Synthesis and blood glucose lowering activity of some novel benzenesulfonylthiourea derivatives substituted with 4-aryl-1-oxophthalazin- 2(1H)yl-ones

Article abstract of DOI:10.3109/14756366.2013.782300

Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a-q) were synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin- 2(¹H)yl benzenesulfonamides with isothiocyanate in dry acetone over anhydrous K₂CO₃. All the synthesized compounds were characterized on the basis of IR, ¹H NMR, MS data and elemental analysis. These synthesized compounds (2a-q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed modest antihyperglycemic activity.

Full text of DOI:10.3109/14756366.2013.782300

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, 2014; 29(3): 362–366
2014 Informa UK Ltd. DOI: 10.3109/14756366.2013.782300
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ORIGINAL ARTICLE
Synthesis and blood glucose lowering activity of some novel
benzenesulfonylthiourea derivatives substituted with
4-aryl-1-oxophthalazin-2(1H)yl-ones
Shafiya Yaseen, Rafia Bashir, Syed Ovais, Pooja Rathore, Mohammed Samim, and Kalim Javed
Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India
Abstract
Keywords
Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a–q) were
synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin-2(1H)yl benzenesulfonamides
with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were
characterized on the basis of IR, 1H NMR, MS data and elemental analysis. These synthesized
compounds (2a–q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the
glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed
modest antihyperglycemic activity.
Antihyperglycemic, diabetes, phthalazone,
sulfonylthiourea
History
Received 4 February 2013
Revised 26 February 2013
Accepted 26 February 2013
Published online 8 April 2013
Introduction
differing at the para-position of the benzene ring at one nitrogen
residue of the urea moiety. Carbutamide (1-butyl-3-sulfonylurea)
became the first drug in the diabetic therapy later withdrawn due
to its adverse effect on bone marrow. However, this compound
initiated the synthesis of many thousands of analogs. Two
generations have been differentiated among them, according to
their substitution patterns. In contrast to the first generation
(tolbutamide, acetohexamide, tolazamide, chlorpropamide), the
aliphatic side chain is substituted with a cyclohexyl ring in the
second generation (glibenclamide, glipizide, glimepiride) of these
oral hypoglycemic agents.
Side effects of SUs include weight gain9–11 and hypogly-
cemia10,12. Hypoglycemia risk becomes a more important issue as
patients’ overall glucose control approaches the normal range.
During the past several years, the cardiology community has
become disquieted because of the potential effect of SUs on
myocardial ischemic preconditioning13. The actual importance of
this issue in clinical practice remains unclear, but it has likely
been exaggerated.
Obesity and weight gain are also contributors to development
of diabetes and Coronary Heart Disease (CHD). The risk of
diabetes for obese adults can be more than 90-fold the risk for
slender adults. Small increase in physical activity and sustained
weight losses of 5% of initial body weight can reduce risk for
developing diabetes by 58%. Thus, an emphasis on weight
management may be the most important therapeutic task14.
Obesity, the principle cause of type 2 diabetes, remains an
important target for possible drug therapy. It is assumed that
weight loss agents will likely play an increasingly important role
in the future therapy of obese type 2 diabetic patients15.
Chronic diabetes is accompanied by complications, such as
neuropathy, nephropathy, cataracts and retinopathy, which are
practically not controlled by insulin. These complications are
Non-Insulin Dependent Diabetes Mellitus (NIDDM) is a multi-
factorial metabolic disease characterized by abnormalities at
multiple organ sites. These defects include insulin resistance and
insulin deficiency1,2. The former is primarily represented by
decreased insulin-stimulated glucose uptake in skeletal muscle,
augmented endogenous glucose production (predominately in the
liver) and enhanced lipolytic activity in fat3. The latter is an
apparent progressive process with both functional defects in islet
cell function and, eventually, apparent loss of b-cell mass4,5
.
These defects are intimately linked with derangements in one
system exacerbating those in the others6. NIDDM is the most
common form of diabetes constituting nearly 90% of the diabetic
population in any country.
