In vitro inhibition effects on erythrocyte carbonic anhydrase I and II and structure-activity relationships of cumarylthiazole derivatives

Article abstract of DOI:10.1134/S1068162016050046

Coumarin and heterocyclic compounds incorporating urea have clinical applications as antiepileptics, diuretics, and antiglaucoma agents due to their carbonic anhydrase inhibitory properties. We investigated inhibition of carbonic anhydrase I and II with a series of coumarylthiazole derivatives containing urea/thiourea groups. All the investigated compounds exhibited inhibitory activity on both hCA I and hCA II, with 1-(3-chlorophenyl)-3-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)urea being the strongest inhibitor. Structure–activity relationship study showed that most of urea derivatives were more inhibiting for hCA I and hCA II than thiourea derivatives. The electron-withdrawing groups at the phenyl ring increased the inhibitory activity compared to electron-donating groups.

Full text of DOI:10.1134/S1068162016050046

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2016, Vol. 42, No. 5, pp. 506–511. © Pleiades Publishing, Ltd., 2016.
In Vitro Inhibition Effects on Erythrocyte Carbonic Anhydrase I
and II and Structure-Activity Relationships
1
of Cumarylthiazole Derivatives
a
b, 2
c
d
d
b
Belma Z. Kurt , Fatih Sonmez , Basak Gokce , Adem Ergun , Nahit Gencer , Taki Demir ,
d
e
Oktay Arslan , and Mustafa Kucukislamoglu
a
Deparment of Medicinal Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, 34093 Turkey
b
Pamukova Vocational High School, Sakarya University, Sakarya, 54900 Turkey
Faculty of Pharmacy, Suleyman Demirel University, Isparta, 32260 Turkey
Department of Chemistry, Faculty of Art and Sciences, Balikesir University, Balikesir, 10145 Turkey
c
d
e
Department of Chemistry, Faculty of Arts and Science, Sakarya University, Sakarya, 54055 Turkey
Received October 23, 2015; in final form, April 1, 2016
Abstract—Coumarin and heterocyclic compounds incorporating urea have clinical applications as antiepilep-
tics, diuretics, and antiglaucoma agents due to their carbonic anhydrase inhibitory properties. We investigated
inhibition of carbonic anhydrase I and II with a series of coumarylthiazole derivatives containing
urea/thiourea groups. All the investigated compounds exhibited inhibitory activity on both hCA I and hCA
II, with 1-(3-chlorophenyl)-3-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)urea being the strongest inhibitor.
Structure–activity relationship study showed that most of urea derivatives were more inhibiting for hCA I and
hCA II than thiourea derivatives. The electron-withdrawing groups at the phenyl ring increased the inhibitory
activity compared to electron-donating groups.
Keywords: carbonic anhydrase, coumarin, inhibitor, structure–activity relationship
DOI: 10.1134/S1068162016050046
INTRODUCTION
demonstrated that this enzyme is involved in retinal
and cerebral edema, and its inhibition may be a valu-
able tool for fighting these pathologies. The CA II is
involved in several diseases, such as glaucoma, edema,
epilepsy, and probably altitude sickness [12]. Although
there are many studies on the carbonic anhydrase, this
enzyme family continues to capture the attention of
drug discovery scientists and clinicians as the knowl-
edge regarding the therapeutic implications associated
with this enzyme class continues to grow [4, 13].
