Synthesis of β-amino acid derivatives and their inhibitory profiles against some metabolic enzymes

Article abstract of DOI:10.1002/ardp.201900200

Sulfamate and its derivatives have a range of biological activities. One-pot cyclocondensation of alkenes (1a–i) with chlorosulfonyl isocyanate generates β-lactams. β-Amino acid derivatives (2a–i) from β-lactams were synthesized. Then, these highly reacti

Full text of DOI:10.1002/ardp.201900200

Received: 11 July 2019
Revised: 9 August 2019
Accepted: 1 September 2019
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DOI: 10.1002/ardp.201900200
F U L L P A P E R
Synthesis of β‐amino acid derivatives and their inhibitory
profiles against some metabolic enzymes
Ufuk Atmaca1,2
İlhami Gülçin1
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Shahla Daryadel1
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Parham Taslimi3
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Murat Çelik1
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1Department of Chemistry, Faculty of Science,
Ataturk University, Erzurum, Turkey
Abstract
2Oltu Vocational School, Ataturk University,
Sulfamate and its derivatives have a range of biological activities. One‐pot
cyclocondensation of alkenes (1a–i) with chlorosulfonyl isocyanate generates
β‐lactams. β‐Amino acid derivatives (2a–i) from β‐lactams were synthesized. Then,
these highly reactive compounds were opened with MeOH to produce the
corresponding sulfamate derivatives in good yields. The inhibitory effects of the
novel sulfamate derivatives were tested on human carbonic anhydrase I and II
isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase
(BChE), and α‐glycosidase (α‐Gly). Novel sulfamate derivatives showed Ki values in
the range of 23.81–42.97 nM against hCA I, 8.95–52.23 nM against hCA II,
8.10–45.51 nM against AChE, 23.16–81.84 nM against BChE, and 14.02–48.68 nM
against α‐Gly. As a result, the novel sulfamate derivatives had potent inhibitory
effects against both isoenzymes. Overall, due to the inhibitory effects of the novel
sulfamate derivatives on the tested metabolic enzymes, they are promising drug
candidates for the treatment of diseases like glaucoma, epilepsy, leukemia,
Alzheimer’s disease, and type 2 diabetes mellitus, which are associated with high
enzymatic activity of the indicated metabolic enzymes.
Oltu‐Erzurum, Turkey
3Department of Biotechnology, Faculty of
Science, Bartin University, Bartin, Turkey
Correspondence
Prof. Murat Çelik, Department of Chemistry,
Faculty of Science, Ataturk University,
Erzurum, Turkey.
Email: mcelik@atauni.edu.tr
Funding information
Türkiye Bilimsel ve Teknolojik Arastirma
Kurumu, Grant/Award Number: 113Z700
K E Y W O R D S
acetylcholinesterase, carbonic anhydrase, enzyme inhibition, α‐glycosidase, β‐amino acid
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1
INTRODUCTION
A lot of sulfamate derivatives exhibit strong inhibition of
isoleucine and valyl transfer RNA. In this study, we have performed
experiments using an equivalent amount of chlorosulfonyl isocya-
nate; β‐amino acid derivatives can be one‐pot synthesized from
alkenes with high efficiency without any catalysts or additives. We
have studied the ideal reaction conditions (Table 1) with high yields
of β‐amino acid derivatives resulting from reaction of commercially
available alkenes with chlorosulfonyl isocyanate (CSI) in dichloro-
methane at 0°C. Conversion of β‐lactams (A) to sulfamates 2a–i
required condition for the ring‐opening step reaction media. Use of
methanol afforded racemic sulfamates (Scheme 1).
Pharmaceutical companies and organic chemists have shown interest
in the potential biological activity of sulfamate and derivatives and
their use in organic chemistry.[1,2] Effective methods for the synthesis
of sulfamate and their derivatives have always been valuable for
organic synthesis and drug discovery. Natural products that include
primary sulfamate compounds in their structure are known. A
number of sulfamate and its derivatives have been synthesized as
potent CA I and II isoenzymes.[3] The primary sulfamate, especially
five‐ring containing sulfamate‐natural products fits according to
dictionary of natural products.[4] First, sulfamates were isolated from
Streptomyces species, which were discovered in the soil microbe
Streptomyces calvus.[5]
The creation of sulfamates with CSI and three pathways has to be
noted. The one‐step (2+2) cycloaddition of alkene and CSI in similar
β‐lactam results in a good yield. The two‐step process is ring‐opening
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Arch Pharm Chem Life Sci. 2019;e1900200.
wileyonlinelibrary.com/journal/ardp
© 2019 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.201900200

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TABLE 1 One‐pot synthesis of β‐amino acid derivatives (2a–i) from alkenes (1a–i)
Entry
Substrate
Product
Yield (%)a
1
76
1a
2a
2
81
1b
2b
3
80
1c
2c
4
74
1d
2d
5
79
1e
2e
6
88
1f
2f
7
85
1g
2g
8
73
1h
(Continues)

ATMACA ET AL.
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TABLE 1 (Continued)
Entry
Substrate
Product
Yield (%)a
2h
9
75
1i
2i
aIsolated yield of pure materials.
with methanol as a nucleophile and the three operate substitution
reaction of sulfamoyl chloride with methanol.
attached to the sulfamoyl function, generating compounds with the
general formula R–O–SO2NH2.[8] Nowadays, there are
large
a
The formation of sulfamate 2i has a wide range of examples in
bicyclic alkene addition of CSI—especially, bicyclic alkene reaction of
CSI, which was expected as the nonclassical carbocation rearrange-
ment product. No rearrangement product was observed (Scheme 2).
The sulfamate (R–OSO2NH2) group is the closest congener and
bioisostere to the primary sulfonamide group (R–SO2NH2).[6] The CA
inhibitory properties of sulfamate derivatives are well known.[7] It
was reported small molecule CA inhibitors incorporate a primary
sulfamate (–OSO2NH2) as a zinc‐binding functional group that blocks
enzyme activity by coordinating with catalytic zinc. The most obvious
bioisosteres of this group are sulfamates, in which an additional
electron‐withdrawing atom/group (O or NH, respectively) is directly
number of aromatic, heterocyclic, aliphatic and sugar‐based sulfa-
mates, which are shown to possess highly effective inhibitory
properties against all known mammalian CA isoforms.[9]
Enzymes play a key role in the regulation of the metabolism of all
organisms.[10,11] Carbonic anhydrases (CAs; E.C.4.2.1.1) catalyze carbon
dioxide (CO2) and reversibly convert them to bicarbonates (HCO3−) and
protons (H+).[12–14] This reaction has a crucial role in some vital
physiologic functions linked to the metabolic pathways involved in CO2.
