Synthesis and carbonic anhydrase inhibitory effects of novel sulfamides derived from 1-aminoindanes and anilines

Article abstract of DOI:10.1002/ardp.201400257

Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3CO2H afforded

Full text of DOI:10.1002/ardp.201400257

950
Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Full Paper
Synthesis and Carbonic Anhydrase Inhibitory Effects of Novel
Sulfamides Derived from 1-Aminoindanes and Anilines
Yusuf Akbaba1,2, Enes Bastem2, Fevzi Topal2,3, Ilhami Gülçin2,4, Ahmet Maraş2*,
_
and Süleyman Göksu2
1
Department of Basic Sciences, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey
Department of Medical Services and Techniques, Vocational School of Health Services, Gumushane
2
3
University, Gumushane, Turkey
Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
4
Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to
give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the
Boc group of the carbamates with CF3CO2H afforded seven novel sulfamides. Human carbonic anhydrase
(hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-
step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the
novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl
acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines
effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the
novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (Ki: 153.88 nM), while
sulfamide derivative 26 showed the highest inhibitory potential against hCA II (Ki: 117.80nM).
Keywords: Aminoindane / Aniline / Carbonic anhydrase / Enzyme inhibition / Sulfamide / Sulfamoyl carbamate
Received: June 30, 2014; Revised: August 6, 2014; Accepted: August 15, 2014
DOI 10.1002/ardp.201400257
Introduction
systems of organisms all over the phylogenetic tree. Its
reaction with water is a slow process at the physiological pH
(7.4). It needs the presence of a catalyst to become effective.
These catalysts are the carbonic anhydrase (CA, EC 4.2.1.1)
enzymes, a superfamily of metal containing enzymes [11–13].
The active site of majority of carbonic anhydrases contains a
zinc ion. Therefore they are called as metalloenzymes. CA
catalyses the hydration of carbon dioxide (CO2) and the
dehydration of carbonic acid (H2CO3), rapidly [14–16].
Sulfamides are interesting compounds in the field of synthetic
organic chemistry and medicinal chemistry [1, 2]. Some drugs,
such as an injectable antibiotic doripenem (1) [3], dopaminer-
gic and anti-hyperprolactinemic agent quinagolide (2) [4], and
anticonvulsant 3 (JNJ-26990990) [5] contain sulfamide func-
tional group in their structures. For this reason, the synthesis
and the biological evaluation of novel sulfamides attract more
attention on the scientific arena. For example, HIV-I protease
inhibitory properties of 4 [6], b-secretase 1 inhibition of 5 [7]
and carbonic anhydrase inhibitory activity of 6–7 [8, 9] have
been reported (Fig. 1). In addition, there are numerous reports
suggesting significant biological activities of the similar kind
of compounds in the literature [10].
CA
CO2 þ H2O , H2CO3 , HCOꢀ3 þ Hþ
CA is one of the fastest enzymes. Typical catalytic rates of
the different isoforms of CA are in the range of 104 and 106
reactions per second [17]. CA isoenzymes are found in Archaea,
prokaryotic and eukaryotic cells, and codified five distinct
unrelated gene families. These distinct CA families are a-, b-, g-,
and d-CAs. There is no significant amino acid sequence
similarity in these families. Mammals, including humans,
Carbon dioxide (CO2) is a naturally occurring chemical
compound. It is a fundamental chemical in various biological
Correspondence: Prof. Süleyman Göksu, Department of Chemistry,
Faculty of Science, Ataturk University, 25240 Erzurum, Turkey.
E-mail: sgoksu@atauni.edu.tr
Fax: þ90 442 2360948
ꢁAdditional correspondence: Assoc. Prof. Ahmet Maraş,
E-mail: amaras@atauni.edu.tr
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides
951
OH
O
N
O
O
H
H
H
N
S
N
S
NH2
O
S
O
O
S
O
H
N
N
O
NH2
H
H
HO
N
H
N
H
OH
S
1
3
2
O
S
O
F
HN
N
O
O
S
N
N
Ph
Ph
O
S
H
N
N
X
NH2
HO
OH
Ph
O
6 X=H
4
5
7
X=OMe
Figure 1. Some selected drugs 1–3 and
biologically active sulfamides 4–7.
possess only a-CAs, which is the first family of the CAs. Up to
now sixteen different isozymes have been characterized. Of
these, CA I, II, III, VII and XIII are cytosolic isozymes. Besides
that, CA IV, IX, XII and XIV are membrane bound ones. Both of
CA VA and VB are mitochondrial isoforms. CA VI is solely
secreted isoenzyme. In addition, there are three acatalytic
forms, which are called as CA-related proteins (CARPs). The
CARPs and their functions remain unclear [18–20]. This CA
family has different subcellular locality and tissue dispersion
[21]. The namely CARP VIII, X and XI are the only known CARPs
[11]. Nevertheless, CARP VIII can be turned into a functional CA
by site-specific mutagenesis [22]. On the other hand, it has been
reported that CA inhibitors (CAIs) have been extensively used
for the management of altitude sickness [11], treatment of
glaucoma, epilepsy, and obesity [23].
convenient methods for the conversion of secondary alcohols
to their azide derivatives [26, 27]. Specifically, the reactions of
benzylic secondary alcohols with diphenylphosphoryl azide
(DPPA) in the presence of DBU, also known as Mitsunobu
reaction, are widely used for the synthesis of benzyl azides [28].
Applying the same procedure as discussed before to 8 afforded
azide 9 which was converted to amine hydrochloride salt 10
via Pd-C catalysed hydrogenation in methanol (MeOH)–
chloroform (CHCl3). Generally, CHCl3 is used for in situ
production of HCl and converting amines to amine hydro-
chloride salts for easy crystallization, purification, and
convenient storage [29]. Hydrochloride 11 was synthesized
as described by Coutts and Malicky [30]. The amine hydro-
chlorides 10 and 11 were reacted with 10% NaOH to give
amines 12 and 13 (Scheme 1).
