Construction of phenoxazine rings containing nitro and sulfonic acid groups leading to phenoxazine-3-sulfonamide derivatives: Their evaluation as novel and potential insulin secretagogues

Article abstract of DOI:10.1039/c3md00377a

A series of N-(alkyl/aryl/heteroaryl)-1-nitro-10H-phenoxazine-3- sulfonamides was designed, synthesized and evaluated for its hypoglycemic, hyperglycemic and oral anti-diabetic activities. These compounds were prepared via the construction of a phenoxazine ring containing nitro and sulfonic acid groups in a single step followed by further transformations. One of these compounds exhibited promising anti-diabetic activities comparable to glibenclamide and increased serum insulin levels indicating its potential as a novel insulin secretagogue. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3md00377a

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Construction of phenoxazine rings containing nitro
and sulfonic acid groups leading to phenoxazine-
3-sulfonamide derivatives: their evaluation as novel
and potential insulin secretagogues†
Cite this: DOI: 10.1039/c3md00377a
a
a
a
*
Seelam Venkata Reddy, Gangula Mohan Rao, Baru Vijaya Kumar,
Koppela Naresh Reddy,b Konda Sravya,b Puchchakayala Goverdhan,b
Vandana Rathore, Girdhar Singh Deora and Manojit Pal
c
d
c
*
A series of N-(alkyl/aryl/heteroaryl)-1-nitro-10H-phenoxazine-3-sulfonamides was designed, synthesized
and evaluated for its hypoglycemic, hyperglycemic and oral anti-diabetic activities. These compounds
were prepared via the construction of a phenoxazine ring containing nitro and sulfonic acid groups in a
single step followed by further transformations. One of these compounds exhibited promising anti-
diabetic activities comparable to glibenclamide and increased serum insulin levels indicating its potential
as a novel insulin secretagogue.
Received 9th December 2013
Accepted 23rd January 2014
DOI: 10.1039/c3md00377a
www.rsc.org/medchemcomm
Type 2 Diabetes Mellitus (T2-DM) is effectively controlled by an phenoxazine moiety on the other hand has been explored in the
approach which is polypharmaceutical1 in nature, targeting the discovery and development of a dual PPAR agonist, DRF 2725,
effects of insulin sensitivity and related dyslipidemia and that has shown potent antihyperglycemic and lipid modulating
therefore cardiovascular diseases. However, this approach is properties.6 This, and our continued interest in novel anti-dia-
not encouraged due to its potential additional risks.2 It is betic agents,7–10 prompted us to design a series of new sulfon-
therefore necessary to search for newer agents to circumvent the amides, represented by
B (Fig. 1), bearing phenoxazine
risks involved in combination therapy. Accordingly, an attempt moieties. The key structural features of A were partly main-
was made to design a unique pan agonist3a of PPARs (peroxi- tained in B with the hope that the resulting analogues would
some proliferator-activated receptors) that has a bulkier hetero- show in vivo pharmacological properties similar to A. Moreover,
cyclic scaffold with a sulfonamide side chain possessing the some of the structural features of glibenclamide (C, Fig. 1), a
necessary geometry and electrostatics which are complemen- well known anti-diabetic drug, were also incorporated in B.
tary to PPARs. Notably, PPAR a, g and d have been the targets of Introduction of the R group into the sulfonamide moiety of B
intense preclinical research to treat dyslipidemia.3b The inves- allowed the generation of a diverse library of small molecules
tigation revealed that these three receptors are closely related for pharmacological studies. Thus a series of sulfonamides,
and the design of a molecule which competently activates them bearing bulky phenoxazine moieties, related to B were prepared
is an intellectual challenge.4 Indeglitazar (A, Fig 1), a sulfon- and evaluated for hypoglycemic, hyperglycemic and anti-dia-
amide based PPAR pan-active anti-diabetic agent, has been betic activities, body weight changes, serum lipid proles, SGOT
discovered using a process that couples low-affinity biochemical (serum glutamic oxaloacetic transaminase) and SGPT (serum
screening with high-throughput co-crystallography.5 The glutamic pyruvic transaminase) levels and the histology of the
pancreas. To the best of our knowledge evaluation of this class
of molecules as potential anti-diabetic agents has not been
previously reported. Herein we report our preliminary results of
aMedicinal Chemistry Laboratory, Research Centre, C.K.M. Arts and Science College,
Warangal 506 006, Andhra Pradesh, India. E-mail: baruvijayakumar@yahoo.com;
this study.