The carbonic anhydrases (CAs; EC 4.2.1.1) are a
superfamily of metalloenzymes that catalyse the inter-
–
conversion between CO and HCO by using a metal
2
3
hydroxide nucleophilic mechanism [1–4]. These
metalloenzymes occur in nature as five different,
genetically distinct families, the α-, β-, γ-, δ-, and
ζ-CAs. The α-, β-, and δ-CAs have Zn(II) ions at the
active site, the γ-CAs are Fe(II)-containing enzymes
(
but they are active also with bound Zn(II) or Co(II)
ions), while the ζ-class uses Cd(II) or Zn(II) to per-
The CA inhibitor (CAI) targeting enzymes from
form physiologic catalysis reactions [5–7]. Addition- mammals, which belong to the α-CA group, have
ally, a new genetic family of CAs, called as the η-CA been classified as (a) metal ion binders (inorganic
class, was discovered by Supuran’s group in the last anions; sulfonamides and their isosteres (such as the
year [8]. Sixteen different α-CA isoforms were isolated sulfamates, sulfamides, N-hydroxysulfonamides)); (b)
from mammals, where they play crucial physiological compounds that anchor to the zinc-coordinated water
roles. Some of them are cytosolic (CA I, CA II, CA molecule/hydroxide ion (phenols, polyamines, sulfo-
III, CA VII, CA XIII), others are membrane-bound coumarins, etc.); (c) compounds occluding the
(
CA IV, CA IX, CA XII, CA XIV and CA XV), CA VA entrance of the active site (coumarins and their
and CA VB are mitochondrial, and CA VI is secreted isosteres); and (d) compounds that bind in an
in saliva and milk [9, 10]. The isozyme CA I is found unknown manner (secondary/tertiary sulfonamides,
in many tissues, but the study by Gao et al. [11] has imatinib, nilotinib, etc.) [14–18].
1
2
The coumarin is a common moiety found in many
biologically active natural and therapeutic products
and thus representing a very important pharmacoph-
The article is published in the original.
Corresponding author: phone: +90-264-2953378; fax: +90-
264-2953679; e-mail: fsonmez@sakarya.edu.tr.
506

IN VITRO INHIBITION EFFECTS ON ERYTHROCYTE CARBONIC ANHYDRASE
507
ore [19, 20]. In addition to the numerous activities of purified from human erythrocytes. Structure–activity
coumarin compounds, they were recently shown to relationship (SAR) is also presented. In the present
constitute a novel class of inhibitors of the metalloen- study, our main aim was to check whether the ary-
zyme carbonic anhydrase [21–24]. The inhibition lurea/thiourea derivatives substituted coumarin mod-
mechanism of coumarins is different compared to that ified by the addition of thiazole ring may show higher
of the classical CA inhibitors (CAIs) of the sul- inhibitory effect on CA enzymes with respect to the
phonamide type [25]. Several kinetic and X-ray crys- compounds previously investigated.
tallographic studies have revealed that coumarins are
mechanism based inhibitors, which undergo hydroly-
RESULTS AND DISCUSSION
sis under the influence of the zinc hydroxide, the nuc-
leophilically active species of the enzyme, with gener-
ation of substituted-2-hydroxycinnamic acids (figure)
Chemistry
The synthetic procedures employed to obtain the
compounds (Va–t) and (VIa–h) are depicted in
Scheme 1. Compounds (IIa, b) were synthesized from
salicyl aldehydes according to the literature [31], then,
they were brominated with molecular bromine in
[
21–23, 26].
There are many reports [27, 28] on aromatic sul-
fonamides or bis-sulfonamide moieties incorporating
urea or thiourea groups as very potent inhibitors
against three isozymes, human CA I, human CA II,
and bovine isozyme CA. A small series of five ureido-
substituted benzenesulfonamide derivatives were
recently investigated as inhibitors of the cytosolic iso-
form hCA II by one of these groups. They mentioned
that the compounds have excellent inhibitory effects
for all these isoforms due to the urea moiety [29].
chloroform. 2-Amino-4-(R -coumarin-3-yl)thiazoles
1
(
(
IVa, b) were obtained by reaction of compounds
IIIa, b) with thiourea. Finally, compounds (IVa, b)
were reacted with arylisocyanates in THF to get cou-
marylthiazole containing urea derivatives (Va–t), but
thiourea derivatives were not synthesized by same pro-
cedure. Consequently, coumarylthiazole containing
In this work, we evaluated effects of coumarylthi- thiourea derivatives (VIa–h) were obtained by reac-
azole substituted arylurea/thiourea derivatives, syn- tion of (IVa, b) with arylisothiocyanates in DMF at
thesized in our previously work [30], on hCA I and II room temperature.