Despite recent advances both in chemistry and molecular
pharmacology of antidiabetic drugs, diabetes still remains as a
life-threatening disease, which tends to spread all over the world.
The clinical profile of diabetic subjects is often worsened by the
presence of several long-term complications, namely neuropathy,
nephropathy, retinopathy and cataract.
Over the last 40 years, oral therapy for type 2 Diabetes
Mellitus (DM) has focused on sulfonylureas (SU) and biguan-
ides7. SU drugs improve glucose levels by stimulating insulin
secretion by the pancreatic b-cells8. The SU were discovered
accidentally; some sulfonamides were demonstrated to induce
hypoglycaemia in experimental animals. This observation led to
the development of a group of substituted arylsulfonylureas
Address for correspondence: Dr Kalim Javed, Department of Chemistry,
Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi
110 062, India. E-mail: kjaved@jamiahamdard.ac.in; kjavedchem@
yahoo.co.in

DOI: 10.3109/14756366.2013.782300
Benzenesulfonylthiourea derivatives
363
considerately caused by an accumulation of sorbitol, which is In addition, insulin has an inhibitory action on 3-hydroxy-3-
produced from glucose by Aldose Reductase (AR) in polyol methyl glutaryl Co A (HMG- Co A) reductase, a key rate-limiting
pathway. AR converts glucose to sorbitol only at high glucose enzyme responsible for the metabolism of cholesterol-rich LDL
levels in plasma and tissue in diabetes. The difficulty in obtaining particles22. Recently two compounds derived from phthalazones
normalization of blood glucose values has underlined the have been reported as HMG- Co A reductase inhibitors23.
importance of the search for new and effective Aldose Azelastine, a phthalazone derivative, has shown the best plasma
Reductase Inhibitors (ARIs) to control the consequences of glucose lowering activity as well as vasorelaxant activity24.
elevated glucose levels and thereby delaying the onset and
Since the phthalazone nucleus have been reported to have
retarding the progression of diabetic complications, such as lipid lowering and AR inhibitory activity, it was considered to
neuropathy, nephropathy, retinopathy and cataract. A large synthesize SU substituted with 4-aryl-1-oxophthalazin-2(1H)yl-
number of AR inhibitors have been prepared synthetically and ones (Figure 1).
some of them are used therapeutically16. Recently compounds
In the present study, 17 new target compounds (2a–q) were
containing pyridazine nucleus have been reported as AR inhibi- synthesized by condensing appropriate 4-aryl-1-oxophthalazin-
tors17–19. Zopolrestat is a phthalazinone derivative that has been 2(1H)yl benzenesulfonamides with isothiocyanate (Scheme 1) and
in clinical trials; it inhibits AR and has potential use in the these compounds were assessed for oral antihyperglycemic effects
prevention of retinopathy, neuropathy and cataract formation in in glucose-fed hyperglycemic normal rats.
diabetes20.
The levels of serum lipids are usually elevated in DM and such
Experimental
an elevation represents a risk factor for CHD21. The abnormal
high level of serum lipids is mainly due to the uninhibited actions
of lipolytic hormones on the fat depots mainly due to the action of
insulin, since under normal circumstances, insulin activates the
enzyme lipoprotein lipase, which hydrolyses triglycerides.
However, in diabetic state, lipoprotein lipase is not activated
due to insulin deficiency resulting in hypertriglyceridaemia21.
Melting points were determined by open capillary tubes and
are uncorrected. Infrared (IR) spectra were recorded (in KBr) on a
BIO-RAD FTS-135 spectrophotometer (Waltham, MA) and ꢀmax
1
values are given in cmꢀ1. H NMR spectra were recorded on a
Bruker Spectrospin DPX 300-MHz/400-MHz spectrometer
¨
(Fallanden, Switzerland) using deuterated DMSO or CDCl3 as
Br
O
HOOC
26
O
Ponalrestat: acts as a potent
N
N
N N
F
20
Zopolrestat: An AR inhibitor
HOOC
S
N
S
O
F
F
N
SO2NHCNH2 R2
F
N
R1
Target compounds (2a-q)
O
O
N
N
R'
SO2NHCNH
R''
Cl
N
Clinically used antidiabetic SU
R'
H3C
R''
Azelastine: plasma glucose
lowering activity
24
CH3
C4H9
Tolbutamide
Chlorpropamide
Cl
C3H7
Acetohexamide
CH3CO
C6H11
Tolazamide
CH3
N
Gliclazide
CH3
N
C6H11
CONHCH2CH2
Glibenclamide
Figure 1. Structure of biologically active agent of benzenesulfonylthiourea’s as blood glucose lowering and rationally designed template for targeted
compound.

