and 6-(furan-2-yl)-pyran-2-one
derivatives were synthesized and evaluated for their in vivo antihyperglycemic activity in sucrose-loaded streptozotocin-induced dia-
betic rat model. Five of the test compounds showed significant lowering of plasma glucose level in STZ-S model.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Type 2 diabetes is characterized by high level of blood glu-
cose, insulin and impaired insulin action.1 The remedies
available in modern system of medicine for the treatment
of type 2 diabetes patients have been focused on dietary
management of obesity2 to improve insulin sensitivity,
sulfonylureas3 to enhance insulin secretion, metformin4
to inhibit hepatic glucose output, and acarbose5 to inhibit
or reduce the rate of glucose absorption from the gut. In
current scenario, the treatment of type 2 diabetes has been
revolutionized with the advent of thiazolidinedione
(TZD) class of drugs (rosiglitazone, pioglitazone) that
ameliorate insulin resistance and thereby normalize ele-
vated blood glucose levels,6 but are associated with hepa-
totoxicity, weight gain, and edema.7 The alarming
situation emphasized the need to discover new antihyper-
glycemic agents with reduced or no hepatotoxicity. One
such alternative is to explore antidiabetic leads from tra-
ditional sources, identify a pharmacophore-based scaf-
fold, which not only retain blood sugar lowering activity
but are also known as hepatoprotectants.
orders.8 Studies have shown that aqueous and alcoholic
extracts of Tinospora cordifolia Miers had caused reduc-
tion in fasting blood glucose level and increased glucose
tolerance in albino rats.9 Aqueous and alcoholic extracts
of T. cordifolia have shown reduction in blood sugar in
alloxan-induced hyperglycemic rats and rabbits. The
chief constituents of the extracts of T. cordifolia were
diterpenoid lactones, furanoid diterpene glucoside
(Fig. 1, I and II), sesquiterpenoids, many of them pos-
sessing 6-(furan-3-yl)-2-pyranone skeleton.10 Naturally
occurring 2-pyranones functionalized at position 6 with
a furan moiety in flexible or rigid conformations, partic-
ularly achrocarpins (III), are the core skeleton found in
Several indigenous medicinal plants of family Meni-
spermaceae have been used as a tonic, vitalizer, and as
traditional remedies for the treatment of metabolic dis-
Keywords: Furanyl-2-pyranones; Synthesis; Antihyperglycemic; STZ-S
model; Antidiabetic.
q
CDRI communication number: 7008.
Fax:
*
Figure 1. Naturally occurring (furan-3-yl)-2-pyranones (I–III) and
(furan-2-yl)-2-pyranones (IV).
Corresponding
agoel13@yahoo.com
author.
+91
522
2623405; e-mail:
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.036

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F. V. Singh et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2425–2429
several natural products of biological importance.11
Molecules embedded with this scaffold have demon-
strated diverse interesting activities such as antifungal,
antioxidant, anticancer, antidiabetic, etc. In addition,
2-pyranones with furan moiety (IV) have been isolated
from fruit bodies of the fungus Ganoderma lucidum,
which is an important constituent of a traditional Chi-
nese drug ‘Lin-Chi’ used in the treatment of mild ail-
ments and to promote good health.12 Studies have also
shown that polysubstituted 2-pyranones possess signifi-
cant hepatoprotective activity. Ram et al.13 found that
6-furanyl-2-pyranones exhibited 71% and 72% protec-
tion in serum glutamate oxaloacetate transaminases
(SGOT) and serum glutamate pyruvate transaminases
(SGPT), respectively, in rats at 6 mg/kg (po · 7 days).
Such informations on furanyl-2-pyranones provided a
template for designing new antihyperglycemic agents
with hepatoprotective action. Thus, we envisaged that
synthesis of repertoire of nature-like 2-pyranones func-
tionalized at position 6 with a furan moiety would be
an interesting scaffold to examine the antihyperglycemic
activity.
ethylfuran-3-yl)-4-methylthio-2-oxo-2H-pyran-3-carbo-
nitrile 3 in good yield. The reaction is possibly initiated
by Michael addition of an enolate of 2 to ketene dith-
ioacetal 1 to form an intermediate A. This intermediate
in presence of a base intramolecularly cyclizes to inter-
mediate C, which on elimination of methanol afforded
furanyllactone 3. Acid hydrolysis of 3 furnished 6-(2,
5-dimethylfuran-3-yl)-4-methylthio-2-oxo-2H-pyran-3-
carboxylic acid amide 4 in 84% yield. The methylthio
group of 2H-pyran-2-one 3 was further replaced by var-
ious secondary amines by reacting lactone 3 with a sec-
ondary amine in methanol at reflux temperature, which
afforded 4-amino-6-(2,5-dimethylfuran-3-yl)-2-oxo-2H-
pyran-3-carbonitrile 5 in 75–90% yield.