In our on-going researches on the synthesis and biological
evaluation of novel sulfamide compounds, we have already
addressed CA I and II inhibition properties of some the
sulfamides synthesized from amino indanes [2], amino-
tetralins [24], and dopamine related compounds [12]. The
results concluded from these investigations encouraged us on
the synthesis of novel compounds and evaluate them for their
CA I and II inhibitory properties. In this context, in the present
work, we have synthesized and evaluated the CA I and CA II
inhibitory actions of some novel sulfamide carbamates and
sulfamides derived from methoxylated 1-aminoindanes and
anilines. From the biological results, our second goal was to
make a comparison about the structure activity relationships
between two different series of compounds, viz. sulfamoyl
carbamates and sulfamides.
On the other hand, amine 14 was synthesized according to
the procedure described in the literature [31]. The reactions of
1 equivalent amines 12–14 and 1.2 equivalent benzyl alcohol
OMe
OMe
OMe
OH
N3
NH3Cl
i
ii
77%
77%
Br
8
Br
9
10
OMe
OMe
R
NH2
NH3Cl
iii
90%
R
12
Results and discussion
10
R=H
R=H
13 R=OMe
11 R=OMe
Chemistry
Scheme 1. The synthesis of amines 12 and 13. Reagents and
conditions: (i) DPPA, DBU/THF, 0–25°C. (ii) H2/Pd-C, MeOH-
CHCl3, 25°C. (iii) 10% NaOH, MeOH, 0–25°C.
The synthesis of alcohol 8 was performed as described by Ling
et al. [25]. The Mitsunobu reaction is one of the most
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952
Y. Akbaba et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
(BnOH) with chlorosulfonyl isocyanate (CSI) yielded new
sulfamoyl carbamates 15–17. Pd-C catalysed hydrogenolysis of
carbamates yield amine related compounds [32]. Therefore,
Pd-C catalysed hydrogenolysis of compounds 15–17 in MeOH
furnished the title compounds novel sulfamides 18–20 with
72–78% yields (Scheme 2).
In addition, sulfamide carbamates can be easily prepared
from amines, tert-BuOH and CSI [12]. Hence, commercially
available methoxylated anilines 21–24 and 1.2 equiv. tert-
BuOH were reacted with CSI to give sulfamide carbamates 25–
28 with the yields ranging from 72–81%. Deprotection of Boc
group with CF3CO2H is a useful method in the synthesis of
target compounds [33]. Therefore, the reactions of carbamates
25–28 with CF3CO2H produced the title compounds 29–32
in high yields (Scheme 3). The chemical structures of all
newly synthesized compounds were characterized by spectro-
scopic techniques, such as 1H- and 13C NMR, IR, and elemental
analysis.
aromatic, heterocyclic and inorganic sulfonamides as well as
by metal complexing sulfonamides. The CAIs are regularly
used for the treatment of elevated intracranial pressure in
Pseudotumor cerebri and increased intraocular pressure in
glaucoma while reducing the production of cerebrospinal
fluid and aqueous humour, respectively [37]. The aromatic
sulfonamides are classical CA inhibitors. Also, several potent
sulfonamides have been reported as potential antitumor [38].
CAIs have a large number of applications in therapy, such as
diagnostic tools and antiepileptics [39]. They are also used in
the treatment of other neurological disorders [40].
In our previous studies, the synthesis of (3,4-dihydroxy-
phenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives
[41], novel sulfamides [2], novel sulfonamide derivatives of
aminotetralins and aminoindanes [28], novel benzylamine
derivatives [42], sulfamide and sulfonamide analogues of
dopamine related compounds [12, 43], sulfamides and
sulfonamides incorporating tetralin scaffold [24] and bromo-
phenols derivatives [44, 45] have been described as novel
therapeutics. These newly synthesised compounds exhibited
hCA I and II inhibition in the range between micromolar and
nanomolar affinities. To continue our research on hCA
inhibitors, sulfamide carbamates 15–17, 25–28, and sulf-
amides 18–20, 29–32 were synthesized and investigated for
their effects against hCA I and II isoforms. Therefore, at first,
the inhibition effects of investigated compounds on hCA I
and II were defined by drawing Lineweaver-Burk charts.
Carbonic anhydrase inhibitory properties
CA isozymes play vital physiological functions, such as
respiration and acid-base balance, bone resorption, electrolyte
secretion, calꢀcification, and biosynthetic reactions, which
require HCO3 as a substrate, in all organisms [34, 35]. The
majority of CA isozymes constitute targets for the design and
development of CA inhibitors for clinical practices [36]. It is
well known that CA isozymes are effectively inhibited by
O
S
O
O
O
S
O
H
N
R3
R3
HN
NH
NH2
R3
NH2
OCH2Ph
ii
i
R2
R2
R2
R1
R1
R1
18 R1=R2=H, R3=OMe, 78%
15 R1=R2=H, R3=OMe, 62%
16 R2=H, R1=R3=OMe, 62%
12 R1=R2=H, R3=OMe
13 R2=H, R1=R3=OMe
19 R2=H, R1=R3=OMe, 72%
20
R1=R3=H, R2=OMe, 78%
17
R1=R3=H, R2=OMe, 60%
14
R1=R3=H, R2=OMe
Scheme 2. The synthesis of sulfamides 18–20. Reagents and conditions: (i) CSI, PhCH2OH/NEt3, CH2Cl2, 0–25°C. (ii) H2/Pd-C, MeOH,
25°C.
R1
R1
R4
R1
R4
O
S
O
O
S
O
O
H
N
H
N
H
N
R2
R3
NH2
R2
R3
R2
R3
NH2
ii
i
O
R4
21 R2=R4=H, R1=R3=OMe
22 R1=R3=H, R2=R4=OMe
25 R2=R4=H, R1=R3=OMe, 81%
26 R1=R3=H, R2=R4=OMe, 78%
29 R2=R4=H, R1=R3=OMe, 85%
30 R1=R3=H, R2=R4=OMe, 82%
23
27
31
R2=R3=H, R1=R4=OMe, 72%
R2=R3=H, R1=R4=OMe
R2=R3=H, R1=R4=OMe, 72%
24 R1=H, R2=R3=R4=OMe
Scheme 3. The synthesis of sulfamides 29–32. Reagents and conditions: (i) CSI, t-BuOH/NEt3, CH2Cl2, 0–25°C. (ii) TFA, CH2Cl2, 0–25°C.