CAs are found in eukaryotic and prokaryotic cells. They are encoded by
seven distinct gene families, α‐, β‐, γ‐, δ‐, ζ‐, η‐ and θ‐CAs.[15–17] Only the α‐
CA family is found in mammals. In mammals, when CO2 in the blood
plasma passes into red blood cells by diffusion, it is rapidly converted to
SCHEME 1 General procedure
synthesis of β‐amino acid derivatives
1a–h
A
2a–h
SCHEME 2 Synthesis of methyl‐3‐((methoxysulfonyl)amino)‐1,2,3,4‐tetrahydro‐1,4‐methanonaphthalene‐2‐carboxylate (2i)

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carbonic acid by CA enzyme.[18–22] To date, 16 different α‐CA isoenzymes
have been characterized in mammals by means of their amino acid
sequence, catalytic activity, biochemical properties, subcellular localiza-
tion, and sensitivity to inhibitors and activators. They are responsible for
numerous processes in vivo and localized in different tissues.[23] These
isoenzymes are grouped as cytoplasmic CAs (CAs I, II, III, VII, and XIII),
membrane bound CAs (CAs IV, IX, XII, XIV, and XV), mitochondrial CAs
(CA V), secretory CAs (CA VI), and CA‐related proteins (CA‐RPs: CAs VIII,
X, and XI). CA‐RPs have not performed CO2 hydration activity and
physiological function.[24,25] Due to these important physiological func-
tions, numerous studies have been carried out on CAs. CAs I and II are
the most‐studied isoenzymes.[26,27] CA I is expressed in erythrocytes and
the gastrointestinal tract, whereas CA II is expressed in almost all tissues.
CAs I and II are involved in important metabolic functions such as gas
exchange, and ion transport.[28,29] CA inhibitors (CAIs) are mainly used in
therapy as diuretics and antiglaucoma agents but some of them also show
marked anticonvulsant, antitumor and antiobesity effects.[30] For this
purpose, development of novel CAIs is very important.
methanol (MeOH). MeOH attacks nucleophiles. So, we synthesized β‐
amino acid derivatives (2a–i) with high efficiency (Scheme 3).
Initially, we examined cyclocondensation of cyclopentene (1a) with
CSI at 0°C, which afforded the corresponding β‐lactams. After this,
methyl 2‐((methoxysulfonyl)amino)cyclopentane‐1‐carboxylate (2a)
yielded β‐lactams as intermediate products by the nucleophilic reaction
of MeOH in Scheme 2 and in a good yield, as shown in Entry 1, Table 1.
Thus, we achieved one‐pot synthesis of β‐amino acid derivatives
from various alkenes in mild condition without any catalysts or
additives by using CSI (Table 1). As reported in the literature,[42]
cyclocondensations were regioselective, and formed selective single‐
regioisomer products (2e–g). β‐Amino acid derivatives are transfor-
mations of β‐lactams in the one‐pot with MeOH.
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2.1
Biochemical studies
Human CA inhibition has been the subject by investigations since the
discovery of the biological importance of CA in living organisms.[43] In
recent years, many novel compounds and their derivatives have been
arising as main classes of hCA inhibitors, including hCA I and II
isoenzymes.[44–46] Considering the fact that novel sulfamate deriva-
tives (2a–i) are found to be effective CA inhibitors, we synthesized
novel sulfamate derivatives (2a–i) to explore their possible hCAs I
and II, AChE, BChE, and α‐glycosidase inhibition effects. The
inhibition data are summarized in Table 2. For evaluation of the
effect of novel sulfamate derivatives (2a–i) on the indicated
metabolic enzymes, the following results have been depicted.
α‐Glycosidase (E.C.3.2.1.20) is released from intestine cells and
hydrolyzes oligosaccharides and polysaccharide to monosaccharide
units including glucose and fructose in small intestine.[31,32] α‐
Glycosidase inhibitors (α‐GIs) have great importance for controlling
of type 2 diabetes mellitus (T2DM) and hyperglycemia in humans.[33,34]
α‐GIs can reduce the uptake of dietary carbohydrates and repress
postprandial hyperglycemia and T2DM. Thus, these α‐GIs are
endowed with sugar molecules such as compete and moieties with
the oligosaccharides for binding to the active site of the enzyme, hence
effectively reducing the postprandial glucose levels in T2DM.[35,36]
Alzheimer’s disease (AD) is a significant problem for old people
worldwide. This disease can affect many aspects of a person’s life.
Also, there is no cure for AD, but several drugs are employed for the
cure.[37,38] For the treatment of AD, one of the most successful
methods developed so far is acetylcholinesterase (AChE; E.C.3.1.1.7)
inhibition. AChE inhibitors (AChEIs) have been developed as an
impact of the cholinergic assumption of cognitive decline.[39] Also, the
effectiveness of these treatments has been investigated in a large
number of randomized controlled tests between cognitive, global,
neuropsychiatric domains, and functional.[40] AChEIs are employed
for the treatment of mild‐to‐moderate AD. These compounds inhibit
AChE, which is responsible for the separation of acetylcholine (ACh),
a neurotransmitter molecule related to memory function.[41]
The physiologically relevant hCA I is found at the highest level in
erythrocytes and is also expressed in normal colorectal mucosa.[47] As
for CA I, novel sulfamate derivatives (2a–i) showed Ki values in the low
nanomolar range. Ki constant refers to the binding affinity of the
inhibitor to the enzyme. Small Ki value indicates that the inhibitor is
bound to the enzyme with strong affinity.[48] To determine the
inhibition types and Ki constants of novel sulfamate derivatives (2a–i),
Lineweaver–Burk graphs were drawn.[49] Novel sulfamate derivatives
(2a–i) demonstrated low nanomolar inhibition levels on CA
I
isoenzyme. The Ki values of novel sulfamate derivatives (2a–i) were
found between 23.81 and 42.97 nM for hCA I (Table 2). Also, methyl 2‐
((methoxysulfonyl)amino)cyclopentane‐1‐carboxylate (2a), which con-
tains cyclopentene moiety, had a strong inhibition effect against hCA I
isoenzyme (Ki: 23.81 8.43 nM). On the contrary, acetazolamide
In the light of this information, in this study, we investigated the
effects of novel sulfamate derivatives (2a–i) on hCA I and II
isoenzymes, acetylcholinesterase, butyrylcholinesterase, and α‐gly-
cosidase enzymes. Also, their inhibition profiles were compared to
acetazolamide as a clinically used inhibitor.