364 S. Yaseen et al.
J Enzyme Inhib Med Chem, 2014; 29(3): 362–366
NH2.HCl
HN
Ar
O
O
O
S O
N
O
N
O
NH2
a
Ar
Ar
H
O
OH
b
Aromatic hydrocarbon
O
O S
O
Phthalic anhydide
NH2
1a-k
c
Ar
N
O
N
O S OH
HN
N
C
S
R1
2a-q
Scheme 1. Reagents and conditions: (a) anhydrous AlCl3, room temperature; (b) absolute alcohol, reflux; (c) isothiocyanate, K2CO3, dry acetone, reflux
24–72 h. 1a, 2a, 2f, 2j, 2o: Ar ¼ Phenyl; 1b, 2b, 2g, 2k, 2p: Ar ¼ 4-Methylphenyl 2a–2e:R1 ¼ –CH2C6H5; 1c, 2c, 2h, 2l: Ar ¼ 4-Chlorophenyl; 1d, 2d, 2i,
2m, 2q: Ar ¼ 4-Chloro-3-methylphenyl; 1e, 2e, 2n, 2k: Ar ¼ 2-Chloro-5-methyl; 2f–2i: R1 ¼ –C3H7; 2j–2n: R1 ¼ –C4H9; 2o–2q: R1 ¼ –C6H11
.
solvent and tetramethyl silane (TMS) as an internal standard. and 2892 (NH of thiouriedo group), 1570 (C¼S of thiourea),
Chemical shifts are given in ꢁ (ppm) scale and coupling constants (J 1664 (cyclic carbonyl), 1592 (C¼N), 1340 and 1134 cmꢀ1
values) are expressed in Hertz. Mass spectra (MS) were scanned by (SO2N). 1H NMR (300 MHz, DMSO, ꢁ): 4.52 (2H, d,
using ESI Bruker Esquire 3000 (Billerica, MA). The m/z values of J ¼ 6.3 Hz, ꢀCH2 of benzyl unit), 7.16–7.29 (5H, m, benzyl
the more intense peaks are mentioned. Purity of the compounds was unit protons), 7.58–7.98 (13H, m, H-40, H-30, H-50, H-20, H-60,
checked on TLC plates (silica gel G), which were visualized by H-6, H-7, H-8/H-5, NHCSNHCH2, H-300, H-500, H-200, H-600),
exposing to iodine vapors. Elemental analysis was carried out on a 8.46–8.47 (1H, m, H-5/H-8). ESI-MS (m/z): 526 [Mþ], 527
CHNS Elementar (Vario EL III, Hanau, Germany).
[Mþ þ 1]. Anal. Calcd. for C28H22N4O3S2; C ¼ 63.86,
H ¼ 4.21, N ¼ 10.64, S ¼ 12.18. Found: C ¼ 63.88, H ¼ 4.18,
N ¼ 10.60, S ¼ 12.16.
General procedure for the synthesis of sulfonylthioureas
(2a–q)
N-(benzylcarbamothioyl)-4-(1-oxo-4-p-tolylphthalazin-2(1H)-
yl)benzenesulfonamide (2b)
A solution of appropriate 4-arylphthalazone (1 mmol) in dry
acetone was refluxed over anhydrous K2CO3 for 1–1.5 h. At
this temperature, a solution of isothiocyanate (1.2 mmol) in dry
acetone of 5 mL was added in a drop-wise manner. Refluxing was
continued for 24–72 h. On completion of the reaction, acetone was
removed by distillation method under reduced pressure and the
residue was suspended in water. The suspension was acidified
with acetic acid. It was filtered, washed and dried residue was
crystallized by ethyl alcohol.