Several syntheses11–15 of substituted phenoxazines have been
Tel: +91 8008098787
bDiabetes and Aging Research Division, Department of pharmacology, Vaagdevi
College of Pharmacy, Kakatiya University, Warangal 506 006, Andhra Pradesh, India
cDr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657
1500
attempted but the incorporation of two substituents, such as
nitro and sulfonic acid groups, in a single step followed by
modication of these substituents remains unexplored. A
recent report16 shows the synthesis of phenoxazine derivatives
starting from 2-aminophenol and substituted diuorobenzene
followed by the introduction of a sulfonic acid group at the C-3
position of the phenoxazine nucleus D (Fig. 2).
dThe University of Queensland, School of Pharmacy, Brisbane, Qld 4072, Australia
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral data for all new compounds, results of pharmacological studies. See DOI:
10.1039/c3md00377a
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promising and representative compounds e.g. 6a, 6b, 6d, 6g, 6l,
6m, 6o and 6s were taken for further screening e.g. intraperi-
toneal glucose tolerance test (IPGTT).
When the selected compounds were administered to glucose
loaded normal rats which had fasted for 18 h, hypoglycemic
effects were observed aer 30 min as shown in Table 2. In the
cases of compounds 6g, 6l and 6m, the decline in blood sugar
levels reached a maximum at 90 min. Nevertheless, compounds
6m and 6g were evaluated further for their anti diabetic effects.
A sub acute study was also performed on 6m. The difference
observed between the initial and nal fasting plasma glucose
levels of different groups under investigation revealed a signif-
icant elevation in blood glucose in the diabetic control group
compared with normal animals at 0 days as shown in Table 3
and at the end of the 14-day experimental period as shown in
Table 4. These results indicated the promising effects of
compound 6m in maintaining the blood glucose levels in
streptozotocin–nicotinamide induced diabetic rats. Adminis-
tration of 6m to diabetic rats showed a signicant decrease in
the blood glucose levels. A marked increase in the total
cholesterol and triglyceride levels has been observed in
untreated diabetic rats. Under normal circumstances insulin
activates the enzyme lipoprotein lipase and hydrolyses triglyc-
erides. An insulin deciency results in failure to activate the
Fig. 1 The design of new molecules, B, based on the known PPAR
pan-active anti-diabetic agent indeglitazar A and another anti-diabetic
drug glibenclamide C.
While the synthesis of 1-nitro-10H-phenoxazine-3-sulfonic
acid E (Fig. 2) or 2 (Scheme 1) was reported17 by Ullmann et al. in
1909, the conversion of the sulfonic acid group to sulfonamide
remained a challenge.18,19 However, the use of phosphorus
oxychloride in the absence of any solvent afforded the expected
sulfonyl chloride 5 (Scheme 1).20 Thus, the key starting material,
i.e. 4-chloro-3,5-dinitrobenzenesulfonic acid (4), was synthe-
sized from chlorobenzene (3) according to a reported procedure
(Scheme 1).21 Compound 4 was then condensed with 2-amino-
phenol (1) to give 1-nitro-10H-phenoxazine-3-sulfonic acid (2)
which was converted to the corresponding sulfonyl chloride (5).