(AZA), which is used as
a reference inhibitor, had Ki values
141.02 50.84 for hCA I isoenzyme. AZA, as a sulfonamide‐based
drug, is widely used as an excellent inhibitor of CA II isoenzyme. It
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2
RESULTS AND DISCUSSION
The cyclocondensation of alkenes with CSI was efficiently carried out
and β‐lactams at low temperature were provided without using any
additives or catalysts. Then, the reaction mixture was added to
SCHEME 3 Synthesis of methyl 2‐((methoxysulfonyl)amino)‐
cyclopentane‐1‐carboxylate (2a)

ATMACA ET AL.
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exhibits minimal toxicity and provides good pharmacokinetic proper-
ties. However, this drug still exhibits a number of undesired side
effects. It causes an increase in the volume of urine, finally leading to
an increased release of sodium and potassium ions[50]; its application
might lead to fatigue or a numbness of extremities.[23,51,52] All of these
undesired side effects are a result of the nonspecific inhibition of CAs.
These results clearly showed that the novel sulfamate derivatives
(2a–i) had a stronger inhibitory effect than AZA against hCA I
isoenzyme (Table 2). Also, the selectivity index values of the novel
sulfamate derivatives (2a–i) are given in Table 3. Recently, it was
proved that eight sulfamates, derived from menthol, inhibited hCA I
isoenzyme in the range of 34.37 8.17 to 53.40 10.61 nM.[53] In
previous studies, it was found that some novel Tris‐chalcones (Ki:
9.9–39.5 nM),[54] new phenolic Mannich bases with piperazines (Ki:
0.209–0.484 nM),[55] bromophenol derivatives (Ki: 7.8–58.3 nM),[56]
and novel pyrazoline derivatives (Ki: 17.4–40.7 nM)[57] had powerful
inhibition effects against hCA I isoenzyme, which were found to be at
the highest level in erythrocytes.
CA II belongs to one of the most important enzyme groups of the
human body. It is a well‐studied isozyme from the CA family. CA II
isoenzyme is also involved in the primary transport mechanism of Na
into the eye. As a consequence of this transport, it is responsible for
the regulation of the intraocular pressure (IOP).[58] Thus, inhibition of
CA II decreases an elevated IOP usually accompanying glaucoma.
This high IOP damages the eye’s optic nerve. The treatment of
glaucoma was a major reason to have a closer look at CA II
inhibitors.[59] Also, another important pharmaceutical application of
CA II inhibitors is their usage for the treatment of bone loss, which is
most often observed during postmenopausal osteoporosis.[60] Most
of the inhibitors for CA II are sulfamates that bind directly to the
metal center in the active site of hCA II, which is the physiologically
dominant and highly active cytosolic isoform.[9,26,34] As shown in
Table 2, the inhibition profile of the considered novel sulfamate
derivatives (2a–i) against cytosolic dominant hCA II revealed to be
quite similar to that shown toward CA II. They demonstrated Ki
values between 8.95 0.49 and 52.23 15.48 nM. On the contrary,
AZA, which is used to treat glaucoma, altitude sickness, epilepsy,
periodic paralysis, heart failure, and idiopathic intracranial hyperten-
sion,[61] has a Ki value of 22.17 0.65 nM against hCA II. In our recent
studies, it was found that eight sulfamates derived from menthol
inhibited hCA II isoenzyme in the range of 12.91 4.57 to
38.67 6.22 nM.[26] Recently, it was found that some novel
Tris‐chalcones (Ki: 3.1–20.1 nM),[54] new phenolic Mannich bases
with piperazines (Ki: 0.342–0.526 nM),[55] bromophenol derivatives
(Ki: 43.1–150.2 nM),[56] and novel pyrazoline derivatives (Ki:
16.1–55.2 nM)[57] had marked inhibitory effects against hCA II
isoenzyme, which is responsible for the regulation of IOP.
AChE and BChE inhibition properties of the novel sulfamate
derivatives (2a–i) were recorded according to the procedure of Ellman
et al.[62] as described previously.[63] Novel sulfamate derivatives (2a–i)
had Ki values ranging from 8.10 0.97 to 45.51 2.01 nM for AChE and
23.16 7.72 to 881.84 24.12 nM for BChE. On the contrary, tacrine
had Ki values of 5.99 1.79 and 2.43 0.92 nM toward both cholinergic

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AChE and BChE, respectively. All evaluated novel sulfamate derivatives
(2a–i) showed effective inhibition against both cholinergic enzymes, but
methyl‐3‐((methoxysulfonyl)amino)‐1,2,3,4‐tetrahydro‐1,4‐methano-
naphthalene‐2‐carboxylate (2i), which had (1R,4S)1,4‐dihydro‐1,4‐metha-
nonaphthalene, showed perfect inhibition effect against AChE (Ki:
8.10 0.97 nM). Also, selectivity index values of novel sulfamate
derivatives (2a–i) are given in Table 3. On the contrary, methyl 2‐
((methoxysulfonyl)amino)cyclopentane‐1‐carboxylate (2a), which contains
cyclopentene moiety, demonstrated the best inhibition effect against
BChE (Ki: 23.16 7.72 nM) enzymes (Table 2). Also, it was found that
some novel Tris‐chalcones (Ki: 3.1–20.1 nM on AChE, and 4.9–14.7 nM
on BChE),[54] novel Tris‐chalcones (Ki: 9.9–39.5 nM),[55] bromophenol
derivatives (Ki: 159.6–924.2 nM against AChE),[56] and novel pyrazoline
derivatives (Ki: 48.2–84.1 nM on AChE)[57] effectively inhibited both
cholinergic enzymes.
β‐amino acid derivatives may be important for organic synthesis
and biological purposes. The inhibitory effects of some sulfonamides
on hCA I and II isoenzymes, AChE, BChE, and α‐glycosidase were
evaluated together. The sulfonamides we used in our study showed
inhibition effects on hCA I and II isoenzymes, AChE, BChE and α‐
glycosidase activities at low concentrations. We believe that these
results may be useful in the synthesis of new CA isoenzyme inhibitors
and in the development of drugs for the treatment of some diseases.