To examine the effect of point of attachment for furan
moiety toward biological activity, a series of 6-(furan-
2-yl)-2H-pyran-2-ones (7, 8, 9a–d) were prepared as
shown in Scheme 2. The reaction of ketene dithioacetal
1 with 2-acetylfuran in presence of KOH afforded 7 in
78% yield. The nitrile group of 7 was further hydrolyzed
to corresponding amide 8 in the presence of poly phos-
phoric acid at 100 ꢁC. The amine-functionalized 2H-pyr-
an-2-ones 9a–d were prepared by replacing methylthio
group of 7 with various secondary amines in methanol
Herein we report synthesis and in vivo antihyperglyce-
mic activity of nature-mimicking 6-(furan-3-yl)-2-pyra-
none and 6-(furan-2-yl)-2-pyranone derivatives in
sucrose-loaded streptozotocin-induced (STZ-S) diabetic
model.
Limited synthetic methodologies are available for the
preparation of furanyllactones. The most common ap-
proaches for the synthesis of furanyl-2-pyranone core
skeleton include aldol condensation14 of 3-furaldehyde
and enol silanes or enolates of substituted cyclohexa-
nones and lewis acid catalyzed aldol reactions of 1-trim-
ethylsilyloxycyclohexene with 1-(3-furanyl)-2-nitro-1-
propene followed by Baeyer–Villiger oxidation.15 Our
approach for the preparation of functionalized 6-(fur-
an-3-yl)-2-pyranones (3, 4, 5) is depicted in Scheme 1.
The ketene dithioacetal16 1 used as a parent precursor
was conveniently prepared by methyl cyanoacetate, car-
bon disulfide, and methyl iodide in presence of a base in
good yield. In order to prepare (furan-3-yl)-2-pyranon-
es, a reaction of ketene dithioacetal 1 and 1-(2,5-dim-
ethylfuran-3-yl)-ethanone
potassium hydroxide in DMSO afforded 6-(2,5-dim-
2
in the presence of
Scheme 2. Reagents and conditions: (i) KOH, DMSO, rt; (ii) PPA,
100 ꢁC; (iii) secondary amine, methanol, reflux.
Scheme 1. Reagents and conditions: (i) KOH, DMSO, rt; (ii) PPA, 100 ꢁC; (iii) secondary amine, methanol, reflux.

F. V. Singh et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2425–2429
2427
Table 1. In vivo antihyperglycemic activity of compounds 3, 4, 5a–d, 7, 8 and 9a–d at 100 mg/kg dose in STZ-S model
Compound
Blood glucose lowering profile (% change over control)a
30 min
60 min
90 min
120 min
180 min
240 min
5 h
5.2
24 hb
3
12.6
13.2
12.5
8.6
16.2
28.8
17.3
9.4
21.2
33.0
20.9
6.8
16.5
29.4
20.9
8.7
2.3
16.3
7.8
2.5
12.6
1.2
04.5
23.9
10.5
19.7
29.7
4.2
4
5a
11.2
4.5
5b
5c
0.8
1.0
5.2
16.6
12.5
11.8
8.5
18.4
16.3
16.5
9.6
24.0
20.9
19.6
6.3
29.0
16.8
19.8
8.9
18.5
2.6
20.7
2.8
20.3
5.5
5d
7
8.1
1.2
2.3
1.3
6.8
5.52
6.7
8
9a
19.3
10.4
0.5
12.8
13.1
12.5
11.8
15.9
17.5
15.9
17.5
15.7
18.2
21.1
19.8
17.3
20.2
24.5
21.3
17.4
22.8
15.9
29.2
7.5
1.8
1.4
5.2
4.8
9.8
9b
9c
16.8
1.9
14.6
3.9
12.8
6.1
20.0
2.5
9d
Metformin
18.7
21.1
20.7
30.0
a Sugar lowering activity was examined at different time intervals after compound treatment.