O
S
O
O
O
O
O
O
H
COMe
L-Pyroline
0°C, 1 h
Br2
H2N
NH2
R1
R1
R1
R1
+
CHCl , 50 C
°
8
3
N
S
OH
Ia): R1 = H
Ib): R1 = 3-OCH3
COOEt
15 min
Br
EtOH, reflux, 1 h
NH2
O
O
(
(
(
IIa): R1 = H
1
(IVa): R = H
(
IIIa): R1 = H
(
IIb): R1 = 3-OCH3
(IVb): R = 3-OCH3
(
IIIb): R1 = 3-OCH3
1
R2
R2
NCS
NCO
DMF, Et3N,
rt, 12 h
THF, Et3N,
reflux, 12 h
8
8
5
O
2
O
2
O O
7
7
R1
R1
3
1
3
N 13
6
N 13
6
1
NH17 NH
S
11
NH
17
5
4
4
NH
1'
15
S
2'
15
S
2'
1'
O
3'
3'
(
VIa−h)
6'
(Va−t)
6'
' R24'
5' R24'
5
Scheme 1. Synthesis of 5-coumaryl-2-(phenylurenyl/thiourenyl)thiazole derivatives [30].
Biological Evaluation of Synthesized Compounds
for hCA I and hCA II Inhibitory Activities
analogues (Va–t) and (VIa–h) against hCA I and hCA
II are summarized in table.
For evaluating the hCA I and hCA II inhibitory
The IC values were between 3.13 and 340.21 μM
50
effect, the compounds were subjected to hCA I and II
for hCA I and between 2.65 and 472.97 μM for hCA II
inhibition assay with CO as a substrate. The result
2
inhibitory activity. Compound (Vh) (IC = 3.13 and
showed that all the investigated compounds (Va–t)
50
and (VIa–h) inhibited the hCA I and hCA II enzyme 2.65 μM, for hCA I and hCA II, respectively) showed
activity. The IC values and inhibition constants of the highest inhibitory activity against hCA I and II.
50
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42 No. 5 2016

5
08
BELMA Z. KURT et al.
OH
OH
O
CA
rt, pH 7.4
−6 h
COO−
4
O
OH
O
O
O
A
A1
CA
rt, pH 7.4
4−6 h
COO−
O
OH
B1
B
Formation of 2-hydroxy-cinnamic acids A1 and B1 by the CA-mediated hydrolysis of coumarin A and B [21–23, 26].
Although coumarin compounds are mentioned as undergo ring opening without pre-incubation of
very potent inhibitor of the cytosolic isoform hCAs enzyme and inhibitor. Also, the acidity of urea moiety
21–24], all the investigated coumarins possess mod- may play important part. The investigated compounds
[
erate inhibitory activity for the hCAs. Up to now, have high binding capacity to zinc cation. So, the sec-
many urea, sulphonamide, and coumarin derivatives ond compound has higher binding capacity than the
have been synthesized as strong CAIs by Supuran’s first one. We also assume that the nitrogen of the thi-
group [18, 21–29]. Their inhibition values ranged azole ring of the investigated compounds contributes
from low micromolar to nanomolar range. These to inhibition by forming hydrogen bonds.
compounds have stronger inhibitory effect than the
coumarylthiazole derivatives in this study. However,
compound (Vh) (IC 3.13 and 2.65 µM, for hCA I and
Structure–Activity Relationship (SAR)
50
hCA II, respectively) showed higher inhibitory prop-
erties against hCA I and II compared to some urea,
sulphonamide, and coumarin derivatives reported in
our previously studies [32–37], with IC values
The following structure–activity relationship
SAR) observations can be drawn from data of table:
(
(a) Generally, similar results were obtained for
5
0
hCA I and hCA II enzymes inhibitions. Most of the
urea derivatives (Va–t) exhibited higher inhibitory
activity than thiourea derivatives (VIa–h).
between 6.79 and 620 µM for hCA I and between 6.54
and 51.45 µM, for hCA II.