Especially, the new β‐amino acid derivatives (2a–i) can be candidates
for anticholinergic, antiepileptic, antiglaucoma, and antidiabetic
applications. Furthermore, it is thought that there will be a need
for clinical studies before application is recommended.
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4
EXPERIMENTAL
Chemistry
Finally, for the α‐glycosidase, which is present on cells lining the
intestine, hydrolyzing monosaccharides are absorbed through the
intestine, and novel sulfamate derivatives (2a–i) exhibit Ki values
between 14.02 3.73 and 48.68 0.24 nM (Table 2). The results
obtained from α‐glycosidase assay showed that all novel sulfamate
derivatives (2a–i) had effective α‐glycosidase inhibition effects than
that of acarbose (IC50: 22.800 mM) as a standard α‐glycosidase
inhibitor.[64] Also, highly effective Ki values were obtained for methyl
2‐((methoxysulfonyl)amino)cyclohexane‐1‐carboxylate (2b) bearing
cyclohexene moiety (Ki value of 14.02 3.73 nM). The inhibition of
α‐glycosidase had great importance in treating and preventing
diabetes, postprandial glucose amounts, and hyperglycemia.[65–68]
In a recent study, it was reported that some novel Tris‐chalcones had
effective inhibition profiles against α‐glycosidase, with hydrolysis of
glycosidic bonds in complex sugars, with Ki values in the range of
3.9–22.4 nM.[54]
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4.1
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4.1.1
General remarks
All chemicals and solvents are commercially available. Infrared (IR)
spectra are obtained from solutions in 0.1‐mm cells and in
dichloromethane (DCM) with a Perkin–Elmer spectrophotometer.
1H‐NMR and 13C‐NMR spectra (see the Supporting Information) are
recorded on Bruker and Varian spectrometers at 400 and 100 MHz,
respectively, and NMR shifts are presented as δ in ppm. Elemental
analyses are performed on LECO CHNS‐932 apparatus. All column
chromatography is performed on silica gel (60‐mesh; Merck).
The InChI codes of the investigated compounds are provided as
Supporting Information.
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4.1.2
General procedure for the synthesis of
β‐amino acid derivatives
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3
CONCLUSION
Alkene (1 eq) was dissolved in 20 ml dichloromethane. The reaction
mixture was cooled to 0°C and CSI (1.1 eq) was added, and resulting
solution was stirred for 2 hr. Then, the reaction mixture was added to
MeOH and stirred for 1 hr. The reaction mixture was extracted with
In summary, starting from the appropriate reagents, the new β‐amino
acid derivatives (2a–i) were synthesized. One‐pot synthesized
TABLE 3 Selectivity index values of novel sulfamate derivatives (2a–i)
Compound
Ki(hCA II)/Ki(hCA I)
0.479
Ki(AZA)/Ki(hCA I)
5.922
Ki(AZA)/Ki(hCA II)
1.941
Ki(AChE II)/Ki(BChE)
0.973
Ki(TAC)/Ki(AChE)
0.265
Ki(TAC)/Ki(BChE)
0.105
2a
2b
2c
2d
2e
2f
0.403
2.281
1.277
1.475
0.131
0.079
0.595
5.584
1.477
0.682
0.139
0.038
0.316
4.973
2.478
0.470
0.225
0.043
0.364
3.393
1.466
0.202
0.406
0.033
0.302
3.285
1.706
0.508
0.415
0.086
2g
2h
2i
0.612
5.516
1.311
0.183
0.531
0.040
1.598
4.314
0.424
0.195
0.374
0.029
0.506
3.797
1.179
0.172
0.740
0.520
Abbreviations: AChE, acetylcholinesterase; AZA, acetazolamide; BChE, butyrylcholinesterase; hCA I, human carbonic anhydrase I isoenzyme; hCA II,
human carbonic anhydrase II isoenzyme; TAC, tacrine.

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DCM. The organic phase was dried over sodium sulfate and
concentrated. Purification was performed through thin layer and
column chromatography on silica gel.
1,174, and 1,001; Elemental analysis: C, 48.34; H, 5.53; N, 5.13; S,
11.73. Found: 48.02; H, 5.42; N, 5.38; S, 11.96.
Methyl 1‐((methoxysulfonyl)amino)‐2,3‐dihydro‐1H‐indene‐2‐car-
boxylate (2g)
Methyl 2‐((methoxysulfonyl)amino)cyclopentane‐1‐carboxylate (2a)
1H‐NMR (400 MHz, CDCl3, ppm): 5.47 (bd, 1H, J: 8.4 Hz), 3.86–3.92
(m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.05–2.99 (m, 1H), and 2.06–1.55
(m, 6H). 13C‐NMR (100 MHz, CDCl3, ppm): δ = 175.1, 57.0, 56.4, 52.2,
46.3, 32,1, 28.3, and 21.8; IR (CH2Cl2, cm−1): 3,559, 3,291, 2,956,
1,716, 1,438, 1,362, 1,176, and 998; Elemental analysis: C, 40.50; H,
6.37; N, 5.90; S, 13.51. Found: 40.58; H, 6.42; N, 5.54; S, 13.28.
1H‐NMR (400 MHz, CDCl3, ppm): 7.47–7.45 (m, 1H), 7.31–7.21 (m,
3H), 5.55 (bd, 1H, J: 9.5 Hz), 5.18–5.14 (m, 1H), 3.85 (s, 3H), 3.73 (s,
3H), and 3.68–3.60 (m, 2H). 13C‐NMR (100 MHz, CDCl3, ppm):
δ = 173.7, 140.4, 140.3, 129.2, 127.8, 125.1, 124.5, 60.2, 52.4, 48.1,
34.5, and 29.9; IR (CH2Cl2, cm−1): 3,418, 2,953, 2,848, 1,720, 1,644,
1,457, 1,364, 1,179, and 982; Elemental analysis: C, 50.52; H, 5.30; N,
4.91; S, 11.24. Found: 50.34; H, 5.28; N, 4.67; S, 11.28.
Methyl 2‐((methoxysulfonyl)amino)cyclohexane‐1‐carboxylate (2b)
1H‐NMR (400 MHz, CDCl3, ppm): 5.62 (bs, 1H), 3.80 (s, 3H), 3.72 (s, 3H),
3.55–3.53 (m, 1H), 2.95–2.93 (m, 1H), and 2.16–1.20 (m, 8H). 13C‐NMR
(100 MHz, CDCl3, ppm): δ = 174.5, 53.7, 52.1, 44.9, 29.9, 29.7, 27.6,
24.3, and 22.5; IR (CH2Cl2, cm−1): 3,606, 3,309, 2,951, 2,862, 1,731,
1,454, 1,367, 1,178, and 997; Elemental analysis: C, 43.02; H, 6.82; N,
5.57; S, 12.76. Found: 43.32; H, 6.51; N, 5.43; S, 12.48.