Compound 5 was then condensed with ammonia20 or various
alkyl/aryl and heteroaryl amines to afford 6a–u.22
All compounds were characterized by IR, NMR and MS
spectral data. Compounds 6a (ref. 20) and 6b–u generally
showed a singlet near d 9.7 (NH group) and two doublets near d
7.9 and 7.0 ppm (with J ¼ 2.0 Hz) due to the C-2 and C-4 protons
of phenoxazine, respectively, in their 1H-NMR spectra. The
remaining protons of phenoxazine (H8, H7, H6 and H9)
appeared as multiplets in the d 7.2–7.1 and 6.8–6.7 ppm regions.
The hypoglycemic activities of all synthesized compounds
were initially evaluated at a dose of 20 mg kgꢀ1. Glibenclamide
is oen used as a standard anti-diabetic drug in streptozotocin-
induced moderate diabetes to compare the efficacy of a variety
of hypoglycemic agents.23 The effect of the test compounds i.e.
6a–u on fasting blood sugar levels was assessed in normal rats
at various time intervals as shown in Table 1. Some of the
compounds caused signicant maximum reductions in blood
glucose levels in normal rats when tested at 10 mg kgꢀ1 along
with 10 mg kgꢀ1 of glibenclamide aer 2 h of treatment e.g. 6a
(ꢁ35%), 6m (ꢁ54%), 6o (ꢁ47%), 6p (ꢁ24%), 6r (ꢁ27%), 6s
(ꢁ25%) 6t (ꢁ28%) and 6u (ꢁ32%). The compounds that
produced encouraging reductions in blood glucose levels aer 6
h are 6a (ꢁ50%), 6b (ꢁ40%), 6d (ꢁ25%), 6m (ꢁ43%), 6n
(ꢁ44%), 6o (ꢁ12%), 6r (ꢁ21%) and 6u (ꢁ30%). Some of these
Scheme 1 Reagents and conditions: (a) oleum, conc. H2SO4, KNO3,
130 ꢂC, 2 h; (b) 2-aminophenol (1), NaOH, ethanol, reflux, 4 h; (c)
POCl3, reflux, 3 h; (d) aqueous NH3, THF, 0 ꢂC, 30 min; (e) aryl/alkyl/
heteroaryl amines, chloroform, Et3N, 60 ꢂC, 30 min.
Fig. 2 Phenoxazine derivatives D and E.
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Table 1 Hypoglycemic effects of the test compounds 6a
Blood glucose (mg dlꢀ1
)
Post treatment
2 h
Dose (mg kgꢀ1 of
body weight (b. wt))
Pre treatment
0 h
Test group
4 h
97.13 ꢃ 2.89
6 h
Control
Glibenclamide
0.5% gum acacia
102.23 ꢃ 4.03
98.13 ꢃ 7.23
91.14 ꢃ 42.84
89.58 ꢃ 24.50
80.20 ꢃ 20.50
115.62 ꢃ 4.41
110.93 ꢃ 7.05
113.54 ꢃ 8.30