The coumaryl-substituted sulfonamide derivatives
inhibit CAs by coordination of the sulphonamide moi-
ety to the metal ion from the enzyme active site and
participation in hydrophobic and hydrophilic interac-
tions of the organic scaffold of the inhibitor with
amino acid residues [26]. Supuran’s group reported
that inhibitor (as for coumarin/sulfocoumarin) and
enzyme solutions were pre-incubated together for ~6 h
prior to assay in order to allow for the formation of the
E–I complex or for the eventual active site mediated
hydrolysis of the inhibitor [38]. Also, the benzene core
of the compound was at van der Waals distance from
the side chain of Leu98 [4, 9, 26].
Additionally, it has been reported that the two
endocyclic nitrogen atoms of the 1,3,4-thidiazole ring
participate in two hydrogen bonds with the OH of
Thr200 [4]. According to X-ray crystallographic stud-
ies [9, 27–29], a highly variable orientation of the R-
ureido moieties was evidenced when the inhibitor was
bound within the enzyme active site.
(
b) For urea derivatives: (i) the compounds that
have electron-donating groups (methoxy, methyl) at
the phenyl ring have lower hCA I and hCA II inhibi-
tory activity than the compounds that have electron-
withdrawing group (nitro) and halogen (F, Cl) groups;
(
ii) the halogen substituent (F or Cl) on meta- position
increased the inhibitory activity compared to orto- or
para-position (for inhibitory activity, compounds
(
(
Vh) > (Vg), (Vi) > (Vj), (Vr) > (Vq), and (Vs) > (Vt));
iii) halogen series on the meta-position of phenyl ring
showed a qualitative relationship for higher inhibitory
activity with increasing size and polarizability (for size
and polarizability, Cl > F, for inhibitory activity, com-
pounds (Vh) (R = H, R = 3-Cl; IC 3.13 and
1
2
50
2
(
.65 µM, for hCA I and hCA II, respectively) > (Vi)
R = H, R = 3-F; IC 26.98 and 34.96 µM, for hCA
1
2
50
I and hCA II, respectively), and (Vr) (R 8-OCH , R
2
1
3
3
-Cl; IC 40.77 and 31.23 µM, for hCA I and hCA II,
50
respectively) > (Vs) (R 8-OCH , R 3-F; IC 44.36
1
3
2
50
and 58.78 µM, for hCA I and hCA II, respectively).
Based on the above consideration, two possibilities
can be considered for the inhibition mechanism of the
investigated compounds. The first one may be hydro-
lysis of coumarinic moiety to cinnamic acid derivative.
The second one can be binding of urea moiety to zinc
(
c) For thiourea derivatives; (i) while R was same
2
substituent, the methoxy group on the coumarin ring
increased the hCA II inhibitory activity (compound
(
VIf) (R = 8-OCH , R = 4-Cl; IC = 82.24 µM for
1 3 2 50
cation. We consider that the coumarin ring should not hCA II) compared to compound (VIa) (R
= H, R =
2
1
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IN VITRO INHIBITION EFFECTS ON ERYTHROCYTE CARBONIC ANHYDRASE
509