Methyl 3‐((methoxysulfonyl)amino)bicyclo[2.2.1]heptane‐2‐carboxy-
late (2h)
1H‐NMR (400 MHz, CDCl3, ppm): 5.58 (bd, 1H, J: 8.4 Hz), 3.78 (s,
3H), 3.68 (s, 3H), 3.64–3.60 (m, 1H), 2.74 (d, 1H, J: 8.4 Hz), 2.43 (m,
1H), 2.37 (m, 1H), 1.86–1.83 (m, 1H), 1.60–1.52 (m, 2H), and
1.27–1.19 (m, 3H). 13C‐NMR (100 MHz, CDCl3, ppm): δ = 174.0,
59.2, 56.4, 52.2, 51.7, 42.7, 41.4, 34.5, 28.8, and 26.4; IR (CH2Cl2,
cm−1): 3,457, 3,289, 2,256, 2,129, 1,658, 1,360, 1,024, and 1,003;
Elemental analysis: C, 45.62; H, 6.51; N, 5.32; S, 12.18. Found:
45.76; H, 6.45; N, 5.61; S, 12.01.
Methyl 2‐((methoxysulfonyl)amino)cycloheptane‐1‐carboxylate (2c)
1H‐NMR (400 MHz, CDCl3, ppm): 5.27 (bd, 1H, J: 8.1 Hz) 3.81 (s, 3H),
3.73 (s, 3H), 3.65–3.63 (m, 1H), 3.07–3.05 (m, 1H), and 1.98–1.25 (m,
10H). 13C‐NMR (100 MHz, CDCl3, ppm): δ = 174.7, 56.9, 48.1, 33.4,
29.9, 27.0, 26.9, 24.8, and 24.4. IR (CH2Cl2, cm−1): 3,542, 3,302, 2,924,
2,855, 1,723, 1,435, 1,360, 1,169, and 1,001; Elemental analysis: C,
45.27; H, 7.22; N, 5.28; S, 12.08. Found: 45.58; H, 7.40; N, 5.76; S, 12.23.
Methyl 3‐((methoxysulfonyl)amino)‐1,2,3,4‐tetrahydro‐1,4‐methano-
naphthalene‐2‐carboxylate (2i)
1H‐NMR (400 MHz, CDCl3, ppm): 7.29–7.25 (m, 1H), 7.19–7.11 (m,
3H), 5.76 (bd, 1H, NH, J: 9.4 Hz), 3.83 (s, 3H), 3.77 (s, 3H), 3.73–3.71
(m, 1H), 3.47 (s, 2H), 2.81 (d, 1H, J: 8.1 Hz), 2.30 (d, 1H, J: 9.8 Hz), and
1.94 (d, 1H, J: 9.8 Hz). 13C‐NMR (100 MHz, CDCl3, ppm): δ = 174.3,
146.8, 145.1, 127.2, 127.0, 122.7, 121.2, 57.6, 52.7, 50.4, 50.3, 48.5,
48.3, 48.2, and 44.9; IR (CH2Cl2, cm−1): 3,427, 3,267, 2,255, 2,128,
1,658, 1,456, 1,236, and 1,027; Elemental analysis: C, 54.01; H, 5.50;
N, 4.50; S, 10.30. Found: C, 54.24; H, 5.73; N, 4.35; S, 10.04.
Methyl 2‐((methoxysulfonyl)amino)cyclooctane‐1‐carboxylate (2d)
1H‐NMR (400 MHz, CDCl3, ppm): 5.21 (bs, 1H, J: 8.0 Hz), 3.86–3.83
(m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 2.98–2.94 (m, 1H), and 1.98–1.54
(m, 12H). 13C‐NMR (100 MHz, CDCl3, ppm): δ = 174.9, 54.3, 52.2,
52.1, 47.5, 32.4, 27.3, 26.4, 26.0, 25.1, and 24.7; IR (CH2Cl2, cm−1):
3,428, 2,923, 2,854, 1,722, 1,643, 1,436, 1,358, 1,174, and 998;
Elemental analysis: C, 47.30; H, 7.58; N, 5.01; S, 11.48. Found: 47.62;
H, 7.66; N, 4.92; S, 11.25.
|
4.2
Biochemical studies
CA inhibition studies
|
4.2.1
Methyl 2‐((methoxysulfonyl)amino)cyclohex‐3‐ene‐1‐carboxylate (2e)
1H‐NMR (400 MHz, CDCl3, ppm): 5.87–5.83 (m, 1H, A part of AB
system), 5.79–5.75 (m, 1H, B part of AB system), 5.36 (bd, 1H, J:
9.7 Hz), 4.27–4.23 (m, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.02–2.97 (m,
1H), and 2.07–1.92 (m, 4H). 13C‐NMR (100 MHz, CDCl3, ppm):
δ = 173.4, 130.4, 126.7, 56.4, 51.9, 50.8, 43.1, 22.8, and 22.5; IR
(CH2Cl2, cm−1): 3,509, 3,284, 2,954, 2,848, 1,726, 1,436, 1,359,
1,222, 1,179, and 996; Elemental analysis: C, 43.36; H, 6.07; N, 5.62;
S, 12.86. Found: 43.18; H, 6.32; N, 5.34; S, 13.01.