106.25 ꢃ 17.56
129.17 ꢃ 13.35
96.43 ꢃ 10.55
99.58 ꢃ 10.84
103.79 ꢃ 6.04
105.30 ꢃ 3.42
71.76 ꢃ 1.44
72.23 ꢃ 6.03
82.11 ꢃ 7.07
102.22 ꢃ 5.06
96.38 ꢃ 7.95
80.27 ꢃ 16.08
95 ꢃ 8.48
101.03 ꢃ 1.93
90.2 ꢃ 4.50*
65.62 ꢃ 40.45**
106.25 ꢃ 16.88
86.45 ꢃ 25.89
116.66 ꢃ 7.03
102.60 ꢃ 9.14
102.60 ꢃ 5.38
95.31 ꢃ 9.42*
122.92 ꢃ 20.02
93.55 ꢃ 7.92
90.22 ꢃ 6.78
95.45 ꢃ 4.97
96.21 ꢃ 3.42*
46.34 ꢃ 4.87***
59.35 ꢃ 4.50
52.43 ꢃ 2.58**
75.48 ꢃ 6.68
78.26 ꢃ 5.42
72.67 ꢃ 20.95
74.28 ꢃ 10.49
71.38 ꢃ 8.81
67.5 ꢃ 7.12
101.01 ꢃ 1.60
69.01 ꢃ 5.93***
51.04 ꢃ 19.90***
60.93 ꢃ 16.62***
84.37 ꢃ 20.05
74.47 ꢃ 17.27**
118.22 ꢃ 3.07
85.93 ꢃ 9.00
89.58 ꢃ 9.19**
118.75 ꢃ 9.68
85.42 ꢃ 4.10
90.20 ꢃ 7.56
93.94 ꢃ 4.69
100.76 ꢃ 4.46
66.14 ꢃ 4.50**
65.27 ꢃ 3.40
87.93 ꢃ 6.60
98.70 ꢃ 4.47
94.28 ꢃ 9.75
78.41 ꢃ 6.30
91.74 ꢃ 11.46
88.88 ꢃ 13.99
69.44 ꢃ 4.91
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
63.73 ꢃ 11.50**
69.79 ꢃ 33.20*
91.66 ꢃ 27.36
114.06 ꢃ 18.19
120.31 ꢃ 16.50
100 ꢃ 7.90
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
102.08 ꢃ 4.70
85.42 ꢃ 14.87**
113.54 ꢃ 17.64
89.88 ꢃ 12.94
85.63 ꢃ 6.94
87.88 ꢃ 4.69
86.36 ꢃ 2.87*
44.65 ꢃ 3.61***
61.56 ꢃ 9.29
73.33 ꢃ 12.81
88.70 ꢃ 7.90
77.74 ꢃ 11.08
69.35 ꢃ 6.74
86.45 ꢃ 9.58
85.0 ꢃ 8.18
6s
6t
6u
89.72 ꢃ 12.63
73.61 ꢃ 6.21
63.05 ꢃ 8.59
a
Values are mean ꢃ SD (standard deviation), n ¼ 6 in each group, *p < 0.05, **p < 0.01 and ***p < 0.001 when compared with the vehicle treated
group (Dunnett's test).
enzymes, thereby causing hypertriglyceridemia. The signicant (alanine transaminase). Elevated activities of serum amino-
lowering of total cholesterol (Table 5) and triglyceride (Table 6) transferases are a common sign of liver and cardiovascular
levels observed with compound 6m is a desirable biochemical diseases and are observed more frequently among people with
state for the prevention of atherosclerosis and ischemic condi- diabetes than in the general population. Such alterations to
tions.24 The observed hypolipidemic effect may be caused by transaminase activity in the tissues are explicable causes of
decreased cholesterogenesis and fatty acid synthesis.