In vitro inhibition IC50 values (µM) of compounds (Va–t) and (VIa–h) on hCA I and hCA II
8
8
O 2
O
2
7
6
O
O
7
R1
3
1
R1
3
N 13
6
N 13
S
1
NH17
O
11
1
5
4
4
NH17
S
5
NH
1
5
S
2'
NH
5
2'
1
'
1
'
3
'
3'
6'
6'
(Va−t)
(VIa−h)
4
'
4'
R2
5'
R2
5'
hCA I
hCA II
IC , µM
50
Compound
R1
R2
a
a
IC , µM
50
(
Va)
Vb)
Vc)
Vd)
Ve)
Vf)
Vg)
Vh)
H
H
H
H
H
H
H
H
H
H
4-OCH3
3-OCH3
4-CH3
4-NO2
3-NO2
H
215.02 ± 1.245
322.15 ± 2.016
340.21 ± 2.741
46.89 ± 0.325
11.62 ± 0.451
210.95 ± 2.584
39.23 ± 1.120
3.13 ± 0.054
105.24 ± 1.547
472.97 ± 2.378
51.17 ± 0.478
20.04 ± 0.147
24.90 ± 0.289
271.35 ± 3.054
116.41 ± 1.214
2.65 ± 0.089
34.96 ± 0.875
86.72 ± 1.721
56.75 ± 1.115
19.64 ± 0.451
140.58 ± 2.533
4.55 ± 0.887
41.67 ± 0.997
27.09 ± 0.566
87.27 ± 1.311
31.23 ± 0.667
58.78 ± 1.322
110.02 ± 3.177
140.92 ± 2.842
62.41 ± 0.887
64.52 ± 2.001
240.21 ± 1.998
87.95 ± 1.271
82.24 ± 0.574
180.35 ± 1.141
44.14 ± 0.522
(
(
(
(
(
(
4-Cl
(
3-Cl
(
Vi)
3-F
26.98 ± 1.325
108.18 ± 1.684
71.19 ± 2.963
24.34 ± 1.113
151.19 ± 2.965
8.81 ± 0.057
(
Vj)
2-F
(Vk)
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
H
4-OCH3
3-OCH3
4-CH3
4-NO2
3-NO2
H
(
Vl)
(Vm)
(
Vn)
Vo)
Vp)
Vq)
(
47.88 ± 1.114
32.88 ± 0.857
45.71 ± 1.117
40.77 ± 1.111
44.36 ± 0.885
61.22 ± 1.774
114.61 ± 1.254
63.38 ± 1.221
68.77 ± 0.997
170.51 ± 2.119
116.88 ± 1.877
123.23 ± 2.211
110.33 ± 1.229
51.06 ± 0.881
(
(
4-Cl
(
Vr)
Vs)
3-Cl
(
3-F
(
Vt)
2-F
(VIa)
(VIb)
(VIc)
(VId)
(VIe)
4-Cl
H
3-F
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OCH3
4-OCH3
4-CH3
H
(
VIf)
4-Cl
(VIg)
4-F
(VIh)
3-F
aIC50 values represent the means ± S.E.M. of three parallel measurements (p < 0.05).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 42 No. 5 2016

5
10
BELMA Z. KURT et al.
4
-Cl; IC 140.92 µM for hCA II); compound (VIh)
CA Enzyme Assay
5
0
(
R = 8-OCH , R = 3-F; IC 44.14 µM for hCA II)
1 3 2 50
Carbonic anhydrase activity was measured accord-
ing to the Maren method [40], which is based on
compared to compound (VIb) (R = H, R = 3-F; IC
1
2
50
6
2.41 µM for hCA II); (ii) halogen series on the para- determination of the time required for the pH to
position of phenyl ring showed a qualitative relation- decrease from 10.0 to 7.4 due to CO hydration. The
2
ship for higher hCA II inhibitory activity with increas- assay solution was 0.5 M Na CO /0.1 M NaHCO
2
3
3
ing size and polarizability (for size and polarizability, (pH 10.0) and phenol red was added as the pH indica-
Cl > F, for hCA II inhibitory activity, compounds (VIf) tor. CO -hydratase activity (enzyme units (EU)) has
2
(
R = 8-OCH , R = 4-Cl; IC 82.24 µM) > (VIg)
1 3 2 50
been calculated by using the equation t – t /t , where
0 c c
(
R = 8-OCH , R = 4-F; IC 180.35 µM)). Interest- t and t are the times for pH change of the non-enzy-
1
3
2
50
0
c
ingly, these two relationship were not seen on hCA I matic and the enzymatic reactions, respectively.