In this study, both hCA I and II isoenzymes were purified by
Sepharose‐4B‐L‐tyrosine‐sulfanilamide affinity chromatography.[69,70]
It was used as an affinity matrix for selective retention of both hCA
isoenzymes.[71] The activity of both hCA isoenzymes was spectro-
photometrically determined according to Verpoorte et al.[72] as
described previously in details.[73] p‐Nitrophenylacetate (PNA) was
used as a substrate and transformed to p‐nitrophenolate ions.[74] One
enzyme unit is accepted as the amount of CA, which had absorbance
change at 348 nm of PNA to PNP (p‐nitrophenolate) over a period of
3 min at 25°C.[75,76] The inhibition parameters of each sulfamate
derivatives (2a–i) and an activity (%; novel sulfamate derivatives)
graph was drawn. From these graphs, IC50 values for each sulfamate
derivatives (2a–i) were determined. Also, for calculation of Ki values,
three different novel sulfamate derivatives (2a–i) concentrations
were used. Then, Lineweaver–Burk graphs were drawn according
Methyl 3‐((methoxysulfonyl)amino)‐3‐phenylpropanoate (2f)
1H‐NMR (400 MHz, CDCl3, ppm): 7.29–7.39 (m, 5H), 5.79 (bd, 1H,
NH, J: 6.7 Hz), 4.85 (dd, 2H, J: 15.8, 8.12 Hz), 3.66 (s, 3H), 3.64 (s, 3H),
and 2.95 (dd, 1H, J: 2.2, 5.86 Hz). 13C‐NMR (100 MHz, CDCl3, ppm):
δ = 171.46, 139.5, 129.1, 128.5, 126.6, 56.7, 54.9, 52.3, and 40.6; IR
(CH2Cl2, cm−1): 3,428, 2,924, 2,853, 2,104, 1,644, 1,456, 1,365,

8 of 9
ATMACA ET AL.
|
to these measurement results. Ki values for novel sulfamate
derivatives (2a–i) were determined from Lineweaver–Burk graphs[77]
as described previously in details.[78,79]
[2] M. Nivsarkar, D. Thavaselvam, S. Prasanna, M. Sharma, M. P.
Kaushik, Bioorg. Med. Chem. Lett. 2005, 15, 1371.
[3] F. Abbate, C. T. Supuran, A. Scozzafava, P. Orioli, M. T. Stubbs, G.
Klebe, J. Med. Chem. 2002, 45, 3583.
Protein quantity during the purification stages was estimated
according to the Bradford technique.[80] Bovine serum albumin was
used as the standard protein.[81] Sodium dodecyl sulfate‐polyacryla-
mide gel electrophoresis was used for visualizing both isoenzymes[82]
and described in previous studies.[83,84]
[4] P. Mujumdar, S. A. Poulsen, J. Nat. Prod. 2015, 78, 1470.
[5] R. I. Hewitt, A. R. Gumble, L. H. Taylor, W. S. Wallace, Antibiot. Annu.
1957, 722.
[6] F. Carta, C. T. Supuran, A. Scozzafava, Fut. Med. Chem. 2014, 6, 1149.
[7] A. Nocentini, D. Moi, G. Balboni, S. Salvadori, V. Onnis, C. T. Supuran,
Bioorg. Chem. 2018, 77, 633.
[8] V. Alterio, A. Di Fiore, K. D’Ambrosio, C. T. Supuran, G. De Simone,
Chem. Rev. 2012, 112, 4421.
[9] C. T. Supuran, Nat. Rev. Drug Discov. 2008, 7, 168.
[10] C. Caglayan, Y. Demir, S. Kucukler, P. Taslimi, F. M. Kandemir, İ.
Gulçin, J. Food Biochem. 2019, 43, e12720.
|
4.2.2
AChE/BChHE inhibition studies
The inhibitory effect of novel sulfamate derivatives (2a–i) on AChE/
BChE activities was performed according to Ellman’s method[62] as
described previously.[85] Acetylthiocholine iodide/butrylcholine io-
dide (AChI/BChI) was used as substrate for both cholinergic
reactions. In brief, an aliquot (100 μl) of Tris/HCl buffer (1.0 M, pH
8.0) and different concentration of sample solutions (10–30 μg/ml)
were added to 50 μl of AChE/BChE enzymes solution
(5.32 × 10−3 EU). The solutions were incubated at 20°C for 10 min.
An aliquot (0.5 mM, 50 μl) of DTNB (5,5′‐dithio‐bis(2‐nitro‐benzoic)
acid) and AChI/BChI were added to incubation mixture and
enzymatic reactions were initiated. AChE/BChE activities were
spectrophotometrically determined at 412 nm.[86]
[11] F. Turkan, A. Cetin, P. Taslimi, M. Karaman, İ. Gulçin, Bioorg. Chem.
2019, 86, 420.
[12] K. Kucukoglu, H. İ. Gul, P. Taslimi, İ. Gulcin, C. T. Supuran, Bioorg.
Chem. 2019, 86, 316.
[13] F. Erdemir, D. B. Celepci, A. Aktaş, Y. Gök, R. Kaya, P. Taslimi, Y.
Demir, İ. Gulçin, Bioorg. Chem. 2019, 91, 103134.
[14] S. Burmaoglu, A. O. Yilmaz, M. F. Polat, R. Kaya, İ. Gulcin, O. Algul,
Bioorg. Chem. 2019, 85, 191.
[15] C. Bayrak, P. Taslimi, H. S. Karaman, İ. Gulcin, A. Menzek, Bioorg.
Chem. 2019, 85, 128.
[16] Ş. Aras Hisar, O. Hisar, Ş. Beydemir, İ. Gülçin, T. Yanik, Acta Vet.
Hung. 2004, 52, 413.
[17] D. Ozmen Ozgun, H. İ. Gul, C. Yamali, H. Sakagami, İ. Gulcin, M.
Sukuroglu, C. T. Supuran, Bioorg. Chem. 2019, 84, 511.
[18] İ. Gülçin, Ş. Beydemir, M. E. Büyükokuroğlu, Biol. Pharm. Bull. 2004,
27, 613.
[19] S. Bayindir, C. Caglayan, M. Karaman, İ. Gülcin, Bioorg. Chem. 2019,
90, 103096.
|
4.2.3
α‐Glycosidase inhibition studies
α‐Glycosidase's inhibition effect of novel sulfamate derivatives (2a–i)
was evaluated according to the method of Tao et al.[64] First, phosphate
buffer (pH 7.4, 75 μl) was mixed with 5 μl of the sample and α‐
glycosidase enzyme solution (20 μl), which was prepared in phosphate
buffer (0.15 U/ml, pH 7.4). After preincubation, 50 μl of p‐nitrophenyl‐D‐
glycopyranoside (p‐NPG) in phosphate buffer (5 mM, pH 7.4) was added,
and the solution was reincubated at 37°C. The absorbance of mixtures
was recorded at 405 nm. For the determination of Ki values, three
different novel sulfamate derivatives (2a–i) concentrations were used.
Then, the Lineweaver–Burk graphs were drawn.[77]
[20] O. Hisar, Ş. Aras Hisar, T. Yanık, Turk. J. Vet. Anim. Sci. 2005, 29, 1081.
[21] I. Gülçin, Ş. Beydemir, M. E. Büyükokuroğlu, Biol. Pharm. Bull. 2004,
27, 613.