b Values in bold font emphasize significant blood sugar lowering.
at reflux temperature. All the synthesized compounds
were characterized by their spectroscopic analyses.17–19
later by glucostrips and animals showing blood glucose
values between 8 and 15 mM were included in the exper-
iments and termed diabetic. The diabetic animals were
divided into groups consisting of five to six animals in
each group. Rats of experimental groups were adminis-
tered suspension of the desired test samples orally (made
in 1.0% gum acacia) at 100 mg/kg dose. Animals of con-
trol group were given an equal amount of 1.0% gum aca-
cia. A sucrose load of 2.5 g/kg body weight was given
after 30 min of drug administration. After 30 min of
sucrose load, blood glucose level was again checked by
glucostrips at 30, 60, 90, 120, 180, 240, 300 min and at
24 h, respectively. Food but not water was withheld from
the cages during the experimentation. Comparing the
AUC of experimental and control groups determined
the percent antihyperglycemic activity.
Most of the synthesized compounds were evaluated for
in vivo antihyperglycemic activity in sucrose-loaded
streptozotocin-induced (STZ-S) male Sprague–Dawley
diabetic rats.20 Metformin was taken as a control.
Among the 12 screened compounds, five compounds
(4, 5b,c, 8, and 9c) demonstrated good antihyperglyce-
mic activity by showing 19–30% blood sugar lowering
at 100 mg/kg dose after 24 h drug treatment (Table 1).
The structure–activity profile revealed that 2H-pyran-
2-ones with amide functionality at position 3 in 4 and
8 showed good sugar lowering activity compared to
their nitrile precursors 3 and 7. It is evident from the
activity data of 4-amino-6-(furan-3-yl)-2H-pyran-2-ones
5a–d that compounds having piperidine (5b: 19.7%) or
morpholine (5c: 29.7%) moiety showed good antihyper-
glycemic activity. Similarly in the series of 4-amino-6-
(furan-2-yl)-2H-pyran-2-ones (9a–d), only 6-(furan-2-
yl)-4-(4-methylpiperazin-1-yl)-2-oxo-2H-pyran-3-carbo-
nitrile (9c) showed 20.0% sugar lowering in Sprague–
Dawley diabetic rats. The most active compound 5c
showed 29.7% sugar lowering activity comparable to
standard drug metformin (30%).
Acknowledgments
Authors are thankful to SAIF, CDRI, for spectral anal-
yses of the synthesized compounds. F.V. Singh is grate-
ful to CSIR, New Delhi, for senior research fellowship.
Financial support from DST, New Delhi under fast
track scheme is gratefully acknowledged.
In summary, we have demonstrated synthesis and
in vivo antihyperglycemic activity of a new class of nat-
ure-mimicking furanyl-2H-pyran-2-ones with donor-
acceptor functionalities, which are promising candidates
for the development of antidiabetic agents. Among var-
ious screened compounds, furanyllactone 5c showed
30% blood sugar lowering at 100 mg/kg dose in STZ-S
induced male Sprague–Dawley diabetic rats. Further
exploratory work on furanyllactone template is cur-
rently in progress.
References and notes
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Sucrose challenged low dosed streptozotocin-induced dia-
betic rats (STZ-S):20 Male albino rats of Sprague–Daw-
ley strain of body weight 140 20 g were selected for this
study. Streptozotocin (Sigma, USA) was dissolved in
100 mM citrate buffer, pH 4.5, and calculated amount
of the fresh solution was injected to overnight fasted rats
(45 mg/kg) intraperitoneally. Blood was checked 48 h

2428
F. V. Singh et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2425–2429
7. (a) Ram, V. J. Prog. Drug Res. 2003, 60, 93; (b) Diamant,
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(CO), 1711 (CO), 3181 (NH), 3398 cmÀ1 (NH); MS (ESI)
279 (M+). Compound 8: yellow solid; yield: 85%; mp: 232–
234 ꢁC; 1H NMR (CDCl3, 200 MHz): d 2.51 (s, 3H, SMe),
5.60 (br s, 1H, NH), 6.58–6.62 (m, 1H, CH), 6.84 (s, 1H,
CH), 7.19 (d, J = 3.40 Hz, 1H, CH), 7.61 (d, J = 1.1 Hz,
1H, CH), 8.70 (br s, 1H, NH); IR (KBr) 1660 (CO), 1708
(CO), 3187 (NH), 3428 cmÀ1 (NH); MS (FAB) 252
(M++1); 13C NMR (200 MHz, CDCl3): d 17.40, 73.21,
98.33, 113.53, 115.36, 145.83, 146.65, 167.25, 171.26.