enzyme inhibition. (iii) Moving fluorine atom on the
phenyl ring from meta-position (compound (VIh),
In Vitro Inhibition Studies
IC 51.06 and 44.14 µM, for hCA I and hCA II,
50
respectively) to para-position (compound (VIg), IC50
For the inhibition studies of coumarin derivatives,
five different concentrations of these compounds were
added to the medium in 4.2 mL of total reaction vol-
ume including the enzyme solution. Duration (in sec-
onds) of the color change from red to yellow in solu-
tion was measured in a 10-mL glass tube with 1 cm
diameter. Carbonic anhydrase enzyme activity with-
out a compound solution was accepted as 100% activ-
ity. All compounds were tested in triplicate at each
concentration used. Activity % values of carbonic
anhydrase for different concentrations of each com-
pound were determined by regression analysis using
Microsoft Office 2000 Excel. For the compounds hav-
ing an inhibition affect, the inhibitor concentration
1
10.33 and 180.35 µM, for hCA I and hCA II, respec-
tively) led to major enhancement of both hCA I and
hCA II inhibitory activity.
EXPERIMENTAL
Chemistry
Sepharose 4B, L-tyrosine, sulphonamide, syn-
thetic starting material, reagents, and solvents were
purchased from Merck, Alfa Easer, Sigma-Aldrich,
and Fluka. The synthesis and characterization of cou-
marylthiazole substituted arylurea/thiourea deriva-
tives was described in our previous work [30].
causing up to 50% inhibition (IC values) was deter-
50
mined from the graphs.
CONCLUSIONS
Preparation and Purification of Haemolysate
from Red Blood Cells
The effects of coumarylthiazole substituted ary-
lurea/thiourea derivatives on hCA I and II were inves-
tigated and the structure–activity relationship was
examined. All the compounds inhibited hCA I and II.
Among them, compound (Vh) exhibited the strongest
Preparation and purification of haemolysate from
red blood cells were made according to the literature
[
39]. Blood samples (25 mL) were taken from healthy
inhibition against hCA I and II with IC values of 3.13
human volunteers. They were anticoagulated with
50
and 2.65 µM, respectively. Most of urea derivatives
inhibited hCA I and hCA II more actively than
thiourea derivatives. The present study revealed that
activity could also be influenced by the type and posi-
tion of substituent in the phenyl ring.
acid–citrate–dextrose and centrifuged at 2000 g for
2
0 min at 4°C and the supernatant was removed. The
packed erythrocytes were washed three times with
.9% NaCl and then haemolysed in cold water. The
0
ghosts and any intact cells were removed by centrifu-
gation at 2000 g for 25 min at 4°C, and the pH of the
haemolysate was adjusted to pH 8.5 with solid Tris-
base. The 25 mL haemolysate was applied to an affin-
ity column containing L-tyrosine-sulfonamide-Sep-
harose-4B equilibrated with 25 mM Tris-HCl/0.1 M
Na SO (pH 8.5). The affinity gel was washed with
ACKNOWLEDGMENTS
This work was supported by Sakarya University Sci-
entific Research Project (Project no. 2012-02-04-035).
2
4
5
0 mL of 25 mM Tris-HCl/22 mM Na SO (pH 8.5).
REFERENCES
. Supuran, C.T., Nat. Rev. Drug. Discov., 2008, vol. 7,
2
4
The human CA (hCA) isozymes were eluted with
.1 M NaCl/25 mM Na HPO (pH 6.3) and 0.1 M
1
0
2
4
pp. 168–181.
CH COONa/0.5 M NaClO (pH 5.6), which recov-
3
4
2. Neri, D. and Supuran, C.T., Nat. Rev. Drug. Discov.,
ered hCA-I and hCA-II respectively. Fractions of
2011, vol. 10, pp. 767–777.
3
2
mL were collected and their absorbance measured at
80 nm.