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28 R1=H, R2=R3=R4=OMe, 75%
32 R1=H, R2=R3=R4=OMe, 70%

Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides
953
Then, half maximal inhibitory concentrations (IC50) and the
mean inhibitory constant (Ki) values were calculated for
synthesized compounds based on the drawn charts (Table 1).
IC50 was used for measurement of the effectiveness of novel
sulfamide carbamates and sulfamides in inhibiting both
hCA isoenzymes.
OCH3
H3CO
H
O
Thr 200
In the first stage, we determined the inhibition effects of
the carbamates 15–17, 25–28, and sulfamides 18–20, 29–32 on
the esterase activity of the cytosolic isoform hCA I and the
physiologically dominant isoform CA II. The inhibition results
are summarized in Table 1. It is well known that the active site
of both CA isoenzyme inhibitors coordinate to the zinc ion.
Among the investigated synthesized compounds, the com-
pound 17 demonstrated to be an effective inhibitor of cytosolic
isoenzyme hCA I (Table 1) with a Ki of 153.88 ꢂ 04.01 nM. On
the other hand, compound 26 showed the highest inhibitory
activity on physiological dominate hCA II isoenzyme with Ki of
117.80 ꢂ 17.87 nM. Also, the rest of sulfamides displayed
moderate activity against cytosolic isoenzyme hCA I with Ki,
which ranged from 169.58 ꢂ 06.40 to 440.97ꢂ 16.28 nM,
and on hCA II with Ki in the range of 158.91 ꢂ 03.77–
O
NH-
S
NH
O
O
O
-HN
O
O
Thr 199
N
C
HO
His94
His119
His94
Figure 2. The proposed binding model of sulfamide 26 to CA by
anchoring to the Zn2þ coordinated water/hydroxide ion (–OH).
1070.25 ꢂ 43.15 nM, respectively. The chemical structure of Conclusion
sulfamide 26, the most powerful HCA II isoenzyme inhibitor, is
shown in Fig. 2, as well as an estimated binding model of this
compound to the active site of CA. Two hydrogen bonds have
been modelled between the amide groups of sulfamide 26 and
hydroxyl groups of Thr-199 and Thr-200 amino acid residues
that are universally conserved in CAs.
Many inhibitors have been designed, developed, and
synthesized for CA isoenzymes including CA I and II in the
literature. Extensive researches on this issue continue to find
novel applications for the widespread CAs inhibitors.
In conclusion, we report the first synthesis of sulfamides,
18–20 and 29–32 from 1-aminoindanes 12–14 and anilines
21–24. As carbamates and sulfamides are biologically active
compounds and some of them are used in the treatment of
some diseases. With this regard, our synthesized sulfamide
carbamates 15–17 and 25–28 and sulfamides 18–20 and
29–32 hold a promise to be further developed as novel
drugs. Further, our synthesized compounds showed inhibi-
tory potential against the hCA I and II isoforms in the
nanomolar range. These results and findings point out that
synthesized novel sulfamide carbamates and sulfamides
may be used as potent hCA isoenzyme inhibitors and can be
potential candidates for treatment of glaucoma, epilepsy,
and obesity.
Table 1. Human carbonic anhydrase isoenzymes (hCA I and hCA
II) inhibition values of some novel sulfamides (15–31) by an
esterase bioassay with NPA as substrate.
IC50 (nM)
Ki (nM)
Experimental
Compounds hCA I hCA II
hCA I
hCA II
All chemicals and solvents are commercially available and
they were used without purification or they were used after
distillation and treatment with drying agents. Melting points
were determined on a capillary melting apparatus (BUCHI 530)
and are uncorrected. IR spectra were obtained from solutions in
0.1 mm cells with a Perkin–Elmer spectrophotometer. The 1H-
and 13C NMR spectra were recorded on Varian and Bruker
spectrometers at 400 and 100 MHz, respectively, and NMR shifts
are presented as d in ppm. The tetramethylsilane was used as an
internal standard. Elemental analyses were performed on a
Leco CHNS-932 apparatus. All column chromatography was
performed on silica gel (60-mesh, Merck). PLC is preparative
thin-layer chromatography: 1 mm of silica gel 60 PF (Merck) on
glass plates.
15
16
17
18
19
20
25
26
27
28
29
30
31
234.20 183.86 321.88 ꢂ 10.52
228.26 184.26 271.05 ꢂ 11.62
262.50 196.04 153.88 ꢂ 04.01
388.89 270.07 440.97 ꢂ 16.28
523.52 266.74 337.81 ꢂ 11.99
410.54 410.54 360.94 ꢂ 17.42
337.55 207.42 424.83 ꢂ 14.69
224.56 159.20 262.22 ꢂ 12.39
294.14 151.00 233.97 ꢂ 06.42
359.44 220.28 335.14 ꢂ 11.85
497.13 259.64 380.15 ꢂ 09.54
297.83 ꢂ 14.22
352.96 ꢂ 16.81
306.83 ꢂ 13.51
219.41 ꢂ 03.61
191.00 ꢂ 10.48
246.15 ꢂ 05.03
158.91 ꢂ 03.77
117.80 ꢂ 17.87
211.52 ꢂ 04.16
173.32 ꢂ 03.17
496.31 ꢂ 13.91
146.94 256.76 174.53 ꢂ 08.04 1070.25 ꢂ 43.15
226.39 200.63 169.58 ꢂ 06.40 331.31 ꢂ 21.75
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954
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Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Chemistry
evaporated. Oily aminoindane 12 (1.47 g, 90% yield) was
synthesized and used without further purification and charac-
terization, in the next step.