19. Synthesis of 6-(2,5-dimethylfuran-3-yl)/(furan-2-yl)-4-
sec.amino-2-oxo-2H-pyran-3-carbonitrile (5a–d and 9a–
d): A mixture of compound 3 or 7 (10 mmol) and
secondary amine (12 mmol) was refluxed in methanol
(20 mL) for 6–8 h. After completion, methanol was
evaporated under vacuum, and reaction mixture was
washed with ice-cooled water. Crude was purified on a
silica gel column using chloroform as eluent. Compound
5a: white solid; yield: 89%; mp: 224–226 ꢁC; 1H NMR
(CDCl3, 200 MHz): d 2.00–2.11 (m, 4H, 2CH2), 2.25 (s,
3H, Me), 2.54 (s, 3H, Me), 3.58–3.62 (m, 2H, CH2), 4.05–
4.09 (m, 2H, CH2), 5.84 (s, 1H, CH), 6.08 (s, 1H, CH); IR
(KBr) 1704 (CO), 2208 cmÀ1 (CN); MS (ESI) 285 (M++1);
13C NMR (200 MHz, CDCl3): d 16.59, 17.85, 28.38, 54.99,
95.09, 103.08, 114.49, 119.10, 123.85, 151.73, 153.90,
158.38, 161.35, 162.81. Compound 5b: white solid; yield:
78%; mp: 188–190 ꢁC; 1H NMR (CDCl3, 200 MHz): d
1.65–1.85 (m, 6H, 3CH2), 2.26 (s, 3H, Me), 2.56 (s, 3H,
Me), 3.74–3.78 (m, 4H, 2CH2), 5.96 (s, 1H, CH), 6.09 (s,
1H, CH); IR (KBr) 1704 (CO), 2209 cmÀ1 (CN); MS (ESI)
299 (M++1); 13C NMR (200 MHz, CDCl3): d 13.65, 15.01,
24.30, 26.71, 51.14, 94.04, 104.44, 109.98, 114.43, 118.08,
151.74, 153.98, 158.42, 161.38, 162.83. Compound 5c:
8. (a) Chopra, R. N.; Chopra, I. C.; Handa, K. L.; Kapur, L.
D. Indigenous Drugs India, Second ed.; U.N. Dhar and
Sons: Calcutta, 1958, 426; (b) Nadkarni, A. K. Indian
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9. (a) Gupta, S. S.; Verma, S. C. L.; Garg, V. P.; Mahesh, R.
Indian J. Med. Res. 1967, 55, 733; (b) Stanely Mainzen
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Res. 2003, 17, 410.
10. (a) Singh, S. S.; Pandey, S. C.; Srivastava, S.; Gupta, V. S.;
Patro, B. Indian J. Pharmacol. 2003, 35, 83; (b) Sarma, D.
N. K.; Khosa, R. L. Indian Drugs 1993, 30, 549; (c) Khan,
M. A.; Gray, A. I.; Waterman, P. G. Phytochemistry 1989,
28, 273; (d) Bhatt, R. K.; Sabata, B. K. Phytochemistry
1989, 28, 2419.
11. Prakash Chaturvedula, V. S.; Schilling, J. K.; Kingston,
D. G. I. J. Nat. Prod. 2002, 65, 965.
12. (a) Tezuka, Y.; Huang, Q.; Kikuchi, T.; Nishi, A.; Tubaki,
K. Chem. Pharm. Bull. 1994, 42, 2612; (b) McGlacken, G.
P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
13. (a) Ram, V. J.; Haque, N.; Nath, M.; Singh, S. K.;
Hussaini, F. A.; Tripathi, S. C.; Shoeb, A. Bioorg. Med.
Chem. Lett. 1997, 7, 3149; (b) Ram, V. J.; Verma, M.