energy metabolism, as these enzymes play a role in gluconeo-
It is known that diabetes raises the serum activity levels of genesis.25 Compound 6m has been found to reverse the
the liver enzymes AST (aspartate aminotransferase) and ALT increased SGPT and SGOT activities towards near normality,
Table 2 Intraperitoneal glucose tolerance test on selected compoundsa
Blood glucose (mg dlꢀ1
)
Before glucose
administration
0 min
Aer glucose administration
Test compound
Dose (mg kgꢀ1 b. wt)
30 min
60 min
90 min
120 min
Control
Glibenclamide
0.5% gum acacia
82.21 ꢃ 5.58
76.75 ꢃ 12.02
98.50 ꢃ 16.87
75.70 ꢃ 18.79
102.33 ꢃ 12.69
83.57 ꢃ 18.44
75.94 ꢃ 5.52
91.89 ꢃ 14.17
74.55 ꢃ 15.03
72.33 ꢃ 14.22
109.28 ꢃ 20.53
107.85 ꢃ 12.91**
124.20 ꢃ 7.74
106.07 ꢃ 13.98
89.0 ꢃ 8.07***
112.31 ꢃ 16.31
106.23 ꢃ 20.93
96.07 ꢃ 7.82
94.44 ꢃ 6.99
77.5 ꢃ 12.66***
105.72 ꢃ 29.27
93.77 ꢃ 17.86
91.42 ꢃ 9.31
101.07 ꢃ 8.98
91.78 ꢃ 23.33**
122.85 ꢃ 8.31
76.90 ꢃ 3.35
10
10
10
10
10
10
10
10
10
6a
6b
6d
6g
6l
6m
6o
6s
100.36 ꢃ 23.30
130.35 ꢃ 29.63
148.35 ꢃ 5.02
107.14 ꢃ 27.28
119.64 ꢃ 20.70
83.89 ꢃ 21.11
98.91 ꢃ 25.37**
100.0 ꢃ 19.61
106.0 ꢃ 23.82
111.4 ꢃ 17.38**
81.89 ꢃ 17.08
95.40 ꢃ 14.41***
100.44 ꢃ 9.79
96.66 ꢃ 10.20
137.5 ꢃ 13.71
80.0 ꢃ 22.74
115.43 ꢃ 13.42
102.43 ꢃ 11.52**
123.21 ꢃ 16.10
124.33 ꢃ 31.17
78.10 ꢃ 25.91***
97.32 ꢃ 20.28
98.0 ꢃ 23.13
a
Values are mean ꢃ SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 and ***p < 0.001 when compared with the vehicle treated group (Dunnett's test).
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Table 3 Anti diabetic effect of test compounds N-(4-bromophenyl)-1-nitro-10H-phenoxazine-3-sulfonamide (6g) and N-(4-hydroxyphenyl)-
1-nitro-10H-phenoxazine-3-sulfonamide (6m)a
Blood glucose (mg dlꢀ1
)
Control
(0.5% gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
Compound 6g
Compound 6m
Time (h)
(10 mg kgꢀ1 b. wt)
(10 mg kgꢀ1 b. wt)
(10 mg kgꢀ1 b. wt)
0
1
2
4
6
8
98.3 ꢃ 6.68
94.4 ꢃ 5.56
89.7 ꢃ 6.10
87.5 ꢃ 9.91
87.5 ꢃ 7.08
96.1 ꢃ 10.55
185.5 ꢃ 10.04
180.8 ꢃ 10.50
173.3 ꢃ 12.86
171.9 ꢃ 7.24
172.5 ꢃ 8.06
178.6 ꢃ 9.45
159.3 ꢃ 11.36
183.8 ꢃ 7.51
165.8 ꢃ 18.12
145.6 ꢃ 13.59**
157.5 ꢃ 8.59
165.6 ꢃ 6.31
172.2 ꢃ 5.46
189.2 ꢃ 6.51
147.2 ꢃ 13.75**
101.9 ꢃ 7.83***
107.5 ꢃ 7.32***
127.2 ꢃ 12.29***
151.9 ꢃ 12.17**
158.6 ꢃ 9.98*
116.4 ꢃ 13.23***
131.4 ꢃ 21.60***
143.3 ꢃ 22.17**
161.4 ꢃ 10.08*
a
Values are mean ꢃ SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 and ***p < 0.001 when compared with the vehicle treated group (Dunnett's test).
Table 4 Anti diabetic effect of N-(4-hydroxyphenyl)-1-nitro-10H-phenoxazine-3-sulfonamide (6m) on different days (sub acute)a
Blood glucose concentration (mg dlꢀ1
)
Control (0.5%
gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
(10 mg kgꢀ1
Compound 6m
(10 mg kgꢀ1
Time (day)
)
)
0
7
14
88.8 ꢃ 6.94
90 ꢃ 10.27
86.1 ꢃ 5.81
173.3 ꢃ 12.86
175.6 ꢃ 9.13
175.8 ꢃ 5.06
101.9 ꢃ 7.83
116.4 ꢃ 13.23
93.3 ꢃ 8.18***
88.3 ꢃ 8.48***
165.8 ꢃ 18.12***
145.6 ꢃ 8.41***
a
Values are mean ꢃ SD, n ¼ 5 in each group, ***p < 0.0001 when compared with the diabetic control group (Dunnett's test).