The syntheses of alcohol 8 [25], hydrochloride 11 [30], and amine
14 [31] were performed as described earlier.
Compound 13 was also synthesized by the same procedure.
Synthesis of 1-azido-4-bromo-7-methoxyindane (9) and
afterwards
Standard procedure for the synthesis of benzyl
sulfamoylcarbamates: Synthesis of benzyl N-(7-methoxy-
Alcohol 8 (2.00 g, 8.23 mmol) was dissolved in dry THF (100 mL).
Diphenylphosphoryl azide (DPPA; 2.71 g, 9.84 mmol) and DBU
(1.49 g, 27.68 mmol) were added to this solution at 0°C under N2
(g). The mixture was stirred for 2 h at the same temperature, then
for 12 h at 25°C. The solvent was evaporated followed by the
addition of 80 mL of dichloromethane (CH2Cl2) and 30 mL of 10%
hydrochloric acid (HCl) to the residue. The organic phase was
separated and washed with 10% HCl (2 ꢃ 20 mL). Organic layer
was dried over Na2SO4 and the solvent was evaporated. The
column chromatography of the residue on silica gel (30 g) with
10% EtOAc/hexane gave colourless oily azide 9 (1.70 g, 77% yield).
1H NMR (400 MHz, CDCl3): d 7.39 (d, 1H, J ¼ 8.6 Hz, Ar-H), 6.66 (d,
1H, J ¼ 8.6 Hz, Ar-H), 5.17 (dd, 1H, Ar-H, J ¼ 2.0, 7.5 Hz), 3.85 (s, 3H,
OCH3), 3.10–3.01 (m, 1H, CH), 2.90–2.82 (m, 1H, CH), 2.39–2.30 (m,
1H, CH), 2.14–2.05 (m, 1H, CH). 13C NMR (100 MHz, CDCl3): d 156.3
(C), 146.3 (C), 133.4 (CH), 130.2 (C), 110.9 (CH), 110.7 (C), 65.0 (CH),
55.8 (OCH3), 32.8 (CH2), 31.8 (CH2). IR (CH2CI2, cmꢀ1): 3393, 3047,
2935, 1734, 1600, 1435, 1319, 1266, 1074, 1054. Anal. calcd. for
(C10H10BrN3O): C, 44.80; H, 3.76; N, 15.67. Found: C, 44.80; H, 3.75;
N, 15.70.
2,3-dihydro-1H-inden-1-yl)sulfamoyl carbamate (15)
Benzylalcohol (0.93 g, 8.58 mmol) was added to a solution of CSI
(0.87 g, 6.13 mmol) in CH2Cl2 (10 mL) at 0°C. A solution of amine
12 (1.00 g, 6.13 mmol) in CH2Cl2 (30 mL) and NEt3 (0.68 g,
6.74 mmol) were added to the solution of CSI drop wise and
stirred at 0°C for 1 h, then at RT for 3 h. The reaction mixture
was cooled to 0°C and a solution of 0.1 N HCl (50 mL) was added
to this mixture. Organic phase was separated and H2O phase
was extracted with H2Cl2 (2 ꢃ 25 mL). Combined organic layers
were dried over Na2SO4. The solvent was evaporated. Column
chromatography of the residue on silica gel (30 g) with 30%
EtOAc/hexane yielded carbamate 15 (1.44 g, 62% yield). White
solid. Mp: 133–135°C. 1H NMR (400 MHz, CDCl3): d 7.7 (bs, 1H, NH),
7.34 (bs, 5H, Ar-H), 7.14 (t, 1H, Ar-H, J ¼ 7.9 Hz), 6.86 (d, 1H, Ar-H,
J ¼ 7.9 Hz), 6.70 (d, 1H, Ar-H, J ¼ 7.9 Hz), 5.72 (d, 1H, NH, J ¼ 4.1 Hz),
5.18 (s, 2H, CH2), 4.99–4.94 (m, 1H, NCH), 3.74 (s, 3H, OCH3), 3.08–
3.02 (m, 1H, CH), 2.84–2.76 (m, 1H, C–H), 2.45–2.36 (m, 1H, C–H),
2.30–2.20 (m, 1H, C–H). 13C NMR (100 MHz, CDCl3): d 156.2 (CO),
151.3 (C), 146.6 (C), 135.0 (C), 130.9 (CH), 128.9 (3CH), 128.5 (2CH),
127.7 (C), 117.7 (CH), 108.6 (CH), 68.5 (OCH2), 58.0 (C–N), 55.4
(OCH3), 33.9 (CH2), 30.8 (CH2). IR (CH2CI2, cmꢀ1): 3275, 2936,
2852, 1732, 1606, 1454, 1267, 1192, 1163, 1057. Anal. calcd. for
(C18H20N2O5S): C, 57.43; H, 5.36; N, 7.44; S, 8.52. Found: C, 57.40;
H, 5.35; N, 7.41; S, 8.49.
1-Amino-7-methoxyindane hydrochloride (10) [46]
Azide 9 (2.00 g, 7.46 mmol) was dissolved in MeOH (50 mL) and
CHCl3 (4 mL) in a 100 mL flask. After addition of Pd-C (50 mg) to
this solution, a balloon filled with H2 gas (3 L) was fitted to the
flask. The mixture was deoxygenated by flushing with H2. After
hydrogenation of the mixture at RT for 20 h, the catalyst was
removed by filtration. Crystallization of the residue with MeOH/
Et2O furnished 10 (1.40 g, 77% yield). White solid. Mp: 221–223°C.