Indian J. Chem. B 1990, 29B, 624; (c) Ram, V. J.;
Srivastava, P.; Agarwal, N.; Sharon, A.; Maulik, P. R.
J. Chem. Soc., Perkin Trans. 1 2001, 16, 1953; (d) Ram, V.
J.; Agarwal, N.; Sharon, A.; Maulik, P. R. Tetrahedron
Lett. 2002, 43, 307.
14. (a) Fernandez Mateos, A.; De la Fuente Blanco, J. A.
J. Org. Chem. 1991, 56, 7084; (b) Renoud-Grappin, M.;
Vanucci, C.; Lhommet, G. J. Org. Chem. 1994, 59, 3902.
15. Fernandez Mateos, A.; De la Fuente Blanco, J. A. J. Org.
Chem. 1990, 55, 1349.
1
white solid; yield: 76%; mp: >250 ꢁC; H NMR (CDCl3,
200 MHz): d 2.26 (s, 3H, Me), 2.57 (s, 3H, Me), 3.78–3.90
(m, 8H, 4CH2), 5.93 (s, 1H, CH), 6.08 (s, 1H, CH); IR
(KBr) 1712 (CO), 2214 cmÀ1 (CN); MS (ESI) 301 (M++1);
13C NMR (200 MHz, CDCl3): d 13.38, 14.85, 50.12, 52.61,
94.45, 104.85, 114.59, 118.81, 124.48, 151.36, 152.90,
156.38, 160.19, 163.49. Compound 5d: white solid; yield:
77%; mp: 184–186 ꢁC; 1H NMR (CDCl3, 200 MHz): d
1.01 (d, 3H, J = 6.0 Hz, Me), 1.29–1.39 (m, 2H, CH2),
1.81–1.91 (m, 3H, CH and CH2), 2.26 (s, 3H, Me), 2.56 (s,
3H, Me), 3.11–3.28 (m, 2H, CH2), 4.26–4.37 (m, 2H,
CH2), 5.96 (s, 1H, CH), 6.09 (s, 1H, CH); IR (KBr) 1686
(CO), 2208 cmÀ1 (CN); MS (ESI) 313 (M++1); 13C NMR
(200 MHz, CDCl3): d 13.61, 14.96, 21.74, 30.99, 34.75,
50.38, 94.16, 104.48, 114.45, 118.09, 151.73, 153.90,
158.39, 161.36, 162.81. Compound 9a: white solid; yield:
80%; mp: 184–186 ꢁC; 1H NMR (CDCl3, 200 MHz): d
1.77–1.81 (m, 6H, 3CH2), 3.80–3.84 (m, 4H, 2CH2), 6.43
(s, 1H, CH), 6.54–6.61 (m, 1H, CH), 7.10 (d,J = 3.4 Hz,
1H, CH), 7.55 (J = 1.1 Hz, 1H, CH); IR (KBr) 1708 (CO),
2216 cmÀ1 (CN); MS (FAB) 271 (M++1); 13C NMR
(200 MHz, CDCl3): d 24.25, 26.78, 51.31, 72.04, 113.29,
114.53, 117.86, 146.03, 146.23, 152.58, 160.68, 162.37.
Compound 9b: white solid; yield: 78%; mp: 248–250 ꢁC;