Yield ¼ 72%, m.p. 218–219 ꢁC, Rf ¼ 0.46 (toluene:ethyl acet-
ate:formic acid, 7.5:2:0.5). IR umax (KBr, in cmꢀ1): 3358 and
2853 (NH of thiouriedo group), 1503 (C¼S of thioureido group),
1656 (cyclic C¼O), 1591 (C¼N), 1372 and 1137 cmꢀ1 (SO2N).
1H NMR (400 MHz, CDCl3, ꢁ): 2.45 (3H, s, CH3), 4.52 (2H, s,
ꢀCH2 of benzyl unit), 7.13–7.19 (5H, m, benzyl unit protons),
7.25 (2H, d, J ¼ 6.8 Hz, H-30, H-50), 7.45 (2H, d, J ¼ 7.2 Hz, H-20,
H-60), 7.63–7.89 (8H, m, H-6, H-7, H-8/H-5, H-300, H-500, H-200,
H-600 and NHCSNHCH2), 8.59 (1H, s, H-5/H-8). ESI-MS (m/z):
541[Mþ þ 1], 563 [Mþ þ Na]. Anal. Calcd. for C29H24N4O3S2;
C ¼ 64.42, H ¼ 4.47, N ¼ 10.36, S ¼ 11.86. Found: C ¼ 64.44,
H ¼ 4.44, N ¼ 10.37, S ¼ 11.85.
N-(benzylcarbamothioyl)-4-(1-oxo-4-phenylphthalazin-2(1H)-
yl)benzenesulfonamide (2a)
Yield ¼ 25%, m.p. 231–232 ꢁC, Rf ¼ 0.30 (toluene:ethyl acet-
ate:formic acid, 7.5: 2: 0.5). IR umax (KBr, in cmꢀ1): 3368

DOI: 10.3109/14756366.2013.782300
Benzenesulfonylthiourea derivatives
365
Table 1. Antihyperglycemic activity of SU derivatives (2a–q) and the
standard drug gliclazide in glucose-fed (3g/kg) hyperglycemic normal
rats.
N-(benzylcarbamothioyl)-4-(4-(4-chlorophenyl)-1-oxophthalazin-
2(1H)-yl)benzenesulfonamide (2c)
Yield ¼ 40%, m.p. 204–206 ꢁC, Rf ¼ 0.66, (toluene:ethyl acet-
ate:formic acid, 7.5:2.0:0.5). IR umax (KBr, in cmꢀ1): 3342 and
2862 (NH of thioureido group), 1531 (C¼S of thiourea), 1662
(cyclic carbonyl), 1584 (C¼N), 1382 and 1106 (SO2N). 1H NMR
(400 MHz, DMSO, ꢁ): 4.64 (2H, d, J ¼ 5.1 Hz, –CH2 of benzyl
unit), 7.07–7.21 (5H, m, benzyl unit protons), 7.50 (2H, d,
J ¼ 8.4 Hz, H-30, H-50), 7.61 (2H, d, J ¼ 8.0 Hz, H-20, H-60), 7.69–
7.72 (1H, m, H-8/H-5), 7.79–7.87 (2H, m, H-6, H-7), 7.89 (2H, d,
J ¼ 8.8 Hz, H-300, H-500), 7.96 (2H, d, J ¼ 8.0 Hz, H-200, H-600),
8.45 (1H, ortho–meta coupled dd, J ¼ 3.2 Hz, J ¼ 5.6 Hz, H-5/H-
8), 8.58–8.59 (1H, m, NHCSNHCH2 protons). ESI-MS (m/z):
562[Mþ þ 2]. Anal. Calcd. for C28H21ClN4O3S2; C ¼ 59.94,
H ¼ 3.77, N ¼ 9.99, S ¼ 11.43. Found: C ¼ 60.00, H ¼ 3.75,
N ¼ 10.00, S ¼ 11.43.