1H NMR (400 MHz, D2O): d 7.26 (t, 1H, Ar-H, J ¼ 7.9 Hz), 6.85 (d, 1H,
Ar-H, J ¼ 7.9 Hz), 6.70 (d, 1H, Ar-H, J ¼ 7.9 Hz), 4.8 (m, 1H, NCH),
3.75 (s, 3H, OCH3), 3.03–3.94 (m 1H, CH), 2.87–2.79 (m 1H, CH),
2.53–2.49 (m 1H, CH), 1.95 (m 1H, CH). 13C NMR (100 MHz, D2O): d
156.4 (C), 146.6 (C), 131.9 (CH), 125.1 (C), 117.6 (CH), 108.9 (CH),
55.4 (CN), 54.2 (OCH3), 30.2 (CH2), 30.0 (CH2).
Carbamates 16 and 17 were also synthesized by the same
method.
Benzyl N-(4,7-dimethoxy-2,3-dihydro-1H-inden-1-yl)-
sulfamoyl carbamate (16)
62% yield. White solid. Mp: 137–139°C. 1H NMR (400 MHz, CDCl3):
d 7.75 (bs, 1H, NH), 7.34 (bs, 5H, Ar-H), 6.72 (d, 1H, A part of AB
system, Ar-H, J ¼ 8.7 Hz), 6.62 (d, 1H, B part of AB system, Ar-H,
J ¼ 8.7Hz,), 5.73 (d, 1H, NH, J ¼ 4.3 Hz), 5.18 (s, 2H, CH2), 4.98–4.94
(m, 1H, NCH), 3.78 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.00–2.92 (m
1H, C–H), 2.80–2.73 (m 1H, C–H), 2.46–2.37 (m 1H, C–H), 2.29–2.21
(m 1H, C–H). 13C NMR (100 MHz, CDCl3): d 151.3 (CO), 150.6 (C),
150.1 (C), 135.0 (C), 134.3 (C), 129.4 (C), 128.92 (2CH), 128.90 (2CH),
128.5 (CH), 111.5 (CH), 109.4 (CH), 68.5 (OCH2), 58.5 (CN), 55.9
(OCH3), 55.7 (OCH3), 33.8 (CH2), 27.7 (CH2). IR (CH2CI2, cmꢀ1):
3275, 2936, 1724, 1607, 1494, 1455, 1193, 1162, 1090, 1056, 1026.
Anal. calcd. for (C19H22N2O6S): C, 56.15; H, 5.46; N, 6.89; S, 7.87.
Found: C, 56.18; H, 5.43; N, 6.90; S, 7.86.
1-Amino-4,7-dimethoxyindane hydrochloride (11)
White solid. Mp: 244–246°C (lit; [24] Mp: 225–226°C). 1H NMR
(400 MHz, D2O): d 6.85 (A part of AB system, d, 1H, Ar-H, J ¼ 8.8 Hz),
6.74 (B part of AB system, d, 1H, Ar-H, J ¼ 8.8 Hz), 4.75 (dd, 1H,
NCH, J ¼ 5.3, J ¼ 8.1 Hz), 4,65 (bs, NH3 and H2O), 3.70 (s, 3H, OCH3),
3.67 (s, 3H, OCH3), 3.93–2.86 (m, 1H, CH), 2.74–2.66 (m, 1H, CH),
2.52–2.43 (m, 1H, CH), 2.05–1.91 (m, 1H, CH). 13C NMR (100 MHz,
D2O): d 150.6 (C), 149.5 (C), 133.9 (C), 126.8 (C), 113.6 (CH), 110.0
(CH), 56.2 (CH–N) 55.7 (OCH3), 54.5 (OCH3), 29.8 (CH2), 27.3 (CH2).
Benzyl N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)sulfamoyl
carbamate (17)
1-Amino-7-methoxyindane (12)
60% yield. White solid. Mp: 153–155°C. 1H NMR (400 MHz, CDCl3):
d 7.7 (bs, 1H, NH), 7.36 (bs, 5H, Ar-H), 7.14 (d, 1H, Ar-H, J ¼ 8.3 Hz),
6.73 (s, 1H, Ar-H), 6.70 (dd, 1H, Ar-H, J ¼ 2.0, 8.3 Hz), 5.38 (d, 1H, NH,
J ¼ 7.8 Hz), 5.17 (d, 2H, CH2, J ¼ 1.6 Hz), 4.81 (dd, 1H, NCH, J ¼ 7.1,
13.9 Hz), 3.78 (s, 3H, OCH3), 2.13–2.05 (m 1H, CH), 2.75–2.67 (m 1H,
CH), 2.46–2.37 (m 1H, CH), 1.96–1.87 (m 1H, CH). 13C NMR
(100 MHz, CDCl3): d 160.6 (CO), 151.6 (C), 145.1 (C), 134.9 (C), 133.2
(C), 129.1 (CH), 129.0 (2CH), 128.9 (2CH), 125.3 (CH), 113.4 (CH),
Amine hydrochloride salt 10 (2.00 g, 10.02 mmol) was dissolved in
MeOH (40 mL) and cooled to 0°C. A solution of 10% NaOH (20 mL)
was added to this solution, the reaction mixture was stirred at RT
for 3 h. After the most of MeOH was evaporated, CH2Cl2 (50 mL)
and H2O (20 mL) were added to the residue. Organic layer was
separated and H2O layer was extracted with CH2Cl2 (2 ꢃ 30 mL).
Combined organic layers were dried over Na2SO4 and CH2Cl2 was
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Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides
955
110.1 (CH), 68.8 (OCH2), 59.3 (CH-N), 55.7 (OCH3), 34.1 (CH2), 30.4
(CH2). IR (CH2CI2, cmꢀ1): 3280, 3020, 2930, 1732, 1628, 1426, 1437,
1404, 1346, 1160, 1056, 1093. Anal. calcd. for (C18H20N2O5S): C, 57.43;
H, 5.36; N, 7.44; S, 8.52. Found: C, 57.44; H, 5.38; N, 7.46; S, 8.50.