[22] O. Hisar, Ş. Beydemir, I. Gülçİn, Ö. İ. Küfrevİoğlu, C. T. Supuran, J.
Enzyme Inhib. Med. Chem. 2008, 20, 35.
[23] C. T. Supuran, Bioorg. Med. Chem. Lett. 2010, 20, 3467.
[24] S. Ökten, M. Ekiz, Ü. M. Koçyiğit, A. Tutar, I. Çelik, M. Akkurt, F.
Gökalp, P. Taslimi, I. Gülçin, J. Mol. Struct. 2019, 1175, 906.
[25] A. Biçer, P. Taslimi, G. Yakalı, I. Gülçin, M. Serdar Gültekin, G. Turgut
Cin, Bioorg. Chem. 2019, 82, 393.
[26] S. Daryadel, U. Atmaca, P. Taslimi, I. Gülçin, M. Çelik, Arch. Pharm.
Chem. Life Sci. 2018, 351, e1800209.
[27] T. A. Çoban, Ş. Beydemir, İ. Gülçin, D. Ekinci, Biol. Pharm. Bull. 2007,
30, 2257.
[28] F. Turkan, A. Cetin, P. Taslimi, İ. Gulçin, Arch. Pharm. Chem. Life Sci.
2018, 351, e1800200.
ACKNOWLEDGMENT
[29] M. Şentürk, İ. Gülçin, A. Daştan, Ö. İrfan Küfrevioğlu, C. T. Supuran,
Bioorg. Med. Chem. 2009, 17, 3207.
Financial support from the Türkiye Bilimsel ve Teknolojik Arastirma
Kurumu (TUBİTAK; 113Z700) is gratefully acknowledged.
[30] A. Scozzafava, M. Passaponti, C. T. Supuran, I. Gülçin, J. Enzyme Inhib.
Med. Chem. 2015, 30, 586.
[31] I. Gulçin, P. Taslimi, A. Aygün, N. Sadeghian, E. Bastem, O. I.
Kufrevioglu, F. Turkan, F. Şen, Int. J. Biol. Macromol. 2018, 119, 741.
[32] P. Taslimi, H. E. Aslan, Y. Demir, N. Oztaskin, A. Maraş, I. Gulçin, S.
Beydemir, S. Goksu, Int. J. Bio. Macromol. 2018, 119, 857.
[33] G. Gondolova, P. Taslimi, A. Medjidov, V. Farzaliyev, A. Sujayev, M.
Huseynova, O. Şahin, B. Yalçın, F. Turkan, I. Gulçin, J. Biochem. Mol.
Toxicol. 2018, 32, e22197.
ORCID
Parham Taslimi
Murat Çelik
http://orcid.org/0000-0002-3171-0633
http://orcid.org/0000-0003-3485-7822
[34] Y. Demir, P. Taslimi, M. S. Ozaslan, N. Oztaskin, Y. Çetinkaya, İ.
Gulçin, Ş. Beydemir, S. Goksu, Arch. Pharm. Chem. Life Sci. 2018, 351,
e1800263.
REFERENCES
[1] J. Mittendorf, F. Kunisch., M. Matzke, H. C. Militzer, A. Schmidt, W.
[35] G. Maharramova, P. Taslimi, A. Sujayev, V. Farzaliyev, L. Durmaz, İ.
Gulçin, J. Biochem. Mol. Toxicol. 2018, 32, e22221.
Schönfeld, Bioorg. Med. Chem. Lett. 2003, 13, 433.

ATMACA ET AL.
9 of 9
|
[36] A. Aktaş, D. Barut Celepci, R. Kaya, P. Taslimi, Y. Gök, M. Aygün, İ.
Gülçin, Polyhedron 2019, 159, 345.
[67] E. Güzel, Ü. M. Koçyiğit, B. S. Arslan, M. Ataş, P. Taslimi, F. Gökalp, M.
Nebioğlu, İ. Şişman, İ. Gulçin, Arch. Pharm. Chem. Life Sci. 2019, 352,
e1800292.
[37] N. Eruygur, U. M. Koçyiğit, P. Taslimi, M. Ataş, M. Tekin, İ. Gülçin, S.
Afr. J. Bot. 2019, 120, 141.
[68] A. Maharramov, R. Kaya, P. Taslimi, M. Kurbanova, A. Sadigova, V.
Farzaliyev, A. Sujayev, İ. Gulçin, Arch. Pharm. Chem. Life Sci. 2019,
352, e1800317.
[38] B. Kuzu, M. Tan, P. Taslimi, İ. Gülçin, M. Taşpınar, N. Menges, Bioorg.
Chem. 2019, 86, 187.
[39] E. Bursal, A. Aras, Ö. Kılıç, P. Taslimi, A. C. Gören, İ. Gülçin, J. Food
Biochem. 2019, 43, e12776.
[69] A. Cetin, F. Türkan, P. Taslimi, İ. Gulçin, J. Biochem. Mol. Toxicol. 2019,
33, 22261.
[40] N. Öztaşkın, R. Kaya, A. Maraş, E. Şahin, İ. Gülcin, S. Göksu, Bioorg.
Chem. 2019, 87, 91.
[70] P. Taslimi, S. Osmanova, C. Caglayan, F. Turkan, S. Sardarova, V.
Farzaliyev, A. Sujayev, N. Sadeghian, I. Gulçin, J. Biochem. Mol. Toxicol.
2018, 32, e22191.
[41] F. Türkan, Z. Huyut, P. Taslimi, İ. Gülçin, Arch. Physiol. Biochem. 2019,
125, 12.
[71] T. Abdülkadir Coban, Ş. Beydemir, İ. Gücin, D. Ekinci, A. Innocenti, D.
Vullo, C. T. Supuran, Bioorg. Med. Chem. 2009, 17, 5791.
[72] J. A. Verpoorte, S. Mehta, J. T. Edsall, J. Biol. Chem. 1967, 242, 4221.
[73] S. Beyza Öztürk Sarıkaya, I. Gülçin, C. T. Supuran, Chem. Biol. Drug
Des. 2010, 75, 515.
[42] E. Forró, F. Fülöp, Tetrahedron: Asymmetry 2004, 15, 2875.
[43] A. Scozzafava, M. Passaponti, C. T. Supuran, I. Gülçin, J. Enzyme Inhib.
Med. Chem. 2015, 30, 586.
[44] M. Boztaş, Y. Çetinkaya, M. Topal, İ. Gülçin, A. Menzek, E. Şahin, M.