3
. Supuran, C.T., Future Med. Chem., 2011, vol. 3,
pp. 1165–1180.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 42
No. 5
2016

IN VITRO INHIBITION EFFECTS ON ERYTHROCYTE CARBONIC ANHYDRASE
511
4
. Supuran, C.T., J. Enzyme Inhib. Med. Chem., 2012, 23. Maresca, A., Temperini, C., Pochet, L., Masereel, B.,
vol. 27, pp. 759–772.
Scozzafava, A., and Supuran, C.T., J. Med. Chem.,
010, vol. 53, pp. 335–344.
2
5. D’Ambrosio, K., Smaine, F.Z., Carta, F., De Simone, G.,
Winum, J.Y., and Supuran, C.T., J. Med. Chem., 2012, 24. Carta, F., Maresca, A., Scozzafava, A., and Supuran, C.T.,
vol. 55, pp. 6776–6783.
Bioorg. Med. Chem., 2012, vol. 20, pp. 2266–2273.
6
. Monti, S.M., Maresca, A., Viparelli, F., Carta, F., De 25. Grandane, A., Tanc, M., Zalubovskis, R., and Supu-
Simone, G., Mühlschlegel, F.A., Scozzafava, A., and
Supuran, C.T., Bioorg. Med. Chem. Lett., 2012, vol. 22,
pp. 859–862.
ran, C.T., Bioorg. Med. Chem. Lett., 2014, vol. 24,
pp. 1256–1260.
2
6. Wagner, J., Avvaru, B.S., Robbins, A.H., Scozzafava, A.,
Supuran, C.T., and McKenna, R., Bioorg. Med. Chem.,
7
8
9
. Vullo, D., Kupriyanova, E.V., Scozzafava, A., Capasso, C.,
and Supuran, C.T., Bioorg. Med. Chem., 2014, vol. 22,
pp. 1667–1671.
2010, vol. 18, pp. 4873–4878.
2
7. Scozzafava, A. and Supuran, C.T., J. Enzyme Inhib.
Med. Chem., 1999, vol. 14, pp. 343–363.
. Prete, S.D., Vullo, D., Fisher, G.M., Andrews, K.T.,
Poulsen, S.A., Capasso, C., and Supuran, C.T., Bioorg.
Med. Chem. Lett., 2014, vol. 24, pp. 4389–4396.
2
8. Pacchiano, F., Aggarwal, M., Avvaru, B.S., Robbins, A.H.,
Scozzafava, A., McKenna, R., and Supuran, C.T.,
Chem. Commun., 2010, vol. 46, pp. 8371–8373.
. Supuran, C.T. and Scozzafava, A., Bioorg. Med. Chem.,
2007, vol. 15, pp. 4336–4350.
2
9. Pacchiano, F., Carta, F., McDonald, P.C., Lou, Y.,
Vullo, D., Scozzafava, A., Dedhar, S., and Supuran, C.T.,
J. Med. Chem., 2011, vol. 54, pp. 1896–1902.
1
0. Husain, A. and Madhesia, D., J. Enzyme Inhib. Med.
Chem., 2012, vol. 27, pp. 773–783.
3
0. Kurt, B.Z., Gazioglu, I., Sonmez, F., and Kucukisl-
1
1. Gao, B.B., Clermont, A., Rook, S., Fonda, S.J., Srini-
vasan, V.J., Wojtkowski, M., Fujimoto, J.G., Avery, R.L.,
Arrigg, P.G., Bursell, S.E., Aiello, L.P., and Feener, E.P.,
Nat. Med., 2007, vol. 13, pp. 181–188.
amoglu, M., Bioorg. Chem., 2015, vol. 59, pp. 80–90.
3
1. Karade, N., Gampawar, S.N., Shinde, S.V., and Jad-
hav, W.N., Chinese J. Chem., 2007, vol. 25, pp. 1686–
689.
1
1
2. Alterio, V., Di Fiore, A., D’Ambrosio, K., Supuran, C.T.,
and De Simone, G., Chem. Rev., 2012, vol. 112,
pp. 4421–4468.