H2O phase was extracted with CH2Cl2 (2 ꢃ 30 mL). Combined
organic layers were dried over Na2SO4 and the solvent was
evaporated. The residue was crystallized from EtOAc/hexane to
give 25 (1.23 g, 81% yield). Yellow solid (Mp: 138–140°C). 1H NMR
(400 MHz, CDCl3): d 7.39 (dm, 1H, Ar-H, J ¼ 8.3 Hz), 7.24 (bs, 1H,
NH), 7.08 (bs, 1H, NH), 6.47 (m, 1H, Ar-H), 6.45 (dm, 1H, Ar-H,
J ¼ 8.3 Hz), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 1.45 (s, 9H, 3CH3).
Hydrogenolysis of benzyl sulfamoyl carbamates; synthesis
of N-(7-methoxy-2,3-dihydro-1H-inden-1-yl)sulfamide (18)
Pd-C (50 mg) was added to a solution of sulfamoylcarbamate 15
(1.40 g, 3.72 mmol) in MeOH (50 mL) into a 100 mL flask. A balloon
filled with H2 gas (3 L) was fitted to the flask. The mixture was
deoxygenated by flushing with H2 and then hydrogenated at RT
for 4 h. The catalyst was removed by filtration. The residue was
crystallized from EtOAc/hexane to give compound 18 (0.70 g, 78%
13
–
C NMR (100 MHz, CDCl ): d 158.7 (C), 151.9 (C O), 149.1 (C),
–
3
123.9 (C), 118.5 (CH), 104.5 (CH), 99.2 (CH), 83.9 (C), 56.0 (OCH3),
55.8 (OCH3), 28.9 (3CH3). IR (CH2Cl2, cmꢀ1) 3260, 2979, 2935, 1731,
1600, 1145, 929, 732. Anal. calcd. for (C13H20N2O6S): C, 46.98; H,
6.07; N, 8.43; S, 9.65. Found: C, 46.97; H, 6.10; N, 8.42; S, 9.63.
Compounds 26–28 were also synthesized by the same
procedure.
1
yield). White solid. Mp: 122–124°C. H NMR (400 MHz, CDCl3): d
7.24 (t, 1H, Ar-H, J ¼ 7.8 Hz), 6.87 (d, 1H, Ar-H, J ¼ 7.8 Hz), 6.70 (d,
1H, Ar-H, J ¼ 7.8 Hz), 5.02 (dd, 1H, NCH, J ¼ 3.9, 7.3 Hz), 4.77 (bs,
2H, NH2), 3.86 (s, 3H, OCH3), 3.09–3.01 (m 1H, CH), 2.85–2.78 (m
1H, CH), 2.49–2.40 (m 1H, CH), 2.30–2.22 (m 1H, CH). 13C NMR
(100 MHz, CDCl3): d 156.2 (C), 146.6 (C), 130.7 (CH), 128.7 (C), 117.9
(CH), 108.8 (CH), 57.7 (CN), 55.7 (OCH3), 33.9 (CH2), 30.9 (CH2). IR
(CH2CI2, cmꢀ1): 3279, 2942, 2846, 1605, 1406, 1341, 1307, 1266,
1163, 1073, 1057. Anal. calcd. for (C10H14N2O3S): C, 49.57; H, 5.82;
N, 11.56; S, 13.23. Found: C, 49.60; H, 5.84; N, 11.54; S, 13.25.
t-Butyl-N-(3,5-dimethoxyphenyl)sulfamoyl carbamate (26)
White solid (78% yield, Mp: 40–42°C). 1H-NMR (400 MHz, CDCl3): d
7.27 (bs, 1H, NH), 7.22 (bs, 1H, NH), 6.41 (d, 2H, Ar-H, J ¼ 2.2 Hz),
6.33 (t, 1H, Ar-H, J ¼ 2.2 Hz), 3.78 (s, 6H, OCH3), 1.41 (s, 9H, CH3).
13
–
C NMR (100 MHz, CDCl ): d 161.5 (C), 150.1 (C O), 137.8 (C),
–
3
100.9 (2CH), 98.8 (CH), 84.3 (C), 55.7 (2OCH3), 28.1 (3CH3). IR
(CH2Cl2, cmꢀ1) 3260, 2979, 2935, 1731, 1600, 1144, 929, 732. Anal.
calcd. for (C13H20N2O6S): C, 46.98; H, 6.07; N, 8.43; S, 9.65. Found:
C, 46.99; H, 6.09; N, 8.40; S, 9.63.
N-(4,7-Dimethoxy-2,3-dihydro-1H-inden-1-yl)sulfamide (19)
72% yield. White solid. Mp: 133–135°C. 1H NMR (400 MHz, CDCl3):
d 6.72 (d, 1H, A part of AB system, Ar-H, J ¼ 8.7 Hz), 6.67 (d, 1H, B
part of AB system, Ar-H, J ¼ 8.7 Hz), 5.05–5.00 (m, 2H, NCH and
NH), 4.85 (bs, 2H, NH2), 3.82 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.01–
2.97 (m, 1H, C–H), 2.82–2.74 (m, 1H, C–H), 2.52–2.42 (m, 1H, C–H),
2.29–2.21 (m 1H, C–H). 13C NMR (100 MHz, CDCl3): d 150.8 (C),
150.1 (C), 134.3 (C), 130.5 (C), 111.2 (CH), 109.7 (CH), 58.2 (NC), 56.1
(OCH3), 55.9 (OCH3), 33.9 (CH2), 27.8 (CH2). IR (CH2CI2, cmꢀ1):
3356, 3276, 2939, 1549, 1496, 1463, 1439, 1303, 1258, 1163, 1088,
1058. Anal. calcd. for (C11H16N2O4S): C, 48.52; H, 5.92; N, 10.29; S,
11.77. Found: C, 48.55; H, 5.89; N, 10.26; S, 11.75.
t-Butyl-N-(2,5-dimethoxyphenyl)sulfamoyl carbamate (27)
White solid (72% yield, Mp: 148–150°C). 1H NMR (400 MHz,
CDCl3): d 7.57 (bs, 1H, NH), 7.40 (bs, 1H, NH), 7.13 (d, 1H, Ar-H,
J ¼ 2.9 Hz), 6.47 (d, 1H, Ar-H, J ¼ 9.1 Hz), 6.63 (dd, 1H, Ar-H, J ¼ 2.9,
9.1 Hz), 3.77 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 1.44 (s, 9H, 3CH3).
13
–
C NMR (100 MHz, CDCl ): d 153.9 (C O), 149.1 (C), 143.3 (C),
–
3
126.2 (C), 111.6 (CH), 109.6 (CH), 106.6 (CH), 83.9 (C), 56.3 (OCH3),
55.8 (OCH3), 27.7 (3CH3). IR (CH2Cl2, cmꢀ1) 3260, 2979, 2935, 1731,
1600, 1145, 929, 732. Anal. calcd. for (C13H20N2O6S): C, 46.98; H,
6.07; N, 8.43; S, 9.65. Found: C, 46.96; H, 6.10; N, 8.45; S, 9.62.