Treatment
Dose per kg b.w. (mg)
% Activity
Significance
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
4.79
8.57
4.61
6.22
11.66
16.0
9.05
11.44
3.27
1.0
1.92
8.40
17.53
9.25
11.09
3.18
12.18
35.0
p50.05
p50.05
p40.05
p50.05
p40.05
p50.05
p50.05
p50.05
p40.05
p50.05
p50.05
p40.05
p50.01
p40.05
p50.05
p40.05
p40.05
p50.01
The characterization data of compounds (2d–q) can be
obtained online as supplementary data.
2p
2q
Effect of synthesized compounds on oral glucose
tolerance in normal rats
Gliclazide
Albino rats (either sex) of Wistar strain weighing 150–200 g were
fasted overnight and divided into groups of six animals each.
Animals of group I received only vehicle (10 ml/kg) orally to
serve as control, while animals of group II were given gliclazide
20 mg/kg orally, suspended in the vehicle (10 ml/kg). The test
compounds in the dose of 20 mg/kg suspended in the vehicle
(10 ml/kg) were administered orally to respective groups. All the
animals were given glucose (3 g/kg, p.o.) 30 min after dosing.
Blood samples were collected from retro-orbital plexus just prior
to and 60 min after the glucose loading and blood glucose levels
were measured with an autoanalyzer by using AccuCheck
Advantage II glucose kit (Roche, West Sussex, UK).
positive control. Quantitative glucose tolerance of each animal
was calculated by the area under curve (AUC) method by using
the Prism software (Irvine, CA). Comparing AUC of experimental
and control groups determined the percentage of antihypergly-
cemic activity. Samples showing significant inhibition (p50.05)
were considered as active samples. Statistical comparison was
made by Dunnett’s test.
The results showed that two compounds namely 2f and 2m
were found to be in abundance. The compounds 2f and 2m
significantly inhibited the rise in postprandial hyperglycemia to
the tune of 16.0% (p50.05) and 17.53% (p50.01), respectively.
The standard drug Gliclazide caused nearly 35% (p50.01)
inhibition. With regard to the SAR, it seems impossible to extract
an obvious structure–activity relationship from the data shown in
Table 1.
Results and discussion
Synthesis of compounds
The synthetic route used to synthesize title compounds (2a–q) is
outlined in Scheme 1. The 4-aryl-phthalazone-substituted benze-
nesulfonamide derivatives (1a–k) synthesized through reported
method25 were converted to SU by refluxing with appriopriate
isothiocyanates in dry acetone containing K2CO3. Purity of the
compounds was checked on TLC plates (Merck, Darmstadt,
Germany) (silica gel G) which were visualized by exposing to
iodine vapors.
Supplementary material
The characterization data of compounds (2d–q) can be obtained
online as supplementary data. Supplementary data associated with
this article can be found, in the online version.
Acknowledgements
Thanks are due to IIM Jammu for providing Mass spectra.
Structures of the synthesized compounds (2a–q) were estab-
lished on the basis of elemental analysis and various spectroscopic
1
methods, viz. IR, H NMR and MS. Elemental analysis (C, H, N
Declaration of interest
and S) data were within ꢂ0.4% of the theoretical values. In the IR
spectra of 2a–q three bands characteristic of SU moiety out of
which one band for thioureido group at (1503–1570 cmꢀ1) and
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
One of the authors, Shafiya Yaseen is thankful to DST for INSPIRE
fellowship.
two bands for NH at (3320–3371 cmꢀ1 and 2850–2960 cmꢀ1
)
were obꢀse1rved. Apart from these a band in the region 1578–
1594 cm corresponding to C¼N stretching, a band at 1647–
1712 cmꢀ1 for cyclic carbonyl group (C¼O) and two bands at
1340–1387 and 1080–1183 cmꢀ1 for 4SO2NH group were also
observed. The structure was further established by proton NMR
spectral data. The H-5/H-8 proton of phthalazone ring appeared in
the NMR spectra at ꢁ 8.41–8.62.
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