Table 5 Total cholesterol levels in diabetic rats and normal rats (sub acute study) treated with compound 6ma
Total cholesterol (mg dlꢀ1
)
Control (0.5%
gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
(10 mg kgꢀ1
Compound 6m
Time (day)
)
(10 mg kgꢀ1
)
0
14
51.4 ꢃ 11.46
54.2 ꢃ 10.83
110.7 ꢃ 16.56
120.7 ꢃ 17.2
98.5 ꢃ 11.46
97.8 ꢃ 18.99
57.8 ꢃ 6.87***
59.2 ꢃ 8.96***
a
Values are mean ꢃ SD, n ¼ 5 in each group, ***p < 0.001 when compared with the diabetic control group (Dunnett's test).
which suggests prevention of cellular and tissue damage under weight compared to the diabetic control (Table 8), suggesting its
diabetic conditions as shown in Table 7. protective effect in controlling muscle wasting, i.e. reversal of
The induction of diabetes with streptozotocin (STZ) is asso- gluconeogenesis, and may also be due to better glycemic
ciated with the characteristic loss of body weight which is due to control.
increased muscle wasting26 and loss of tissue proteins. Diabetic
It is well established that glibenclamide causes hypogly-
rats treated with compound 6m showed an increase in body cemia by increasing the secretion of insulin from the existing
Table 6 Serum triglyceride levels in diabetic rats and normal rats (sub acute study) treated with compound 6ma
Serum triglyceride (mg dlꢀ1
)
Control (0.5%
gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
(10 mg kgꢀ1
Compound 6m
(10 mg kgꢀ1
Time (day)
)
)
0
14
60.5 ꢃ 15.36
61.0 ꢃ 11.4
108.1 ꢃ 25.28
117.3 ꢃ 19.64
102.7 ꢃ 18.33
61.0 ꢃ 7.78***
101.6 ꢃ 13.59
63.2 ꢃ 11.24***
a
Values are mean ꢃ SD, n ¼ 5 in each group, ***p < 0.001 when compared with the diabetic control group (Dunnett's test).
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Table 7 SGOT and SGPT levels after 14 days in diabetic rats and normal rats (sub acute study) treated with compound 6ma
Serum SGOT, SGPT levels (U dlꢀ1
)
Control (0.5%
gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
(10 mg kgꢀ1
Compound 6m
Liver transaminase
)
(10 mg kgꢀ1
)
SGOT
SGPT
41.0 ꢃ 4.47
38.4 ꢃ 7.92
86.0 ꢃ 5.47
45.8 ꢃ 5.89***
42.0 ꢃ 7.51***
47.2 ꢃ 5.26***
44.8 ꢃ 5.84***
87.4 ꢃ 10.67
a
Values are mean ꢃ SD, n ¼ 5 in each group, ***p < 0.001 when compared with the diabetic control group (Dunnett's test).
Table 8 Body weights of diabetic rats and normal rats (sub acute study) treated with compound 6ma
Body weight (g)
Control (0.5%
gum acacia)
Diabetic control
(0.5% gum acacia)
Glibenclamide
Compound 6m
Time (day)
(10 mg kgꢀ1
)
(10 mg kgꢀ1
)
0
14
200 ꢃ 25.00
220 ꢃ 44.72
189 ꢃ 36.81
212 ꢃ 22.95
217 ꢃ 28.62
248 ꢃ 17.53**
244 ꢃ 16.85*
242 ꢃ 28.07*
a
Values are mean ꢃ SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 when compared with the diabetic control group (Dunnett's test).