t-Butyl-N-(3,4,5-trimethoxyphenyl)sulfamoyl carbamate
N-(5-Methoxy-2,3-dihydro-1H-inden-1-yl)sulfamide (20)
78% yield. White solid. Mp: 112–114°C. 1H NMR (400 MHz, CDCl3):
d 7.33 (d, 1H, Ar-H, J ¼ 8.3 Hz), 6.79–6.74 (m, 2H, Ar-H), 4.91 (dd, 1H,
NCH, J ¼ 7.3, 14.7 Hz), 4.71 (bs, 2H, NH2), 4.6 (d, 1H, NH, J ¼ 8.4 Hz),
3.78 (s, 3H, OCH3), 3.02–2.93 (m 1H, CH), 2.84–2.76 (m 1H, CH),
2.65–2.56 (m 1H, CH), 2.06–1.97 (m 1H, CH). 13C NMR (100 MHz,
CDCl3): d 160.5 (C), 145.2 (C), 134.2 (C), 125.4 (CH), 113.3 (CH), 110.2
(CH), 58.9 (CN), 55.7 (OCH3), 35.1 (CH2), 30.4 (CH2). IR (CH2CI2,
cmꢀ1): 3274, 3109, 3019, 2929, 1607, 1434, 1343, 1326, 1264,
1105, 1056. Anal. calcd. for (C10H14N2O3S): C, 49.57; H, 5.82; N,
11.56; S, 13.23. Found: C, 49.55; H, 5.80; N, 11.55; S, 13.20.
(28)
Yellow solid (75% yield, Mp, 158–160°C). 1H NMR (400 MHz,
CDCl3): d 8.14 (bs, 1H, NH), 6.65 (bs, 2H, Ar-H), 6.31 (bs, 1H, NH),
3.77 (s, 6H, 2OCH3), 3.66 (s, 3H, OCH3), 1.41 (s, 9H, 3CH3). 13C NMR
–
(100 MHz, CDCl ): d 161.5 (2C), 150.1 (C O), 137.8 (C), 100.9 (2CH),
–
3
98.8 (C), 84.3 (C), 55.7 (OCH3), 28.1 (CH3). IR (CH2Cl2, cmꢀ1) 3254,
2974, 2935, 1717, 1606, 1134, 937, 742. Anal. calcd. for
(C14H22N2O7S): C, 46.40; H, 6.12; N, 7.73; S, 8.85. Found: C,
46.43; H, 6.15; N, 7.74; S, 8.84.
Standard procedure for the synthesis of sulfamides derived
from anilines: Synthesis of N-(2,4-dimethoxyphenyl)-
sulfamide (29)
Standard procedure for the synthesis of t-butyl sulfamoyl
carbamates: t-Butyl N-(2,4-dimethoxyphenyl)sulfamoyl
carbamate (25)
t-BuOH (0.58 g, 7.83 mmol) and CSI (1.02 g, 7.18 mmol) were
dissolved in CH2Cl2 (20 mL) at 0°C. A solution of 21 (1.00 g,
6.53 mmol) in CH2Cl2 (40 mL) and NEt3 (0.80 g, 7.83 mmol) were
added to the solution of CSI-t-BuOH drop wise and it was stirred at
0°C for 1 h then for 3 h at RT under N2 atmosphere. The reaction
mixture was cooled to 0°C and to this mixture was added a
solution of 0.1 N HCl (70 mL). Organic phase was separated and
To a solution of 25 (1.00 g, 3.01 mmol) in CH2Cl2 (20 mL) was
added trifluoro acetic acid (CF3CO2H) (3.43 g, 30.10 mmol) drop
wise and it was stirred at 0°C for 2 h then at RT for 24 h under N2
atmosphere. The reaction mixture was cooled to 0°C and to this
mixture was added a solution of 1 N NaHCO3 (100 mL). Organic
phase was separated and H2O phase was extracted with CH2Cl2
(2 ꢃ 40 mL). Combined organic layers were dried over Na2SO4 and
the solvent was evaporated. The residue was crystallized from
EtOAc/hexane to give sulfamide 29 (0.59 g, 85% yield). White solid.
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956
Y. Akbaba et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
Mp: 118–120°C. 1H NMR (400 MHz, DMSO-d6): d 7.34 (d, 1H, Ar-H,
J ¼ 8.7 Hz), 7.09 (bs, 1H, NH), 6.61 (d, 1H, Ar-H, J ¼ 2.7 Hz), 6.45 (dd,
1H, Ar-H, J ¼ 2.7, 8.7 Hz), 6.13 (bs, 2H, NH2), 3.86 (s, 3H, OCH3), 3.78
(s, 3H, OCH3). 13C NMR (100 MHz, DMSO-D6): d 154.3 (CH), 143.5
(CH), 128.9 (C), 111.9 (C), 107.4 (CH), 106.3 (C), 56.2 (OCH3), 55.2
(OCH3). IR (CH2Cl2, cmꢀ1) 3272, 3092, 2935, 1597, 1155, 922, 711.
Anal. calcd. for (C8H12N2O4S): C, 41.37; H, 5.21; N, 12.06; S, 13.80.