Tanc, C. T. Supuran, J. Med. Chem. 2015, 58, 640.
[45] A. Yıldırım, U. Atmaca, A. Keskin, M. Topal, M. Çelik, I. Gülçin, C. T.
Supuran, Bioorg. Med. Chem. 2015, 23, 2598.
[74] A. Innocenti, S. Beyza Öztürk Sarıkaya, İ. Gülçin, C. T. Supuran,
Bioorg. Med. Chem. 2010, 18, 2159.
[75] M. Şentürk, İ. Gülçin, Ş. Beydemir, Ö. İ. Küfrevioğlu, C. T. Supuran,
Chem. Biol. Drugs Des. 2011, 77, 494.
[46] B. Aydin, I. Gulcin, S. H. Alwasel, Int. J. Food Prop. 2015, 18, 2735.
[47] A. Akıncıoğlu, H. Akıncıoğlu, I. Gülçin, S. Durdagi, C. T. Supuran, S.
Göksu, Bioorg. Med. Chem. 2015, 23, 3592.
[76] A. Innocenti, İ. Gülçin, A. Scozzafava, C. T. Supuran, Bioorg. Med.
Chem. Lett. 2010, 20, 5050.
[48] N. Öztaşkın, Y. Çetinkaya, P. Taslimi, S. Göksu, İ. Gülçin, Bioorg. Chem.
2015, 60, 49.
[77] H. Lineweaver, D. Burk, J. Am. Chem. Soc. 1934, 56, 658.
[78] M. Tugrak, H. Inci Gul, H. Sakagami, I. Gulcin, C. T. Supuran, Bioorg.
Chem. 2018, 81, 433.
[49] A. Scozzafava, P. Kalın, C. T. Supuran, İ. Gülçin, S. H. Alwasel, J.
Enzyme Inhib. Med. Chem. 2015, 30, 941.
[79] S. B. Öztürk Sarikaya, F. Topal, M. Şentürk, İ. Gülçin, C. T. Supuran,
Bioorg. Med. Chem. Lett. 2011, 21, 4259.
[50] G. Splendiani, S. Condo, G. Ital, J. Ital. Nefrol. 2006, 23, 74.
[51] B. Arabaci, I. Gulcin, S. Alwasel, Molecules 2014, 19, 10103.
[52] S. Göksu, A. Naderi, Y. Akbaba, P. Kalın, A. Akıncıoğlu, I. Gülçin, S.
Durdagi, R. E. Salmas, Bioorg. Chem. 2014, 56, 75.
[53] H. Göçer, A. Akincioğlu, S. Göksu, I. Gülçin, C. T. Supuran, J. Enzyme
Inhib. Med. Chem. 2015, 30, 316.
[80] M. M. Bradford, Anal. Biochem. 1976, 72, 248.
[81] K. Aksu, H. Akıncıoğlu, A. Akıncıoğlu, S. Göksu, F. Tümer, I. Gülçin,
Arch. Pharm. Chem. Life Sci. 2018, 351, e1800150.
[82] M. Huseynova, P. Taslimi, A. Medjidov, V. Farzaliyev, M. Aliyeva, G.
Gondolova, O. Şahin, B. Yalçın, A. Sujayev, E. B. Orman, A. R. Özkaya,
I. Gulçin, Polyhedron 2018, 155, 25.
[54] S. Burmaoğlu, A. O. Yılmaz, M. F. Polat, R. Kaya, İ. Gülçin, Ö. Algül,
Arch. Physiol. Biochem. 2019, 43, e12908.
[83] M. Zengin, H. Genc, P. Taslimi, A. Kestane, E. Guclu, A. Ogutlu, O.
Karabay, I. Gulçin, Bioorg. Chem. 2018, 81, 119.
[55] H. İ. Gul, M. Tugrak, M. Gul, S. Mazlumoglu, H. Sakagami, İ. Gulcin, C.
T. Supuran, Bioorg. Chem. 2019, 90, 103057.
[84] B. Yiğit, M. Yiğit, D. Barut Celepci, Y. Gök, A. Aktaş, M. Aygün, P.
Taslimi, İ. Gülçin, ChemistrySelect 2018, 3, 7976.
[56] M. Boztas, P. Taslimi, M. A. Yavari, İ. Gulcin, E. Sahin, A. Menzek,
Bioorg. Chem. 2019, 89, 103017.
[85] P. Taslimi, I. Gulçin, J. Food Biochem. 2018, 42, e12516.
[86] M. Rezai, C. Bayrak, P. Taslimi, I. Gulcin, A. Menzek, Turk. J. Chem.
2018, 42, 808.
[57] F. Turkan, A. Cetin, P. Taslimi, H. S. Karaman, İ. Gulçin, Arch. Pharm
Chem. Life Sci. 2019, 352, e1800359.
[58] P. J. Wistrand, M. Schenholm, G. Lonnerholm, Invest. Ophthalmol. Vis.
Sci. 1986, 27, 419.
[59] S. Schwarz, S. Sommerwerk, S. D. Lucas, L. Heller, R. Csuk, Eur. J. Med.
Chem. 2014, 86, 95.
SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
[60] A. D. Kenny, SAAS Bull. Biochem. Biotechnol. 1991, 4, 6.
[61] I. Gulçin, P. Taslimi, Expert Opin. Ther. Pat. 2018, 28, 541.
[62] G. L. Ellman, K. D. Courtney, V. Andres Jr, R. M. Featherstone,
Biochem. Pharmacol. 1961, 7, 88.
[63] U. Atmaca, R. Kaya, H. S. Karaman, M. Çelik, İ. Gülçin, Bioorg. Chem.
2019, 88, 102980.
How to cite this article: Atmaca U, Daryadel S, Taslimi P,
Çelik M, Gülçin İ. Synthesis of β‐amino acid derivatives and
their inhibitory profiles against some metabolic enzymes. Arch
Pharm Chem Life Sci. 2019;e1900200.
[64] Y. Tao, Y. Zhang, Y. Cheng, Y. Wang, Biomed. Chromatogr. 2013,
27, 148.
[65] H. Genç Bilgiçli, A. Kestane, P. Taslimi, O. Karabay, A. Bytyqi‐
Damoni, M. Zengin, İ. Gulçin, Bioorg. Chem. 2019, 88, 102931.
[66] R. Kaya, P. Taslimi, M. E. Naldan, İ. Gülçin, Lett. Drug Des. Discov.
2019, 14, 573.
https://doi.org/10.1002/ardp.201900200