pancreatic b-cells.27 The hypoglycemic effect of 6m is generally 1-nitro-10H-phenoxazine-3-sulfonic acid via 1-nitro-1H-phe-
dependent upon the degree of b-cell destruction. Treatment of noxazine-3-sulfonyl chloride and the synthetic method adopted
moderately diabetic rats with 6m resulted in the stimulation does not require the use of any expensive reagents or catalysts
of b-cells of the islets of Langerhans. Histopathological studies and can be used to prepare a library of compounds. All the
of the pancreas revealed that test compound 6m signicantly synthesized compounds were evaluated for their hypoglycemic,
improved the histological architectures of the islets of Langer- hyperglycemic and oral anti-diabetic activities. Normoglycemic
hans (Fig. 3). Groups treated with 6m showed greater islet and STZ-nicotinamide induced diabetic rats were treated with
persistence and a smaller degree of necrotic changes compared the sulfonamides under investigation at concentrations of
to the untreated STZ diabetic rats.
10 mg kgꢀ1 of body weight and signicant (p < 0.001) reductions
To rationalize the anti-diabetic activity of this class of
molecules we performed in vitro transactivation28 of PPARg with
6m and compared it with the known PPARg specic activator
rosiglitazone. PPARs (a group of nuclear receptor proteins that
function as transcription factors regulating the expression of
genes) play essential roles in the regulation of cellular differ-
entiation and in the development and metabolism (carbohy-
drate, lipid and protein) of higher organisms. PPARg is the
molecular target of antidiabetic drugs such as TZDs (thiazoli-
dinediones). Compound 6m and rosiglitazone showed 15.48 ꢃ
1.32 and 18.5 ꢃ 1.17 [values are expressed as mean ꢃ SD (n ¼ 4)]
fold activation of PPARg respectively when tested at 1.0 mM,
indicating that 6m exerts its anti-diabetic effects through ago-
nising the nuclear receptor. Since PPARg agonists are known to
be cytotoxic to rat primary hepatocytes in a time and dose
dependent manner,29 compound 6m along with rosiglitazone
were tested for cytotoxicity to rat primary hepatocytes. Prelimi-
nary data, i.e. IC50 values of 343 mM for 6 h and 274 mM for 16 h
treatment in the case of compound 6m and 225 mM for 6 h and
165 mM for 16 h treatment in the case of rosiglitazone, indicated Fig. 3 Histology of the pancreas in experimental rats after 14 days of
treatment with 6m (10 mg kgꢀ1). (A) Normal control – presence of
that 6m may have advantages over rosiglitazone.
normal pancreatic islet cells. (B) Diabetic control – degranulated and
In conclusion, we report for the rst time the
design, synthesis and evaluation of a novel series of N-(alkyl/
aryl/heteroaryl)-1-nitro-10H-phenoxazine-3-sulfonamides as
dilated islet cells. (C) Diabetic + glibenclamide (10 mg kgꢀ1) – granu-
lated, absence of dilation and prominent hyperplasticity. (D) Diabetic +
6m (10 mg kgꢀ1 b. wt) granulated pancreatic islets, showing prominent
insulin secretagogues. These compounds were prepared from hyperplasticity.
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in fasting blood glucose levels were observed. In addition,
changes in body weight, serum lipid proles, and SGOT and
SGPT levels were assessed for 14 days. Signicant results were
observed in the estimated parameters when comparing the
diabetic control and normal animals. Of the 21 compounds
N-(4-hydroxyphenyl)-1-nitro-10H-phenoxazine-3-sulfonamide
(6m) exhibited pronounced anti-diabetic activities comparable
to glibenclamide. The histology of the pancreas of test
compound 6m substantiated the cytoprotective action of the
drug. Additionally, the increase in serum insulin levels aer
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BVK thanks UGC, New Delhi, India for the Major Research 14 N. M. Cullinane, H. G. Davey and H. J. H. Padeld, J. Chem.
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