Found: C, 41.35; H, 5.20; N, 12.05; S, 13.84.
nonenzymatic and the enzymatic reactions, respectively. On the
other hand, esterase activity was assayed by following the change
in absorbance at 348 nm of NPA to 4-nitrophenoxide ion over a
period of 3 min at 25°C using a spectrophotometric method [53].
The enzymatic reaction, in a total volume of 3.0 mL, contained
1.4 mL Tris-SO4 buffer (0.05 M, pH 7.4), 1 mL NPA (3 mM), distilled
water (0.5 mL) and enzyme solution (0.1 mL).
Compounds 30–32 were also prepared by the same procedure.
Protein determination
During the purification studies, the quantity of protein was
determined spectrophotometrically at 595 nm according to the
Bradford’s method [54]. Bovine serum albumin was used as
standard protein [55].
N-(3,5-Dimethoxyphenyl)sulfamide (30)
White solid (82% yield, Mp: 93–95°C). 1H NMR (400 MHz, acetone-
d6): d 6.51 (s, 2H, Ar-H), 6.20 (s, 1H, Ar-H), 3.72 (s, 6H, OCH3). 13C
NMR (100 MHz, acetone-d6): d 161.6 (2C), 141.2 (C), 97.6 (2CH), 94.9
(CH), 54.9 (OCH3). IR (CH2Cl2, cmꢀ1) 3266, 3109, 2914, 1603, 1148,
934, 724. Anal. calcd. for (C8H12N2O4S): C, 41.37; H, 5.21; N, 12.06;
S, 13.81. Found: C, 41.49; H, 5.52; N, 11.97; S, 13.50.
SDS-polyacrylamide gel electrophoresis
Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-
PAGE) was used in this study for separation of both isoenzymes. It
was carried out according to Laemmli’s procedure [56]. Briefly, it
was applied in 10% and 3% acrylamide for the running and the
stacking gel, respectively, containing SDS (0.1%). This method has
been described in detail previously [57].
N-(2,5-Dimethoxyphenyl)sulfamide (31)
White solid (72% yield, Mp: 108–110°C). 1H-NMR (400 MHz,
acetone-d6): d 7.11 (d, 1H, Ar-H, J ¼ 3.0 Hz), 6.91 (d, 1H, Ar-H,
J ¼ 8.9Hz), 6.58 (dd, 1H, Ar-H, J ¼ 3.0, 8.9 Hz), 3.81 (s, 3H, OCH3),
3.72 (s, 3H, OCH3). 13C NMR (100 MHz, acetone-d6): d 154.2 (C),
143.5 (C), 128.9 (C), 111.9 (CH), 107.4 (CH), 106.3 (CH), 55.7 (OCH3),
55.1 (OCH3). IR (CH2Cl2, cmꢀ1) 3272, 3092, 2935, 1597, 1155, 922,
711. Anal. calcd. for (C8H12N2O4S): C, 41.37; H, 5.21; N, 12.06; S,
13.81. Found: C, 41.39; H, 5.25; N, 12.04; S, 13.79.
Inhibition assay
The inhibitory effects of some novel sulfamide carbamates and
sulfamides 15–31 were examined in vitro. All compounds (15–31)
were tested in triplicate at each concentration used. Both
isoenzyme activities were measured in the presence of different
concentration of each novel compound [58]. Control activity in
the absence of inhibitor was taken as 100%. For each sulfamide,
an Activity (%)-[Sulfamides] graph was obtained. To determine Ki
values, several different concentrations were used. In these
experiments, as stated previously NPA was used as a CA substrate
at five different concentrations. The Lineweaver–Burk curves
were used to determine kinetic parameters and inhibition
constants [59, 60].
N-(3,4,5-Trimethoxyphenyl)sulfamide (32)
70% yield. Yellow solid. Mp: 168–170°C. 1H NMR (400 MHz,
acetone-d6): d 6.64 (s, 2H, Ar-H), 3.77 (s, 6H, 2OCH3), 3.65 (s, 3H,
OCH3). 13C NMR (100 MHz, acetone-d6): d 153.8 (2C), 135.4 (2C),
134.9 (C), 98.3 (2CH), 59.9 (OCH3), 55.9 (2OCH3). IR (CH2Cl2, cmꢀ1
)
3361, 3260, 2913, 1602, 1126, 1004. Anal. calcd. for (C9H14N2O5S):
C, 41.21; H, 5.38; N, 10.68; S, 12.23. Found: C, 41.24; H, 5.40; N,
10.68; S, 12.20.
We are greatly indebted to The Scientific and Technological Research
Council of Turkey (TUBITAK, Grant no. TBAG-109T241) and Ataturk
University (BAP2012/152, BAP 2013/284) for their financial support of this
study. I.G. would like to extend his sincere appreciation to the Research
Chairs Program at King Saud University for funding this research.
Biochemical methods
Purification of CA isoenzymes by affinity chromatography
Both CA isoenzymes (hCA I and II) were purified from fresh
human erythrocytes by Sepharose 4B-L-tyrosine sulfanilamide
affinity chromatography. This chromatographic method was
described previously [47–49]. Briefly, erythrocytes were taken
from human blood, following low-speed centrifugation at
2000 ꢃ g for 20 min (Hermle, Z323 K, Grand rotor) by removal
of plasma and buffy coat. The pH of haemolysate was adjusted to
8.7 with solid Tris. The homogenate was applied to the formerly
prepared Sepharose 4B-L-tyrosine-sulfanylamide affinity column.
Then column was equilibrated with Tris-HCl/Na2SO4 (pH 8.7;
25 mM/0.1 M). The affinity gel was washed with Tris-HCl/Na2SO4
(pH 8.7; 25 mM/22 mM). Finally, hCA I and II were eluted with
NaCl/sodium phosphate (pH 6.3; 1.0 M/25 mM) and CH3COONa/
NaClO4 (pH 5.6; 0.1 M/0.5 M), respectively [50–52].
The authors have declared no conflict of interest.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 950–957
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