1H NMR (CDCl3, 200 MHz): d 3.88 (s, 8H, 4CH2), 6.40
(s, 1H, CH), 6.56–6.62 (m, 1H, CH), 7.12 (d, J = 3.4 Hz,
1H, CH), 7.56 (d, J = 1.1 Hz, 1H, CH); IR (KBr) 1686
(CO), 2208 cmÀ1 (CN); MS (FAB) 273 (M++1); 13C NMR
(200 MHz, CDCl3): d 51.78, 53.25, 92.37, 112.29, 114.53,
116.51, 146.97, 147.03, 152.68, 161.58, 163.81. Compound
9c: white solid; yield: 80%; mp: 172–174 ꢁC; 1H NMR
(CDCl3, 200 MHz): d 2.37 (s, 3H, NCH3), 2.56–2.65 (m,
4H, 2CH2), 3.85–3.94 (m, 4H, 2CH2), 6.41 (s, 1H, CH),
6.54–6.62 (m, 1H, CH), 7.11 (d, J = 3.4 Hz, 1H, CH), 7.55
(d, J = 1.1 Hz, 1H, CH); IR (KBr) 1706 (CO), 2214 cmÀ1
(CN); MS (FAB) 286 (M++1); 13C NMR (200 MHz,
CDCl3): d 37.87, 52.25, 53.81, 92.58, 112.29, 114.86,
16. Tominaga, Y. Trends Heterocycl. Chem. 1991, 2, 43.
17. Synthesis of 6-furanyl-4-methylthio-2-oxo-2H-pyran-3-car-
bonitrile (3 and 7): A mixture of methyl 2-cyano-3,3-
di(methylthio)acrylate 1 (10 mmol), acetylfuran (2 or 6,
12 mmol), and powdered KOH (15 mmol) in dry DMSO
(25 mL) was stirred at room temperature for 15–18 h.
After completion, the reaction mixture was poured into ice
water with constant stirring. The precipitate thus obtained
was filtered and purified on a silica gel column using
chloroform as eluent. Compound 3: yellow solid; yield:
85%; mp: 250–252 ꢁC; 1H NMR (200 MHz, CDCl3): d
2.29 (s, 3H, Me), 2.61 (s, 3H, Me), 2.64 (s, 3H, SMe), 6.15
(s, 1H, CH), 6.21 (s, 1H, CH); IR (KBr) 1718 (CO),
À1
2213 cm
(CN); MS (ESI) 262 (M++1); 13C NMR
(200 MHz, CDCl3): d 13.86, 15.18, 23.27, 94.41, 104.48,
114.52, 118.19, 123.92, 151.36, 152.90, 156.38, 160.81,
165.49. Compound 7: yellow solid; yield: 78%; mp: 208–
210 ꢁC; 1H NMR (CDCl3, 200 MHz): d 2.70 (s, 3H, SMe),
6.66 (s, 2H, 2CH), 7.24 (d, J = 3.4 Hz, 1H, CH), 7.66 (d,
J = 1.1 Hz, 1H, CH); IR (KBr) 1718 (CO), 2214 cmÀ1
(CN); MS (ESI) 234 (M++1).
18. Synthesis of 6-(2,5-dimethylfuran-3-yl)/(furan-2-yl)-4-
methylthio-2-oxo-2H-pyran-3-carboxylic acid amide (4
and 8): Compound 3 or 7 (10 mmol) was heated at 90–
100 ꢁC for 8–10 h. After completion, the reaction mixture
was poured into ice water with constant stirring. The
precipitate thus obtained was filtered and purified on a
silica gel column using chloroform as eluent. Compound
4: yellow solid; yield: 84%; mp: 214–216 ꢁC; 1H NMR
(CDCl3, 200 MHz): d 2.29 (s, 3H, Me), 2.45 (s, 3H, Me),
2.62 (s, 3H, SMe), 5.56 (br s, 1H, NH), 6.18 (s, 1H, CH),
6.41 (s, 1H, CH), 8.70 (br s, 1H, NH); IR (KBr) 1664

F. V. Singh et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2425–2429
2429
116.51, 146.53, 147.63, 153.08, 161.37, 162.78. Compound
9d: white solid; yield: 82%; mp: >250 ꢁC; 1H NMR
(CDCl3, 200 MHz): d 3.39–3.47 (m, 4H, 2CH2), 4.04–
4.20 (m, 4H, 2CH2), 6.47 (s, 1H, CH), 6.58–6.64 (m, 1H,
CH), 6.91–7.00 (m, 3H, ArH), 7.15 (d, J = 3.4 Hz, 1H,
CH), 7.28–7.38 (m, 2H, ArH), 7.59 (d, J = 1.1 Hz, 1H,
CH); IR (KBr) 1700 (CO), 2218 cmÀ1 (CN); MS (FAB)
348 (M++1); 13C NMR (200 MHz, CDCl3): d 49.97, 66.93,
73.11, 92.45, 113.47, 115.11, 117.52, 145.83, 146.53,
153.15, 161.48, 161.78.
20. Kumar, A.; Pathak, S. R.; Ahmad, P.; Ray, S.; Tewari, P.;
Sivastava, A. K. Bioorg. Med. Chem. Lett. 2006, 16, 2719.