3
2. Karatas, M.O., Alici, B., Cakir, U., Cetinkaya, E.,
Demir, D., Ergun, A., Gencer, N., and Arslan, O.,
J. Enzyme Inhib. Med. Chem., 2013, vol. 28, pp. 299–
13. Poulsen, S.A., Exp. Opin. Ther. Pat., 2010, vol. 20,
304.
pp. 795–806.
3
3. Karatas, M.O., Alici, B., Cakir, U., Cetinkaya, E.,
Demir, D., Ergun, A., Gencer, N., and Arslan, O.,
Artif. Cells Nanomed. Biotechnol., 2014, vol. 42,
pp. 192–198.
1
4. Durdagi, S., Senturk, M., Ekinci, D., Balaydın, H.T.,
Goksu, S., Kufrevioglu, O.I., Innocenti, A., Scozzaf-
ava, A., and Supuran, C.T., Bioorg. Med. Chem., 2011,
vol. 19, pp. 1381–1389.
3
4. Celik, F., Arslan, M., Kaya, M.O., Yavuz, E., Gencer, N.,
and Arslan, O., Artif. Cells Nanomed. Biotechnol., 2014,
vol. 42, pp. 58–62.
15. Aggarwal, M., Kondeti, B., and McKenna, R., Exp.
Opin. Ther. Pat., 2013, vol. 23, pp. 717–724.
1
6. De Simone, G., Alterio, V., and Supuran, C.T., Exp.
3
5. Celik, F., Arslan, M., Yavuz, E., Demir, D., and
Gencer, N., J. Enzyme Inhib. Med. Chem., 2014,
vol. 29, pp. 18–22.
Opin. Drug. Discov., 2013, vol. 8, pp. 793–810.
17. Supuran, C.T., Exp. Opin. Ther. Pat., 2013, vol. 23,
pp. 677–679.
36. Kuday, H., Sonmez, F., Bilen, C., Yavuz, E., Gencer, N.,
and Kucukislamoglu, M., Biomed. Res. Int., 2014, Arti-
cle ID 594879, pp. 1–8.
18. Congiu, C., Onnis, V., Balboni, G., and Supuran, C.T.,
Bioorg. Med. Chem. Lett., 2014, vol. 24, pp. 1776–1779.
37. Sonmez, F., Bilen, C., Sumersan, S., Gencer, N., Isik, S.,
1
9. Parvez, A., Meshram, J., Tiwari, V., Sheik, J., Dongre, R.,
Youssoufi, M.H., and Hadda, T.B., Eur. J. Med.
Chem., 2010, vol. 45, pp. 4370–4378.
Arslan, O., and Kucukislamoglu, M., J. Enzyme Inhib.
Med. Chem., 2014, vol. 29, pp. 118–123.
3
8. Tars, K., Vullo, D., Kazaks, A., Leitans, J., Lends, A.,
Grandane, A., Zalubovskis, R., Scozzafava, A., and
Supuran, C.T., J. Med. Chem., 2013, vol. 56,
pp. 293−300.
20. Kumar, A., Gupta, M.K., and Kumar, M., Tetrahedron
Lett., 2011, vol. 52, pp. 4521–4525.
21. Maresca, A., Temperini, C., Vu H., Pham, N.B.,
Poulsen, S.A., Scozzafava, A., Quinn, R.J., and Supu- 39. Arslan, O., Nalbantoglu, B., Demir, N., Ozdemir, H.,
ran, C.T., J. Am. Chem. Soc., 2009, vol. 131, pp. 3057–
062.
and Kufrevioglu, O.I., Turk. J. Med. Sci., 1996, vol. 26,
pp. 163–166.
3
2
2. Maresca, A., Scozzafava, A., and Supuran, C.T., Bio- 40. Maren, T.H., J. Pharm. Exp. Ther., 1960, vol. 130,
org. Med. Chem. Lett., 2010, vol. 20, pp. 7255–7258. pp. 2629–2634.
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